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Söğüt F, Uzun C, Kibar D, Çömelekoğlu Ü. Investigation of the role of K ATP channels in the cytotoxic effect of cypermethrin on rat-derived aortic smooth muscle cells. Drug Chem Toxicol 2024; 47:1218-1225. [PMID: 38747368 DOI: 10.1080/01480545.2024.2352082] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2023] [Revised: 04/12/2024] [Accepted: 05/01/2024] [Indexed: 11/21/2024]
Abstract
We investigate role of ATP sensitive potassium (KATP) channel in cytotoxic effect of cypermethrin on rat aortic smooth muscle cells. Cytotoxicity analysis was performed at 0, 0.1, 0.5, 10, 50, and 100 µM concentrations of cypermethrin and the cell index (CI) was calculated. KATP currents were recorded using patch clamp technique for 50 and 100 µM concentrations and channel conductivity was determined by obtaining current-voltage characteristics. No cytotoxic effect was observed in the first 72 hours. At the 96th hour, only at 100 µM concentration, the CI value decreased significantly compared to control group and at 120 and 144th hours, it was observed that the CI value decreased significantly at all concentrations. Currents and conductivities were significantly decreased at 50 and 100 µM concentrations. Results gave clues that cypermethrin causes a cytotoxic effect on vascular smooth muscles and that KATP channels may have a role in the emergence of this effect.
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Affiliation(s)
- Fatma Söğüt
- Department of Medical Services and Techniques, Vocational School of Medical Services, Mersin University, Mersin, Turkey
| | - Coşar Uzun
- Department of Biophysics, Faculty of Medicine, Mersin University, Mersin, Turkey
| | - Deniz Kibar
- Department of Histology and Embryology, Faculty of Medicine, Mersin University, Mersin, Turkey
| | - Ülkü Çömelekoğlu
- Department of Biophysics, Faculty of Medicine, Mersin University, Mersin, Turkey
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Asiri A, Al Qarni A, Bakillah A. The Interlinking Metabolic Association between Type 2 Diabetes Mellitus and Cancer: Molecular Mechanisms and Therapeutic Insights. Diagnostics (Basel) 2024; 14:2132. [PMID: 39410536 PMCID: PMC11475808 DOI: 10.3390/diagnostics14192132] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2024] [Revised: 09/15/2024] [Accepted: 09/16/2024] [Indexed: 10/20/2024] Open
Abstract
Type 2 diabetes mellitus (T2DM) and cancer share common risk factors including obesity, inflammation, hyperglycemia, and hyperinsulinemia. High insulin levels activate the PI3K/Akt/mTOR signaling pathway promoting cancer cell growth, survival, proliferation, metastasis, and anti-apoptosis. The inhibition of the PI3K/Akt/mTOR signaling pathway for cancer remains a promising therapy; however, drug resistance poses a major problem in clinical settings resulting in limited efficacy of agents; thus, combination treatments with therapeutic inhibitors may solve the resistance to such agents. Understanding the metabolic link between diabetes and cancer can assist in improving the therapeutic strategies used for the management of cancer patients with diabetes and vice versa. This review provides an overview of shared molecular mechanisms between diabetes and cancer as well as discusses established and emerging therapeutic anti-cancer agents targeting the PI3K/Akt/mTOR pathway in cancer management.
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Affiliation(s)
- Abutaleb Asiri
- King Abdullah International Medical Research Center (KAIMRC), Eastern Region, Al Ahsa 36428, Saudi Arabia; (A.A.); (A.A.Q.)
- Division of Medical Research Core-A, King Saud bin Abdulaziz University for Health Sciences (KSAU-HS), Al Ahsa 36428, Saudi Arabia
- King Abdulaziz Hospital, Ministry of National Guard-Health Affairs (MNG-HA), Al Ahsa 36428, Saudi Arabia
| | - Ali Al Qarni
- King Abdullah International Medical Research Center (KAIMRC), Eastern Region, Al Ahsa 36428, Saudi Arabia; (A.A.); (A.A.Q.)
- Division of Medical Research Core-A, King Saud bin Abdulaziz University for Health Sciences (KSAU-HS), Al Ahsa 36428, Saudi Arabia
- King Abdulaziz Hospital, Ministry of National Guard-Health Affairs (MNG-HA), Al Ahsa 36428, Saudi Arabia
| | - Ahmed Bakillah
- King Abdullah International Medical Research Center (KAIMRC), Eastern Region, Al Ahsa 36428, Saudi Arabia; (A.A.); (A.A.Q.)
- Division of Medical Research Core-A, King Saud bin Abdulaziz University for Health Sciences (KSAU-HS), Al Ahsa 36428, Saudi Arabia
- King Abdulaziz Hospital, Ministry of National Guard-Health Affairs (MNG-HA), Al Ahsa 36428, Saudi Arabia
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Zhou M, Li TS, Abe H, Akashi H, Suzuki R, Bando Y. Expression levels of K ATP channel subunits and morphological changes in the mouse liver after exposure to radiation. World J Exp Med 2024; 14:90374. [PMID: 38948415 PMCID: PMC11212743 DOI: 10.5493/wjem.v14.i2.90374] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Revised: 01/28/2024] [Accepted: 03/27/2024] [Indexed: 06/19/2024] Open
Abstract
BACKGROUND ATP sensitive K+ (KATP) channels are ubiquitously distributed in various of cells and tissues, including the liver. They play a role in the pathogenesis of myocardial and liver ischemia. AIM To evaluate the radiation-induced changes in the expression of KATP channel subunits in the mouse liver to understand the potential role of KATP channels in radiation injury. METHODS Adult C57BL/6 mice were randomly exposed to γ-rays at 0 Gy (control, n = 2), 0.2 Gy (n = 6), 1 Gy (n = 6), or 5 Gy (n = 6). The livers were removed 3 and 24 h after radiation exposure. Hematoxylin and eosin staining was used for morphological observation; immunohistochemical staining was applied to determine the expression of KATP channel subunits in the liver tissue. RESULTS Compared with the control group, the livers exposed to 0.2 Gy γ-ray showed an initial increase in the expression of Kir6.1 at 3 h, followed by recovery at 24 h after exposure. Exposure to a high dose of 5.0 Gy resulted in decreased expression of Kir6.1 and increased expression of SUR2B at 24 h. However, the expression of Kir6.2, SUR1, or SUR2A had no remarkable changes at 3 and 24 h after exposure to any of these doses. CONCLUSION The expression levels of Kir6.1 and SUR2B in mouse liver changed differently in response to different radiation doses, suggesting a potential role for them in radiation-induced liver injury.
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Affiliation(s)
- Ming Zhou
- Department of Anatomy, Akita University Graduate School of Medicine, Akita 010-8543, Japan
| | - Tao-Sheng Li
- Department of Stem Cell Biology, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki 852-8523, Japan
| | - Hiroshi Abe
- Sendai Old Age Refresh Station, A Long-term Care Health Facility, Sendai 981-1105, Japan
| | - Hideo Akashi
- Department of Anatomy, Akita University Graduate School of Medicine, Akita 010-8543, Japan
| | - Ryoji Suzuki
- Department of Anatomy, Akita University Graduate School of Medicine, Akita 010-8543, Japan
| | - Yoshio Bando
- Department of Anatomy, Akita University Graduate School of Medicine, Akita 010-8543, Japan
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Moon DO. Exploring the Role of Surface and Mitochondrial ATP-Sensitive Potassium Channels in Cancer: From Cellular Functions to Therapeutic Potentials. Int J Mol Sci 2024; 25:2129. [PMID: 38396807 PMCID: PMC10888650 DOI: 10.3390/ijms25042129] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2024] [Revised: 02/08/2024] [Accepted: 02/08/2024] [Indexed: 02/25/2024] Open
Abstract
ATP-sensitive potassium (KATP) channels are found in plasma membranes and mitochondria. These channels are a type of ion channel that is regulated by the intracellular concentration of adenosine triphosphate (ATP) and other nucleotides. In cell membranes, they play a crucial role in linking metabolic activity to electrical activity, especially in tissues like the heart and pancreas. In mitochondria, KATP channels are involved in protecting cells against ischemic damage and regulating mitochondrial function. This review delves into the role of KATP channels in cancer biology, underscoring their critical function. Notably responsive to changes in cellular metabolism, KATP channels link metabolic states to electrical activity, a feature that becomes particularly significant in cancer cells. These cells, characterized by uncontrolled growth, necessitate unique metabolic and signaling pathways, differing fundamentally from normal cells. Our review explores the intricate roles of KATP channels in influencing the metabolic and ionic balance within cancerous cells, detailing their structural and operational mechanisms. We highlight the channels' impact on cancer cell survival, proliferation, and the potential of KATP channels as therapeutic targets in oncology. This includes the challenges in targeting these channels due to their widespread presence in various tissues and the need for personalized treatment strategies. By integrating molecular biology, physiology, and pharmacology perspectives, the review aims to enhance the understanding of cancer as a complex metabolic disease and to open new research and treatment avenues by focusing on KATP channels. This comprehensive approach provides valuable insights into the potential of KATP channels in developing innovative cancer treatments.
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Affiliation(s)
- Dong-Oh Moon
- Department of Biology Education, Daegu University, 201, Daegudae-ro, Gyeongsan-si 38453, Gyeongsangbuk-do, Republic of Korea
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Achimba F, Faezov B, Cohen B, Dunbrack R, Holford M. Targeting Dysregulated Ion Channels in Liver Tumors with Venom Peptides. Mol Cancer Ther 2024; 23:139-147. [PMID: 38015557 PMCID: PMC10831335 DOI: 10.1158/1535-7163.mct-23-0256] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Revised: 10/04/2023] [Accepted: 11/14/2023] [Indexed: 11/29/2023]
Abstract
The regulation of cellular processes by ion channels has become central to the study of cancer mechanisms. Designing molecules that can modify ion channels specific to tumor cells is a promising area of targeted drug delivery and therapy. Despite their potential in drug discovery, venom peptides-a group of natural products-have largely remained understudied and under-characterized. In general, venom peptides display high specificity and selectivity for their target ion channels. Therefore, they may represent an effective strategy for selectively targeting the dysregulation of ion channels in tumor cells. This review examines existing venom peptide therapies for different cancer types and focuses on the application of snail venom peptides in hepatocellular carcinoma (HCC), the most common form of primary liver cancer worldwide. We provide insights into the mode of action of venom peptides that have been shown to target tumors. We also explore the benefit of using new computational methods like de novo protein structure prediction to screen venom peptides and identify potential druggable candidates. Finally, we summarize the role of cell culture, animal, and organoid models in developing effective therapies against HCC and highlight the need for creating models that represent the most disproportionately affected ethnicities in HCC.
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Affiliation(s)
- Favour Achimba
- The PhD Program in Biochemistry, Graduate Center, City University of New York, New York, New York
- Hunter College, City University of New York, New York, New York
| | - Bulat Faezov
- Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia, Pennsylvania
- Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russian Federation
| | - Brandon Cohen
- Hunter College, City University of New York, New York, New York
| | - Roland Dunbrack
- Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia, Pennsylvania
| | - Mandë Holford
- The PhD Program in Biochemistry, Graduate Center, City University of New York, New York, New York
- Hunter College, City University of New York, New York, New York
- The PhD Program in Chemistry, Graduate Center of the City University of New York, New York, New York
- The PhD Program in Biology, Graduate Center of the City University of New York, New York, New York
- Department of Invertebrate Zoology, The American Museum of Natural History, New York, New York
- Department of Biochemistry, Weill Cornell Medicine, New York, New York
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da Silva Prado L, Grivicich I, Miri JM, Charão MF, Bonfada A, Endres da Rocha G, Bondan da Silva J, Menezes Boaretto FB, Garcia ALH, da Silva J, Picada JN. Toxicological assessment of minoxidil: A drug with therapeutic potential besides alopecia. Food Chem Toxicol 2023; 182:114211. [PMID: 38007212 DOI: 10.1016/j.fct.2023.114211] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2023] [Revised: 11/07/2023] [Accepted: 11/18/2023] [Indexed: 11/27/2023]
Abstract
Minoxidil is regularly prescribed for alopecia, and its therapeutic potential has expanded in recent times. However, few studies have been conducted to evaluate its toxicity, and controversial findings regarding its mutagenic activities remain unsolved. This study aimed to access cytotoxic, genotoxic, and mutagenic properties of minoxidil using the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) assay, comet assay, and micronucleus test in mouse fibroblast (L929) cells and its point mutation induction potential in the Salmonella/microsome assay. Furthermore, an in vivo toxicity assessment was conducted in Caenorhabditis elegans. Minoxidil showed cytotoxicity at 2.0 mg/mL in MTT assay. Genotoxicity was observed after 3 h treatment in L929 cells using comet assay. No mutagenic effect was observed in both the micronucleus test and the Salmonella/microsome assay. The lethal dose 50 in C. elegans was determined to be 1.75 mg/mL, and a delay in body development was detected at all concentrations. In conclusion, minoxidil induces DNA damage only in early treatment, implying that this DNA damage may be repairable. This observation corroborates the absence of mutagenic activities observed in L929 cells and Salmonella typhimurium strains. However, the toxicity of minoxidil was evident in both C. elegans and L929 cells, underscoring the need for caution in its use.
