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Rao H, An X, Qu X, Yu J, Xie J, Ke J, Liu Z, You L, Qiu Z, Tian L, Du W, Li W, Jia J, Liu D, Li S. SGLT2i delays c-Myc-induced HCC progression via targeting mTOR. Biochim Biophys Acta Mol Basis Dis 2025; 1871:167805. [PMID: 40113049 DOI: 10.1016/j.bbadis.2025.167805] [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: 11/27/2024] [Revised: 02/23/2025] [Accepted: 03/15/2025] [Indexed: 03/22/2025]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) stands as a primary malignant liver tumor characterized by metabolic reprogramming. The oncogene c-Myc exerts substantial influence by driving the transcription of numerous genes. Empagliflozin (EMPA), a sodium-glucose cotransporter-2 inhibitor (SGLT2i), is widely used in the treatment of type 2 diabetes and has recently attracted attention for its potential anti-cancer effects. This study aims to unravel the complex interplay among c-Myc, EMPA, and the mammalian target of rapamycin (mTOR) in HCC development and progression. METHODS HCC induction in mice utilized high-pressure hydrodynamic transfection of the c-Myc plasmid. QPCR and immunohistochemistry experiments were performed to detect the expression of SGLT2 in HCC tissues. In vivo experiments were conducted to corroborate the upregulation of SGLT2 following c-Myc transfection. In invo and vitro investigations were conducted to evaluate the anti-cancer effects of two SGLT2i: EMPA and canagliflozin (CANA). Network pharmacology, molecular docking analyses, CETSA experiments, and additional western blot experiments were used to reveal EMPA's interaction inhibition with mTOR. RESULTS The study identified an increase in SGLT2 expression in HCC tissues as a result of c-Myc overexpression. In vitro experiments confirmed the upregulation of SGLT2 following c-Myc transfection. Notably, the administration of SGLT2i effectively curtailed liver cancer progression, and reduced hepatic fat accumulation in mice. EMPA exhibited significant suppression of cell proliferation in c-Myc-transfected cells. In vitro experiments unveiled EMPA's interaction and with inhibition the activation of mTOR. CONCLUSION Our study highlights EMPA's potential as a therapeutic agent in delaying the development and progression of HCC.
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Affiliation(s)
- Huiling Rao
- School of Basic Medical Sciences, Taihe Hospital, Hubei University of Medicine, Shiyan 442000, People's Republic of China; Department of Medical Engineering, The First Affiliated Hospital of Army Medical University, Chongqing 400000, People's Republic of China
| | - Xiaotong An
- School of Basic Medical Sciences, Taihe Hospital, Hubei University of Medicine, Shiyan 442000, People's Republic of China
| | - Xinyang Qu
- School of Basic Medical Sciences, Taihe Hospital, Hubei University of Medicine, Shiyan 442000, People's Republic of China
| | - Juan Yu
- School of Basic Medical Sciences, Taihe Hospital, Hubei University of Medicine, Shiyan 442000, People's Republic of China; Department of Anesthesiology, People's Hospital of Yunxi County of Hubei Province, Yunxi 442600, People's Republic of China
| | - Jin Xie
- School of Basic Medical Sciences, Taihe Hospital, Hubei University of Medicine, Shiyan 442000, People's Republic of China
| | - Jing Ke
- Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei University of Medicine, Shiyan 442000, People's Republic of China
| | - Zhixin Liu
- Shiyan Key Laboratory of Virology, Hubei University of Medicine, Shiyan 442000, People's Republic of China
| | - Lei You
- Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei University of Medicine, Shiyan 442000, People's Republic of China
| | - Zhenpeng Qiu
- College of Pharmacy, Hubei University of Chinese Medicine, Wuhan 430065, People's Republic of China
| | - Lin Tian
- Department of Pathology, Renming Hospital, Hubei University of Medicine, Shiyan 442000, People's Republic of China
| | - Weixing Du
- Department of Pathology, Renming Hospital, Hubei University of Medicine, Shiyan 442000, People's Republic of China
| | - Wanrong Li
- School of Basic Medical Sciences, Taihe Hospital, Hubei University of Medicine, Shiyan 442000, People's Republic of China
| | - Jie Jia
- School of Basic Medical Sciences, Taihe Hospital, Hubei University of Medicine, Shiyan 442000, People's Republic of China; Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei University of Medicine, Shiyan 442000, People's Republic of China.
| | - Danwen Liu
- School of Basic Medical Sciences, Taihe Hospital, Hubei University of Medicine, Shiyan 442000, People's Republic of China; Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei University of Medicine, Shiyan 442000, People's Republic of China.
| | - Shan Li
- School of Basic Medical Sciences, Taihe Hospital, Hubei University of Medicine, Shiyan 442000, People's Republic of China; Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei University of Medicine, Shiyan 442000, People's Republic of China.
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Wang X, Li J, Nong J, Deng X, Chen Y, Han B, Zeng L, Huang X. MiR-518b Promotes the Tumorigenesis of Hepatocellular Carcinoma by Targeting EGR1 to Regulate PI3K/AKT/mTOR Signaling Pathway. Cell Biochem Biophys 2025:10.1007/s12013-025-01752-z. [PMID: 40221539 DOI: 10.1007/s12013-025-01752-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/02/2025] [Indexed: 04/14/2025]
Abstract
Hepatocellular carcinoma (HCC) is a prevalent malignancy originating from hepatocytes and is characterized by high invasiveness and fatality. Dysregulation of microRNAs (miRNAs) is frequently observed during HCC progression. This study aimed to investigate the role of miR-518b in HCC cell malignancy and tumor growth. MiR-518b expression in HCC cells was measured by RT-qPCR. The proliferative, migratory and invasive capabilities of Hep3B and SNU-387 were assessed by colony formation, wound healing and transwell assays, respectively. RNA immunoprecipitation and luciferase reporter assays were utilized to verify the binding between miR-518b and its target gene, early growth response factor 1 (EGR1). Results revealed that miR-518b was highly expressed while EGR1 was downregulated in HCC cells. Knockdown of miR-518b significantly repressed cell proliferation, migration and invasion. Moreover, miR-518b bound to 3'untranslated region of EGR1 and negatively regulated its expression in HCC cells. EGR1 knockdown counteracted the inhibitory impact of miR-518b inhibition on malignant cell behaviors. In addition, the silencing of EGR1 activated the PI3K/AKT/mTOR signaling in HCC cells, while miR-518b depletion had the opposite effect. Importantly, the suppressive impact of miR-518b on the pathway was rescued by EGR1 knockdown. In vivo experiments demonstrated that inhibition of miR-518b suppressed HCC tumor growth, reduced EGR1 and Ki67 (a proliferation marker) expression, and inactivated the PI3K/AKT/mTOR signaling. In conclusion, miR-518b promotes HCC tumorigenesis by targeting EGR1 and regulating the PI3K/AKT/mTOR signaling pathway.
