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Kim D, Ansari MM, Ghosh M, Heo Y, Choi KC, Son YO. Implications of obesity-mediated cellular dysfunction and adipocytokine signaling pathways in the pathogenesis of osteoarthritis. Mol Aspects Med 2025; 103:101361. [PMID: 40156972 DOI: 10.1016/j.mam.2025.101361] [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: 11/22/2024] [Revised: 03/17/2025] [Accepted: 03/25/2025] [Indexed: 04/01/2025]
Abstract
Osteoarthritis (OA) is a degenerative joint disease characterized by cartilage degradation, bone sclerosis, and chronic low-grade inflammation. Aging and injury play key roles in OA pathogenesis by triggering the release of proinflammatory factors from adipose tissue and other sources. Obesity and aging impair the function of endoplasmic reticulum (ER) chaperones, leading to ER stress, protein misfolding, and cellular apoptosis. Obesity also induces mitochondrial dysfunction in OA through oxidative stress and disrupts mitochondrial dynamics, exacerbating chondrocyte damage. These factors contribute to inflammation, matrix imbalance, and chondrocyte apoptosis. Adipocytes, the primary source of adipokines, release inflammatory mediators that affect joint cells. Several adipocytokines have a central role in the regulation of many aspects of inflammation. Adiponectin and leptin are the two most abundant adipocytokines that are strongly associated with OA progression. This literature review suggests that adipokines activate many signaling pathways to exert downstream effects and play significant roles in obesity-induced OA. Understanding this rapidly growing family of mainly adipocyte-derived mediators and obesity-mediated cellular dysfunction may be important in the development of new therapies for obesity-associated OA management.
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Affiliation(s)
- Dahye Kim
- Animal Genomics and Bioinformatics Division, National Institute of Animal Science, Wanju, 55365, Republic of Korea.
| | - Md Meraj Ansari
- Department of Animal Biotechnology, Faculty of Biotechnology, College of Applied Life, Sciences Jeju National University, Jeju-si, 63243, Republic of Korea; Interdisciplinary Graduate Program in Advanced Convergence Technology and Science, Jeju National University, Jeju-si, 63243, Republic of Korea.
| | - Mrinmoy Ghosh
- Department of Animal Biotechnology, Faculty of Biotechnology, College of Applied Life, Sciences Jeju National University, Jeju-si, 63243, Republic of Korea.
| | - Yunji Heo
- Department of Animal Biotechnology, Faculty of Biotechnology, College of Applied Life, Sciences Jeju National University, Jeju-si, 63243, Republic of Korea.
| | - Ki-Choon Choi
- Grassland and Forage Division, Rural Development Administration, National Institute of Animal Science, Cheonan, 31000, Republic of Korea.
| | - Young-Ok Son
- Department of Animal Biotechnology, Faculty of Biotechnology, College of Applied Life, Sciences Jeju National University, Jeju-si, 63243, Republic of Korea; Interdisciplinary Graduate Program in Advanced Convergence Technology and Science, Jeju National University, Jeju-si, 63243, Republic of Korea; Bio-Health Materials Core-Facility Center, Jeju National University, Jeju-si, 63243, Republic of Korea; Practical Translational Research Center, Jeju National University, Jeju, 63243, Republic of Korea.
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Ratajczak-Pawłowska AE, Szymczak-Tomczak A, Hryhorowicz S, Zawada A, Skoracka K, Rychter AM, Skrzypczak-Zielińska M, Słomski R, Dobrowolska A, Krela-Kaźmierczak I. Relationship of visfatin with obesity and osteoporosis in patients with inflammatory bowel disease: a narrative review. Front Immunol 2025; 16:1533955. [PMID: 40170859 PMCID: PMC11959099 DOI: 10.3389/fimmu.2025.1533955] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2024] [Accepted: 02/21/2025] [Indexed: 04/03/2025] Open
Abstract
Background Inflammatory bowel disease (IBD) is an increasingly prevalent condition in developed countries. Alongside the growing number of patients, there is a rising incidence of disease-related complications, including osteoporosis. While well-established risk factors for low bone mineral density in IBD-such as low body mass or steroid therapy-are widely recognized, other contributing factors warrant further investigation. One such factor is visfatin, a proinflammatory adipokine encoded by the NAMPT gene. Objectives This review aimed to explore the association between visfatin level, bone health, and obesity among patients with inflammatory bowel disease. Key findings Although visfatin is primarily associated with metabolic syndrome, it may also influence bone mineral density by affecting osteoblast and osteoclast differentiation and function. Additionally, some studies have identified a correlation between visfatin levels and bone mineral density. A deeper understanding of visfatin's role in osteoporosis development may contribute to the identification of novel therapeutic strategies. Therefore, lower bone mineral density in inflammatory bowel disease may be associated with obesity and visfatin levels. However, visfatin concentrations depend on many factors, including genetics, immunology, and nutritional factors, which may affect visfatin levels. Implications Current research highlights visfatin as both a potential biomarker and a therapeutic target for osteoporosis treatment. Nevertheless, limited studies have specifically examined the relationship between visfatin and bone mineral density in IBD. Further research is required to clarify this association and to explore how variations in visfatin levels impact bone density in IBD patients.
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Affiliation(s)
- Alicja Ewa Ratajczak-Pawłowska
- Department of Gastroenterology, Dietetics and Internal Diseases, Poznan University of Medical Sciences, Poznan, Poland
- Laboratory of Nutrigenetics, Department of Gastroenterology, Dietetics and Internal Diseases, Poznan University of Medical Sciences, Poznan, Poland
| | - Aleksandra Szymczak-Tomczak
- Department of Gastroenterology, Dietetics and Internal Diseases, Poznan University of Medical Sciences, Poznan, Poland
| | - Szymon Hryhorowicz
- Institute of Human Genetics, Polish Academy of Sciences Poznan, Poznan, Poland
| | - Agnieszka Zawada
- Department of Gastroenterology, Dietetics and Internal Diseases, Poznan University of Medical Sciences, Poznan, Poland
| | - Kinga Skoracka
- Department of Gastroenterology, Dietetics and Internal Diseases, Poznan University of Medical Sciences, Poznan, Poland
- Doctoral School, Poznan University of Medical Sciences, Poznan, Poland
| | - Anna Maria Rychter
- Department of Gastroenterology, Dietetics and Internal Diseases, Poznan University of Medical Sciences, Poznan, Poland
- Laboratory of Nutrigenetics, Department of Gastroenterology, Dietetics and Internal Diseases, Poznan University of Medical Sciences, Poznan, Poland
| | | | - Ryszard Słomski
- Institute of Medical Sciences, College of Social and Media Culture in Torun, Torun, Poland
- Laboratory of Molecular Genetics, Poznan, Poland
| | - Agnieszka Dobrowolska
- Department of Gastroenterology, Dietetics and Internal Diseases, Poznan University of Medical Sciences, Poznan, Poland
| | - Iwona Krela-Kaźmierczak
- Department of Gastroenterology, Dietetics and Internal Diseases, Poznan University of Medical Sciences, Poznan, Poland
- Laboratory of Nutrigenetics, Department of Gastroenterology, Dietetics and Internal Diseases, Poznan University of Medical Sciences, Poznan, Poland
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John J, Das S, Kunnath A, Mudgal J, Nandakumar K. Effects of quercetin and derivatives on NAMPT/Sirtuin-1 metabolic pathway in neuronal cells: an approach to mitigate chemotherapy-induced cognitive impairment. Metab Brain Dis 2025; 40:151. [PMID: 40085284 PMCID: PMC11909064 DOI: 10.1007/s11011-025-01567-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2024] [Accepted: 03/02/2025] [Indexed: 03/16/2025]
Abstract
BACKGROUND The cognitive alterations observed in individuals undergoing cancer treatments have garnered more attention recently. Chemotherapy can reduce nicotinamide adenine dinucleotide (NAD+) levels by inhibiting nicotinamide phosphoribosyl transferase (NAMPT). This reduction can make cancer cells more susceptible to oxidative damage and death and may also affect non-cancerous cells, particularly the brain cells. During chemotherapy-induced suppression, the downregulation of the NAMPT-mediated NAD+/Sirtuin 1 (SIRT1) pathway may cause dyscognition. Objective: This study aimed to assess the role of quercetin and analogues in chemobrain and the associated mechanisms. Methods: The potential of quercetin and its derivatives interaction with NAMPT and SIRT1 proteins was performed using computational studies followed by their in vitro evaluation in SH-SY5Y cells. Molecular docking and simulation studies of human SIRT1 and NAMPT proteins with quercetin and its derivatives were performed. Differentiated SH-SY5Y cell lines were treated with quercetin and selected derivatives against Methotrexate and 5-Fluorouracil (MF) toxicity, by subjecting to cytotoxicity assay, flow cytometry, and RT-PCR analysis. Results: Quercetin, Rutin, and Isoquercetin showed interactions necessary in the activation process of both proteins. Cytotoxicity and flow cytometric studies demonstrated that the phytochemicals shield the differentiated SH-SY5Y cells from MF toxicity. As determined by RT-PCR investigations, NAMPT and SIRT1 gene mRNA expression was higher in test drug-treated cells at quercetin (0.12, 0.6 µM), rutin, and isoquercetin (16, 80 µM) and lower in MF-treated cells. Conclusion: The treatment of phytochemicals alleviated CICI by targeting NAMPT and SIRT1 proteins, which could lead to the identification of effective treatment strategies for the chemobrain.
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Affiliation(s)
- Jeena John
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, 576104, Karnataka, India
| | - Subham Das
- Department of Pharmaceutical Chemistry, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, 576104, Karnataka, India
| | - Anu Kunnath
- Department of Pharmaceutical Chemistry, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, 576104, Karnataka, India
| | - Jayesh Mudgal
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, 576104, Karnataka, India
- School of Pharmaceutical Sciences, Manipal University Jaipur, Jaipur, 303007, Rajasthan, India
| | - Krishnadas Nandakumar
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, 576104, Karnataka, India.