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Affiliation(s)
- Lismare da Silva Prado
- Toxicological Genetics Laboratory, Graduate Program in Cellular and Molecular Biology Applied to Health, Luteran University of Brazil (ULBRA), Av. Farroupilha, 8001, 92425-900, Canoas, RS, Brazil
| | - Ivana Grivicich
- Cancer Biology Laboratory, Graduate Program in Cellular and Molecular Biology Applied to Health, Luteran University of Brazil (ULBRA), Av. Farroupilha 8001, 92425-900, Canoas, RS, Brazil
| | - Jessica Machado Miri
- Cancer Biology Laboratory, Graduate Program in Cellular and Molecular Biology Applied to Health, Luteran University of Brazil (ULBRA), Av. Farroupilha 8001, 92425-900, Canoas, RS, Brazil
| | - Mariele Feiffer Charão
- Graduate Program in Toxicology and Analytical Toxicology, Feevale University, ERS-239, 93525-075, Novo Hamburgo, Brazil
| | - Amanda Bonfada
- Graduate Program in Toxicology and Analytical Toxicology, Feevale University, ERS-239, 93525-075, Novo Hamburgo, Brazil
| | - Gabriela Endres da Rocha
- Graduate Program in Toxicology and Analytical Toxicology, Feevale University, ERS-239, 93525-075, Novo Hamburgo, Brazil
| | - Juliana Bondan da Silva
- Toxicological Genetics Laboratory, Graduate Program in Cellular and Molecular Biology Applied to Health, Luteran University of Brazil (ULBRA), Av. Farroupilha, 8001, 92425-900, Canoas, RS, Brazil
| | - Fernanda Brião Menezes Boaretto
- Toxicological Genetics Laboratory, Graduate Program in Cellular and Molecular Biology Applied to Health, Luteran University of Brazil (ULBRA), Av. Farroupilha, 8001, 92425-900, Canoas, RS, Brazil
| | - Ana Letícia Hilario Garcia
- Toxicological Genetics Laboratory, Graduate Program in Cellular and Molecular Biology Applied to Health, Luteran University of Brazil (ULBRA), Av. Farroupilha, 8001, 92425-900, Canoas, RS, Brazil; Toxicological Genetics Laboratory, LaSalle University, Av. Victor Barreto, 2288, 92010-000, Canoas, RS, Brazil
| | - Juliana da Silva
- Toxicological Genetics Laboratory, Graduate Program in Cellular and Molecular Biology Applied to Health, Luteran University of Brazil (ULBRA), Av. Farroupilha, 8001, 92425-900, Canoas, RS, Brazil; Toxicological Genetics Laboratory, LaSalle University, Av. Victor Barreto, 2288, 92010-000, Canoas, RS, Brazil
| | - Jaqueline Nascimento Picada
- Toxicological Genetics Laboratory, Graduate Program in Cellular and Molecular Biology Applied to Health, Luteran University of Brazil (ULBRA), Av. Farroupilha, 8001, 92425-900, Canoas, RS, Brazil.
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Allegra A, Caserta S, Genovese S, Pioggia G, Gangemi S. Gender Differences in Oxidative Stress in Relation to Cancer Susceptibility and Survival. Antioxidants (Basel) 2023; 12:1255. [PMID: 37371985 DOI: 10.3390/antiox12061255] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2023] [Revised: 06/08/2023] [Accepted: 06/10/2023] [Indexed: 06/29/2023] Open
Abstract
Genetic, developmental, biochemical, and environmental variables interact intricately to produce sex differences. The significance of sex differences in cancer susceptibility is being clarified by numerous studies. Epidemiological research and cancer registries have revealed over the past few years that there are definite sex variations in cancer incidence, progression, and survival. However, oxidative stress and mitochondrial dysfunction also have a significant impact on the response to treatment of neoplastic diseases. Young women may be more protected from cancer than men because most of the proteins implicated in the regulation of redox state and mitochondrial function are under the control of sexual hormones. In this review, we describe how sexual hormones control the activity of antioxidant enzymes and mitochondria, as well as how they affect several neoplastic diseases. The molecular pathways that underlie the gender-related discrepancies in cancer that have been identified may be better understood, which may lead to more effective precision medicine and vital information on treatment options for both males and females with neoplastic illnesses.
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Affiliation(s)
- Alessandro Allegra
- Division of Hematology, Department of Human Pathology in Adulthood and Childhood 'Gaetano Barresi', University of Messina, 98125 Messina, Italy
| | - Santino Caserta
- Division of Hematology, Department of Human Pathology in Adulthood and Childhood 'Gaetano Barresi', University of Messina, 98125 Messina, Italy
| | - Sara Genovese
- Institute for Biomedical Research and Innovation (IRIB), National Research Council of Italy (CNR), 98164 Messina, Italy
| | - Giovanni Pioggia
- Institute for Biomedical Research and Innovation (IRIB), National Research Council of Italy (CNR), 98164 Messina, Italy
| | - Sebastiano Gangemi
- Allergy and Clinical Immunology Unit, Department of Clinical and Experimental Medicine, University of Messina, 98100 Messina, Italy
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Maqoud F, Zizzo N, Attimonelli M, Tinelli A, Passantino G, Antonacci M, Ranieri G, Tricarico D. Immunohistochemical, pharmacovigilance, and omics analyses reveal the involvement of ATP-sensitive K + channel subunits in cancers: role in drug-disease interactions. Front Pharmacol 2023; 14:1115543. [PMID: 37180726 PMCID: PMC10167295 DOI: 10.3389/fphar.2023.1115543] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2022] [Accepted: 04/10/2023] [Indexed: 05/16/2023] Open
Abstract
Background: ATP-sensitive-K+ channels (KATP) are involved in diseases, but their role in cancer is poorly described. Pituitary macroadenoma has been observed in Cantu' syndrome (C.S.), which is associated with the gain-of-function mutations of the ABCC9 and KCNJ8 genes. We tested the role of the ABCC8/Sur1, ABCC9/Sur2A/B, KCNJ11/Kir6.2, and KCNJ8/Kir6.1 genes experimentally in a minoxidil-induced renal tumor in male rats and in the female canine breast cancer, a spontaneous animal model of disease, and in the pharmacovigilance and omics databases. Methods: We performed biopsies from renal tissues of male rats (N = 5) following a sub-chronic high dosing topical administration of minoxidil (0.777-77.7 mg/kg/day) and from breast tissues of female dogs for diagnosis (N = 23) that were analyzed by immunohistochemistry. Pharmacovigilance and omics data were extracted from EudraVigilance and omics databases, respectively. Results: An elevated immunohistochemical reactivity to Sur2A-mAb was detected in the cytosol of the Ki67+/G3 cells other than in the surface membrane in the minoxidil-induced renal tumor and the breast tumor samples. KCNJ11, KCNJ8, and ABCC9 genes are upregulated in cancers but ABCC8 is downregulated. The Kir6.2-Sur2A/B-channel opener minoxidil showed 23 case reports of breast cancer and one case of ovarian cancer in line with omics data reporting, respectively, and the negative and positive prognostic roles of the ABCC9 gene in these cancers. Sulfonylureas and glinides blocking the pancreatic Kir6.2-Sur1 subunits showed a higher risk for pancreatic cancer in line with the positive prognostic role of the ABCC8 gene but low risks for common cancers. Glibenclamide, repaglinide, and glimepiride show a lower cancer risk within the KATP channel blockers. The Kir6.2-Sur1 opener diazoxide shows no cancer reactions. Conclusion: An elevated expression of the Sur2A subunit was found in proliferating cells in two animal models of cancer. Immunohistochemistry/omics/pharmacovigilance data reveal the role of the Kir6.1/2-Sur2A/B subunits as a drug target in breast/renal cancers and in C.S.
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Affiliation(s)
- Fatima Maqoud
- Functional Gastrointestinal Disorders Research Group, National Institute of Gastroenterology Saverio de Bellis, I.R.C.C.S. Research Hospital, Milan, Italy
- Section of Pharmacology, Department of Pharmacy-Pharmaceutical Sciences, University of Bari "Aldo Moro", Bari, Italy
| | - Nicola Zizzo
- Section of Veterinary Pathology and Comparative Oncology, Department of Veterinary Medicine, University of Bari "Aldo Moro", Valenzano, Italy
| | - Marcella Attimonelli
- Department of Biosciences, Biotechnologies, and Biopharmaceutics, University "Aldo Moro" Bari, Bari, Italy
| | - Antonella Tinelli
- Section of Veterinary Pathology and Comparative Oncology, Department of Veterinary Medicine, University of Bari "Aldo Moro", Valenzano, Italy
| | - Giuseppe Passantino
- Section of Veterinary Pathology and Comparative Oncology, Department of Veterinary Medicine, University of Bari "Aldo Moro", Valenzano, Italy
| | - Marina Antonacci
- Section of Pharmacology, Department of Pharmacy-Pharmaceutical Sciences, University of Bari "Aldo Moro", Bari, Italy
| | - Girolamo Ranieri
- Department of Interventional Radiology and Integrated Medical Oncology, I.R.C.C.S. Istituto Tumori "Giovanni Paolo II", Bari, Italy
| | - Domenico Tricarico
- Section of Pharmacology, Department of Pharmacy-Pharmaceutical Sciences, University of Bari "Aldo Moro", Bari, Italy
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Li M, Liu H, Shao H, Zhang P, Gao M, Huang L, Shang P, Zhang Q, Wang W, Feng F. Glyburide attenuates B(a)p and LPS-induced inflammation-related lung tumorigenesis in mice. ENVIRONMENTAL TOXICOLOGY 2021; 36:1713-1722. [PMID: 34037304 DOI: 10.1002/tox.23293] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Accepted: 05/11/2021] [Indexed: 06/12/2023]
Abstract
Glyburide (Gly) could inhibit NLRP3 inflammasome, as well as could be treated with Type 2 diabetes as a common medication. Despite more and more studies show that Gly could influence cancer risk and tumor growth, it remains unclear about the effect of Gly in lung tumorigenesis. To evaluate whether Gly inhibited lung tumorigenesis and explore the possible mechanisms, a benzo(a)pyrene [B(a)p] plus lipopolysaccharide (LPS)-induced non-diabetes mice model was established with B(a)p for 4 weeks and once a week (1 mg/mouse), then instilled with LPS for 15 weeks and once every 3 weeks (2.5 μg/mouse) intratracheally. Subsequently, Gly was administered by gavage (10 μl/g body weight) 1 week before B(a)p were given to the mice until the animal model finished (when Gly was first given named Week 0). At the end of the experiment called Week 34, we analyzed the incidence, number and histopathology of lung tumors, and detected the expression of NLRP3, IL-1β, and Cleaved-IL-1β protein. We found that vehicles and tricaprylin+Gly could not cause lung carcinogenesis in the whole process. While the incidence and mean tumor count of mice in B(a)P/LPS+Gly group were decreased compared with B(a)p/LPS group. Moreover, Gly could alleviate inflammatory changes and reduce pathological tumor nest numbers compared with mice administrated with B(a)p/LPS in histopathological examination. The B(a)p/LPS increased the expression of NLRP3, IL-1β, and Cleaved-IL-1β protein significantly than Vehicle, whereas decreased in B(a)P/LPS+Gly (0.96 mg/kg) group compared with B(a)p/LPS group. Results suggested glyburide might inhibit NLRP3 inflammasome to attenuate inflammation-related lung tumorigenesis caused by intratracheal instillation of B(a)p/LPS in non-diabetes mice.