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Affiliation(s)
- Xinyuan Wang
- College of Zhuang Medicine, Guangxi University of Chinese Medicine, Nanning, China
| | - Juan Li
- Department of pediatrics, The First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning, China
| | - Jiao Nong
- College of Osteopathy, Guangxi University of Chinese Medicine, Nanning, China
| | - Xin Deng
- School of basic medicine, The First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning, China
| | - Yiping Chen
- Emergency department, The First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning, China
| | - Bing Han
- Guangxi University of Chinese Medicine, Nanning, China
| | - Lin Zeng
- Guangxi University of Chinese Medicine, Nanning, China
| | - Xiabing Huang
- Emergency department, The First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning, China.
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Basile L, Cannarella R, Magni P, Condorelli RA, Calogero AE, La Vignera S. Role of gliflozins on hepatocellular carcinoma progression: a systematic synthesis of preclinical and clinical evidence. Expert Opin Drug Saf 2025; 24:413-426. [PMID: 39714931 DOI: 10.1080/14740338.2024.2447057] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2024] [Revised: 11/02/2024] [Accepted: 12/22/2024] [Indexed: 12/24/2024]
Abstract
INTRODUCTION The risk of HCC is twice as high in diabetic patients compared to non-diabetic ones, suggesting that diabetes advances carcinogenesis in the liver through a variety of mechanisms. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have been shown to improve liver outcomes, emerging as promising agents to treat hepatocellular carcinoma (HCC) in patients with type 2 diabetes mellitus (T2DM). METHODS We searched PubMed and Scopus databases for articles presenting an association between SGLT2is and HCC to explore the putative mechanisms of action underlying the anti-proliferative activity of SGLT2is. RESULTS A total of 24 articles were selected for inclusion, of which 14 were preclinical and 10 were clinical. Preclinical studies were mainly focused on canagliflozin, used alone or in combination with other drugs. CONCLUSIONS Overall, canagliflozin had a negative effect on HCC cell proliferation by interfering with glucose-dependent and independent metabolic pathways, negatively impacting angiogenesis, and inducing apoptosis in in-vitro cell models. In-vivo, a protective effect on hepatic steatosis and fibrosis and HCC development has been reported. Human studies showed a lower risk of developing HCC in patients on SGLT2is. However, this is supported by retrospective cohort studies. Clinical trials are needed to confirm the causal relationship between SGLT2i administration and HCC development.
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Affiliation(s)
- Livia Basile
- Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
| | - Rossella Cannarella
- Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
- Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Paolo Magni
- Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy
- IRCCS MultiMedica, Sesto S. Giovanni, Milan, Italy
| | - Rosita A Condorelli
- Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
| | - Aldo E Calogero
- Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
| | - Sandro La Vignera
- Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
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Flausino LE, Carrasco AGM, Furuya TK, Tuan WJ, Chammas R. Impact of SGLT2 inhibitors on survival in gastrointestinal cancer patients undergoing chemotherapy and/or radiotherapy: a real-world data retrospective cohort study. BMC Cancer 2025; 25:542. [PMID: 40133838 PMCID: PMC11938601 DOI: 10.1186/s12885-025-13966-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2025] [Accepted: 03/19/2025] [Indexed: 03/27/2025] Open
Abstract
BACKGROUND The role of sodium-glucose co-transporter 2 inhibitor (SGLT2i) drugs in the management of diabetes and cardiovascular disease is well-established, but emerging evidence suggests potential effects on cancer outcomes, including gastrointestinal (GI) cancers. We conducted an extensive, sex-oriented, real-world data analysis to investigate whether SGLT2i can enhance GI cancer outcomes when used alongside standard therapies such as chemotherapy and radiotherapy. METHODS The study applied a retrospective cohort design with data from the TriNetX research database ( https://trinetx.com ), examining GI cancer patients treated with chemotherapy and/or radiotherapy between 2013 and 2023. The intervention cohort consisted of Gl cancer patients who received SGLT2i, while the control cohort did not. A 5-year follow-up period was used, and baseline characteristics were balanced using a 1:1 propensity score matching technique. Cox proportional-hazards and logistic regression models assessed mortality and morbidity risks between the cohorts. RESULTS The study included 6,389 male and 3,457 female patients with GI cancer (ICD-10: C15-C25). The use of SGLT2i was significantly associated with improved survival for both male (HR 0.568; 95% CI 0.534-0.605) and female (HR 0.561; 95% CI 0.513-0.614) patients undergoing chemotherapy and/or radiotherapy. SGLT2i use also correlated significantly with lower hospitalisation rates both in male (OR 0.684; 95% CI 0.637-0.734) and female (OR, 0.590; 95% CI 0.536-0.650) patients. The analysis of GI cancer subtypes also demonstrated similar benefits, without significant adverse effects. CONCLUSIONS Repurposing SGLT2 inhibitors for cancer treatment could potentially improve outcomes for GI cancer patients without causing significant side effects. Further clinical trials are needed to confirm these findings and establish the optimal condition for its application in GI cancer treatment.
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Affiliation(s)
- Lucas E Flausino
- Center for Translational Research in Oncology, Instituto do Câncer do Estado de São Paulo, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
- Comprehensive Center for Precision Oncology, Universidade de São Paulo, São Paulo, Brazil
| | - Alexis Germán Murillo Carrasco
- Center for Translational Research in Oncology, Instituto do Câncer do Estado de São Paulo, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
- Comprehensive Center for Precision Oncology, Universidade de São Paulo, São Paulo, Brazil
| | - Tatiane Katsue Furuya
- Center for Translational Research in Oncology, Instituto do Câncer do Estado de São Paulo, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
- Comprehensive Center for Precision Oncology, Universidade de São Paulo, São Paulo, Brazil
| | - Wen-Jan Tuan
- Department of Family and Community Medicine, and Public Health Sciences, Penn State College of Medicine, Hershey, PA, USA
| | - Roger Chammas
- Center for Translational Research in Oncology, Instituto do Câncer do Estado de São Paulo, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.
- Comprehensive Center for Precision Oncology, Universidade de São Paulo, São Paulo, Brazil.