- Centre for Animal Research, Ethics and Training, Manipal Academy of Higher Education, Manipal, India.
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Semerena E, Nencioni A, Masternak K. Extracellular nicotinamide phosphoribosyltransferase: role in disease pathophysiology and as a biomarker. Front Immunol 2023; 14:1268756. [PMID: 37915565 PMCID: PMC10616597 DOI: 10.3389/fimmu.2023.1268756] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Accepted: 10/03/2023] [Indexed: 11/03/2023] Open
Abstract
Nicotinamide phosphoribosyltransferase (NAMPT) plays a central role in mammalian cell metabolism by contributing to nicotinamide adenine dinucleotide biosynthesis. However, NAMPT activity is not limited to the intracellular compartment, as once secreted, the protein accomplishes diverse functions in the extracellular space. Extracellular NAMPT (eNAMPT, also called visfatin or pre-B-cell colony enhancing factor) has been shown to possess adipocytokine, pro-inflammatory, and pro-angiogenic activities. Numerous studies have reported the association between elevated levels of circulating eNAMPT and various inflammatory and metabolic disorders such as obesity, diabetes, atherosclerosis, arthritis, inflammatory bowel disease, lung injury and cancer. In this review, we summarize the current state of knowledge on eNAMPT biology, proposed roles in disease pathogenesis, and its potential as a disease biomarker. We also briefly discuss the emerging therapeutic approaches for eNAMPT inhibition.
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Affiliation(s)
- Elise Semerena
- Light Chain Bioscience - Novimmune SA, Plan-les-Ouates, Switzerland
| | - Alessio Nencioni
- Department of Internal Medicine and Medical Specialties, University of Genoa, Genoa, Italy
- Ospedale Policlinico San Martino IRCCS, Genoa, Italy
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Bocchi M, de Sousa Pereira N, de Oliveira KB, Amarante MK. Involvement of CXCL12/CXCR4 axis in colorectal cancer: a mini-review. Mol Biol Rep 2023:10.1007/s11033-023-08479-1. [PMID: 37219666 DOI: 10.1007/s11033-023-08479-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Accepted: 04/19/2023] [Indexed: 05/24/2023]
Abstract
Migration of metastatic tumor cells is similar to the traffic of leukocytes and has been reported that can be guided by chemokines and their receptors, through the circulation to distant organs. The chemokine CXCL12 and its receptor CXCR4 play an essential role in hematopoietic stem cell homing and the activation of this axis supports malignant events. Binding of CXCL12 to CXCR4 activates signal transduction pathways, with broad effects on chemotaxis, cell proliferation, migration and gene expression. Thus, this axis serves as a bridge for tumor-stromal cell communication, creating a permissive microenvironment for tumor development, survival, angiogenesis and metastasis. Evidence suggests that this axis may be involved in the colorectal cancer (CRC) carcinogenesis. Therefore, we review emerging data and correlations between CXCL12/CXCR4 axis in CRC, the implications for cancer progression and possible therapeutic strategies that exploit this system.
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Affiliation(s)
- Mayara Bocchi
- Oncology Laboratory, Department of Pathology, Clinical and Toxicological Analysis, Health Sciences Center, Londrina State University, Londrina, PR, Brazil
| | - Nathália de Sousa Pereira
- Oncology Laboratory, Department of Pathology, Clinical and Toxicological Analysis, Health Sciences Center, Londrina State University, Londrina, PR, Brazil
| | - Karen Brajão de Oliveira
- Oncology Laboratory, Department of Pathology, Clinical and Toxicological Analysis, Health Sciences Center, Londrina State University, Londrina, PR, Brazil
- Department of Pathological Sciences, Biological Sciences Center, Londrina State University, Londrina, PR, Brazil
| | - Marla Karine Amarante
- Oncology Laboratory, Department of Pathology, Clinical and Toxicological Analysis, Health Sciences Center, Londrina State University, Londrina, PR, Brazil.
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Lee KC, Wu KL, Chang SF, Chang HI, Chen CN, Chen YY. Fermented Ginger Extract in Natural Deep Eutectic Solvent Enhances Cytotoxicity by Inhibiting NF-κB Mediated CXC Chemokine Receptor 4 Expression in Oxaliplatin-Resistant Human Colorectal Cancer Cells. Antioxidants (Basel) 2022; 11:2057. [PMID: 36290780 PMCID: PMC9598626 DOI: 10.3390/antiox11102057] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Revised: 10/08/2022] [Accepted: 10/18/2022] [Indexed: 11/21/2022] Open
Abstract
Ginger extracts have been shown to have health-promoting pharmacological activity and beneficial effects, including antioxidant and anticancer properties. The extraction of ginger by natural deep eutectic solvents (NaDES) has been shown to enhance bioactivity, but the cytotoxicity of NaDES extracts needs to be further determined. Signaling through the CXC chemokine receptor 4 (CXCR4) expressed on colorectal cancer (CRC) cells has a pivotal role in tumor cell chemosensitivity. Oxaliplatin is a third-generation platinum compound used as an effective chemotherapeutic drug for CRC treatment. However, whether ginger extract and oxaliplatin could induce a synergistic cytotoxic effect in oxaliplatin-resistant CRC cells through modulating CXCR4 expression is not known. In this study, oxaliplatin-resistant HCT-116 (HCT-116/R) cells were generated first. Ginger was extracted using the NaDES mixture betaine/lactate/water (1:2:2.5). Lactobacillus reuteri fermentation of NaDES-ginger extract increased the total polyphenol content (12.42 mg gallic acid/g in non-fermented NaDES-ginger extract and 23.66 mg gallic acid/g in fermented NaDES-ginger extract). It also increased the antioxidant activity by about 20−30% compared to non-fermented NaDES-ginger extract. In addition, it achieved low cytotoxicity to normal colonic mucosal cells and enhanced the anticancer effect on HCT-116/R cells. On the other hand, the inhibition of NF-κB activation by fermented NaDES-ginger extract significantly decreased the CXCR4 expression (p < 0.05) in HCT-116/R cells. The inactivation of NF-κB by pharmacological inhibitor pyrrolidine dithiocarbamate further enhanced the fermented NaDES-ginger extract-reduced CXCR4 expression levels (p < 0.05). Moreover, fermented NaDES-ginger extract could synergistically increase the cytotoxicity of oxaliplatin by inhibiting CXCR4 expression and inactivating NF-κB, resulting in HCT-116/R cell death. These findings demonstrate that fermented NaDES-ginger extract reduces the NF-kB-mediated activation of CXCR4 and enhances oxaliplatin-induced cytotoxicity in oxaliplatin-resistant CRC cells.
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Affiliation(s)
- Ko-Chao Lee
- Division of Colorectal Surgery, Department of Surgery, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan
| | - Kuen-Lin Wu
- Division of Colorectal Surgery, Department of Surgery, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan
| | - Shun-Fu Chang
- Department of Medical Research and Development, Chang Gung Memorial Hospital Chiayi Branch, Chiayi 613, Taiwan
| | - Hsin-I Chang
- Department of Biochemical Science and Technology, National Chiayi University, Chiayi 600, Taiwan
| | - Cheng-Nan Chen
- Department of Biochemical Science and Technology, National Chiayi University, Chiayi 600, Taiwan
| | - Yih-Yuan Chen
- Department of Biochemical Science and Technology, National Chiayi University, Chiayi 600, Taiwan
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Lee KC, Yen CK, Chen CN, Chang SF, Lu YC, Huang WS. Drug Resistance of CPT-11 in Human DLD-1 Colorectal Cancer Cells through MutS Homolog 2 Upregulation. Int J Med Sci 2021; 18:1269-1276. [PMID: 33526988 PMCID: PMC7847627 DOI: 10.7150/ijms.52620] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Accepted: 12/18/2020] [Indexed: 11/20/2022] Open
Abstract
Colorectal cancers (CRCs) is the most commonly diagnosed and deadly cancer types in the world. Despite advances in chemotherapy for CRCs, drug resistance remains a major challenge to high incurable and eventually deadly rates for patients. CPT-11 is one of the current chemotherapy agents for CRC patients and the CPT-11 resistance development of CRCs is also inevitable. Recently, accumulating data has suggested that DNA repair system might be an inducer of chemotherapy resistance in cancer cells. Thus, this study was aimed to examine whether MutS homolog (MSH) 2, one member of DNA repair system, plays a role to affect the cytotoxicity of CPT-11 to CRCs. Human DLD-1 CRC cells were used in this study. It was shown that MSH2 gene and protein expression could be upregulated in DLD-1 cells under CPT-11 treatment and this upregulation subsequently attenuates the sensitivity of DLD-1 cells to CPT-11. Moreover, ERK1/2 and Akt signaling and AP-1 transcription factor have been found to modulate these effects. These results elucidate the drug resistance role of MSH2 upregulation in the CPT-11-treated DLD-1 CRC cells. Our findings may provide a useful thought for new adjuvant drug development by controlling the DNA repair system.