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Affiliation(s)
- Mengyuan Li
- Department of Toxicology, Zhengzhou University School of Public Health, Zhengzhou, Henan, China
| | - Hong Liu
- Department of Pulmonary Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Hua Shao
- Department of Toxicology, Zhengzhou University School of Public Health, Zhengzhou, Henan, China
| | - Peng Zhang
- Department of Bone and Soft Tissue Cancer, The Affiliated Cancer Hospital of Zhengzhou University (Henan Cancer Hospital), Zhengzhou, Henan, China
| | - Min Gao
- Department of Toxicology, Zhengzhou University School of Public Health, Zhengzhou, Henan, China
| | - Li Huang
- Department of Toxicology, Zhengzhou University School of Public Health, Zhengzhou, Henan, China
| | - Pingping Shang
- Key Laboratory of Tobacco Chemistry, Zhengzhou Tobacco Research Institute, CNC, Zhengzhou, Henan, China
| | - Qiao Zhang
- Department of Toxicology, Zhengzhou University School of Public Health, Zhengzhou, Henan, China
| | - Wei Wang
- Department of Occupational Medicine, Zhengzhou University School of Public Health, Zhengzhou, Henan, China
| | - Feifei Feng
- Department of Toxicology, Zhengzhou University School of Public Health, Zhengzhou, Henan, China
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Mathen C, Dsouza W. In vitro and clinical evaluation of umbilical cord-derived mesenchymal stromal cell-conditioned media for hair regeneration. J Cosmet Dermatol 2021; 21:740-749. [PMID: 33780589 DOI: 10.1111/jocd.14114] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Revised: 03/15/2021] [Accepted: 03/25/2021] [Indexed: 11/29/2022]
Abstract
BACKGROUND The field of regenerative medicine may present a non-drug, non-steroid, and non-invasive alternative toward addressing male and female pattern hair loss, a global concern. OBJECTIVE The aim was to carry out the in vitro and in vivo safety and efficacy evaluation of human umbilical cord-derived mesenchymal stromal cell-conditioned media (MSC-CM) for hair regeneration. METHODS Various in vitro parameters were used to estimate the consistency across various batches of MSC-CM. Total protein content was measured by the Biuret method and antioxidant activity by the 2,2-diphenyl-1-picryl hydrazyl (DPPH) assay. Fourier transform infrared spectroscopy (FTIR) analysis was used to determine spectral signatures and biocompatibility was carried out by the Neutral Red Uptake (NRU) and Sulforhodamine B (SRB) assays. In vivo safety and efficacy was evaluated in an experimental pilot study on 15 volunteers. RESULTS The in vitro results confirmed stability in the protein content (7 mg/ml), antioxidant activity (49.50%), and FTIR fingerprints of the MSC-CM. In the biocompatibility experiments by both SRB and NRU methods, no IC50 value could be derived at 100% concentration indicating safety at the cellular level. The in vivo results indicated safety with no side effects or adverse reactions, while 86.6% of the subjects experienced a positive effect of hair regeneration. CONCLUSION MSC-CM comprises a rich cocktail of physiologically balanced growth factors, cytokines, and beneficial proteins which may explain the bioactivity and mechanism of action in hair regrowth. This may indicate a biocompatible, gentle, and safe regenerative approach to address hair loss.
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Affiliation(s)
- Caroline Mathen
- Clinical R & D, OCT Therapies and Research Pvt Ltd, Mumbai, India
| | - Wilfrid Dsouza
- Clinical R & D, OCT Therapies and Research Pvt Ltd, Mumbai, India
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Szymczak-Pajor I, Fleszar K, Kasznicki J, Gralewska P, Śliwińska A. A potential role of calpains in sulfonylureas (SUs) -mediated death of human pancreatic cancer cells (1.2B4). Toxicol In Vitro 2021; 73:105128. [PMID: 33652124 DOI: 10.1016/j.tiv.2021.105128] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Revised: 02/01/2021] [Accepted: 02/25/2021] [Indexed: 12/25/2022]
Abstract
Sulfonylureas (SUs) are suggested to accelerate the pancreatic β-cells mass loss via apoptosis. However, little is known whether calpains mediate this process. The aim of the present study is to evaluate the involvement of calpains in SUs-induced death of human pancreatic cancer (PC) cell line 1.2B4. The cells were exposed to: glibenclamide, glimepiride and gliclazide for 72 h. The expression analysis of caspase-3 (CASP-3), TP53, calpain 1 (CAPN-1), calpain 2 (CAPN-2) and calpain 10 (CAPN-10) was detected using RT-PCR method. Intracellular Ca2+ concentrations, CASP-3 activity and total calpain activity were also evaluated. Our results have shown that glibenclamide and glimepiride decrease 1.2B4 cells viability with accompanied increase in intracellular Ca2+ concentration and increased expression of apoptosis-related CASP-3 and TP53. Gliclazide did not affect 1.2B4 cell viability and Ca2+ concentration, however, it downregulated CASP-3 and upregulated TP53. Interestingly, 50 μM glimepiride increased expression of CAPN-1, CAPN-2 and CAPN-10 whereas 50 μM glibenclamide solely upregulated CAPN-2 expression. We have shown that 10 μM and 50 μM glibenclamide and glimepiride increased the activity of CASP-3, but decreased total calpain activity. Our results suggest that calpains may be involved in glibenclamide- and glimepiride-induced death of PC cells. However, further investigation is required to confirm the engagement of calpains in SUs-mediated death of PC cells, especially studies on protein level of particular isoforms of calpains should be conducted.
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Affiliation(s)
- Izabela Szymczak-Pajor
- Department of Nucleic Acid Biochemistry, Medical University of Lodz, 251 Pomorska, 92-213 Lodz, Poland.
| | - Krzysztof Fleszar
- Student Scientific Society of Civilization Diseases, Medical University of Lodz, 251 Pomorska, 92-213 Lodz, Poland.
| | - Jacek Kasznicki
- Department of Internal Diseases, Diabetology and Clinical Pharmacology, Medical University of Lodz, 251 Pomorska, 92-213 Lodz, Poland.
| | - Patrycja Gralewska
- Department of Medical Biophysics, Institute of Biophysics, Faculty of Biology and Environmental Protection, University of Lodz, Pomorska 141/143, 90-236 Lodz, Poland.
| | - Agnieszka Śliwińska
- Department of Nucleic Acid Biochemistry, Medical University of Lodz, 251 Pomorska, 92-213 Lodz, Poland.
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12
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Novel Therapeutic Approaches of Ion Channels and Transporters in Cancer. Rev Physiol Biochem Pharmacol 2020; 183:45-101. [PMID: 32715321 DOI: 10.1007/112_2020_28] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The expression and function of many ion channels and transporters in cancer cells display major differences in comparison to those from healthy cells. These differences provide the cancer cells with advantages for tumor development. Accordingly, targeting ion channels and transporters have beneficial anticancer effects including inhibition of cancer cell proliferation, migration, invasion, metastasis, tumor vascularization, and chemotherapy resistance, as well as promoting apoptosis. Some of the molecular mechanisms associating ion channels and transporters with cancer include the participation of oxidative stress, immune response, metabolic pathways, drug synergism, as well as noncanonical functions of ion channels. This diversity of mechanisms offers an exciting possibility to suggest novel and more effective therapeutic approaches to fight cancer. Here, we review and discuss most of the current knowledge suggesting novel therapeutic approaches for cancer therapy targeting ion channels and transporters. The role and regulation of ion channels and transporters in cancer provide a plethora of exceptional opportunities in drug design, as well as novel and promising therapeutic approaches that may be used for the benefit of cancer patients.
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13
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Zhou M, Yoshikawa K, Akashi H, Miura M, Suzuki R, Li TS, Abe H, Bando Y. Localization of ATP-sensitive K + channel subunits in rat liver. World J Exp Med 2019; 9:14-31. [PMID: 31938690 PMCID: PMC6955576 DOI: 10.5493/wjem.v9.i2.14] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2019] [Revised: 09/05/2019] [Accepted: 11/21/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND ATP-sensitive K+ (KATP) channels were originally found in cardiac myocytes by Noma in 1983. KATP channels were formed by potassium ion-passing pore-forming subunits (Kir6.1, Kir6.2) and regulatory subunits SUR1, SU2A and SUR2B. A number of cells and tissues have been revealed to contain these channels including hepatocytes, but detailed localization of these subunits in different types of liver cells was still uncertain.
AIM To investigate the expression of KATP channel subunits in rat liver and their localization in different cells of the liver.
METHODS Rabbit anti-rat SUR1 peptide antibody was raised and purified by antigen immunoaffinity column chromatography. Four of Sprague-Dawley rats were used for liver protein extraction for immunoblot analysis, seven of them were used for immunohistochemistry both for the ABC method and immunofluorescence staining. Four of Wistar rats were used for the isolation of hepatic stellate cells (HSCs) and Kupffer cells for both primary culture and immunocytochemistry.
RESULTS Immunoblot analysis showed that the five kinds of KATP channel subunits, i.e. Kir6.1, Kir6.2, SUR1, SUR2A, and SUR2B, were detected in liver. Immunohistochemical staining showed that Kir6.1 and Kir6.2 were weakly to moderately expressed in parenchymal cells and sinusoidal lining cells, while SUR1, SUR2A, and SUR2B were mainly localized to sinusoidal lining cells, such as HSCs, Kupffer cells, and sinusoidal endothelial cells. Immunoreactivity for SUR2A and SUR2B was expressed in the hepatocyte membrane. Double immunofluorescence staining further showed that the pore-forming subunits Kir6.1 and/or Kir6.2 colocalized with GFAP in rat liver sections and primary cultured HSCs. These KATP channel subunits also colocalized with CD68 in liver sections and primary cultured Kupffer cells. The SUR subunits colocalized with GFAP in liver sections and colocalized with CD68 both in liver sections and primary cultured Kupffer cells. In addition, five KATP channel subunits colocalized with SE-1 in sinusoidal endothelial cells.
CONCLUSION Observations from the present study indicated that KATP channel subunits expressed in rat liver and the diversity of KATP channel subunit composition might form different types of KATP channels. This is applicable to hepatocytes, HSCs, various types of Kupffer cells and sinusoidal endothelial cells.
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Affiliation(s)
- Ming Zhou
- Department of Anatomy, Akita University Graduate School of Medicine, Akita 010-8543, Japan
| | - Kiwamu Yoshikawa
- Department of Cell Biology and Morphology, Akita University Graduate School of Medicine, Akita 010-8543, Japan
| | - Hideo Akashi
- Department of Anatomy, Akita University Graduate School of Medicine, Akita 010-8543, Japan
| | - Mitsutaka Miura
- Department of Cell Biology and Morphology, Akita University Graduate School of Medicine, Akita 010-8543, Japan
| | - Ryoji Suzuki
- Department of Anatomy, Akita University Graduate School of Medicine, Akita 010-8543, Japan
| | - Tao-Sheng Li
- Department of Stem Cell Biology, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki 852-8523, Japan
| | - Hiroshi Abe
- TRUST, A Long-Term Care Health Facility, Sendai 980-0011, Japan
| | - Yoshio Bando
- Department of Anatomy, Akita University Graduate School of Medicine, Akita 010-8543, Japan
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14
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Hendriks AM, Schrijnders D, Kleefstra N, de Vries EGE, Bilo HJG, Jalving M, Landman GWD. Sulfonylurea derivatives and cancer, friend or foe? Eur J Pharmacol 2019; 861:172598. [PMID: 31408647 DOI: 10.1016/j.ejphar.2019.172598] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2019] [Revised: 08/07/2019] [Accepted: 08/08/2019] [Indexed: 02/07/2023]
Abstract
Type 2 diabetes mellitus (T2DM) is associated with a higher risk of cancer and cancer-related mortality. Increased blood glucose and insulin levels in T2DM patients may be, at least in part, responsible for this effect. Indeed, lowering glucose and/or insulin levels pharmacologically appears to reduce cancer risk and progression, as has been demonstrated for the biguanide metformin in observational studies. Studies investigating the influence of sulfonylurea derivatives (SUs) on cancer risk have provided conflicting results, partly due to comparisons with metformin. Furthermore, little attention has been paid to within-class differences in systemic and off-target effects of the SUs. The aim of this systematic review is to discuss the available preclinical and clinical evidence on how the different SUs influence cancer development and risk. Databases including PubMed, Cochrane, Database of Abstracts on Reviews and Effectiveness, and trial registries were systematically searched for available clinical and preclinical evidence on within-class differences of SUs and cancer risk. The overall preclinical and clinical evidence suggest that the influence of SUs on cancer risk in T2DM patients differs between the various SUs. Potential mechanisms include differing affinities for the sulfonylurea receptors and thus differential systemic insulin exposure and off-target anti-cancer effects mediated for example through potassium transporters and drug export pumps. Preclinical evidence supports potential anti-cancer effects of SUs, which are of interest for further studies and potentially repurposing of SUs. At this time, the evidence on differences in cancer risk between SUs is not strong enough to guide clinical decision making.