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Takawy MW, Abdelmalek MF. Impact of Weight Loss on Metabolic Dysfunction Associated Steatohepatitis and Hepatic Fibrosis. Curr Diab Rep 2025; 25:23. [PMID: 39964660 DOI: 10.1007/s11892-025-01579-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/10/2025] [Indexed: 05/10/2025]
Abstract
PURPOSE OF REVIEW This review highlights the impact of weight loss on metabolic dysfunction associated steatotic liver disease (MASLD), formally known as nonalcoholic fatty liver disease (NAFLD), and its progressive form of metabolic dysfunction associated steatohepatitis (MASH), formally known as nonalcoholic steatohepatitis (NASH). The effects of weight loss, as achieved through lifestyle modification, pharmacotherapy, bariatric surgery or endobariatric procedures on MASLD/MASH and hepatic fibrosis are discussed. RECENT FINDINGS Although foundational in the treatment of MASLD/MASH, weight loss through life-style modification is challenging for most patients to achieve and sustain long-term. In patients with MASLD/MASH, a multidisciplinary approach may facilitate success with lifestyle modification, individualized consideration of pharmacotherapies and/or surgical approaches that have potential to lend an improvement in MASLD/MASH. Effective and sustained weight loss improves hepatic steatosis, steatohepatitis and potentially hepatic fibrosis. Improvement in hepatic fibrosis can improve patient-related outcomes associated with complications of advanced hepatic fibrosis or cirrhosis in patients with MASLD/MASH. Identifying risk factors that influence MASLD/MASH and early implementation of therapeutic weight loss strategies may improve chronic liver injury and decrease risk for adverse clinical outcomes related to progressive hepatic fibrosis attributable to MASLD/MASH.
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Affiliation(s)
- Marina W Takawy
- Division of Gastroenterology & Hepatology, Department of Medicine, Mayo Clinic, Rochester Rochester, MN, 55905, USA
| | - Manal F Abdelmalek
- Division of Gastroenterology & Hepatology, Department of Medicine, Mayo Clinic, Rochester Rochester, MN, 55905, USA.
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Xiong SX, Huang LJ, Liu HS, Zhang XX, Li M, Cui YB, Shao C, Hu XL. Dapagliflozin exerts anti-apoptotic effects by mitigating macrophage polarization via modulation of the phosphoinositide 3-kinase/protein kinase B signaling pathway. World J Diabetes 2025; 16:97287. [PMID: 39959262 PMCID: PMC11718488 DOI: 10.4239/wjd.v16.i2.97287] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2024] [Revised: 10/13/2024] [Accepted: 11/22/2024] [Indexed: 12/30/2024] Open
Abstract
BACKGROUND Macrophages are central to the orchestration of immune responses, inflammatory processes, and the pathogenesis of diabetic complications. The dynamic polarization of macrophages into M1 and M2 phenotypes critically modulates inflammation and contributes to the progression of diabetic nephropathy. Sodium-glucose cotransporter 2 inhibitors such as dapagliflozin, which are acclaimed for their efficacy in diabetes management, may influence macrophage polarization, thereby ameliorating diabetic nephropathy. This investigation delves into these mechanistic pathways, aiming to elucidate novel therapeutic strategies for diabetes. AIM To investigate the inhibitory effect of dapagliflozin on macrophage M1 polarization and apoptosis and to explore its mechanism of action. METHODS We established a murine model of type 2 diabetes mellitus and harvested peritoneal macrophages following treatment with dapagliflozin. Concurrently, the human monocyte cell line cells were used for in vitro studies. Macrophage viability was assessed in a cell counting kit 8 assay, whereas apoptosis was evaluated by Annexin V/propidium iodide staining. Protein expression was examined through western blotting, and the expression levels of macrophage M1 surface markers, inflammatory cytokines, and apoptotic factors were quantified using flow cytometry, enzyme linked immunosorbent assay, and quantitative real-time polymerase chain reaction analyses. RESULTS Dapagliflozin attenuated M1 macrophage polarization and mitigated apoptosis in the abdominal macrophages of diabetic mice, evidenced by the downregulation of proapoptotic genes (Caspase 3), inflammatory cytokines [interleukin (IL)-6, tumor necrosis factor-α, and IL-1β], and M1 surface markers (inducible nitric oxide synthase, and cluster of differentiation 86), as well as the upregulation of the antiapoptotic gene BCL2. Moreover, dapagliflozin suppressed the expression of proteins associated with the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway (PI3K, AKT, phosphorylated protein kinase B). These observations were corroborated in vitro, where we found that the modulatory effects of dapagliflozin were abrogated by 740Y-P, an activator of the PI3K/AKT signaling pathway. CONCLUSION Dapagliflozin attenuates the polarization of macrophages toward the M1 phenotype, thereby mitigating inflammation and promoting macrophage apoptosis. These effects are likely mediated through the inhibition of the PI3K/AKT signaling pathway.
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Affiliation(s)
- Sheng-Xi Xiong
- Department of Endocrinology, The First Affiliated Hospital of Bengbu Medical University, Bengbu 233000, Anhui Province, China
| | - Lin-Juan Huang
- Department of Endocrinology, The First Affiliated Hospital of Bengbu Medical University, Bengbu 233000, Anhui Province, China
| | - Han-Shuang Liu
- Department of Endocrinology, The First Affiliated Hospital of Bengbu Medical University, Bengbu 233000, Anhui Province, China
| | - Xiao-Xiao Zhang
- Department of Endocrinology, The First Affiliated Hospital of Bengbu Medical University, Bengbu 233000, Anhui Province, China
| | - Min Li
- Department of Endocrinology, The First Affiliated Hospital of Bengbu Medical University, Bengbu 233000, Anhui Province, China
| | - Yu-Bing Cui
- Department of Endocrinology, The First Affiliated Hospital of Bengbu Medical University, Bengbu 233000, Anhui Province, China
| | - Chen Shao
- Department of Endocrinology, The Second Affiliated Hospital of Bengbu Medical University, Bengbu 233000, Anhui Province, China
| | - Xiao-Lei Hu
- Department of Endocrinology, The First Affiliated Hospital of Bengbu Medical University, Bengbu 233000, Anhui Province, China
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Wang J, Yang W. Advances in sodium-glucose transporter protein 2 inhibitors and tumors. Front Oncol 2025; 15:1522059. [PMID: 40007997 PMCID: PMC11850236 DOI: 10.3389/fonc.2025.1522059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2024] [Accepted: 01/15/2025] [Indexed: 02/27/2025] Open
Abstract
Tumor is a major challenge to global health and has received extensive attention worldwide due to its high degree of malignancy and poor prognosis. Although the clinical application of targeted therapy and immunotherapy has improved the status quo of tumor treatment, the development of new therapeutic tools for tumors is still necessary. Sodium-glucose transporter protein 2 (SGLT2) inhibitors are a new type of glycemic control drugs, which are widely used in clinical practice because of their effects on weight reduction and protection of cardiac and renal functions. SGLT2 has been found to be overexpressed in many tumors and involved in tumorigenesis, progression and metastasis, suggesting that SGLT2i has a wide range of applications in tumor therapy. The aim of this article is to provide a comprehensive understanding of the research progress of SGLT2i in different tumors by integrating the latest studies and to encourage further exploration of SGLT2i therapies in clinical trials. This could pave the way for more effective management strategies and improved outcomes for tumor patients.