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Affiliation(s)
- Ko-Chao Lee
- Department of Colorectal Surgery, Department of Surgery, Chang Gung Memorial Hospital; Kaohsiung Medical Center, Kaohsiung 833, Taiwan
| | - Chia-Kung Yen
- Department of Food Science, National Chiayi University, Chiayi 600, Taiwan
| | - Cheng-Nan Chen
- Department of Biochemical Science and Technology, National Chiayi University, Chiayi 600, Taiwan
| | - Shun-Fu Chang
- Department of Medical Research and Development, Chiayi Chang Gung Memorial Hospital, Chiayi 613, Taiwan
| | - Ying-Chen Lu
- Department of Food Science, National Chiayi University, Chiayi 600, Taiwan
| | - Wen-Shih Huang
- Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan.,Division of Colon and Rectal Surgery, Department of Surgery, Chiayi Chang Gung Memorial Hospital, Chiayi 613, Taiwan
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Han DF, Li Y, Xu HY, Li RH, Zhao D. An Update on the Emerging Role of Visfatin in the Pathogenesis of Osteoarthritis and Pharmacological Intervention. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE : ECAM 2020; 2020:8303570. [PMID: 32831881 PMCID: PMC7429770 DOI: 10.1155/2020/8303570] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/06/2020] [Revised: 06/10/2020] [Accepted: 06/18/2020] [Indexed: 02/08/2023]
Abstract
Osteoarthritis (OA) is one of the most common degenerative joint diseases that affects millions of people worldwide, mainly the aging population. Despite numerous published reports, little is known about the pathology of this disease, and no feasible treatment plan exists to stop OA progression. Recently, extensive basic and clinical studies have shown that adipokines play a key role in OA development. Moreover, some drugs associated with adipokines have shown chondroprotective and anti-inflammatory effects on OA. Visfatin has been shown to play a detrimental role in the progression of OA. It increases the production of matrix metalloproteinases and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS), induces the production of interleukin (IL)-1β, IL-6, and tumor necrosis factor-α, affects the differentiation of mesenchymal stem cells to adipocytes, and induces osteophyte formation by inhibiting osteoclastogenesis. Although some side effects of chemical visfatin inhibitors have been reported, they were shown to be successful in the treatment of diabetes, cancer, and other diseases that can utilize Chinese herbs, further suggesting that similar therapeutic strategies could be used in OA prevention and treatment. Here, we describe the pathophysiological mechanism of visfatin in OA and discuss some potential pharmacological interventions using Chinese herbs.
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Affiliation(s)
- Dong-Feng Han
- Department of Emergency Medicine, The First Hospital of Jilin University, Changchun, Jilin 130021, China
| | - Yang Li
- Department of Thoracic Surgery, The First Hospital of Jilin University, Changchun, Jilin 130021, China
| | - Hui-Ying Xu
- Department of Ultrasound, The First Hospital of Jilin University, Changchun, Jilin 130021, China
| | - Rong-Hang Li
- Department of Orthopedic Surgery, The Second Hospital of Jilin University, Changchun, Jilin 130021, China
| | - Ding Zhao
- Department of Orthopedic Surgery, The First Hospital of Jilin University, Changchun, Jilin 130021, China
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Deng L, Zhao X, Chen M, Ji H, Zhang Q, Chen R, Wang Y. Plasma adiponectin, visfatin, leptin, and resistin levels and the onset of colonic polyps in patients with prediabetes. BMC Endocr Disord 2020; 20:63. [PMID: 32393372 PMCID: PMC7216429 DOI: 10.1186/s12902-020-0540-7] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2019] [Accepted: 04/28/2020] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Prediabetes is associated with a high risk of colon cancer, and abdominal obesity, which can result in the secretion of several obesity-related adipocytokines, is an independent influencing factor for colonic polyps in prediabetes subjects. However, the correlation between adipocytokine levels and colonic polyps in prediabetes subjects is unclear. This research explores the relationship between plasma adiponectin, visfatin, leptin, and resistin levels and the development of colonic polyps in prediabetes subjects. METHODS A total of 468 prediabetes subjects who underwent electronic colonoscopy examinations were enrolled in this study; there were 248 cases of colonic polyps and 220 cases without colonic mucosal lesions. Then, colonic polyps patients with prediabetes were subdivided into a single-polyp group, multiple-polyps group, low-risk polyps group, or high-risk polyps group. In addition, 108 subjects with normal glucose tolerance who were frequency matched with prediabetes subjects by sex and age were selected as the control group; 46 control subjects had polyps, and 62 control subjects were polyp-free. Plasma adiponectin, visfatin, leptin, and resistin levels were measured in all the subjects, and the related risk factors of colonic polyps in prediabetes subjects were analysed. RESULTS Plasma adiponectin levels were significantly lower in the polyps group than in the polyp-free group [normal glucose tolerance (9.8 ± 4.8 vs 13.3 ± 3.9) mg/L, P = 0.013; prediabetes (5.6 ± 3.7 vs 9.2 ± 4.4) mg/L, P = 0.007]. In prediabetes subjects, plasma adiponectin levels were decreased significantly in the multiple polyps group [(4.3 ± 2.6 vs 6.7 ± 3.9) mg/L, P = 0.031] and the high-risk polyps group [(3.7 ± 2.9 vs 7.4 ± 3.5) mg/L, P < 0.001] compared to their control groups. Plasma visfatin levels were higher in the polyps group and the multiple-polyps group than those in their control groups (P = 0.041 and 0.042, respectively), and no significant difference in plasma leptin and resistin levels was observed between these three pairs of groups (all P > 0.05). The multivariate logistic regression analysis showed that lower levels of plasma adiponectin was a risk factor for colonic polyps, multiple colonic polyps, and high-risk colonic polyps in prediabetes subjects. CONCLUSIONS Plasma adiponectin levels are inversely associated with colonic polyps, multiple colonic polyps, and high-risk colonic polyps in prediabetes subjects. And adiponectin may be involved in the development of colon tumours in prediabetes subjects.
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Affiliation(s)
- Lili Deng
- Department of Endocrinology, the First Affiliated Hospital of Anhui Medical University, No.218 Jixi Road, Hefei, 230032, Anhui Province, China
| | - Xiaotong Zhao
- Department of Endocrinology, the First Affiliated Hospital of Anhui Medical University, No.218 Jixi Road, Hefei, 230032, Anhui Province, China
| | - Mingwei Chen
- Department of Endocrinology, the First Affiliated Hospital of Anhui Medical University, No.218 Jixi Road, Hefei, 230032, Anhui Province, China.
- Institute of Traditional Chinese Medicine for the Prevention and Control of Diabetes, Anhui Academy of Chinese Medicine, Hefei, 230032, Anhui Province, China.
| | - Hua Ji
- Department of Endocrinology, the First Affiliated Hospital of Anhui Medical University, No.218 Jixi Road, Hefei, 230032, Anhui Province, China
| | - Qunhui Zhang
- Department of Endocrinology, the First Affiliated Hospital of Anhui Medical University, No.218 Jixi Road, Hefei, 230032, Anhui Province, China
| | - Ruofei Chen
- Anhui Medical University Clinical College, No.81 Meishan Road, Hefei, 230032, Anhui Province, China
| | - Yalei Wang
- Department of Gastroenterology, the First Affiliated Hospital of Anhui Medical University, No.218 Jixi Road, Hefei, 230032, Anhui Province, China
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Mohammadi M, Moradi A, Farhadi J, Akbari A, Pourmandi S, Mehrad-Majd H. Prognostic value of visfatin in various human malignancies: A systematic review and meta-analysis. Cytokine 2020; 127:154964. [PMID: 31901760 DOI: 10.1016/j.cyto.2019.154964] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2019] [Revised: 11/24/2019] [Accepted: 12/25/2019] [Indexed: 12/16/2022]
Abstract
Although numerous studies have shown that visfatin is linked to several cancers, its prognostic value is still unclear. This first comprehensive meta-analysis was performed to evaluate the prognostic effect of visfatin in cancer patients. A systematic search was conducted for relevant studies in health-related electronic databases up to May 2019. The pooled hazard ratios (HRs) and ORs with 95% confidence intervals (CIs) for total and stratified analyses were calculated to demonstrate the prognostic value of visfatin expression level in cancer patients. Heterogeneity and publication bias were also investigated. A total of 14 eligible studies with 1616 patients were included in the current meta-analysis. Pooling results revealed that, high visfatin expression was significantly associated with poorer overall survival (OS) (HR = 2.43, 95% CI 1.64-3.62, P < 0.001). Elevated visfatin level was also correlated with positive lymph node metastasis (OR = 2.45, 95% CI 1.43-4.17, P ≤ 0.001), positive distance metastasis (OR = 2014, 95% CI 1.25-3.69, P ≤ 0.001), advanced tumor stage (OR = 3.01, 95% CI 1.91-7.72, P ≤ 0.001), and larger tumor size (OR = 1.99, 95% CI 1.49-2.69, P ≤ 0.001). Our meta-results indicates that altered visfatin expression is a potential indicator of poor clinical outcomes in tumor patients, suggesting that high visfatin expression may serve as a potential biomarker of poor prognosis and metastasis in cancers.