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Affiliation(s)
- Anne M Hendriks
- Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Dennis Schrijnders
- Langerhans Medical Research Group, Zwolle, the Netherlands; Diabetes Center, Isala Hospital, Zwolle, the Netherlands
| | | | - Elisabeth G E de Vries
- Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Henk J G Bilo
- Diabetes Center, Isala Hospital, Zwolle, the Netherlands; Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Mathilde Jalving
- Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
| | - Gijs W D Landman
- Langerhans Medical Research Group, Zwolle, the Netherlands; Department of Internal Medicine, Gelre Hospital, Apeldoorn, the Netherlands
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15
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Suchonwanit P, Thammarucha S, Leerunyakul K. Minoxidil and its use in hair disorders: a review. Drug Des Devel Ther 2019; 13:2777-2786. [PMID: 31496654 PMCID: PMC6691938 DOI: 10.2147/dddt.s214907] [Citation(s) in RCA: 212] [Impact Index Per Article: 35.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2019] [Accepted: 07/22/2019] [Indexed: 12/20/2022] Open
Abstract
Minoxidil was first introduced as an antihypertensive medication and the discovery of its common adverse event, hypertrichosis, led to the development of a topical formulation for promoting hair growth. To date, topical minoxidil is the mainstay treatment for androgenetic alopecia and is used as an off-label treatment for other hair loss conditions. Despite its widespread application, the exact mechanism of action of minoxidil is still not fully understood. In this article, we aim to review and update current information on the pharmacology, mechanism of action, clinical efficacy, and adverse events of topical minoxidil.
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Affiliation(s)
- Poonkiat Suchonwanit
- Division of Dermatology, Department of Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Sasima Thammarucha
- Division of Dermatology, Department of Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Kanchana Leerunyakul
- Division of Dermatology, Department of Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
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16
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Domanska B, Fortea E, West MJ, Schwartz JL, Crickmore N. The role of membrane-bound metal ions in toxicity of a human cancer cell-active pore-forming toxin Cry41Aa from Bacillus thuringiensis. Toxicon 2019; 167:123-133. [PMID: 31181295 DOI: 10.1016/j.toxicon.2019.06.003] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2019] [Revised: 05/09/2019] [Accepted: 06/03/2019] [Indexed: 12/30/2022]
Abstract
Bacillus thuringiensis crystal (Cry) proteins, used for decades as insecticidal toxins, are well known to be toxic to certain insects, but not to mammals. A novel group of Cry toxins called parasporins possess a strong cytocidal activity against some human cancer cells. Cry41Aa, or parasporin3, closely resembles commercially used insecticidal toxins and yet is toxic to the human hepatic cancer cell line HepG2, disrupting membranes of susceptible cells, similar to its insecticidal counterparts. In this study, we explore the protective effect that the common divalent metal chelator EGTA exerts on Cry41Aa's activity on HepG2 cells. Our results indicate that rather than interfering with a signalling pathway as a result of chelating cations in the medium, the chelator prevented the toxin's interaction with the membrane, and thus the subsequent steps of membrane damage and p38 phosphorylation, by removing cations bound to plasma membrane components. BAPTA and DTPA also inhibited Cry41Aa toxicity but at higher concentrations. We also show for the first time that Cry41Aa induces pore formation in planar lipid bilayers. This activity is not altered by EGTA, consistent with a biological context of chelation. Salt supplementation assays identified Ca2+, Mn2+ and Zn2+ as being able to reinstate Cry41Aa activity. Our data suggest the existence of one or more metal cation-dependent receptors in the Cry41Aa mechanism of action.
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Affiliation(s)
- Barbara Domanska
- School of Life Sciences, University of Sussex, Falmer, Brighton, BN1 9QG, UK.
| | - Eva Fortea
- Département de Pharmacologie et Physiologie, Université de Montréal, Montréal, Québec, H3C 3J7, Canada; Cornell Graduate School of Medical Sciences, 1300 York Avenue, New York, NY, 10065, USA
| | - Michelle J West
- School of Life Sciences, University of Sussex, Falmer, Brighton, BN1 9QG, UK
| | - Jean-Louis Schwartz
- Département de Pharmacologie et Physiologie, Université de Montréal, Montréal, Québec, H3C 3J7, Canada
| | - Neil Crickmore
- School of Life Sciences, University of Sussex, Falmer, Brighton, BN1 9QG, UK
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17
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Zhang X, Yang W, Wang J, Meng Y, Guan Y, Yang J. FAM3 gene family: A promising therapeutical target for NAFLD and type 2 diabetes. Metabolism 2018; 81:71-82. [PMID: 29221790 DOI: 10.1016/j.metabol.2017.12.001] [Citation(s) in RCA: 53] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2017] [Revised: 11/08/2017] [Accepted: 12/01/2017] [Indexed: 12/15/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) and diabetes are severe public health issues worldwide. The Family with sequence similarity 3 (FAM3) gene family consists of four members designated as FAM3A, FAM3B, FAM3C and FAM3D, respectively. Recently, there had been increasing evidence that FAM3A, FAM3B and FAM3C are important regulators of glucose and lipid metabolism. FAM3A expression is reduced in the livers of diabetic rodents and NAFLD patients. Hepatic FAM3A restoration activates ATP-P2 receptor-Akt and AMPK pathways to attenuate steatosis and hyperglycemia in obese diabetic mice. FAM3C expression is also reduced in the liver under diabetic condition. FAM3C is a new hepatokine that activates HSF1-CaM-Akt pathway and represses mTOR-SREBP1-FAS pathway to suppress hepatic gluconeogenesis and lipogenesis. In contrast, hepatic expression of FAM3B, also called PANDER, is increased under obese state. FAM3B promotes hepatic lipogenesis and gluconeogenesis by repressing Akt and AMPK activities, and activating lipogenic pathway. Under obese state, the imbalance among hepatic FAM3A, FAM3B and FAM3C signaling networks plays important roles in the pathogenesis of NAFLD and type 2 diabetes. This review briefly discussed the latest research progress on the roles and mechanisms of FAM3A, FAM3B and FAM3C in the regulation of hepatic glucose and lipid metabolism.
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Affiliation(s)
- Xiaoyan Zhang
- Advanced Institute for Medical Sciences, Dalian Medical University, Dalian 116044, China
| | - Weili Yang
- Department of Physiology and Pathophysiology, Center for Noncoding RNA Medicine, Key Laboratory of Molecular Cardiovascular Science of the Ministry of Education, Peking University Health Science Center, Beijing 100191, China
| | - Junpei Wang
- Department of Physiology and Pathophysiology, Center for Noncoding RNA Medicine, Key Laboratory of Molecular Cardiovascular Science of the Ministry of Education, Peking University Health Science Center, Beijing 100191, China
| | - Yuhong Meng
- Department of Physiology and Pathophysiology, Center for Noncoding RNA Medicine, Key Laboratory of Molecular Cardiovascular Science of the Ministry of Education, Peking University Health Science Center, Beijing 100191, China
| | - Youfei Guan
- Advanced Institute for Medical Sciences, Dalian Medical University, Dalian 116044, China.
| | - Jichun Yang
- Department of Physiology and Pathophysiology, Center for Noncoding RNA Medicine, Key Laboratory of Molecular Cardiovascular Science of the Ministry of Education, Peking University Health Science Center, Beijing 100191, China.
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18
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Vázquez-Sánchez AY, Hinojosa LM, Parraguirre-Martínez S, González A, Morales F, Montalvo G, Vera E, Hernández-Gallegos E, Camacho J. Expression of K ATP channels in human cervical cancer: Potential tools for diagnosis and therapy. Oncol Lett 2018; 15:6302-6308. [PMID: 29849783 PMCID: PMC5962834 DOI: 10.3892/ol.2018.8165] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2017] [Accepted: 10/18/2017] [Indexed: 11/19/2022] Open
Abstract
Various ion channels, including ATP-sensitive potassium (KATP) channels, are expressed in cancer and have been suggested as potential tumor markers and therapeutic targets. KATP channels are composed of at least two types of subunit, an inwardly rectifying K+ channel (Kir6.x) and a sulfonylurea receptor (SUR). However, the association between KATP channels and cervical cancer remains elusive. The present study determined that the Kir6.2, SUR1 and SUR2 subunits are expressed in cervical cancer cell lines and/or human biopsies. The potential association of subunit expression with tumor differentiation and invasion was analyzed. The effect of the KATP channel blocker glibenclamide on the proliferation of cervical cancer cell lines was also studied. Five cervical cancer cell lines, two primary cultures of cervical cancer cells, one normal keratinocyte cell line and 74 human biopsies were used in the experiments. The mRNA and protein levels of the Kir6.2 subunit were assessed by reverse transcription-polymerase chain reaction and immunochemistry, respectively. Cell proliferation was evaluated by MTT assay. Kir6.2 subunit overexpression compared with control, was observed in some cervical cancer cell lines and cervical tumor tissues. Additionally, increased KATP channel expression was observed in high-grade, poorly differentiated and invasive human cervical cancer biopsies. Kir6.2 subunit expression was not observed in the majority of the non-cancerous cervical tissues. The effect of the KATP channel blocker glibenclamide on the proliferation of five different cervical cancer cell lines was studied, revealing that as Kir6.2 mRNA expression increased, the inhibitory effect of glibenclamide also increased. The results of the present study suggest, for the first time to the best of our knowledge, that the KATP channel subunits, Kir6.2 and SUR2, could potentially represent tools for diagnosing and treating cervical cancer.
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Affiliation(s)
- Alma Yolanda Vázquez-Sánchez
- Department of Pharmacology, Center for Research and Advanced Studies of The National Polytechnic Institute, Mexico City 07360, Mexico
| | - Luz María Hinojosa
- Service of Dysplasia, Gynecology and Obstetrics, 'Dr Manuel Gea González' Hospital General, Mexico City 14080, Mexico
| | - Sara Parraguirre-Martínez
- Division of Anatomical Pathology, 'Dr Manuel Gea González' Hospital General, Mexico City 14080, Mexico
| | - Aarón González
- Service of Colposcopy, Instituto Nacional de Cancerología, Mexico City 14080, Mexico
| | - Flavia Morales
- Medical Oncology, Instituto Nacional de Cancerología, Mexico City 14080, Mexico
| | - Gonzalo Montalvo
- Service of Gynecology, Instituto Nacional de Cancerología, Mexico City 14080, Mexico
| | - Eunice Vera
- Department of Pharmacology, Center for Research and Advanced Studies of The National Polytechnic Institute, Mexico City 07360, Mexico
| | - Elisabeth Hernández-Gallegos
- Department of Pharmacology, Center for Research and Advanced Studies of The National Polytechnic Institute, Mexico City 07360, Mexico
| | - Javier Camacho
- Department of Pharmacology, Center for Research and Advanced Studies of The National Polytechnic Institute, Mexico City 07360, Mexico
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19
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Li P, Zhang C, Gao P, Chen X, Ma B, Yu D, Song Y, Wang Z. Metformin use and its effect on gastric cancer in patients with type 2 diabetes: A systematic review of observational studies. Oncol Lett 2017; 15:1191-1199. [PMID: 29391902 DOI: 10.3892/ol.2017.7370] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2016] [Accepted: 08/23/2017] [Indexed: 02/06/2023] Open
Abstract
Increasing evidence suggests that metformin use is associated with a decreased risk of cancer. The traditional therapies for gastric cancer (GC) are gastrectomy and chemoradiotherapy; however, these therapies may cause certain adverse effects, which affect a patient's quality of life, and the overall survival rate is low. At present, little is known about whether the use of metformin decreases the risk of GC in patients with type 2 diabetes. Therefore, in the present study, a systematic review was performed to analyze the effect of metformin on GC. A literature search was conducted in PubMed, EMBASE, and the Cochrane Library databases for articles published up to June 30th, 2016. The studies that evaluated GC patients treated with metformin and compared them with GC patients treated with other antidiabetic drugs were reviewed. Eligible studies were evaluated using the Newcastle-Ottawa Scale. Adjusted hazard ratio and 95% confidence intervals were determined to evaluate the effect of metformin on GC. From the 422 articles evaluated, 5 studies involving a total of 1,804,479 patients met the inclusion criteria and were qualitatively analyzed. The quality of all selected articles was classified as moderate. These studies reported that the long-term use of metformin was associated with a lower risk of GC compared with the lack of use of metformin or the use of other hypoglycemic drugs. In GC patients with diabetes who were subjected to gastrectomy, the cumulative use of metformin reduced the rates of disease recurrence and of all-cause and cancer-specific mortality. Despite the limited number of studies on this subject, currently available evidence indicates that metformin is associated with a decreased risk of GC and improves survival in patients with type 2 diabetes. However, more well-designed trials are required to elucidate this association.