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Affiliation(s)
- Jiaqi Wang
- Department of Oncology, Guangyuan Central Hospital, Guangyuan, Sichuan, China
| | - Wenyong Yang
- Department of Respiratory and Critical Care Medicine, Guangyuan Central Hospital, Guangyuan, Sichuan, China
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Pandey A, Alcaraz M, Saggese P, Soto A, Gomez E, Jaldu S, Yanagawa J, Scafoglio C. Exploring the Role of SGLT2 Inhibitors in Cancer: Mechanisms of Action and Therapeutic Opportunities. Cancers (Basel) 2025; 17:466. [PMID: 39941833 PMCID: PMC11815934 DOI: 10.3390/cancers17030466] [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: 01/08/2025] [Revised: 01/23/2025] [Accepted: 01/27/2025] [Indexed: 02/16/2025] Open
Abstract
Cancer cells utilize larger amounts of glucose than their normal counterparts, and the expression of GLUT transporters is a known diagnostic target and a prognostic factor for many cancers. Recent evidence has shown that sodium-glucose transporters are also expressed in different types of cancer, and SGLT2 has raised particular interest because of the current availability of anti-diabetic drugs that block SGLT2 in the kidney, which could be readily re-purposed for the treatment of cancer. The aim of this article is to perform a narrative review of the existing literature and a critical appraisal of the evidence for a role of SGLT2 inhibitors for the treatment and prevention of cancer. SGLT2 inhibitors block Na-dependent glucose uptake in the proximal kidney tubules, leading to glycosuria and the improvement of blood glucose levels and insulin sensitivity in diabetic patients. They also have a series of systemic effects, including reduced blood pressure, weight loss, and reduced inflammation, which also make them effective for heart failure and kidney disease. Epidemiological evidence in diabetic patients suggests that individuals treated with SGLT2 inhibitors may have a lower incidence and better outcomes of cancer. These studies are confirmed by pre-clinical evidence of an effect of SGLT2 inhibitors against cancer in xenograft and genetically engineered models, as well as by in vitro mechanistic studies. The action of SGLT2 inhibitors in cancer can be mediated by the direct inhibition of glucose uptake in cancer cells, as well as by systemic effects. In conclusion, there is evidence suggesting a potential role of SGLT2 inhibitors against different types of cancer. The most convincing evidence exists for lung and breast adenocarcinomas, hepatocellular carcinoma, and pancreatic cancer. Several ongoing clinical trials will provide more information on the efficacy of SGLT2 inhibitors against cancer.
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Affiliation(s)
- Aparamita Pandey
- Division of Pulmonary and Critical Care Medicine, David Geffen School of Medicine, University of California Los Angeles, 700 Tiverton Drive, Los Angeles, CA 90095, USA; (A.P.); (A.S.); (E.G.); (S.J.)
| | - Martín Alcaraz
- Division of Pulmonary and Critical Care Medicine, David Geffen School of Medicine, University of California Los Angeles, 700 Tiverton Drive, Los Angeles, CA 90095, USA; (A.P.); (A.S.); (E.G.); (S.J.)
| | - Pasquale Saggese
- Department of Biology and Biotechnologies Charles Darwin, University of Rome “Sapienza”, Piazzale Aldo Moro 5, 00185 Rome, Italy;
| | - Adriana Soto
- Division of Pulmonary and Critical Care Medicine, David Geffen School of Medicine, University of California Los Angeles, 700 Tiverton Drive, Los Angeles, CA 90095, USA; (A.P.); (A.S.); (E.G.); (S.J.)
| | - Estefany Gomez
- Division of Pulmonary and Critical Care Medicine, David Geffen School of Medicine, University of California Los Angeles, 700 Tiverton Drive, Los Angeles, CA 90095, USA; (A.P.); (A.S.); (E.G.); (S.J.)
| | - Shreya Jaldu
- Division of Pulmonary and Critical Care Medicine, David Geffen School of Medicine, University of California Los Angeles, 700 Tiverton Drive, Los Angeles, CA 90095, USA; (A.P.); (A.S.); (E.G.); (S.J.)
| | - Jane Yanagawa
- Department of Surgery, David Geffen School of Medicine, University of California Los Angeles, 700 Tiverton Drive, Los Angeles, CA 90095, USA;
| | - Claudio Scafoglio
- Division of Pulmonary and Critical Care Medicine, David Geffen School of Medicine, University of California Los Angeles, 700 Tiverton Drive, Los Angeles, CA 90095, USA; (A.P.); (A.S.); (E.G.); (S.J.)
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Abdelaziz AM, Rasheed NOA, Zaki HF, Salem HA, El-Sayed RM. Canagliflozin attenuates neurodegeneration and ameliorates dyskinesia through targeting the NLRP3/Nurr1/GSK-3β/SIRT3 pathway and autophagy modulation in rotenone-lesioned rats. Int Immunopharmacol 2025; 146:113839. [PMID: 39700958 DOI: 10.1016/j.intimp.2024.113839] [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: 10/01/2024] [Revised: 11/20/2024] [Accepted: 12/09/2024] [Indexed: 12/21/2024]
Abstract
Despite a deep understanding of Parkinson's disease (PD) and levodopa-induced dyskinesia (LID) pathogenesis, current therapies are insufficient to effectively manage the progressive nature of PD or halt LID. Growing hypotheses suggested the NOD-like receptor 3 (NLRP3) inflammasome and orphan nuclear receptor-related 1 (Nurr1)/glycogen synthase kinase-3β (GSK-3β) and peroxisome proliferator-activated receptor γ (PPARγ) coactivator-1α (PGC-1α)/sirtuin 3 (SIRT3) pathways as potential avenues for halting neuroinflammation and oxidative stress in PD. AIMS This study investigated for the first time the neuroprotective effect of canagliflozin against PD and LID in rotenone-intoxicated rats, emphasizing the crosstalk among the NLRP3/caspase-1 cascade, PGC-1α/SIRT3 pathway, mammalian target of rapamycin (mTOR)/beclin-1, and Nurr1/β-catenin/GSK-3β pathways as possible treatment strategies in PD and LID. Also, correlating NLRP3 expression with all evaluated parameters. MAIN METHODS The PD rat model was induced via eleven rotenone (1.5 mg/kg) subcutaneous injections day after day. Canagliflozin (20 mg/kg) and/or L-dopa/carbidopa (100/25 mg/kg) were orally administered daily from the beginning until the end of the experiment. KEY FINDINGS Canagliflozin significantly improved neurobehavioral and histological assessments, whereas dyskinesia scores declined. The improvement was confirmed through tyrosine hydroxylase and β-catenin upregulation in contrast to NLRP3 and caspase-1 in substantia nigra pars compacta, as revealed immunohistochemically. In addition, canagliflozin induced a prominent elevation in dopamine, Nurr1, PGC-1α, SIRT3, and beclin-1, whereas mTOR and GSK-3β expressions were downregulated. SIGNIFICANCE Our results revealed the aspiring canagliflozin neuroprotective properties against PD and LID in rotenone-lesioned rats via the assumed anti-inflammatory activity and implication of NLRP3/caspase-1, Nurr1/GSK-3β/β-catenin, PGC-1α/SIRT3, and beclin-1/mTOR pathways.