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Affiliation(s)
- Masoumeh Mohammadi
- Cellular and Molecular Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ali Moradi
- Orthopedic Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Javad Farhadi
- Department of Biochemistry and Molecular Biology, Neyshabur Branch, Islamic Azad University, Neyshabur, Iran
| | - Abolfazl Akbari
- Colorectal Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Shokoufeh Pourmandi
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hassan Mehrad-Majd
- Cancer Molecular Pathology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
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11
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Daniel SK, Seo YD, Pillarisetty VG. The CXCL12-CXCR4/CXCR7 axis as a mechanism of immune resistance in gastrointestinal malignancies. Semin Cancer Biol 2019; 65:176-188. [PMID: 31874281 DOI: 10.1016/j.semcancer.2019.12.007] [Citation(s) in RCA: 137] [Impact Index Per Article: 22.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2019] [Revised: 12/03/2019] [Accepted: 12/11/2019] [Indexed: 02/07/2023]
Abstract
Single agent checkpoint inhibitor therapy has not been effective for most gastrointestinal solid tumors, but combination therapy with drugs targeting additional immunosuppressive pathways is being attempted. One such pathway, the CXCL12-CXCR4/CXCR7 chemokine axis, has attracted attention due to its effects on tumor cell survival and metastasis as well as immune cell migration. CXCL12 is a small protein that functions in normal hematopoietic stem cell homing in addition to repair of damaged tissue. Binding of CXCL12 to CXCR4 leads to activation of G protein signaling kinases such as P13K/mTOR and MEK/ERK while binding to CXCR7 leads to β-arrestin mediated signaling. While some gastric and colorectal carcinoma cells have been shown to make CXCL12, the primary source in pancreatic cancer and peritoneal metastases is cancer-associated fibroblasts. Binding of CXCL12 to CXCR4 and CXCR7 on tumor cells leads to anti-apoptotic signaling through Bcl-2 and survivin upregulation, as well as promotion of the epithelial-to-mesechymal transition through the Rho-ROCK pathway and alterations in cell adhesion molecules. High levels of CXCL12 seen in the bone marrow, liver, and spleen could partially explain why these are popular sites of metastases for many tumors. CXCL12 is a chemoattractant for lymphocytes at lower levels, but becomes chemorepellant at higher levels; it is unclear exactly what gradient exists in the tumor microenvironment and how this influences tumor-infiltrating lymphocytes. AMD3100 (Plerixafor or Mozobil) is a small molecule CXCR4 antagonist and is the most frequently used drug targeting the CXCL12-CXCR4/CXCR7 axis in clinical trials for gastrointestinal solid tumors currently. Other small molecules and monoclonal antibodies against CXCR4 are being trialed. Further understanding of the CXCL12- CXCR4/CXCR7 chemokine axis in the tumor microenvironment will allow more effective targeting of this pathway in combination immunotherapy.
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Affiliation(s)
- Sara K Daniel
- University of Washington, Dept. of Surgery, Seattle, WA, USA
| | - Y David Seo
- University of Washington, Dept. of Surgery, Seattle, WA, USA
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12
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Zhang J, Guo S, Li J, Bao W, Zhang P, Huang Y, Ling P, Wang Y, Zhao Q. Effects of high-fat diet-induced adipokines and cytokines on colorectal cancer development. FEBS Open Bio 2019; 9:2117-2125. [PMID: 31665829 PMCID: PMC6886304 DOI: 10.1002/2211-5463.12751] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2019] [Revised: 10/21/2019] [Accepted: 10/28/2019] [Indexed: 12/16/2022] Open
Abstract
Colorectal cancer (CRC) is the third most common tumor worldwide, and recent epidemiological studies have indicated that obesity contributes to the morbidity and mortality of CRC. Furthermore, obesity‐related adipokines have been shown to be closely related to the incidence of CRC, but the underlying mechanisms are unclear. Here, we investigated the effects of high‐fat diet‐induced adipokines and cytokines on the development of CRC in vitro and in vivo. For the in vivo assays, we divided 2‐week‐old C57BL/6J‐ApcMin/J male mice into three groups: normal‐fat diet (ND), high‐fat and high‐sugar feed (HFHS), and high‐fat and low‐sugar feed (HFLS). After 1 week, all mice were injected with 20 mg·kg−1 1,2‐dimethylhydrazine once weekly for 10 consecutive weeks. Body weight, liver weight, epididymal fat weight and blood glucose levels were greatly increased in HFHS and HFLS groups compared with the ND group, and the expression levels of some adipokines and cytokines were obviously higher in HFHS or HFLS mice compared with ND mice. For the in vitro assays, HCT116 CRC cells were treated with sera of ND, HFHS or HFLS groups, or serum‐free media as a negative control. We observed that sera derived from HFHS or HFLS mice that contain excess adipokines and cytokines promoted the proliferation, migration and invasion of HCT116 cells compared with the ND sera‐conditioned medium or serum‐free medium group. Therefore, high‐fat diet‐induced adipokines and cytokines may promote the progression of CRC in vivo and in vitro. We investigated the effects of high‐fat diet‐induced adipokines and cytokines in the development of colorectal cancer. Some adipokines and cytokines were obviously higher in obese mice than in normal mice. Obesity‐induced adipokines and cytokines promoted the proliferation, migration and invasion of HCT116 cells. Therefore, high‐fat diet‐induced adipokines and cytokines may accelerate the progression of colorectal cancer.![]()
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Affiliation(s)
- Jian Zhang
- Department of General Surgery I, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, China
| | - Shikui Guo
- Department of General Surgery I, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, China
| | - Jinyuan Li
- Medical Faculty, Kunming University of Science and Technology, China
| | - Weimin Bao
- Department of General Surgery I, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, China
| | - Peng Zhang
- Department of General Surgery I, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, China
| | - Yingguang Huang
- Department of General Surgery I, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, China
| | - Ping Ling
- Department of General Surgery I, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, China
| | - Yongzhi Wang
- Department of General Surgery I, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, China
| | - Quan Zhao
- Department of General Surgery I, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, China
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Guo Q, Han N, Shi L, Yang L, Zhang X, Zhou Y, Yu S, Zhang M. NAMPT: A potential prognostic and therapeutic biomarker in patients with glioblastoma. Oncol Rep 2019; 42:963-972. [PMID: 31322259 PMCID: PMC6667917 DOI: 10.3892/or.2019.7227] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2019] [Accepted: 07/03/2019] [Indexed: 12/19/2022] Open
Abstract
Glioblastoma (GBM) is the most common primary intracranial malignancy. GBM still exhibits high recurrence and mortality rates even following combined treatment with surgery, radiotherapy and chemotherapy, Therefore, the identification of novel therapeutic targets is urgent. Previous research has shown that nicotinamide phosphoribosyltransferase (NAMPT) plays a key role in cell metabolism and is closely related to the occurrence and development of many tumor types; yet, little is known concerning its relationship with GBM. Oncomine database analysis showed that the expression of NAMPT in GBM was higher than that in normal tissues; this finding was further confirmed by immunohistochemical staining of a tissue microarray. Data analysis with the R2 platform showed that patients with higher expression of NAMPT had worse prognoses than those with lower NAMPT expression. Using the GBM data in TCGA, four pathways enriched in the high NAMPT expression group were identified by gene set enrichment analysis (GSEA). NAMPT expression was knocked down in U87 and U251 GBM cells by lentiviral vectors carrying a small hairpin RNA (shRNA) targeting NAMPT. CCK-8, colony formation, wound healing, Transwell and apoptosis assays were carried out. The results showed that NAMPT knockdown decreased cell proliferation, migration, and invasion and promoted apoptosis. U87 GBM cells were used in a model of subcutaneous tumorigenesis in nude mice. The results showed that NAMPT knockdown slowed the growth of tumors in vivo. Therefore, we speculate that NAMPT may be a potential prognostic and therapeutic biomarker for glioblastoma.
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Affiliation(s)
- Qiuyun Guo
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
| | - Na Han
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
| | - Lei Shi
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
| | - Li Yang
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
| | - Xiaoxi Zhang
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
| | - Yangmei Zhou
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
| | - Shiying Yu
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
| | - Mengxian Zhang
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
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14
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Type-II endometrial cancer: role of adipokines. Arch Gynecol Obstet 2019; 300:239-249. [PMID: 31062150 DOI: 10.1007/s00404-019-05181-1] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2019] [Accepted: 04/24/2019] [Indexed: 12/25/2022]
Abstract
BACKGROUND Type-II endometrial cancer is an estrogen independent and one of the most lethal types of cancer having poor prognosis. Adipokines play a crucial role in the triggering Type-II EMC. In addition, adipokines modulators, therefore, may have beneficial effects in the treatment of Type-II endometrial cancer, which was clinically evidenced. AREAS COVERED This review presents the role of various adipokines involved and also the suitable modulators to treat Type-II endometrial cancer. CONCLUSION In the present review, we try to discuss the role of individual adipokines in the pathogenesis of Type-II endometrial cancer, and also the possible beneficial effects of adipokines modulator in the treatment of Type-II endometrial cancer.
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15
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Moskalenko RA, Korneva YS. [Role of adipose tissue in the development and progression of colorectal cancer]. Arkh Patol 2019; 81:52-56. [PMID: 30830106 DOI: 10.17116/patol20198101152] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
The paper gives the current data available in the literature on the relationship and pathogenetic mechanisms of influence of adipose tissue on colorectal carcinogenesis. It considers the aspects of changes in adipose tissue and microenvironment of the tumor itself, including those under the influence of biologically active substances secreted by adipocytes; differences in subcutaneous and visceral fat and their importance in the development and progression of colorectal cancer (CRC), as well as the role of adipose tissue-derived stem cells. Understanding these mechanisms for adipose tissue influence on CRC will assist not only in preventing this disease, but also in searching for new therapeutic targets.
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Affiliation(s)
- R A Moskalenko
- Medical Institute, Sumy State University, Ministry of Education and Science of Ukraine, Sumy, Ukraine
| | - Yu S Korneva
- Smolensk State Medical University, Ministry of Health of Russia, Smolensk, Russia; Smolensk Regional Institute of Pathology, Smolensk, Russia
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16
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Heras SCDL, Martínez-Balibrea E. CXC family of chemokines as prognostic or predictive biomarkers and possible drug targets in colorectal cancer. World J Gastroenterol 2018; 24:4738-4749. [PMID: 30479461 PMCID: PMC6235799 DOI: 10.3748/wjg.v24.i42.4738] [Citation(s) in RCA: 88] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2018] [Revised: 09/27/2018] [Accepted: 10/15/2018] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) is the third most common cancer in men and the second most common cancer in women, worldwide. In the early stages of the disease, biomarkers predicting early relapse would improve survival rates. In metastatic patients, the use of predictive biomarkers could potentially result in more personalized treatments and better outcomes. The CXC family of chemokines (CXCL1 to 17) are small (8 to 10 kDa) secreted proteins that attract neutrophils and lymphocytes. These chemokines signal through chemokine receptors (CXCR) 1 to 8. Several studies have reported that these chemokines and receptors have a role in either the promotion or inhibition of cancer, depending on their capacity to suppress or stimulate the action of the immune system, respectively. In general terms, activation of the CXCR1/CXCR2 pathway or the CXCR4/CXCR7 pathway is associated with tumor aggressiveness and poor prognosis; therefore, the specific inhibition of these receptors is a possible therapeutic strategy. On the other hand, the lesser known CXCR3 and CXCR5 axes are generally considered to be tumor suppressor signaling pathways, and their stimulation has been suggested as a way to fight cancer. These pathways have been studied in tumor tissues (using immunohistochemistry or measuring mRNA levels) or serum [using enzyme-linked immuno sorbent assay (ELISA) or multiplexing techniques], among other sample types. Common variants in genes encoding for the CXC chemokines have also been investigated as possible biomarkers of the disease. This review summarizes the most recent findings on the role of CXC chemokines and their receptors in CRC and discusses their possible value as prognostic or predictive biomarkers as well as the possibility of targeting them as a therapeutic strategy.