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Affiliation(s)
- Peiwen Li
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China
| | - Cong Zhang
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China
| | - Peng Gao
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China
| | - Xiaowan Chen
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China
| | - Bin Ma
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China
| | - Dehao Yu
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China
| | - Yongxi Song
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China
| | - Zhenning Wang
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China
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20
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Gao R, Yang T, Xu W. Enemies or weapons in hands: investigational anti-diabetic drug glibenclamide and cancer risk. Expert Opin Investig Drugs 2017; 26:853-864. [PMID: 28541801 DOI: 10.1080/13543784.2017.1333104] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Epidemiological evidence suggests that diabetes is associated with elevated cancer risk through the actions of hyperglycemia, hyperinsulinemia and chronic inflammation. Metformin, a first-line medication for type 2 diabetes mellitus, arouses growing concerns on its anti-cancer effect. However, data regarding the effect of glibenclamide on tumor growth and cancer risk are less consistent, which may be a potential anti-cancer drug. Areas covered: In this review, we clarified probable underlying mechanisms in preclinical studies and reviewed epidemiological evidence on glibenclamide's cancer risk in clinical studies. Glibenclamide inhibited carcinogenesis through ATP-binding cassette protein super-family and ATP-sensitive potassium channels, while majority of clinical researches reported an increased or non-significant elevated cancer risk of glibenclamide users compared with metformin users. Other sulfonylureas and diarylsulfonylureas were also briefly introduced. Expert opinion: The inconsistency between the results of studies was probably ascribed to undiscovered mechanisms, confounding factors, inconsistent comparators and publication bias. Existing clinical trials were prone to be afflicted by time-related bias including immortal time bias, time-window bias, and time-lag bias. Glibenclimiade could be a promising and well-tolerated anti-neoplastic drug targeting ATP-binding cassette protein super-family and KATP channels, but its efficacy still needs to be proven in well-designed long-term randomized controlled clinical trials.
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Affiliation(s)
- Rui Gao
- a Department of Endocrinology , The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital , Nanjing , China
- b Department of Hematology , The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital , Nanjing , China
| | - Tao Yang
- a Department of Endocrinology , The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital , Nanjing , China
| | - Wei Xu
- b Department of Hematology , The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital , Nanjing , China
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21
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Ren B, Tao C, Swan MA, Joachim N, Martiniello-Wilks R, Nassif NT, O'Brien BA, Simpson AM. Pancreatic Transdifferentiation and Glucose-Regulated Production of Human Insulin in the H4IIE Rat Liver Cell Line. Int J Mol Sci 2016; 17:534. [PMID: 27070593 PMCID: PMC4848990 DOI: 10.3390/ijms17040534] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2016] [Revised: 03/24/2016] [Accepted: 04/01/2016] [Indexed: 12/13/2022] Open
Abstract
Due to the limitations of current treatment regimes, gene therapy is a promising strategy being explored to correct blood glucose concentrations in diabetic patients. In the current study, we used a retroviral vector to deliver either the human insulin gene alone, the rat NeuroD1 gene alone, or the human insulin gene and rat NeuroD1 genes together, to the rat liver cell line, H4IIE, to determine if storage of insulin and pancreatic transdifferentiation occurred. Stable clones were selected and expanded into cell lines: H4IIEins (insulin gene alone), H4IIE/ND (NeuroD1 gene alone), and H4IIEins/ND (insulin and NeuroD1 genes). The H4IIEins cells did not store insulin; however, H4IIE/ND and H4IIEins/ND cells stored 65.5 ± 5.6 and 1475.4 ± 171.8 pmol/insulin/5 × 106 cells, respectively. Additionally, several β cell transcription factors and pancreatic hormones were expressed in both H4IIE/ND and H4IIEins/ND cells. Electron microscopy revealed insulin storage vesicles in the H4IIE/ND and H4IIEins/ND cell lines. Regulated secretion of insulin to glucose (0–20 mmol/L) was seen in the H4IIEins/ND cell line. The H4IIEins/ND cells were transplanted into diabetic immunoincompetent mice, resulting in normalization of blood glucose. This data shows that the expression of NeuroD1 and insulin in liver cells may be a useful strategy for inducing islet neogenesis and reversing diabetes.
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Affiliation(s)
- Binhai Ren
- School of Life Sciences and Centre for Health Technologies, University of Technology Sydney, P.O. Box 123, Broadway, 2007 Sydney, NSW, Australia.
| | - Chang Tao
- School of Life Sciences and Centre for Health Technologies, University of Technology Sydney, P.O. Box 123, Broadway, 2007 Sydney, NSW, Australia.
| | - Margaret Anne Swan
- School of Medical Sciences (Anatomy & Histology) and Bosch Institute, University of Sydney, 2006 Sydney, NSW, Australia.
| | - Nichole Joachim
- School of Medical Sciences (Anatomy & Histology) and Bosch Institute, University of Sydney, 2006 Sydney, NSW, Australia.
| | - Rosetta Martiniello-Wilks
- School of Life Sciences and Centre for Health Technologies, University of Technology Sydney, P.O. Box 123, Broadway, 2007 Sydney, NSW, Australia.
| | - Najah T Nassif
- School of Life Sciences and Centre for Health Technologies, University of Technology Sydney, P.O. Box 123, Broadway, 2007 Sydney, NSW, Australia.
| | - Bronwyn A O'Brien
- School of Life Sciences and Centre for Health Technologies, University of Technology Sydney, P.O. Box 123, Broadway, 2007 Sydney, NSW, Australia.
| | - Ann M Simpson
- School of Life Sciences and Centre for Health Technologies, University of Technology Sydney, P.O. Box 123, Broadway, 2007 Sydney, NSW, Australia.
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Label-free cell phenotypic profiling decodes the composition and signaling of an endogenous ATP-sensitive potassium channel. Sci Rep 2014; 4:4934. [PMID: 24816792 PMCID: PMC4017216 DOI: 10.1038/srep04934] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2014] [Accepted: 04/24/2014] [Indexed: 11/27/2022] Open
Abstract
Current technologies for studying ion channels are fundamentally limited because of their inability to functionally link ion channel activity to cellular pathways. Herein, we report the use of label-free cell phenotypic profiling to decode the composition and signaling of an endogenous ATP-sensitive potassium ion channel (KATP) in HepG2C3A, a hepatocellular carcinoma cell line. Label-free cell phenotypic agonist profiling showed that pinacidil triggered characteristically similar dynamic mass redistribution (DMR) signals in A431, A549, HT29 and HepG2C3A, but not in HepG2 cells. Reverse transcriptase PCR, RNAi knockdown, and KATP blocker profiling showed that the pinacidil DMR is due to the activation of SUR2/Kir6.2 KATP channels in HepG2C3A cells. Kinase inhibition and RNAi knockdown showed that the pinacidil activated KATP channels trigger signaling through Rho kinase and Janus kinase-3, and cause actin remodeling. The results are the first demonstration of a label-free methodology to characterize the composition and signaling of an endogenous ATP-sensitive potassium ion channel.
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Pasello G, Urso L, Conte P, Favaretto A. Effects of sulfonylureas on tumor growth: a review of the literature. Oncologist 2013; 18:1118-25. [PMID: 24043597 DOI: 10.1634/theoncologist.2013-0177] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Type 2 diabetes mellitus patients are at higher cancer risk, probably because of hyperinsulinemia and insulin growth factor 1 pathway activation. The effects of antidiabetic drugs on cancer risk have been described and discussed in several studies suggesting opposite effects of the biguanide metformin and sulfonylureas on cancer incidence and mortality. The anticancer mechanisms of metformin have been clarified, and some clinical studies, particularly in breast cancer patients, have been published or are currently ongoing; however, data about the effects of sulfonylureas on cancer growth are less consistent. The aims of this work are to review preclinical evidence of second-generation sulfonylureas effects on tumor growth, to clarify the potential mechanisms of action, and to identify possible metabolic targets for patient selection. Most evidence is on the adenosine triphosphate-sensitive potassium channels inhibitor glibenclamide, which interacts with reactive oxygen species production thus inducing cancer cell death. Among diarylsulfonylureas, next-generation DW2282 derivatives are particularly promising because of the proapoptotic activity in multidrug-resistant cells.
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Affiliation(s)
- Giulia Pasello
- Second Medical Oncology Unit, Istituto Oncologico Veneto, Padua, Italy
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Ouadid-Ahidouch H, Ahidouch A. K(+) channels and cell cycle progression in tumor cells. Front Physiol 2013; 4:220. [PMID: 23970866 PMCID: PMC3747328 DOI: 10.3389/fphys.2013.00220] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2013] [Accepted: 07/31/2013] [Indexed: 11/24/2022] Open
Abstract
K+ ions play a major role in many cellular processes. The deregulation of K+ signaling is associated with a variety of diseases such as hypertension, atherosclerosis, or diabetes. K+ ions are important for setting the membrane potential, the driving force for Ca2+ influx, and regulate volume of growing cells. Moreover, it is increasingly recognized that K+ channels control cell proliferation through a novel signaling mechanisms triggered and modulated independently of ion fluxes. In cancer, aberrant expression, regulation and/or sublocalization of K+ channels can alter the downstream signals that converge on the cell cycle machinery. Various K+ channels are involved in cell cycle progression and are needed only at particular stages of the cell cycle. Consistent with this idea, the expression of Eag1 and HERG channels fluctuate along the cell cycle. Despite of acquired knowledge, our understanding of K+ channels functioning in cancer cells requires further studies. These include identifying the molecular mechanisms controlling the cell cycle machinery. By understanding how K+ channels regulate cell cycle progression in cancer cells, we will gain insights into how cancer cells subvert the need for K+ signal and its downstream targets to proliferate.
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Affiliation(s)
- Halima Ouadid-Ahidouch
- Laboratory of Cellular and Molecular Physiology EA4667, SFR CAP-SANTE FED 4231, UFR Sciences, University of Picardie Jules Verne Amiens, France
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Buchanan PJ, McNally P, Harvey BJ, Urbach V. Lipoxin A₄-mediated KATP potassium channel activation results in cystic fibrosis airway epithelial repair. Am J Physiol Lung Cell Mol Physiol 2013; 305:L193-201. [PMID: 23686859 DOI: 10.1152/ajplung.00058.2013] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
The main cause of morbidity and mortality in cystic fibrosis (CF) is progressive lung destruction as a result of persistent bacterial infection and inflammation, coupled with reduced capacity for epithelial repair. Levels of the anti-inflammatory mediator lipoxin A₄ (LXA₄) have been reported to be reduced in bronchoalveolar lavages of patients with CF. We investigated the ability of LXA₄ to trigger epithelial repair through the initiation of proliferation and migration in non-CF (NuLi-1) and CF (CuFi-1) airway epithelia. Spontaneous repair and cell migration were significantly slower in CF epithelial cultures (CuFi-1) compared with controls (NuLi-1). LXA₄ triggered an increase in migration, proliferation, and wound repair of non-CF and CF airway epithelia. These responses to LXA₄ were completely abolished by the ALX/FPR2 receptor antagonist, Boc2 and ALX/FPR2 siRNA. The KATP channel opener pinacidil mimicked the LXA₄ effect on migration, proliferation, and epithelial repair, whereas the KATP channel inhibitor, glibenclamide, blocked the responses to LXA₄. LXA₄ did not affect potassium channel expression but significantly upregulated glibenclamide-sensitive (KATP) currents through the basolateral membrane of NuLi-1 and CuFi-1 cells. MAP kinase (ERK1/2) inhibitor, PD98059, also inhibited the LXA₄-induced proliferation of NuLi-1 and CuFi-1 cells. Finally, both LXA₄ and pinacidil stimulated ERK-MAP kinase phosphorylation, whereas the effect of LXA₄ on ERK phosphorylation was inhibited by glibenclamide. Taken together, our results provided evidence for a role of LXA₄ in triggering epithelial repair through stimulation of the ALX/FPR2 receptor, KATP potassium channel activation, and ERK phosphorylation. This work suggests exogenous delivery of LXA₄, restoring levels in patients with CF, perhaps as a potential therapeutic strategy.
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Affiliation(s)
- Paul J Buchanan
- National Children's Research Center, Our Lady's Children Hospital, Dublin, Ireland
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Khanfar MA, AbuKhader MM, Alqtaishat S, Taha MO. Pharmacophore modeling, homology modeling, and in silico screening reveal mammalian target of rapamycin inhibitory activities for sotalol, glyburide, metipranolol, sulfamethizole, glipizide, and pioglitazone. J Mol Graph Model 2013; 42:39-49. [PMID: 23545333 DOI: 10.1016/j.jmgm.2013.02.009] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2012] [Revised: 02/21/2013] [Accepted: 02/24/2013] [Indexed: 12/18/2022]
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Zertal-Zidani S, Busiah K, Edelman A, Polak M, Scharfmann R. Small-molecule inhibitors of the cystic fibrosis transmembrane conductance regulator increase pancreatic endocrine cell development in rat and mouse. Diabetologia 2013; 56. [PMID: 23178930 PMCID: PMC3536988 DOI: 10.1007/s00125-012-2778-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
AIMS/HYPOTHESIS The main objective of this work was to discover new drugs that can activate the differentiation of multipotent pancreatic progenitors into endocrine cells. METHODS In vitro experiments were performed using fetal pancreatic explants from rats and mice. In this assay, we examined the actions on pancreatic cell development of glibenclamide, a sulfonylurea derivative, and glycine hydrazide (GlyH-101), a small-molecule inhibitor of cystic fibrosis transmembrane conductance regulator (CFTR). We next tested the actions of GlyH-101 on in vivo pancreatic cell development. RESULTS Glibenclamide (10 nmol/l-100 μmol/l) did not alter the morphology or growth of the developing pancreas and exerted no deleterious effects on exocrine cell development in the pancreas. Unexpectedly, glibenclamide at its highest concentration promoted endocrine differentiation. This glibenclamide-induced promotion of the endocrine pathway could not be reproduced when other sulfonylureas were used, suggesting that glibenclamide had an off-target action. This high concentration of glibenclamide had previously been reported to inhibit CFTR. We found that the effects of glibenclamide on the developing pancreas could be mimicked both in vitro and in vivo by GlyH-101. CONCLUSIONS/INTERPRETATION Collectively, we demonstrate that two small-molecule inhibitors of the CFTR, glibenclamide and GlyH-101, increase the number of pancreatic endocrine cells by increasing the size of the pool of neurogenin 3-positive endocrine progenitors in the developing pancreas.