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Affiliation(s)
- Ahmed M Abdelaziz
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Sinai University- Arish Branch, Arish 45511, Egypt.
| | - Nora O Abdel Rasheed
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Hala F Zaki
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Hesham A Salem
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Rehab M El-Sayed
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Sinai University- Arish Branch, Arish 45511, Egypt
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Bishr A, El-Mokadem BM, Gomaa AA. Canagliflozin alleviates acetaminophen-induced renal and hepatic injury in mice by modulating the p-GSK3β/Fyn-kinase/Nrf-2 and p-AMPK-α/STAT-3/SOCS-3 pathways. Sci Rep 2025; 15:729. [PMID: 39753621 PMCID: PMC11699121 DOI: 10.1038/s41598-024-82163-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2024] [Accepted: 12/03/2024] [Indexed: 01/06/2025] Open
Abstract
Despite the fact that canagliflozin (Cana), a sodium-glucose cotransporter 2 inhibitor, is an anti-diabetic medication with additional effects on the kidney, there is limited experimental data to deliberate its hepato-reno-protective potentiality. Acetaminophen (APAP) overdose remains one of the prominent contributors to hepato-renal damage. AIM Our study assessed the novel effect of Cana against APAP-induced toxicities. MAIN METHODS mice were randomized into five groups: negative control, Cana25, APAP, Cana10 + APAP, and Cana25 + APAP. Cana was given for 5 days; a single dose of APAP was injected on the 6th day, followed by the scarification of animals 24 h later. KEY FINDINGS Pre-treatment with Cana ameliorated hepatic and renal functions, whereas, on the molecular levels, Cana promoted hepatic/renal P-AMP-activated protein kinase-α/ protein kinase B (p-Akt)/Glycogen synthase kinase (p-GSK3β) protein expression. Alternatively, Cana dampened the expression of STAT-3 and Fyn-kinase genes with a subsequent increase in the contents of suppressor of cytokine signaling (SOCS)-3 and also boosted the contents of the nuclear factor erythroid related factor 2 (Nrf-2)/heme oxygenase (HO)-1/ NADPH quinone oxidoreductase (NQO)-1 axis. The crosstalk between these paths ameliorated the APAP-induced hepatorenal structural alterations. SIGNIFICANCE Cana hepatorenal protective impact was provoked partly through modulating p-AMPK-α /SOCS-3/STAT-3 and GSK3β/Fyn-kinase signaling for its anti-inflammatory and antioxidant effects.
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Affiliation(s)
- Abeer Bishr
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ahram Canadian University, Giza, Egypt.
| | - Bassant M El-Mokadem
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Egyptian Chinese University, Cairo, Egypt
| | - Asmaa A Gomaa
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ahram Canadian University, Giza, Egypt
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11
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Wei J, Tang X, He Y, Peng Z, Liu H, He Y, Gao J. Aronia Melanocarpa Elliot Anthocyanins Inhibits Alcoholic Liver Disease by Activation of α7nAChR. PLANT FOODS FOR HUMAN NUTRITION (DORDRECHT, NETHERLANDS) 2024; 79:779-794. [PMID: 38985368 DOI: 10.1007/s11130-024-01213-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 06/28/2024] [Indexed: 07/11/2024]
Abstract
The study wanted to explore the preventative effects of Aornia melanocarpa Elliot anthocyanins (AMA) to Alcoholic liver disease (ALD) by bioinformatics prediction and experimental verification. We founded 419 differentially expressed genes (DEGs) in GSE28619 related to ALD from GEO database, COL1A1 was selected by the core gene module construction and molecular docking. Mice were treated by intragastric administration of gradient 50% ethanol, AMA alleviated liver injury by ALD and ameliorated the model's body weight, lessened the liver inflammation according to histopathological evaluation, increased serum liver biochemical index (AST, ALT, TC, TG and LDL-C) and decreased HDL-C, reversed the expression of enzymes (ALDH and GSH-PX), decreased cytokines expression (Ki67, TNF-α and IL-6), reversed the expression of α7nAChR and collagen I, downregulated the PI3K-Akt pathway and Keap1/HO-1 pathway (p-PI3K, PI3K, p-Akt, Akt, Keap1, Nrf2, HO-1,GSK-3β and Bcl-2), indicated that α7nAChR and collagen I may be the AMA action targets.
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Affiliation(s)
- Jie Wei
- School of Life Science, Liaoning University, Chongshan Middle Road 66, Huanggu District, Shenyang, Liaoning, 110036, China.
| | - Xian Tang
- School of Life Science, Liaoning University, Chongshan Middle Road 66, Huanggu District, Shenyang, Liaoning, 110036, China
| | - Yujing He
- School of Life Science, Liaoning University, Chongshan Middle Road 66, Huanggu District, Shenyang, Liaoning, 110036, China
| | - Ziheng Peng
- School of Life Science, Liaoning University, Chongshan Middle Road 66, Huanggu District, Shenyang, Liaoning, 110036, China
| | - Hongwei Liu
- School of Life Science, Liaoning University, Chongshan Middle Road 66, Huanggu District, Shenyang, Liaoning, 110036, China
| | - Yin He
- School of Life Science, Liaoning University, Chongshan Middle Road 66, Huanggu District, Shenyang, Liaoning, 110036, China
| | - Jun Gao
- Liaoning Academy of Forestry, Yalujiang Street 12, Huanggu District, Shenyang, 110032, China.
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12
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Chen J, Liu J, Nie W, Hou X, Zhang X, Liu C, Si L, Zhang M, Xu S, Xie Q, Liang J, Li Y. Research progress on the structural and anti-colorectal malignant tumor properties of Shikonin. J Cancer Res Ther 2024; 20:1957-1963. [PMID: 39792404 DOI: 10.4103/jcrt.jcrt_933_24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2024] [Accepted: 10/17/2024] [Indexed: 01/12/2025]
Abstract
ABSTRACT Colorectal cancer is the third most prevalent malignant tumor worldwide. Despite the advancements in surgical procedures and treatment options, CRC remains a considerable cause of cancer-related mortality. Shikonin is a naphthoquinone compound that exhibits multiple biological activities, including anti-inflammatory and anti-tumor effects as well as wound healing promotion. Recently, Shikonin has been increasingly used in basic research on colorectal malignant tumors. Therefore, we explored the mechanisms of action and structural improvements of Shikonin in colorectal cancer through a literature review to provide valuable insights for the advancement of research and development of related pharmaceuticals.