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MESH Headings
- Antineoplastic Agents/pharmacology
- Antineoplastic Agents/therapeutic use
- Biomarkers, Tumor/antagonists & inhibitors
- Biomarkers, Tumor/immunology
- Biomarkers, Tumor/metabolism
- Chemokines, CXC/antagonists & inhibitors
- Chemokines, CXC/immunology
- Chemokines, CXC/metabolism
- Colorectal Neoplasms/drug therapy
- Colorectal Neoplasms/immunology
- Colorectal Neoplasms/mortality
- Colorectal Neoplasms/pathology
- Humans
- Neoplasm Recurrence, Local/diagnosis
- Prognosis
- Receptors, CXCR/antagonists & inhibitors
- Receptors, CXCR/immunology
- Receptors, CXCR/metabolism
- Signal Transduction/drug effects
- Survival Rate
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Affiliation(s)
- Sara Cabrero-de las Heras
- Program Against Cancer Therapeutic Resistance (ProCURE), Catalan Institute of Oncology (ICO), Germans Trias i Pujol health research institute (IGTP), Badalona, Barcelona 08916, Catalunya, Spain
- Program of Predictive and Personalized Cancer Medicine (PMPPC), Germans Trias i Pujol health research institute (IGTP), Badalona, Barcelona 08916, Catalunya, Spain
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17
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Underrated enemy - from nonalcoholic fatty liver disease to cancers of the gastrointestinal tract. Clin Exp Hepatol 2018; 4:55-71. [PMID: 29904722 PMCID: PMC6000748 DOI: 10.5114/ceh.2018.75955] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2018] [Accepted: 04/17/2018] [Indexed: 12/12/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is intrahepatic ectopic lipid deposition which is present despite a lack of other causes of secondary hepatic fat accumulation. It is the most common chronic liver disorder in the welldeveloped countries. NAFLD is a multidisciplinary disease that affects various systems and organs and is inextricably linked to simple obesity, metabolic syndrome, insulin resistance and overt diabetes mellitus type 2. The positive energy balance related to obesity leads to a variety of systemic changes including modified levels of insulin, insulin- like growth factor-1, adipokines, hepatokines and cytokines. It is strongly linked to carcinogenesis and new evidence proves that NAFLD is associated with higher risk of all-cause mortality and cancer-specific mortality among cancer survivors. This article focuses on the association between NAFLD and extrahepatic gastrointestinal tract cancers, aiming to shed light on the pathomechanism of changes leading to the development of tumors.
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18
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Sun Y, Zhu S, Wu Z, Huang Y, Liu C, Tang S, Wei L. Elevated serum visfatin levels are associated with poor prognosis of hepatocellular carcinoma. Oncotarget 2017; 8:23427-23435. [PMID: 28178643 PMCID: PMC5410315 DOI: 10.18632/oncotarget.15080] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2016] [Accepted: 11/24/2016] [Indexed: 01/08/2023] Open
Abstract
Visfatin is considered a pro-inflammatory adipocytokine, and it is commonly increased in obesity-related diseases. This study aimed to evaluate the levels of serum visfatin in patients with hepatocellular carcinoma (HCC) and its diagnostic and predictive value in detecting HCC. Fasting serum levels of visfatin of 135 HCC patients, 115 chronic hepatitis B (CHB) patients, 129 liver cirrhosis (LC) patients, and 149 healthy controls were determined via enzyme-linked immunosorbent assay. Meanwhile, serum alpha fetal protein (AFP) and interleukin-6 (IL-6) were also assayed. The median serum visfatin concentration in HCC patients was 1.113 ng/mL (range: 0.823-2.214 ng/mL), which was significant higher than those of healthy controls, CHB patients, and LC patients (P<0.05). The serum visfatin concentration in HCC patients was positively correlated with AFP (r=0.595, P<0.001) and IL-6 (r=0.261, P<0.015) and was also associated with tumor size and tumor node metastasis stage. Moreover, elevated levels of serum visfatin were associated with a higher HCC risk for CHB and LC patients. Multivariate Cox regression analysis had shown that HCC patients with high levels of serum visfatin had significantly shorter overall survival times than those with low serum visfatin levels (P<0.001). Using a cutoff visfatin level of 1.403 ng/mL, the receiver operating characteristic curve analysis showed unappealing sensitivity and specificity values (45.76% and 74.79%, respectively; AUC=0.626) regarding visfatin's use as a diagnostic marker for HCC. Our results indicate that increased serum visfatin levels are associated with poor prognosis of HCC. Visfatin may be a potential therapeutic target of HCC.
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Affiliation(s)
- Yifan Sun
- Department of Clinical Laboratory, Affiliated Liutie Central Hospital of Guangxi Medical University, Liuzhou, Guangxi, China
| | - Shengbo Zhu
- Department of Clinical Laboratory, Third Affiliated Hospital of Guangxi University of Chinese Medicine, Liuzhou, Guangxi, China
| | - Zhitong Wu
- Department of Clinical Laboratory, Eighth Affiliated Hospital of Guangxi Medical University, Guigang City People's Hospital, Guigang, Guangxi, China
| | - Yiyong Huang
- Department of Clinical Laboratory, Third Affiliated Hospital of Guangxi University of Chinese Medicine, Liuzhou, Guangxi, China
| | - Chunming Liu
- Department of Clinical Laboratory, Third Affiliated Hospital of Guangxi University of Chinese Medicine, Liuzhou, Guangxi, China
| | - Shifu Tang
- Department of Clinical Laboratory, Third Affiliated Hospital of Guangxi University of Chinese Medicine, Liuzhou, Guangxi, China
| | - Lili Wei
- Department of Science and Education, Third Affiliated Hospital of Guangxi University of Chinese Medicine, Liuzhou, Guangxi, China
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19
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Vora M, Alattia LA, Ansari J, Ong M, Cotelingam J, Coppola D, Shackelford R. Nicotinamide Phosphoribosyl Transferase a Reliable Marker of Progression in Cervical Dysplasia. Anticancer Res 2017; 37:4821-4825. [PMID: 28870901 DOI: 10.21873/anticanres.11889] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2017] [Revised: 06/29/2017] [Accepted: 07/12/2017] [Indexed: 12/21/2022]
Abstract
BACKGROUND/AIM Nicotinamide phosphoribosyl transferase (Nampt) catalyses the rate-limiting step of the mammalian nicotinamide adenine dinucleotide (NAD) salvage pathway. Nampt is highly expressed in several epithelial and mesenchymal neoplasms, where is promotes cell-cycle progression ans chemotherapy resistance. To our knowledge, alterations in Nampt expression have not been examined in cervical intraepithelial neoplasia (CIN) or squamous cell carcinoma (SCC). MATERIALS AND METHODS We performed immunohistochemical analysis for Nampt using tissue microarrays on 14 samples of benign cervical squamous epithelium and 15 CIN I, 15 CIN II, and 13 samples of CIN III. The SCCs included 5 low-grade, 67 intermediate-grade, and 81 high-grade tumors. RESULTS Nampt levels increased with increased CIN grades were compared to benign cervical squamous epithelium. Similarly, Nampt levels increased with increasing SCC grade. CONCLUSION Nampt expression is a reliable marker of progression in cervical dysplasia and SCC.
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Affiliation(s)
- Moiz Vora
- Department of Pathology and Translational Pathobiology, LSU Health, Shreveport, LA, U.S.A
| | - Lubna A Alattia
- Department of Pathology and Translational Pathobiology, LSU Health, Shreveport, LA, U.S.A
| | - Junaid Ansari
- Department of Molecular and Cellular Physiology, LSU Health Sciences Center, Shreveport, LA, U.S.A
| | - Menchu Ong
- Department of Pathology and Translational Pathobiology, LSU Health, Shreveport, LA, U.S.A
| | - James Cotelingam
- Department of Pathology and Translational Pathobiology, LSU Health, Shreveport, LA, U.S.A
| | - Domenico Coppola
- Department of Anatomic Pathology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, U.S.A
| | - Rodney Shackelford
- Department of Pathology and Translational Pathobiology, LSU Health, Shreveport, LA, U.S.A.