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Affiliation(s)
- S. Zertal-Zidani
- Inserm U845, Research Center Growth and Signalling, Faculté de Médecine, Université Paris Descartes, Sorbonne Paris Cité, Faculty Necker, 156 Rue de Vaugirard, 75015 Paris, France
| | - K. Busiah
- Inserm U845, Research Center Growth and Signalling, Faculté de Médecine, Université Paris Descartes, Sorbonne Paris Cité, Faculty Necker, 156 Rue de Vaugirard, 75015 Paris, France
| | - A. Edelman
- Inserm U845, Research Center Growth and Signalling, Faculté de Médecine, Université Paris Descartes, Sorbonne Paris Cité, Faculty Necker, 156 Rue de Vaugirard, 75015 Paris, France
| | - M. Polak
- Inserm U845, Research Center Growth and Signalling, Faculté de Médecine, Université Paris Descartes, Sorbonne Paris Cité, Faculty Necker, 156 Rue de Vaugirard, 75015 Paris, France
| | - R. Scharfmann
- Inserm U845, Research Center Growth and Signalling, Faculté de Médecine, Université Paris Descartes, Sorbonne Paris Cité, Faculty Necker, 156 Rue de Vaugirard, 75015 Paris, France
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Núñez M, Medina V, Cricco G, Croci M, Cocca C, Rivera E, Bergoc R, Martín G. Glibenclamide inhibits cell growth by inducing G0/G1 arrest in the human breast cancer cell line MDA-MB-231. BMC Pharmacol Toxicol 2013; 14:6. [PMID: 23311706 PMCID: PMC3558386 DOI: 10.1186/2050-6511-14-6] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2012] [Accepted: 01/07/2013] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Glibenclamide (Gli) binds to the sulphonylurea receptor (SUR) that is a regulatory subunit of ATP-sensitive potassium channels (KATP channels). Binding of Gli to SUR produces the closure of KATP channels and the inhibition of their activity. This drug is widely used for treatment of type 2-diabetes and it has been signaled as antiproliferative in several tumor cell lines. In previous experiments we demonstrated the antitumoral effect of Gli in mammary tumors induced in rats. The aim of the present work was to investigate the effect of Gli on MDA-MB-231 breast cancer cell proliferation and to examine the possible pathways involved in this action. RESULTS The mRNA expression of the different subunits that compose the KATP channels was evaluated in MDA-MB-231 cells by reverse transcriptase-polymerase chain reaction. Results showed the expression of mRNA for both pore-forming isoforms Kir6.1 and Kir6.2 and for the regulatory isoform SUR2B in this cell line. Gli inhibited cell proliferation assessed by a clonogenic method in a dose dependent manner, with an increment in the population doubling time. The KATP channel opener minoxidil increased clonogenic proliferation, effect that was counteracted by Gli. When cell cycle analysis was performed by flow cytometry, Gli induced a significant cell-cycle arrest in G0/G1 phase, together with an up-regulation of p27 levels and a diminution in cyclin E expression, both evaluated by immunoblot. However, neither differentiation evaluated by neutral lipid accumulation nor apoptosis assessed by different methodologies were detected. The cytostatic, non toxic effect on cell proliferation was confirmed by removal of the drug.Combination treatment of Gli with tamoxifen or doxorubicin showed an increment in the antiproliferative effect only for doxorubicin. CONCLUSIONS Our data clearly demonstrated a cytostatic effect of Gli in MDA-MB-231 cells that may be mediated through KATP channels, associated to the inhibition of the G1-S phase progression. In addition, an interesting observation about the effect of the combination of Gli with doxorubicin leads to future research for a potential novel role for Gli as an adjuvant in breast cancer treatment.
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Affiliation(s)
- Mariel Núñez
- Radioisotopes Laboratory, School of Pharmacy and Biochemistry, University of Buenos Aires, Buenos Aires, Argentina
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Bahde R, Kapoor S, Bandi S, Bhargava KK, Palestro CJ, Gupta S. Directly acting drugs prostacyclin or nitroglycerine and endothelin receptor blocker bosentan improve cell engraftment in rodent liver. Hepatology 2013; 57:320-30. [PMID: 22899584 PMCID: PMC3524382 DOI: 10.1002/hep.26005] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2012] [Accepted: 07/23/2012] [Indexed: 01/07/2023]
Abstract
UNLABELLED To optimize strategies for liver-directed cell therapy, prevention of initial transplanted cell losses is particularly important for subsequent liver repopulation. After cell transplantation in hepatic sinusoids, perturbations in hepatic microcirculation along with changes in various liver cell types are among the earliest changes. Therefore, for advancing further concepts in cell engraftment we studied vascular and related events in the liver after transplanting syngeneic hepatocytes into dipeptidyl peptidase IV-deficient rats. We treated rats with vascular drugs to define whether deleterious cell transplantation-induced events could be controlled followed by improvements in transplanted cell engraftment and proliferation. We found cell transplantation altered liver gene expression related to vessel tone, inflammation, cell adhesion, thrombosis, or tissue damage/remodeling. This was due to hepatic ischemia, endothelial injury, and activation of neutrophils, Kupffer cells, and hepatic stellate cells. Treatment of rats before cell transplantation with the angiotensin converting enzyme blocker, lisinopril, or angiotensin II receptor blocker, losartan, did not improve cell engraftment. By contrast, direct-acting nitroglycerine or prostacyclin improved cell engraftment and also kinetics of liver repopulation. These drugs lowered hepatic ischemia and inflammation, whereas pretreatment of rats with the dual endothelin-1 receptor blocker, bosentan, improved cell engraftment independently of hepatic ischemia or inflammation, without improving liver repopulation. However, incubation of hepatocytes with bosentan protected cells from cytokine toxicity in vitro and produced superior cell engraftment and proliferation in vivo. CONCLUSION Cell transplantation-induced changes in hepatic microcirculation contributed to transplanted cell clearances from liver. Vascular drugs, such as nitroglycerine, prostacyclin, and bosentan, offer opportunities for improving cell therapy results through superior cell engraftment and liver repopulation. Ongoing clinical use of these drugs will permit rapid translation of the findings in people.
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Affiliation(s)
- Ralf Bahde
- Department of Medicine, Albert Einstein College of Medicine, Bronx, NY,Department of Visceral and General Surgery, University Hospital of Muenster
| | - Sorabh Kapoor
- Department of Medicine, Albert Einstein College of Medicine, Bronx, NY
| | - Sriram Bandi
- Department of Medicine, Albert Einstein College of Medicine, Bronx, NY
| | - Kuldeep K. Bhargava
- Division of Nuclear Medicine and Molecular Imaging, North Shore-LIJ Health System, New Hyde Park, NY
| | - Christopher J. Palestro
- Division of Nuclear Medicine and Molecular Imaging, North Shore-LIJ Health System, New Hyde Park, NY
| | - Sanjeev Gupta
- Department of Medicine, Albert Einstein College of Medicine, Bronx, NY,Department of Pathology, Marion Bessin Liver Research Center, Diabetes Center, Cancer Center, Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, and Institute for Clinical and Translational Research, Albert Einstein College of Medicine, Bronx, NY,Author Correspondence: Sanjeev Gupta, MD, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Ullmann Bldg., Rm 625, Bronx, NY 10461; Tel: 718 430 3309; Fax: 718 430 8975; ,
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Enhancement of liver regeneration by adenosine triphosphate-sensitive K⁺ channel opener (diazoxide) after partial hepatectomy. Transplantation 2012; 93:1094-100. [PMID: 22466787 DOI: 10.1097/tp.0b013e31824ef1d1] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
BACKGROUND Enhancement of liver regeneration is a matter of importance after partial liver transplantation including small-for-size grafting. Mitochondrial adenosine triphosphate (ATP)-sensitive K⁺ (mitoKATP) channel plays an important role in mitochondrial bioenergetics, which is a prerequisite for liver regeneration. However, the ATP-sensitive K⁺ (KATP) channel in hepatocytes is incompletely understood. We investigated the KATP channel in hepatocytes and examined the effects of diazoxide, a potent KATP channel opener, on liver regeneration using a rat model. METHODS Using rat primary hepatocytes, expression and localization of KATP channel subunits, Kir6.x and sulfonylurea receptor (SUR)x, were studied by polymerase chain reaction, Western blotting, and immunostaining. To investigate the role of KATP channel openers in liver regeneration, we allocated rats into four groups: control (vehicle) (n=24), diazoxide (n=24), vehicle plus channel blocker (n=6), and diazoxide plus channel blocker (n=6) groups. After 70% partial hepatectomy, hepatic tissue ATP levels, liver-to-body weight ratio, and proliferation rate of hepatocytes were examined. RESULTS KATP channel subunits, Kir6.1 and SUR1, were detected on hepatic mitochondria. During liver regeneration, liver-to-body weight ratio, proliferation rate of hepatocytes, and the hepatic ATP level were significantly higher in the diazoxide group than the control group at 2 days after partial hepatectomy. These effects of diazoxide were neutralized by a KATP channel blocker. CONCLUSIONS We demonstrated the existence of a mitoKATP channel in hepatocytes composed of Kir6.1 and SUR1. Diazoxide could enhance liver regeneration by keeping a higher ATP content of the liver tissue. These results suggest that diazoxide will sustain the mitochondrial energetics through the mitoKATP channel opening.
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Yang JZ, Huang X, Zhao FF, Xu Q, Hu G. Iptakalim enhances adult mouse hippocampal neurogenesis via opening Kir6.1-composed K-ATP channels expressed in neural stem cells. CNS Neurosci Ther 2012; 18:737-44. [PMID: 22742873 DOI: 10.1111/j.1755-5949.2012.00359.x] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2012] [Revised: 04/19/2012] [Accepted: 04/27/2012] [Indexed: 01/12/2023] Open
Abstract
BACKGROUND AND PURPOSE Emerging evidence indicates that stimulating adult neurogenesis provides novel strategies for central nervous system diseases. Iptakalim (Ipt), a novel ATP-sensitive potassium (K-ATP) channel opener, has been demonstrated to play multipotential neuroprotective effects in vivo and in vitro. However, it remains unknown whether Ipt could regulate the adult neurogenesis. METHODS AND RESULTS Based on the finding that adult neural stem cells (ANSCs) in hippocampus expressed Kir6.1/SUR1-composed K-ATP channel, Kir6.1 heterozygotic (Kir6.1(+/-) ) mice were used to investigate whether and how Ipt regulates adult hippocampal neurogenesis. We showed that administration of Ipt (10 mg/kg) or fluoxetine (Flx, 10 mg/kg) for 4 weeks significantly increased newborn ANSCs in subgranular zone (SGZ) of Kir6.1(+/+) mice but failed to affect those of Kir6.1(+/-) mice. Meanwhile, ANSCs in Kir6.1(+/-) mice exhibited decreased survival rate and impaired ability of differentiation into astrocytes. We further found that Kir6.1(+/-) mice showed lower level of brain-derived neurotrophic factor (BDNF) in hippocampus compared with Kir6.1(+/+) mice. Furthermore, Ipt increased the levels of BDNF and basic fibroblast growth factor (FGF-2) throughout the hippocampus in Kir6.1(+/+) mice but not in Kir6.1(+/-) mice. Moreover, Ipt and Flx enhanced the phosphorylation of Akt and CREB in the hippocampus of Kir6.1(+/+) mice. Notably, these effects were completely abolished in Kir6.1(+/-) mice. CONCLUSIONS Our findings demonstrate that Ipt stimulates the adult hippocampal neurogenesis via activation of Akt and CREB signal following the opening of Kir6.1-composed K-ATP channels, which gives us an insight into the therapeutic implication of Ipt in the diseases with adult neurogenesis deficiency, such as major depression.