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Affiliation(s)
- Jinghua Chen
- Department of Oncology, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Shandong Key Laboratory of Rheumatic Disease and Translational Medicine, Shandong Lung Cancer Institute, Jinan, China
- Department of Oncology, People's Hospital of Zhangdian District, Zibo, China
| | - Jie Liu
- Department of Pediatric Intensive Care Unit, Shandong Provincial Maternal and Child Health Care Hospital Affiliated to Qingdao University, Jinan, China
| | - Weiwei Nie
- Department of Oncology, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Shandong Key Laboratory of Rheumatic Disease and Translational Medicine, Shandong Lung Cancer Institute, Jinan, China
| | - Xingqin Hou
- South Ward, The Second Hospital of Shandong University, Jinan, China
| | - Xi Zhang
- Department of Oncology, People's Hospital of Zhangdian District, Zibo, China
| | - Chao Liu
- Department of Oncology, People's Hospital of Zhangdian District, Zibo, China
| | - Linxin Si
- Department of Oncology, People's Hospital of Zhangdian District, Zibo, China
| | - Mingzhu Zhang
- Department of Oncology, People's Hospital of Zhangdian District, Zibo, China
| | - Shutao Xu
- Department of Oncology, People's Hospital of Zhangdian District, Zibo, China
| | - Qi Xie
- Department of Oncology, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Shandong Key Laboratory of Rheumatic Disease and Translational Medicine, Shandong Lung Cancer Institute, Jinan, China
| | - Jing Liang
- Department of Oncology, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Shandong Key Laboratory of Rheumatic Disease and Translational Medicine, Shandong Lung Cancer Institute, Jinan, China
| | - Yan Li
- Department of Oncology, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Shandong Key Laboratory of Rheumatic Disease and Translational Medicine, Shandong Lung Cancer Institute, Jinan, China
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Prasad MK, Victor PS, Ganesh GV, Juttada U, Kumpatla S, Viswanathan V, Ramkumar KM. Sodium-Glucose Cotransporter-2 Inhibitor Suppresses Endoplasmic Reticulum Stress and Oxidative Stress in Diabetic Nephropathy Through Nrf2 Signaling: A Clinical and Experimental Study. J Clin Pharmacol 2024; 64:1193-1203. [PMID: 38831713 DOI: 10.1002/jcph.2465] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2024] [Accepted: 05/08/2024] [Indexed: 06/05/2024]
Abstract
Diabetic nephropathy (DN), a severe complication of type 2 diabetes mellitus (T2DM), is marked by heightened endoplasmic reticulum stress (ERS) and oxidative stress (OS) due to protein misfolding and free radical generation. We investigated the sodium-glucose co-transporter-2 inhibitor (SGLT2i), canagliflozin (Cana), in alleviating ERS and OS in DN patients and THP-1 cells under hyperglycemic condition. A total of 120 subjects were divided into four groups, with 30 subjects in each group: healthy controls, T2DM individuals, DN patients receiving standard treatment, and those treated with Cana. The control group had no history of diabetes, cardiovascular or renal diseases, or other comorbidities. Cana was administered at doses of either 100 or 300 mg per day based on the estimated glomerular filtration rate (eGFR) value of DN individuals, with a mean follow-up of 6 months. Additionally, THP-1 monocytes were exposed to HGM (33.3 mM glucose with a cytokine cocktail of TNF-α and IFN-γ at 50 ng/mL each) to evaluate the relative levels of ERS, OS markers, and nuclear factor erythroid 2-related factor 2 (Nrf2), the transcription factor regulating cellular redox, which is downregulated in diabetes. Our results revealed that ERS markers GRP78 and PERK, as well as OS markers TXNIP and p22phox, were elevated in both DN patients and HGM-treated THP-1 monocytes and were reduced by Cana intervention. Furthermore, Cana regulated the phosphorylation of Nrf2, Akt, and EIF2α in HGM-treated monocytes. In conclusion, our findings highlight the role of Cana in activating Nrf2, thereby attenuating ERS and OS to mitigate DN progression.
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Affiliation(s)
- Murali Krishna Prasad
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur, Tamilnadu, India
| | - Paul S Victor
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur, Tamilnadu, India
| | - Goutham V Ganesh
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur, Tamilnadu, India
| | - Udayama Juttada
- Department of Biochemistry and Molecular Genetics, Prof. M. Viswanathan's Diabetes Research Center, M.V. Hospital for Diabetes, Royapuram Chennai, Tamilnadu, India
| | - Satyavani Kumpatla
- Department of Biochemistry and Molecular Genetics, Prof. M. Viswanathan's Diabetes Research Center, M.V. Hospital for Diabetes, Royapuram Chennai, Tamilnadu, India
| | - Vijay Viswanathan
- Department of Biochemistry and Molecular Genetics, Prof. M. Viswanathan's Diabetes Research Center, M.V. Hospital for Diabetes, Royapuram Chennai, Tamilnadu, India
| | - Kunka Mohanram Ramkumar
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur, Tamilnadu, India
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Hao X, Li Y, Gao H, Wang Z, Fang B. Inhalation Anesthetics Play a Janus-Faced Role in Self-Renewal and Differentiation of Stem Cells. Biomolecules 2024; 14:1167. [PMID: 39334933 PMCID: PMC11430341 DOI: 10.3390/biom14091167] [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: 07/27/2024] [Revised: 09/05/2024] [Accepted: 09/13/2024] [Indexed: 09/30/2024] Open
Abstract
Inhalation anesthesia stands as a pivotal modality within clinical anesthesia practices. Beyond its primary anesthetic effects, inhaled anesthetics have non-anesthetic effects, exerting bidirectional influences on the physiological state of the body and disease progression. These effects encompass impaired cognitive function, inhibition of embryonic development, influence on tumor progression, and so forth. For many years, inhaled anesthetics were viewed as inhibitors of stem cell fate regulation. However, there is now a growing appreciation that inhaled anesthetics promote stem cell biological functions and thus are now regarded as a double-edged sword affecting stem cell fate. In this review, the effects of inhaled anesthetics on self-renewal and differentiation of neural stem cells (NSCs), embryonic stem cells (ESCs), and cancer stem cells (CSCs) were summarized. The mechanisms of inhaled anesthetics involving cell cycle, metabolism, stemness, and niche of stem cells were also discussed. A comprehensive understanding of these effects will enhance our comprehension of how inhaled anesthetics impact the human body, thus promising breakthroughs in the development of novel strategies for innovative stem cell therapy approaches.