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Tabuso M, Homer-Vanniasinkam S, Adya R, Arasaradnam RP. Role of tissue microenvironment resident adipocytes in colon cancer. World J Gastroenterol 2017; 23:5829-5835. [PMID: 28932075 PMCID: PMC5583568 DOI: 10.3748/wjg.v23.i32.5829] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2017] [Revised: 06/25/2017] [Accepted: 08/02/2017] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) is a multifactorial disease characterized by several genetic and epigenetic alterations occurring in epithelial cells. It is increasingly recognized that tumour progression is also regulated by tumour microenvironment (TME). The bidirectional cross-talk between tumour resident adipocytes and cancer cells within TME has been proposed as active contributor to carcinogenesis. Tumour resident adipocytes exhibit an activated phenotype characterized by increased secretion of pro-tumorigenic factors (angiogenic/inflammatory/immune) which contribute to cancer cell proliferation, invasion, neoangiogenesis, evasion of immune surveillance and therapy resistance. Furthermore, adipocytes represent a fuel rich source for increasing energy demand of rapidly proliferating tumour cells. Interestingly, a relationship between obesity and molecular variants in CRC has recently been identified. Whether adipose tissue promotes cancer progression in subsets of molecular phenotypes or whether local tissue adipocytes are involved in inactivation of tumour suppressor genes and/or activation of oncogenes still needs to be explored. This editorial highlights the major findings related to cross-talk between adipocytes and colon cancer cells and how local paracrine interactions may promote cancer progression. Furthermore, we provide future strategies in studying colonic TME which could provide insights in bidirectional cross-talk mechanisms between adipocytes and colonic epithelial cells. This could enable to decipher critical signalling pathways of both early colonic carcinogenesis and cancer progression.
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Affiliation(s)
- Maria Tabuso
- Department of Gastroenterology, University Hospitals Coventry and Warwickshire, Clifford Bridge Road, Coventry CV2 2DX, United Kingdom
| | - Shervanthi Homer-Vanniasinkam
- Warwick Medical School, University of Warwick, Coventry CV4 7AL, United Kingdom
- Leeds Institute of Cardiovascular and Metabolic Medicine, Faulty of Medicine and Health, University of Leeds, Leeds LS2 9JT, United Kingdom
- Division of Surgical and Interventional Sciences, UCL Medical School Building, 21 University Street, London WC1E 6AU, United Kingdom
| | - Raghu Adya
- Warwick Medical School, University of Warwick, Coventry CV4 7AL, United Kingdom
| | - Ramesh P Arasaradnam
- Department of Gastroenterology, University Hospitals Coventry and Warwickshire, Clifford Bridge Road, Coventry CV2 2DX, United Kingdom
- Warwick Medical School, University of Warwick, Coventry CV4 7AL, United Kingdom
- Applied Biological and Experimental Sciences, University of Coventry, Coventry CV1 5FB, United Kingdom
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21
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Adipokine Contribution to the Pathogenesis of Osteoarthritis. Mediators Inflamm 2017; 2017:5468023. [PMID: 28490838 PMCID: PMC5401756 DOI: 10.1155/2017/5468023] [Citation(s) in RCA: 104] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2016] [Revised: 02/25/2017] [Accepted: 03/07/2017] [Indexed: 12/13/2022] Open
Abstract
Recent studies have shown that overweight and obesity play an important role in the development of osteoarthritis (OA). However, joint overload is not the only risk factor in this disease. For instance, the presence of OA in non-weight-bearing joints such as the hand suggests that metabolic factors may also contribute to its pathogenesis. Recently, white adipose tissue (WAT) has been recognized not only as an energy reservoir but also as an important secretory organ of adipokines. In this regard, adipokines have been closely associated with obesity and also play an important role in bone and cartilage homeostasis. Furthermore, drugs such as rosuvastatin or rosiglitazone have demonstrated chondroprotective and anti-inflammatory effects in cartilage explants from patients with OA. Thus, it seems that adipokines are important factors linking obesity, adiposity, and inflammation in OA. In this review, we are focused on establishing the physiological mechanisms of adipokines on cartilage homeostasis and evaluating their role in the pathophysiology of OA based on evidence derived from experimental research as well as from clinical-epidemiological studies.
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22
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Carbone F, Liberale L, Bonaventura A, Vecchiè A, Casula M, Cea M, Monacelli F, Caffa I, Bruzzone S, Montecucco F, Nencioni A. Regulation and Function of Extracellular Nicotinamide Phosphoribosyltransferase/Visfatin. Compr Physiol 2017; 7:603-621. [PMID: 28333382 DOI: 10.1002/cphy.c160029] [Citation(s) in RCA: 79] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Nicotinamide phosphoribosyltransferase (NAMPT) is an adipokine-enzyme, which was described as to play bioactivities both in the intracellular and in the extracellular environment. However, while the functions of intracellular NAMPT (iNAMPT) are well known, much less is known on extracellular NAMPT (eNAMPT), also called visfatin or pre-B cell colony-enhancing factor. iNAMPT catalyzes the rate-limiting step in the NAD+ biosynthesis pathway from nicotinamide. Its inhibition severely reduces intracellular NAD+ levels, achieving anti-inflammatory and anti-cancer effects. eNAMPT can be detected in the human circulation and in many extracellular environments. Studies show that eNAMPT can act as a growth factor, as an enzyme, and as a cytokine, but its true mechanism of secretion and its physiological functions are still debated. Increased levels of eNAMPT have been associated with different metabolic disorders and cancers. eNAMPT was demonstrated to modulate the pathways involved in the pathophysiology of obesity, diabetes, atherosclerosis, and cardiovascular events by regulating the oxidative stress response, apoptosis, and inflammation. In cancer, eNAMPT was shown to play a pivotal role in modulating cancer cell metabolism, in promoting epithelial-to-mesenchymal transition and in shaping the tumor microenvironment. In line with these functions, circulating eNAMPT levels are frequently increased in cancer patients. Given these pleiotropic roles of eNAMPT in human disease, this protein has attracted attention as a therapeutic target. In this narrative review, we will discuss recent evidence on eNAMPT-driven signalling, highlighting the emerging pathophysiological roles of this protein in different disorders and the potential therapeutic opportunities linked to its targeting. © 2017 American Physiological Society. Compr Physiol 7:603-621, 2017.
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Affiliation(s)
- Federico Carbone
- First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, Genoa, Italy
| | - Luca Liberale
- First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, Genoa, Italy
| | - Aldo Bonaventura
- First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, Genoa, Italy
| | - Alessandra Vecchiè
- First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, Genoa, Italy
| | - Matteo Casula
- First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, Genoa, Italy
| | - Michele Cea
- Department of Internal Medicine, University of Genoa, Genoa, Italy
- IRCCS AOU San Martino-IST, Genoa, Italy
| | - Fiammetta Monacelli
- Department of Internal Medicine, University of Genoa, Genoa, Italy
- IRCCS AOU San Martino-IST, Genoa, Italy
| | - Irene Caffa
- Department of Internal Medicine, University of Genoa, Genoa, Italy
| | - Santina Bruzzone
- Department of Experimental Medicine, University of Genoa, Genoa, Italy
- Centre of Excellence for Biomedical Research (CEBR), University of Genoa, Genoa, Italy
| | - Fabrizio Montecucco
- First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, Genoa, Italy
- IRCCS AOU San Martino-IST, Genoa, Italy
- Centre of Excellence for Biomedical Research (CEBR), University of Genoa, Genoa, Italy
| | - Alessio Nencioni
- Department of Internal Medicine, University of Genoa, Genoa, Italy
- IRCCS AOU San Martino-IST, Genoa, Italy
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24
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Dalamaga M, Christodoulatos GS. Visfatin, Obesity, and Cancer. ADIPOCYTOKINES, ENERGY BALANCE, AND CANCER 2017. [DOI: 10.1007/978-3-319-41677-9_6] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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25
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Kennedy BE, Sharif T, Martell E, Dai C, Kim Y, Lee PWK, Gujar SA. NAD + salvage pathway in cancer metabolism and therapy. Pharmacol Res 2016; 114:274-283. [PMID: 27816507 DOI: 10.1016/j.phrs.2016.10.027] [Citation(s) in RCA: 98] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2016] [Accepted: 10/30/2016] [Indexed: 12/22/2022]
Abstract
Nicotinamide adenine dinucleotide (NAD+) is an essential coenzyme for various physiological processes including energy metabolism, DNA repair, cell growth, and cell death. Many of these pathways are typically dysregulated in cancer cells, making NAD+ an intriguing target for cancer therapeutics. NAD+ is mainly synthesized by the NAD+ salvage pathway in cancer cells, and not surprisingly, the pharmacological targeting of the NAD+ salvage pathway causes cancer cell cytotoxicity in vitro and in vivo. Several studies have described the precise consequences of NAD+ depletion on cancer biology, and have demonstrated that NAD+ depletion results in depletion of energy levels through lowered rates of glycolysis, reduced citric acid cycle activity, and decreased oxidative phosphorylation. Additionally, depletion of NAD+ causes sensitization of cancer cells to oxidative damage by disruption of the anti-oxidant defense system, decreased cell proliferation, and initiation of cell death through manipulation of cell signaling pathways (e.g., SIRT1 and p53). Recently, studies have explored the effect of well-known cancer therapeutics in combination with pharmacological depletion of NAD+ levels, and found in many cases a synergistic effect on cancer cell cytotoxicity. In this context, we will discuss the effects of NAD+ salvage pathway inhibition on cancer cell biology and provide insight on this pathway as a novel anti-cancer therapeutic target.
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Affiliation(s)
- Barry E Kennedy
- Department of Microbiology & Immunology, Dalhousie University, Halifax, NS, Canada
| | - Tanveer Sharif
- Department of Microbiology & Immunology, Dalhousie University, Halifax, NS, Canada
| | - Emma Martell
- Department of Microbiology & Immunology, Dalhousie University, Halifax, NS, Canada
| | - Cathleen Dai
- Department of Microbiology & Immunology, Dalhousie University, Halifax, NS, Canada
| | - Youra Kim
- Department of Pathology, Dalhousie University, Halifax, NS, Canada
| | - Patrick W K Lee
- Department of Microbiology & Immunology, Dalhousie University, Halifax, NS, Canada; Department of Pathology, Dalhousie University, Halifax, NS, Canada
| | - Shashi A Gujar
- Department of Microbiology & Immunology, Dalhousie University, Halifax, NS, Canada; Department of Pathology, Dalhousie University, Halifax, NS, Canada; Centre for Innovative and Collaborative Health Systems Research, IWK Health Centre, Halifax, NS, Canada.