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Affiliation(s)
- Jing-Zhe Yang
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, China
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Fröhlich E, Wahl R. Do antidiabetic medications play a specific role in differentiated thyroid cancer compared to other cancer types? Diabetes Obes Metab 2012; 14:204-13. [PMID: 21883805 DOI: 10.1111/j.1463-1326.2011.01491.x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The risk for differentiated thyroid cancer, like for many other types of cancer, is increased in obese individuals and people with intermediate hyperglycaemia. The incidence of all cancers, with the exception of thyroid cancer, is also increased in type 2 diabetes mellitus patients. The review compares the prevalence of thyroid carcinoma and other cancers in obese, people with intermediate hyperglycaemia and patients with diabetes and summarizes mode of action and anti-tumourigenic effect of common antidiabetic medications. The over-expression of dipeptidyl peptidase IV in the tumours, not seen in the other cancer types, is suggested as a potential reason for the unique situation in thyroid cancer.
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Affiliation(s)
- E Fröhlich
- Internal Medicine, Department of Endocrinology, University of Tuebingen, Otfried-Muellerstrasse 10, Tuebingen, Germany
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Zhang D, Lijuan G, Jingjie L, Zheng L, Wang C, Wang Z, Liu L, Mira L, Sung C. Cow placenta extract promotes murine hair growth through enhancing the insulin - like growth factor-1. Indian J Dermatol 2011; 56:14-8. [PMID: 21572784 PMCID: PMC3088926 DOI: 10.4103/0019-5154.77544] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
BACKGROUND Hair loss is seen as an irreversible process. Most research concentrates on how to elongate the anagen, reduce the negative factors of obstructing hair growth and improve the hair number and size. AIM In our experiment, we tried to prove that the cow placenta extract can promote hair growth by elongating hair shaft and increasing hair follicle number. MATERIALS AND METHODS Cow placenta extract (CPE), water and minoxidil applied separately on the back of depilated B57CL/6 mice for the case, negative and positive control respectively. We checked the proliferation of cells which are resident in hair sheath, and the expression of a few growth factors which stimulate hair growth. RESULTS Result shows that placenta extract more efficiently accelerates cell division and growth factor expression, by raising the insulin-like growth factor (IGF-1) mRNA and protein level to increase HF size and hair length. CONCLUSIONS The extract is not a purified product; so, it is less effective than minoxidil, which is approved by the US FDA for the treatment of male pattern baldness. If refinement is done, the placenta extract would be a good candidate medicine for hair loss.
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Affiliation(s)
- Dongliang Zhang
- from Department of Food Science and Technology, College of Agriculture and Biotechnology, Chungnam National University, Daejeon 305-764, Korea
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Cannata D, Fierz Y, Vijayakumar A, LeRoith D. Type 2 diabetes and cancer: what is the connection? ACTA ACUST UNITED AC 2011; 77:197-213. [PMID: 20309918 DOI: 10.1002/msj.20167] [Citation(s) in RCA: 61] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Epidemiological studies have demonstrated an association between type 2 diabetes and cancer. Type 2 diabetes is characterized by insulin resistance and hyperinsulinemia. Hyperinsulinemia may lead to cancer through insulin's effect on its cognate receptor and the insulin-like growth factor system. The effects of insulin and insulin-like growth factor I on cancer development and progression have been demonstrated in animal and human studies. Type 2 diabetes has been positively associated with cancers of the breast, colon, and pancreas. An inverse relationship has been observed between type 2 diabetes and prostate cancer, and this may be due to lower testosterone levels in men with type 2 diabetes. Medications used to treat type 2 diabetes may affect cancer cells directly or indirectly by affecting serum insulin levels. Hyperinsulinemia may be an important risk factor for cancer as well as a target for cancer therapy.
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Affiliation(s)
- Dara Cannata
- Mount Sinai School of Medicine, New York, NY, USA
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Barbaric I, Gokhale PJ, Jones M, Glen A, Baker D, Andrews PW. Novel regulators of stem cell fates identified by a multivariate phenotype screen of small compounds on human embryonic stem cell colonies. Stem Cell Res 2010; 5:104-19. [PMID: 20542750 DOI: 10.1016/j.scr.2010.04.006] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2009] [Revised: 03/24/2010] [Accepted: 04/20/2010] [Indexed: 11/17/2022] Open
Abstract
Understanding the complex mechanisms that govern the fate decisions of human embryonic stem cells (hESCs) is fundamental to their use in cell replacement therapies. The progress of dissecting these mechanisms will be facilitated by the availability of robust high-throughput screening assays on hESCs. In this study, we report an image-based high-content assay for detecting compounds that affect hESC survival or pluripotency. Our assay was designed to detect changes in the phenotype of hESC colonies by quantifying multiple parameters, including the number of cells in a colony, colony area and shape, intensity of nuclear staining, and the percentage of cells in the colony that express a marker of pluripotency (TRA-1-60), as well as the number of colonies per well. We used this assay to screen 1040 compounds from two commercial compound libraries, and identified 17 that promoted differentiation, as well as 5 that promoted survival of hESCs. Among the novel small compounds we identified with activity on hESC are several steroids that promote hESC differentiation and the antihypertensive drug, pinacidil, which affects hESC survival. The analysis of overlapping targets of pinacidil and the other survival compounds revealed that activity of PRK2, ROCK, MNK1, RSK1, and MSK1 kinases may contribute to the survival of hESCs.
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Affiliation(s)
- Ivana Barbaric
- Centre for Stem Cell Biology, University of Sheffield, Western Bank, Sheffield, UK
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Sun XL, Hu G. ATP-sensitive potassium channels: A promising target for protecting neurovascular unit function in stroke. Clin Exp Pharmacol Physiol 2010; 37:243-52. [DOI: 10.1111/j.1440-1681.2009.05190.x] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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Permanent Neonatal Diabetes in a Patient with a KCNJ11/Q52R Mutation Accompanied by Intermittent Hypoglycemia and Liver Failure. INTERNATIONAL JOURNAL OF PEDIATRIC ENDOCRINOLOGY 2009; 2009:453240. [PMID: 19956803 PMCID: PMC2774578 DOI: 10.1155/2009/453240] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/07/2009] [Revised: 07/12/2009] [Accepted: 07/16/2009] [Indexed: 11/27/2022]
Abstract
The most common monogenic cause of neonatal diabetes is mutation in KCNJ11, which encodes a potassium channel in pancreatic beta cells. Some mutations in this gene, including Q52R, have been described in association with neurological deficits, but never with hepatic involvement. We report the second case of neonatal diabetes in a patient with a KCNJ11/Q52R mutation. This patient's clinical course did not include obvious neurological deficits despite the presence of prematurity, but did include transient hyperbilirubinemia, and recurrent hypoglycemia. The phenotypic spectrum of KCNJ11 mutations is variable and is likely influenced by additional genetic and environmental factors.
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Levin M. Bioelectric mechanisms in regeneration: Unique aspects and future perspectives. Semin Cell Dev Biol 2009; 20:543-56. [PMID: 19406249 DOI: 10.1016/j.semcdb.2009.04.013] [Citation(s) in RCA: 140] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2009] [Accepted: 04/22/2009] [Indexed: 01/14/2023]
Abstract
Regenerative biology has focused largely on chemical factors and transcriptional networks. However, endogenous ion flows serve as key epigenetic regulators of cell behavior. Bioelectric signaling involves feedback loops, long-range communication, polarity, and information transfer over multiple size scales. Understanding the roles of endogenous voltage gradients, ion flows, and electric fields will contribute to the basic understanding of numerous morphogenetic processes and the means by which they can robustly restore pattern after perturbation. By learning to modulate the bioelectrical signals that control cell proliferation, migration, and differentiation, we gain a powerful set of new techniques with which to manipulate growth and patterning in biomedical contexts. This chapter reviews the unique properties of bioelectric signaling, surveys molecular strategies and reagents for its investigation, and discusses the opportunities made available for regenerative medicine.
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Affiliation(s)
- Michael Levin
- Tufts Center for Regenerative and Developmental Biology, Biology Department, Tufts University, Medford, MA 02155, USA.
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Huang L, Li B, Li W, Guo H, Zou F. ATP-sensitive potassium channels control glioma cells proliferation by regulating ERK activity. Carcinogenesis 2009; 30:737-44. [PMID: 19176641 DOI: 10.1093/carcin/bgp034] [Citation(s) in RCA: 66] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
Ion channels are found in a variety of cancer cells and necessary for cell cycle and cell proliferation. The roles of K(+) channels in the process are, however, poorly understood. In the present study, we report that adenosine triphosphate (ATP)-sensitive potassium channel activity plays a critical role in the proliferation of glioma cells. The expression of K(ATP) channels in glioma tissues was greatly increased than that in normal tissues. Treatment of glioma cells with tolbutamide, K(ATP) channels inhibitor, suppressed the proliferation of glioma cells and blocked glioma cell cycle in G(0)/G(1) phase. Similarly, downregulation of K(ATP) channels by small interfering RNA (siRNA) inhibited glioma cell proliferation. On the other hand, K(ATP) channels agonist diazoxide and overexpression of K(ATP) channels promoted the proliferation of glioma cells. Moreover, inhibiting K(ATP) channels slowed the formation of tumor in nude mice generated by injection of glioma cells. Whereas activating K(ATP) channels promoted development of tumor in vivo. The effect of K(ATP) channels activity on glioma cells proliferation is mediated by extracellular signal-regulated kinase (ERK) activation. We found that activating K(ATP) channel triggered ERK activation and inhibiting K(ATP) channel depressed ERK activation. U-0126, the mitogen-activated protein kinase kinase (MAPK kinase) inhibitors blocked ERK activation and cell proliferation induced by diazoxide. Furthermore, constitutively activated MEK plasmids transfection reversed the inhibitory effects of tolbutamide on glioma proliferation, lending further support for a role of ERK in mediating this process. Our results suggest that K(ATP) channels control glioma cell proliferation via regulating ERK pathway. We concluded that K(ATP) channels are important in pathological cell proliferation and open a promising pathway for novel targeted therapies.
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Affiliation(s)
- Lianyan Huang
- Department of Occupational Health and Occupational medicine, School of Public Health and Tropical Medicine, Southern Medical University, Guangzhou, Guangdong 510515, China.
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Shaw N, Majzoub J. Permanent Neonatal Diabetes in a Patient with a KCNJ11/Q52R Mutation Accompanied by Intermittent Hypoglycemia and Liver Failure. INTERNATIONAL JOURNAL OF PEDIATRIC ENDOCRINOLOGY 2009. [DOI: 10.1186/1687-9856-2009-453240] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
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Affiliation(s)
- Susumu Otomo
- Department of Pharmacy, Saitama Prefectural Cancer Center
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Bardou O, Trinh NTN, Brochiero E. Molecular diversity and function of K+ channels in airway and alveolar epithelial cells. Am J Physiol Lung Cell Mol Physiol 2008; 296:L145-55. [PMID: 19060226 DOI: 10.1152/ajplung.90525.2008] [Citation(s) in RCA: 60] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Multiple K(+) channels are expressed in the respiratory epithelium lining airways and alveoli. Of the three main classes [1) voltage-dependent or Ca(2+)-activated, 6-transmembrane domains (TMD), 2) 2-pores 4-TMD, and 3) inward-rectified 2-TMD K(+) channels], almost 40 different transcripts have already been detected in the lung. The physiological and functional significance of this high molecular diversity of lung epithelial K(+) channels is intriguing. As detailed in the present review, K(+) channels are located at both the apical and basolateral membranes in the respiratory epithelium, where they mediate K(+) currents of diverse electrophysiological and regulatory properties. The main recognized function of K(+) channels is to control membrane potential and to maintain the driving force for transepithelial ion and liquid transport. In this manner, KvLQT1, KCa and K(ATP) channels, for example, contribute to the control of airway and alveolar surface liquid composition and volume. Thus, K(+) channel activation has been identified as a potential therapeutic strategy for the resolution of pathologies characterized by ion transport dysfunction. K(+) channels are also involved in other key functions in lung physiology, such as oxygen-sensing, inflammatory responses and respiratory epithelia repair after injury. The purpose of this review is to summarize and discuss what is presently known about the molecular identity of lung K(+) channels with emphasis on their role in lung epithelial physiology.