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Affiliation(s)
- Xiaotong Hao
- Department of Anesthesiology, The First Hospital of China Medical University, Shenyang 110001, China
| | - Yuan Li
- Department of Anesthesiology, The First Hospital of China Medical University, Shenyang 110001, China
| | - Hairong Gao
- Department of Anesthesiology, The First Hospital of China Medical University, Shenyang 110001, China
| | - Zhilin Wang
- Department of Pain Medicine, The First Hospital of China Medical University, Shenyang 110001, China
| | - Bo Fang
- Department of Anesthesiology, The First Hospital of China Medical University, Shenyang 110001, China
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15
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Cristovão A, Andrade N, Martel F, Silva C. Effect of Sodium-Glucose Co-Transporter 2 Inhibitors Combined with Metformin on Pancreatic Cancer Cell Lines. Int J Mol Sci 2024; 25:9932. [PMID: 39337420 PMCID: PMC11432055 DOI: 10.3390/ijms25189932] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2024] [Revised: 09/06/2024] [Accepted: 09/11/2024] [Indexed: 09/30/2024] Open
Abstract
Pancreatic cancer (PC) is the ninth-leading cause of cancer-related deaths worldwide. Diabetic patients have an increased risk and mortality rates for PC. Sodium-glucose co-transporter 2 (SGLT2) inhibitors and metformin (Met) are widely used anti-diabetic medications. Both Met and SGLT2 inhibitors have anticancer properties in PC, but nothing is known concerning their combined effect. So, we investigated the in vitro effect of SGLT2 inhibitors combined with Met. Canagliflozin and dapagliflozin possessed cytotoxic, antiproliferative, and pro-apoptotic properties in the tested PC cell lines. In PANC-1 cells, the antimigratory and pro-apoptotic effects were enhanced when dapagliflozin was combined with Met, and G1 cell cycle arrest was enhanced when dapagliflozin or canagliflozin was combined with Met. In AsPC-1 cells, the cytotoxic effect and the G1 cell cycle arrest were enhanced when canagliflozin and dapagliflozin, respectively, were combined with Met. Only the cytotoxic effects of SGLT2 inhibitors, but not the combination treatments, involved PI3K and JNK-dependent pathways in AsPC-1 cells. In conclusion, combination treatments increased the anticancer effects in a cell type-dependent way in the two investigated cell lines. Additionally, the cytotoxic effect of SGLT2 inhibitors was dependent on the PI3K and JNK pathways in AsPC-1 cells, but Met appears to act via a distinct mechanism.
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Affiliation(s)
- André Cristovão
- Unit of Biochemistry, Department of Biomedicine, Faculty of Medicine of Porto, University of Porto, 4200-319 Porto, Portugal; (A.C.); (N.A.); (C.S.)
| | - Nelson Andrade
- Unit of Biochemistry, Department of Biomedicine, Faculty of Medicine of Porto, University of Porto, 4200-319 Porto, Portugal; (A.C.); (N.A.); (C.S.)
- REQUIMTE/LAQV, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, 4200-135 Porto, Portugal
| | - Fátima Martel
- Unit of Biochemistry, Department of Biomedicine, Faculty of Medicine of Porto, University of Porto, 4200-319 Porto, Portugal; (A.C.); (N.A.); (C.S.)
- Instituto de Investigação e Inovação em Saúde (I3S), University of Porto, 4200-135 Porto, Portugal
| | - Cláudia Silva
- Unit of Biochemistry, Department of Biomedicine, Faculty of Medicine of Porto, University of Porto, 4200-319 Porto, Portugal; (A.C.); (N.A.); (C.S.)
- REQUIMTE/LAQV, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, 4200-135 Porto, Portugal
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16
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Yao X, Liu Y, Sui Y, Zheng M, Zhu L, Li Q, Irwin MG, Yang L, Zhan Q, Xiao J. Dexmedetomidine facilitates autophagic flux to promote liver regeneration by suppressing GSK3β activity in mouse partial hepatectomy. Biomed Pharmacother 2024; 177:117038. [PMID: 39002441 DOI: 10.1016/j.biopha.2024.117038] [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: 05/07/2024] [Revised: 06/16/2024] [Accepted: 06/25/2024] [Indexed: 07/15/2024] Open
Abstract
INTRODUCTION Dexmedetomidine (DEX), a highly selective α2-adrenergic receptor agonist, is widely used for sedation and anesthesia in patients undergoing hepatectomy. However, the effect of DEX on autophagic flux and liver regeneration remains unclear. OBJECTIVES This study aimed to determine the role of DEX in hepatocyte autophagic flux and liver regeneration after PHx. METHODS In mice, DEX was intraperitoneally injected 5 min before and 6 h after PHx. In vitro, DEX was co-incubated with culture medium for 24 h. Autophagic flux was detected by LC3-II and SQSTM1 expression levels in primary mouse hepatocytes and the proportion of red puncta in AML-12 cells transfected with FUGW-PK-hLC3 plasmid. Liver regeneration was assessed by cyclinD1 expression, Edu incorporation, H&E staining, ki67 immunostaining and liver/body ratios. Bafilomycin A1, si-GSK3β and Flag-tagged GSK3β, α2-ADR antagonist, GSK3β inhibitor, AKT inhibitor were used to identify the role of GSK3β in DEX-mediated autophagic flux and hepatocyte proliferation. RESULTS Pre- and post-operative DEX treatment promoted liver regeneration after PHx, showing 12 h earlier than in DEX-untreated mice, accompanied by facilitated autophagic flux, which was completely abolished by bafilomycin A1 or α2-ADR antagonist. The suppression of GSK3β activity by SB216763 and si-GSK3β enhanced the effect of DEX on autophagic flux and liver regeneration, which was abolished by AKT inhibitor. CONCLUSION Pre- and post-operative administration of DEX facilitates autophagic flux, leading to enhanced liver regeneration after partial hepatectomy through suppression of GSK3β activity in an α2-ADR-dependent manner.
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Affiliation(s)
- Xueya Yao
- Department of Anesthesiology, Renji Hospital, Shanghai Jiao Tong University of Medicine, Shanghai, China; Key Laboratory of Anesthesiology (Shanghai Jiao Tong University), Ministry of Education, Shanghai, China; Shanghai Engineering Research Center of Peri-operative Organ Support and Function Preservation, Shanghai, China.
| | - Yingxiang Liu
- Department of Anesthesiology, Renji Hospital, Shanghai Jiao Tong University of Medicine, Shanghai, China; Key Laboratory of Anesthesiology (Shanghai Jiao Tong University), Ministry of Education, Shanghai, China; Shanghai Engineering Research Center of Peri-operative Organ Support and Function Preservation, Shanghai, China.
| | - Yongheng Sui
- Department of Anesthesiology, Renji Hospital, Shanghai Jiao Tong University of Medicine, Shanghai, China; Key Laboratory of Anesthesiology (Shanghai Jiao Tong University), Ministry of Education, Shanghai, China; Shanghai Engineering Research Center of Peri-operative Organ Support and Function Preservation, Shanghai, China.