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26
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Yang J, Zhang K, Song H, Wu M, Li J, Yong Z, Jiang S, Kuang X, Zhang T. Visfatin is involved in promotion of colorectal carcinoma malignancy through an inducing EMT mechanism. Oncotarget 2016; 7:32306-17. [PMID: 27058759 PMCID: PMC5078014 DOI: 10.18632/oncotarget.8615] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2015] [Accepted: 03/28/2016] [Indexed: 02/05/2023] Open
Abstract
Increasing evidences suggested visfatin, a newly discovered obesity-induced adipocytokine, is involved in promotion of cancer malignancy and correlated with worse clinical prognosis. While its effects and mechanisms on progression of colorectal cancer (CRC) remain unclear. Our clinical data show that visfatin protein is over expressed, positive associated with lymph node metastasis, high-grade tumor, and poor prognosis in 87 CRC patients. The levels of plasma visfatin are significantly upregulated in Stage IV colon cancer. Visfatin can significantly promote the in vitro migration and invasion of CRC cells via induction epithelial mesenchymal transition (EMT). It can increase the expression and nuclear translocation of Snail, a key transcription factor in regulating EMT. While silencing of Snail attenuates visfatin induced EMT. Further studies reveal visfatin can inhibit the association of Snail with GSK-3β and subsequently suppress ubiquitylation of Snail. In addition, visfatin can increase the expression and nuclear translocation of β-catenin, elevate its binding with Snail promoter, and then increase the transcription of Snail. While inhibitor of PI3K/Akt, LY294002, abolishes visfatin induced up regulation of Snail, Vimentin (Vim), β-catenin, and phosphorylated GSK-3β. In summary, our data suggest that increased expression of visfatin are associated with a more aggressive phenotype of CRC patients. It can trigger the EMT of CRC cells via Akt/GSK-3β/β-catenin signals.
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Affiliation(s)
- Jing Yang
- School of Biomedical Sciences, Chengdu Medical College, Chengdu, China
| | - Kun Zhang
- School of Biomedical Sciences, Chengdu Medical College, Chengdu, China
| | - Haixing Song
- School of Biomedical Sciences, Chengdu Medical College, Chengdu, China
| | - Mingbo Wu
- School of Biomedical Sciences, Chengdu Medical College, Chengdu, China
| | - Jingyi Li
- School of Biomedical Sciences, Chengdu Medical College, Chengdu, China
| | - Ziyi Yong
- School of Pharmacy, Chengdu Medical College, Chengdu, China
| | - Sheng Jiang
- School of Basic Medical Sciences, Chengdu Medical College, Chengdu, China
| | - Xi Kuang
- Department of Pharmacology, Key Laboratory of Drug Targeting and Drug Delivery Systems, West China School of Pharmacy, Sichuan University, Sichuan, China
| | - Tao Zhang
- School of Biomedical Sciences, Chengdu Medical College, Chengdu, China
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27
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Grolla AA, Torretta S, Gnemmi I, Amoruso A, Orsomando G, Gatti M, Caldarelli A, Lim D, Penengo L, Brunelleschi S, Genazzani AA, Travelli C. Nicotinamide phosphoribosyltransferase (NAMPT/PBEF/visfatin) is a tumoural cytokine released from melanoma. Pigment Cell Melanoma Res 2015; 28:718-29. [DOI: 10.1111/pcmr.12420] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2015] [Accepted: 09/08/2015] [Indexed: 12/20/2022]
Affiliation(s)
- Ambra A. Grolla
- Department of Pharmaceutical Sciences and Department of Medical Sciences; Università del Piemonte Orientale; Novara Italy
| | - Simone Torretta
- Department of Pharmaceutical Sciences and Department of Medical Sciences; Università del Piemonte Orientale; Novara Italy
| | - Ilaria Gnemmi
- Department of Pharmaceutical Sciences and Department of Medical Sciences; Università del Piemonte Orientale; Novara Italy
| | - Angela Amoruso
- Department of Pharmaceutical Sciences and Department of Medical Sciences; Università del Piemonte Orientale; Novara Italy
| | - Giuseppe Orsomando
- Section of Biochemistry; Department of Clinical Sciences; Polytechnic University of Marche; Ancona Italy
| | - Marco Gatti
- Department of Pharmaceutical Sciences and Department of Medical Sciences; Università del Piemonte Orientale; Novara Italy
| | - Antonio Caldarelli
- Department of Pharmaceutical Sciences and Department of Medical Sciences; Università del Piemonte Orientale; Novara Italy
| | - Dmitry Lim
- Department of Pharmaceutical Sciences and Department of Medical Sciences; Università del Piemonte Orientale; Novara Italy
| | - Lorenza Penengo
- Department of Pharmaceutical Sciences and Department of Medical Sciences; Università del Piemonte Orientale; Novara Italy
- Institute of Pharmacology and Toxicology; University of Zürich-Vetsuisse; Zürich Switzerland
| | - Sandra Brunelleschi
- Department of Pharmaceutical Sciences and Department of Medical Sciences; Università del Piemonte Orientale; Novara Italy
| | - Armando A. Genazzani
- Department of Pharmaceutical Sciences and Department of Medical Sciences; Università del Piemonte Orientale; Novara Italy
| | - Cristina Travelli
- Department of Pharmaceutical Sciences and Department of Medical Sciences; Università del Piemonte Orientale; Novara Italy
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28
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Chin CC, Chen CN, Kuo HC, Shi CS, Hsieh MC, Kuo YH, Tung SY, Lee KF, Huang WS. Interleukin-17 induces CC chemokine receptor 6 expression and cell migration in colorectal cancer cells. J Cell Physiol 2015; 230:1430-7. [PMID: 25201147 DOI: 10.1002/jcp.24796] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2013] [Accepted: 09/05/2014] [Indexed: 12/12/2022]
Abstract
The CC chemokine receptor 6 (CCR6) and its ligand CCL20 are involved in human colorectal cancer (CRC) carcinogenesis and can promote the progression of CRC. In addition, interleukin-17 (IL-17), produced by a T cell subset named "Th17," has been identified as an important player in inflammatory responses, and has emerged as a mediator in inflammation-associated cancer. However, the relevance of IL-17 in the development and progression of CRC still remains to be explored. This study aimed to investigate the effect of IL-17 on the cell migration of CRC cells. Human CRC HCT-116 cells were used to study the effect of IL-17 on CCR6 expression and cell migration in CRC cells. IL-17 treatment induced migration of HCT-116 cells across the Boyden chamber membrane and increased the expression level of the CCR6. Inhibition of CCR6 by small interfering RNA (siRNA) and neutralizing antibody inhibited IL-17-induced cell migration. By using specific inhibitors and short hairpin RNA (shRNA), we demonstrated that the activation of ERK and p38 pathways are critical for IL-17-induced CCR6 expression and cell migration. Promoter activity and transcription factor ELISA assays showed that IL-17 increased NF-κB-DNA binding activity in HCT-116 cells. Inhibition of NF-κB activation by specific inhibitors and siRNA blocked the IL-17-induced CCR6 expression. Our findings support the hypothesis that CCR6 up-regulation stimulated by IL-17 may play an active role in CRC cell migration.
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Affiliation(s)
- Chih-Chien Chin
- Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Division of Colon and Rectal Surgery, Department of Surgery, Chang Gung Memorial Hospital, Chiayi, Taiwan
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29
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Beloribi-Djefaflia S, Siret C, Lombardo D. Exosomal lipids induce human pancreatic tumoral MiaPaCa-2 cells resistance through the CXCR4-SDF-1α signaling axis. Oncoscience 2014; 2:15-30. [PMID: 25821841 PMCID: PMC4341461 DOI: 10.18632/oncoscience.96] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2014] [Accepted: 11/09/2014] [Indexed: 12/18/2022] Open
Abstract
We previously reported that exosomes secreted by human pancreatic tumor cells induce cell death through the inhibition of the Notch-1 survival pathway (Ristorcelli et al., 2009). We demonstrated that exosomal lipids evoked apoptosis of human pancreatic cancer SOJ-6 cells. Based on the lipid composition of efficient exosomes we designed Synthetic Exosome-Like Nanoparticles (SELN) in which the ratio ordered lipids versus disordered lipids was equal to 6.0 (SELN6.0). These SELN decreased SOJ-6 cells survival by inhibiting the Notch-1 pathway. However MiaPaCa-2 cells were resistant to exosomes (Ristorcelli et al., 2008) and to SELN6.0 (Beloribi et al.,2012). In this paper we aimed at deciphering the reason(s) of this resistance. We observed, in presence of SELN6.0, that the expression of the Notch IntraCytoplasmic Domain (NICD) decreases in MiaPaCa-2 cells but neither Hes-1, the nuclear target of NICD, nor the ratio Bax/Bcl-2 were affected. We further showed that in MiaPaCa-2 cells SELN6.0 induced the activation of NF-kB, which promotes the expression and the secretion of SDF-1α. This chemokine interacts with its receptor CXCR4 on MiaPaCa-2 cells and activates the Akt survival pathway protecting cells from death. This activation process promoted by exosomal lipids could have implications in tumor progression and drug resistance.