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Affiliation(s)
- Olivier Bardou
- Centre de recherche du CHUM, Hôtel-Dieu, 3840, Saint-Urbain, Montréal, Québec H2W 1T8, Canada
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Yeung CK, Chiang SWY, Chan KP, Pang CP, Lam DSC. Potassium Channel Openers Reduce the Caspase-3 Expression of Triamcinolone-Treated Retinal Pigment Epithelial (ARPE19) Cells. Cutan Ocul Toxicol 2008. [DOI: 10.1080/15569520500371636] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
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Qian X, Li J, Ding J, Wang Z, Duan L, Hu G. Glibenclamide exerts an antitumor activity through reactive oxygen species-c-jun NH2-terminal kinase pathway in human gastric cancer cell line MGC-803. Biochem Pharmacol 2008; 76:1705-15. [PMID: 18840412 DOI: 10.1016/j.bcp.2008.09.009] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2008] [Revised: 08/28/2008] [Accepted: 09/05/2008] [Indexed: 02/08/2023]
Abstract
Glibenclamide, a blocker of ATP-sensitive potassium (K(ATP)) channels, can suppress progression of many cancers, but the involved mechanism is unclear. Herein we reported that MGC-803 cells expressed the K(ATP) channels composed of Kir6.2 and SUR1 subunits. Glibenclamide induced cellular viability decline, coupled with cell apoptosis and reactive oxygen species (ROS) generation in MGC-803 cells. Meanwhile, glibenclamide increased NADPH oxidase catalytic subunit gp91(phox) expression and superoxide anion (O2-) generation, and caused mitochondrial respiration dysfunction in MGC-803 cells, suggesting that glibenclamide induced an increase of ROS derived from NADPH oxidase and mitochondria. Glibenclamide could also lead to loss of mitochondrial membrane potential, release of cytochrome c and apoptosis-inducing factor (AIF), and activation of c-jun NH2-terminal kinase (JNK) in MGC-803 cells. Pretreatment with antioxidant N-acetyl-l-cysteine (NAC) prevented glibenclamide-induced JNK activation, apoptosis and cellular viability decline. Furthermore, glibenclamide greatly decreased the cellular viability, induced apoptosis and inhibited Akt activation in wild-type mouse embryonic fibroblast (MEF) cells but not in JNK1-/- or JNK2-/- MEF cells. Taken together, our study reveals that glibenclamide exerts an antitumor activity in MGC-803 cells by activating ROS-dependent, JNK-driven cell apoptosis. These findings provide insights into the use of glibenclamide in the treatment of human gastric cancer.
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Affiliation(s)
- Xia Qian
- Department of Pharmacology, Nanjing Medical University, 140 Hanzhong Road, Nanjing, Jiangsu 210029, PR China
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Trinh NTN, Privé A, Maillé E, Noël J, Brochiero E. EGF and K+ channel activity control normal and cystic fibrosis bronchial epithelia repair. Am J Physiol Lung Cell Mol Physiol 2008; 295:L866-80. [PMID: 18757521 DOI: 10.1152/ajplung.90224.2008] [Citation(s) in RCA: 64] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Severe lesions of airway epithelia are observed in cystic fibrosis (CF) patients. The regulatory mechanisms of cell migration and proliferation processes, involved in the repair of injured epithelia, then need to be better understood. A model of mechanical wounding of non-CF (NuLi) and CF (CuFi) bronchial monolayers was employed to study the repair mechanisms. We first observed that wound repair, under paracrine and autocrine EGF control, was slower (up to 33%) in CuFi than in NuLi. Furthermore, EGF receptor (EGFR) activation, following wounding, was lower in CuFi than in NuLi monolayers. Cell proliferation and migration assays indicated a similar rate of proliferation in both cell lines but with reduced (by 25%) CuFi cell migration. In addition, cell migration experiments performed in the presence of conditioned medium, collected from NuLi and CuFi wounded bronchial monolayers, suggested a defect in EGF/EGFR signaling in CF cells. We (49) recently demonstrated coupling between the EGF response and K(+) channel function, which is crucial for EGF-stimulated alveolar repair. In CuFi cells, lower EGF/EGFR signaling was accompanied by a 40-70% reduction in K(+) currents and KvLQT1, ATP-sensitive potassium (K(ATP)), and Ca(2+)-activated K(+) (KCa3.1) channel expression. In addition, EGF-stimulated bronchial wound healing, cell migration, and proliferation were severely decreased by K(+) channel inhibitors. Finally, acute CFTR inhibition failed to reduce wound healing, EGF secretion, and K(+) channel expression in NuLi. In summary, the delay in CuFi wound healing could be due to diminished EGFR signaling coupled with lower K(+) channel function, which play a crucial role in bronchial repair.
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Han X, Xi L, Wang H, Huang X, Ma X, Han Z, Wu P, Ma X, Lu Y, Wang G, Zhou J, Ma D. The potassium ion channel opener NS1619 inhibits proliferation and induces apoptosis in A2780 ovarian cancer cells. Biochem Biophys Res Commun 2008; 375:205-9. [PMID: 18706395 DOI: 10.1016/j.bbrc.2008.07.161] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2008] [Accepted: 07/30/2008] [Indexed: 11/17/2022]
Abstract
Diverse types of voltage-gated potassium (K+) channels have been shown to be involved in regulation of cell proliferation. The maxi-conductance Ca2+-activated K+ channels (BK channels) may play an important role in the progression of human cancer. To explore the role of BK channels in regulation of apoptosis in human ovarian cancer cells, the effects of the specific BK channel activator NS1619 on induction of apoptosis in A2780 cells were observed. Following treatment with NS1619, cell proliferation was measured by MTT assay. Apoptosis of A2780 cells pretreated with NS1619 was detected by agarose gel electrophoresis of cellular DNA and flow cytometry. Our data demonstrate that NS1619 inhibits the proliferation of A2780 cells in a dosage and time dependent manner IC50=31.1 microM, for 48 h pretreatment and induces apoptosis. Western blot analyses showed that the anti-proliferation effect of NS1619 was associated with increased expression of p53, p21, and Bax. These results indicate that BK channels play an important role in regulating proliferation of human ovarian cancer cells and may induce apoptosis through induction of p21(Cip1) expression in a p53-dependent manner.
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Affiliation(s)
- Xiaobing Han
- Cancer Biology Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, PR China
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Matsumura S, Saitou K, Miyaki T, Yoneda T, Mizushige T, Eguchi A, Shibakusa T, Manabe Y, Tsuzuki S, Inoue K, Fushiki T. Mercaptoacetate inhibition of fatty acid β-oxidation attenuates the oral acceptance of fat in BALB/c mice. Am J Physiol Regul Integr Comp Physiol 2008; 295:R82-91. [DOI: 10.1152/ajpregu.00060.2008] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
We investigated the effect of β-oxidation inhibition on the fat ingestive behavior of BALB/c mice. Intraperitoneal administration to mice of mercaptoacetate, an inhibitor of fatty acid oxidation, significantly suppressed intake of corn oil but not intake of sucrose solution or laboratory chow. To further examine the effect of mercaptoacetate on the acceptability of corn oil in the oral cavity, we examined short-term licking behavior. Mercaptoacetate significantly and specifically decreased the number of licks of corn oil within a 60-s period but did not affect those of a sucrose solution, a monosodium glutamate solution, or mineral oil. In contrast, the administration of 2-deoxyglucose, an inhibitor of glucose metabolism, did not affect the intake or short-term licking counts of any of the tasted solutions. These findings suggest that fat metabolism is involved in the mechanism underlying the oral acceptance of fat as an energy source.
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Park SH, Ramachandran S, Kwon SH, Cha SD, Seo EW, Bae I, Cho C, Song DK. Upregulation of ATP-sensitive potassium channels for estrogen-mediated cell proliferation in human uterine leiomyoma cells. Gynecol Endocrinol 2008; 24:250-6. [PMID: 18569028 DOI: 10.1080/09513590801893315] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/21/2022] Open
Abstract
OBJECTIVES The objectives of the present study were to evaluate the expression level of ATP-sensitive potassium (K(ATP)) channels in smooth muscle cells in human uterine leiomyoma and the involvement of the channel in potentiating effect of estrogen on leiomyoma growth. METHODS Reverse transcription-polymerase chain reaction (RT-PCR), real-time PCR and Western blot were used for the identification and quantification of K(ATP)-channel subunits in the control myometrial and leiomyoma cells. Furthermore, we measured the K(ATP)-channel activity in enzymatically isolated single uterine smooth muscle cells by whole-cell patch-clamp recordings. The estrogen-induced cell proliferation in leiomyoma was measured by the MTT assay. RESULTS The subunits of K(ATP) channels (Kir6.1, Kir6.2, SUR2B) were more highly expressed in leiomyoma cells than in control cells. The whole-cell currents mainly through K(ATP) channels were also greater in the leiomyoma cells. Estrogen applied in the bath solution could acutely enhance the channel activity. Estrogen-induced proliferation of the leiomyoma cells was inhibited by pretreatment with glibenclamide, a K(ATP)-channel inhibitor. CONCLUSION Estrogen may induce the proliferation of leiomyoma cells, at least in part, by activating the K(ATP) channel. Increased expression of the K(ATP) channel may be a causal factor for the high growth rate of uterine leiomyoma.
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Affiliation(s)
- Sung-Hee Park
- Department of Physiology, Keimyung University School of Medicine, Daegu, South Korea
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Ashrafpour M, Eliassi A, Sauve R, Sepehri H, Saghiri R. ATP regulation of a large conductance voltage-gated cation channel in rough endoplasmic reticulum of rat hepatocytes. Arch Biochem Biophys 2007; 471:50-6. [PMID: 18187033 DOI: 10.1016/j.abb.2007.12.012] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2007] [Revised: 12/09/2007] [Accepted: 12/11/2007] [Indexed: 10/22/2022]
Abstract
ATP-sensitive K+ channels play an important role in regulating membrane potential during metabolic stress. In this work we report the effect of ATP and ADP-Mg on a K+ channel present in the membrane of rough endoplasmic reticulum (RER) from rat hepatocytes incorporated into lipid bilayers. Channel activity was found to decrease in presence of ATP 100 microM on the cytoplasmic side and was totally inhibited at ATP concentrations greater than 0.25mM. The effect appeared voltage dependent, suggesting that the ATP binding site was becoming available upon channel opening. Channel activity was suppressed by the nonhydrolyzable ATP analog (ATPgammaS), ruling out a phosphorylation-based mechanism. Notably addition of 2.5mM ADP-Mg to the cytosolic side increased the channel open probability at negative potentials. We conclude that the large conductance voltage-gated cation channel in RER of rat hepatocytes is an ATP and ADP sensitive channel likely to be involved in cellular processes such as Ca(2+) signaling or control of membrane potential across the endoplasmic reticulum membrane.
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Affiliation(s)
- Manoochehr Ashrafpour
- Department of Physiology and Neuroscience Research Center, Shaheed Beheshti University (Medical Sciences), Evin, Tehran 19834, Iran
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Trinh NTN, Privé A, Kheir L, Bourret JC, Hijazi T, Amraei MG, Noël J, Brochiero E. Involvement of KATP and KvLQT1 K+ channels in EGF-stimulated alveolar epithelial cell repair processes. Am J Physiol Lung Cell Mol Physiol 2007; 293:L870-82. [PMID: 17631610 DOI: 10.1152/ajplung.00362.2006] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Several respiratory diseases are associated with extensive damage of lung epithelia, and the regulatory mechanisms involved in their regeneration are not clearly defined. Growth factors released by epithelial cells or fibroblasts from injured lungs are important regulators of alveolar repair by stimulating cell motility, proliferation, and differentiation. In addition, K(+) channels regulate cell proliferation/migration and are coupled with growth factor signaling in several tissues. We decided to explore the hypothesis, never investigated before, that K(+) could play a prominent role in alveolar repair. We employed a model of mechanical wounding of rat alveolar type II epithelia, in primary culture, to study their response to injury. Wound healing was suppressed by one-half upon epidermal growth factor (EGF) titration with EGF-antibody (Ab) or erbB1/erbB2 tyrosine-kinase inhibition with AG-1478/AG-825. The addition of exogenous EGF slightly stimulated the alveolar wound healing and enhanced, by up to five times, alveolar cell migration measured in a Boyden-type chamber. Conditioned medium collected from injured alveolar monolayers also stimulated cell migration; this effect was abolished in the presence of EGF-Ab. The impact of K(+) channel modulators was examined in basal and EGF-stimulated conditions. Wound healing was stimulated by pinacidil, an ATP-dependent K(+) channel (K(ATP)) activator, which also increased cell migration, by twofold, in basal conditions and potentiated the stimulatory effect of EGF. K(ATP) or KvLQT1 inhibitors (glibenclamide, clofilium) reduced EGF-stimulated wound healing, cell migration, and proliferation. Finally, EGF stimulated K(ATP) and KvLQT1 currents and channel expression. In summary, stimulation of K(+) channels through autocrine activation of EGF receptors could play a crucial role in lung epithelia repair processes.
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Affiliation(s)
- Nguyen Thu Ngan Trinh
- Centre de Recherche, Centre Hospitalier de l'Université de Montréal-Hôtel-DieuMontréal, Québec, Canada H2W 1T7
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