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Affiliation(s)
| | - Carole Siret
- Aix-Marseille Université, CRO2, INSERM, UMR 911, Marseille cedex 5, France
| | - Dominique Lombardo
- Aix-Marseille Université, CRO2, INSERM, UMR 911, Marseille cedex 5, France
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30
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Muc-Wierzgoń M, Nowakowska-Zajdel E, Dzięgielewska-Gęsiak S, Kokot T, Klakla K, Fatyga E, Grochowska-Niedworok E, Waniczek D, Wierzgoń J. Specific metabolic biomarkers as risk and prognostic factors in colorectal cancer. World J Gastroenterol 2014; 20:9759-9774. [PMID: 25110413 PMCID: PMC4123364 DOI: 10.3748/wjg.v20.i29.9759] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2013] [Revised: 11/05/2013] [Accepted: 04/23/2014] [Indexed: 02/06/2023] Open
Abstract
Advances in genomics, molecular pathology and metabolism have generated many candidate biomarkers of colorectal cancer with potential clinical value. Epidemiological and biological studies suggest a role for adiposity, dyslipidaemia, hyperinsulinemia, altered glucose homeostasis, and elevated expression of insulin-like growth factor (IGF) axis members in the risk and prognosis of cancer. This review discusses some recent past and current approaches being taken by researches in obesity and metabolic disorders. The authors describe three main systems as the most studied metabolic candidates of carcinogenesis: dyslipidemias, adipokines and insulin/IGF axis. However, each of these components is unsuccessful in defining the diseases risk and progression, while their co-occurrence increases cancer incidence and mortality in both men and women.
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31
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Laiyemo AO. The risk of colonic adenomas and colonic cancer in obesity. Best Pract Res Clin Gastroenterol 2014; 28:655-63. [PMID: 25194182 PMCID: PMC4159619 DOI: 10.1016/j.bpg.2014.07.007] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2014] [Revised: 06/10/2014] [Accepted: 07/05/2014] [Indexed: 01/31/2023]
Abstract
Increasing body fatness has been associated with an increased burden from colorectal cancer. An increased susceptibility spanning the entire continuum from precancerous adenomatous polyps to the development of colorectal cancer, poor outcome with treatment, and reduced survival when compared to those with normal body weight has been described. It is unknown which age period and which degree and duration of excess weight are associated with increased colorectal cancer risk. It is uncertain whether weight loss can reverse this risk. If it can, how long will the new lower or normal weight be maintained to effect enduring risk reduction? Furthermore, it is controversial whether the increased burden of colorectal cancer warrants earlier and/or more frequent screening for obese persons. This article reviews the relationship between obesity and colorectal neoplasia, explores the postulated mechanism of carcinogenesis, discusses interventions to reduce the burden of disease, and suggests future directions of research.
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Affiliation(s)
- Adeyinka O. Laiyemo
- Division of Gastroenterology, Department of Medicine, Howard University College of Medicine, Washington DC
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32
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Shackelford RE, Mayhall K, Maxwell NM, Kandil E, Coppola D. Nicotinamide phosphoribosyltransferase in malignancy: a review. Genes Cancer 2014; 4:447-56. [PMID: 24386506 DOI: 10.1177/1947601913507576] [Citation(s) in RCA: 103] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2013] [Accepted: 08/26/2013] [Indexed: 12/15/2022] Open
Abstract
Nicotinamide phosphoribosyltransferase (Nampt) catalyzes the rate-limiting step of nicotinamide adenine dinucleotide (NAD) synthesis. Both intracellular and extracellular Nampt (iNampt and eNampt) levels are increased in several human malignancies and some studies demonstrate increased iNampt in more aggressive/invasive tumors and in tumor metastases. Several different molecular targets have been identified that promote carcinogenesis following iNampt overexpression, including SirT1, CtBP, and PARP-1. Additionally, eNampt is elevated in several human cancers and is often associated with a higher tumor stage and worse prognoses. Here we review the roles of Nampt in malignancy, some of the known mechanisms by which it promotes carcinogenesis, and discuss the possibility of employing Nampt inhibitors in cancer treatment.
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Affiliation(s)
| | - Kim Mayhall
- Tulane University School of Medicine, New Orleans, LA, USA
| | | | - Emad Kandil
- Tulane University School of Medicine, New Orleans, LA, USA
| | - Domenico Coppola
- Anatomic Pathology Department, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
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33
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Oh BY, Kim KH, Chung SS, Hong KS, Lee RA. Role of β1-Integrin in Colorectal Cancer: Case-Control Study. Ann Coloproctol 2014; 30:61-70. [PMID: 24851215 PMCID: PMC4022754 DOI: 10.3393/ac.2014.30.2.61] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2013] [Accepted: 08/05/2013] [Indexed: 12/16/2022] Open
Abstract
Purpose In the metastatic process, interactions between circulating tumor cells (CTCs) and the extracellular matrix or surrounding cells are required. β1-Integrin may mediate these interactions. The aim of this study was to investigate whether β1-integrin is associated with the detection of CTCs in colorectal cancer. Methods We enrolled 30 patients with colorectal cancer (experimental group) and 30 patients with benign diseases (control group). Blood samples were obtained from each group, carcinoembryonic antigen (CEA) mRNA for CTCs marker and β1-integrin mRNA levels were estimated by using reverse transcription-polymerase chain reaction, and the results were compared between the two groups. In the experimental group, preoperative results were compared with postoperative results for each marker. In addition, we analyzed the correlation between the expressions of β1-integrin and CEA. Results CEA mRNA was detected more frequently in colorectal cancer patients than in control patients (P = 0.008). CEA mRNA was significantly reduced after surgery in the colorectal cancer patients (P = 0.032). β1-Integrin mRNA was detected more in colorectal cancer patients than in the patients with benign diseases (P < 0.001). In colorectal cancer patients, expression of β1-integrin mRNA was detected more for advanced-stage cancer than for early-stage cancer (P = 0.033) and was significantly decreased after surgery (P < 0.001). In addition, expression of β1-integrin mRNA was significantly associated with that of CEA mRNA in colorectal cancer patients (P = 0.001). Conclusion In conclusion, β1-integrin is a potential factor for forming a prognosis following surgical resection in colorectal cancer patients. β1-Integrin may be a candidate for use as a marker for early detection of micrometastatic tumor cells and for monitoring the therapeutic response in colorectal cancer patients.
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Affiliation(s)
- Bo-Young Oh
- Department of Surgery, Ewha Womans University School of Medicine, Seoul, Korea
| | - Kwang Ho Kim
- Department of Surgery, Ewha Womans University School of Medicine, Seoul, Korea
| | - Soon Sup Chung
- Department of Surgery, Ewha Womans University School of Medicine, Seoul, Korea
| | - Kyoung Sook Hong
- Department of Surgery, Ewha Womans University School of Medicine, Seoul, Korea
| | - Ryung-Ah Lee
- Department of Surgery, Ewha Womans University School of Medicine, Seoul, Korea
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Pham NM, Nanri A, Yasuda K, Kurotani K, Kuwahara K, Akter S, Sato M, Hayabuchi H, Mizoue T. Habitual consumption of coffee and green tea in relation to serum adipokines: a cross-sectional study. Eur J Nutr 2014; 54:205-14. [PMID: 24752775 DOI: 10.1007/s00394-014-0701-4] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2013] [Accepted: 04/08/2014] [Indexed: 12/28/2022]
Abstract
PURPOSE Coffee and green tea consumption may be associated with circulating adipokines, but data are inconsistent, scarce or lacking. We examined the association of coffee and green tea consumption with serum adiponectin, leptin, visfatin, resistin and plasminogen activator inhibitor-1 (PAI-1) among a Japanese working population. METHODS The authors analyzed data (n = 509) from a cross-sectional survey among Japanese workers aged 20-68 years. Serum adipokines were measured using a Luminex suspension bead-based multiplexed array. Coffee and green tea consumption was assessed using a validated diet history questionnaire, and caffeine consumption from these beverages was estimated. Multiple regression analysis was performed with adjustment for potential confounding variables. RESULTS Coffee consumption was significantly, inversely associated with leptin and PAI-1 (P for trend = 0.007 and 0.02, respectively); compared with subjects consuming <1 cup per day, those consuming ≥4 cups per day had 13 and 10 % lower means of leptin and PAI-1, respectively. Similar associations were observed for caffeine consumption (P for trend = 0.02 for both leptin and PAI-1). Additionally, we noted a significant positive association between coffee consumption and adiponectin in men (P for trend = 0.046), but not in women (P for trend = 0.43, P for interaction = 0.11). Moreover, there was a positive association between coffee consumption and resistin in current male smokers (P for trend = 0.01), but not in male non-smokers (P for trend = 0.35, P for interaction = 0.11). Green tea consumption was not associated with any adipokine. CONCLUSIONS Higher consumption of coffee and caffeine but not green tea was associated with lower serum levels of leptin and PAI-1 in Japanese adults.
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Affiliation(s)
- Ngoc Minh Pham
- Department of Epidemiology and Prevention, Center for Clinical Sciences, National Center for Global Health and Medicine, Toyama 1-21-1, Shinjuku-ku, Tokyo, 162-8655, Japan,
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Mao S, Huang S. The signaling pathway of stromal cell-derived factor-1 and its role in kidney diseases. J Recept Signal Transduct Res 2013; 34:85-91. [PMID: 24303939 DOI: 10.3109/10799893.2013.865746] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
The chemokine stromal cell-derived factor-1 (SDF-1) regulates the trafficking of progenitor cell (PGC) during embryonic development, cell chemotaxis, and postnatal homing into injury sites. SDF-1 also regulates cell growth, survival, adhesion and angiogenesis. However, in different tissues/cells, the role of SDF-1 is different, such as that it is increased in most of the tumors and associated with cancer metastasis, whereas it is essential for the development of vasculature. For kidney diseases, its role remains controversial. Signaling pathways might be very important in the pathogenesis of kidney diseases. We performed this review to provide a relatively complete signaling pathway flowchart for SDF-1 to the investigators who were interested in the role of SDF-1 in the pathogenesis of kidney diseases. Here, we reviewed the signal transduction pathway of SDF-1 and its role in the pathogenesis of kidney diseases.
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Affiliation(s)
- Song Mao
- Department of Nephrology, Nanjing Children's Hospital, Affiliated to Nanjing Medical University , Nanjing , China
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