| | - Miao Zheng
- Department of Anesthesiology, Renji Hospital, Shanghai Jiao Tong University of Medicine, Shanghai, China; Key Laboratory of Anesthesiology (Shanghai Jiao Tong University), Ministry of Education, Shanghai, China; Shanghai Engineering Research Center of Peri-operative Organ Support and Function Preservation, Shanghai, China.
| | - Ling Zhu
- Department of Anesthesiology, Renji Hospital, Shanghai Jiao Tong University of Medicine, Shanghai, China; Key Laboratory of Anesthesiology (Shanghai Jiao Tong University), Ministry of Education, Shanghai, China; Shanghai Engineering Research Center of Peri-operative Organ Support and Function Preservation, Shanghai, China.
| | - Quanfu Li
- Department of Anesthesiology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China.
| | | | - Liqun Yang
- Department of Anesthesiology, Renji Hospital, Shanghai Jiao Tong University of Medicine, Shanghai, China; Key Laboratory of Anesthesiology (Shanghai Jiao Tong University), Ministry of Education, Shanghai, China; Shanghai Engineering Research Center of Peri-operative Organ Support and Function Preservation, Shanghai, China.
| | - Qionghui Zhan
- Department of Anesthesiology, Renji Hospital, Shanghai Jiao Tong University of Medicine, Shanghai, China; Key Laboratory of Anesthesiology (Shanghai Jiao Tong University), Ministry of Education, Shanghai, China; Shanghai Engineering Research Center of Peri-operative Organ Support and Function Preservation, Shanghai, China.
| | - Jie Xiao
- Department of Anesthesiology, Renji Hospital, Shanghai Jiao Tong University of Medicine, Shanghai, China; Key Laboratory of Anesthesiology (Shanghai Jiao Tong University), Ministry of Education, Shanghai, China; Shanghai Engineering Research Center of Peri-operative Organ Support and Function Preservation, Shanghai, China.
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17
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Anastasio C, Donisi I, Del Vecchio V, Colloca A, Mele L, Sardu C, Marfella R, Balestrieri ML, D'Onofrio N. SGLT2 inhibitor promotes mitochondrial dysfunction and ER-phagy in colorectal cancer cells. Cell Mol Biol Lett 2024; 29:80. [PMID: 38811901 PMCID: PMC11134909 DOI: 10.1186/s11658-024-00599-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2024] [Accepted: 05/17/2024] [Indexed: 05/31/2024] Open
Abstract
BACKGROUND Sodium-glucose transporter 2 (SGLT2) inhibitors (iSGLT2) are approved medications for type 2 diabetes. Recent studies indicate that iSGLT2 inhibit the growth of some cancer cells. However, the mechanism(s) remains to be fully elucidated. METHODS The SGLT2 levels were determined in normal colon CCD 841 CoN and, HCT 116, HT-29, SW480 and LoVo colorectal cancer (CRC) cell lines by quantitative real-time PCR and western blot. The effect of iSGLT2 canagliflozin on cell proliferation was examined using CCK-8, as its role on CRC cells metabolism and tumorigenesis has been evaluated by XF HS Seahorse Bioanalyzer and flow cytometric analyses. Transient gene silencing experiments and analysis of protein-protein interaction network were conducted to evaluate the SGLT2 molecular targets in CRC cells. RESULTS Data showed that the treatment with iSGLT2 (50 µM) for 72 h induced cell cycle arrest (p < 0.001), impaired glucose and energetic metabolism (p < 0.001), promoted apoptotic cell death and ER stress flowing into autophagy (p < 0.001) in HCT 116 and HT-29 cells. These cellular events were accompanied by sirtuin 3 (SIRT3) upregulation (p < 0.01), as also supported by SIRT3 transient silencing experiments resulting in the attenuation of the effects of iSGLT2 on the cellular metabolic/energetic alterations and the induction of programmed cell death. The identification and validation of dipeptidyl peptidase 4 (DPP4) as potential common target of SGLT2 and SIRT3 were also assessed. CONCLUSIONS These results deepened knowledge on the iSGLT2 contribution in limiting CRC tumorigenesis unveiling the SGLT2/SIRT3 axis in the cytotoxic mechanisms.
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Affiliation(s)
- Camilla Anastasio
- Department of Precision Medicine, University of Campania Luigi Vanvitelli, 80138, Naples, Italy
| | - Isabella Donisi
- Department of Precision Medicine, University of Campania Luigi Vanvitelli, 80138, Naples, Italy
| | - Vitale Del Vecchio
- Department of Experimental Medicine, University of Campania Luigi Vanvitelli, Via Luciano Armanni 5, 80138, Naples, Italy
| | - Antonino Colloca
- Department of Precision Medicine, University of Campania Luigi Vanvitelli, 80138, Naples, Italy
| | - Luigi Mele
- Department of Experimental Medicine, University of Campania Luigi Vanvitelli, Via Luciano Armanni 5, 80138, Naples, Italy
| | - Celestino Sardu
- Department of Advanced Clinical and Surgical Sciences, University of Campania Luigi Vanvitelli, 80138, Naples, Italy
| | - Raffaele Marfella
- Department of Advanced Clinical and Surgical Sciences, University of Campania Luigi Vanvitelli, 80138, Naples, Italy
| | - Maria Luisa Balestrieri
- Department of Precision Medicine, University of Campania Luigi Vanvitelli, 80138, Naples, Italy
| | - Nunzia D'Onofrio
- Department of Precision Medicine, University of Campania Luigi Vanvitelli, 80138, Naples, Italy.
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18
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Shi Z, Hu C, Zheng X, Sun C, Li Q. Feedback loop between hypoxia and energy metabolic reprogramming aggravates the radioresistance of cancer cells. Exp Hematol Oncol 2024; 13:55. [PMID: 38778409 PMCID: PMC11110349 DOI: 10.1186/s40164-024-00519-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Accepted: 05/07/2024] [Indexed: 05/25/2024] Open
Abstract
Radiotherapy is one of the mainstream approaches for cancer treatment, although the clinical outcomes are limited due to the radioresistance of tumor cells. Hypoxia and metabolic reprogramming are the hallmarks of tumor initiation and progression and are closely linked to radioresistance. Inside a tumor, the rate of angiogenesis lags behind cell proliferation, and the underdevelopment and abnormal functions of blood vessels in some loci result in oxygen deficiency in cancer cells, i.e., hypoxia. This prevents radiation from effectively eliminating the hypoxic cancer cells. Cancer cells switch to glycolysis as the main source of energy, a phenomenon known as the Warburg effect, to sustain their rapid proliferation rates. Therefore, pathways involved in metabolic reprogramming and hypoxia-induced radioresistance are promising intervention targets for cancer treatment. In this review, we discussed the mechanisms and pathways underlying radioresistance due to hypoxia and metabolic reprogramming in detail, including DNA repair, role of cancer stem cells, oxidative stress relief, autophagy regulation, angiogenesis and immune escape. In addition, we proposed the existence of a feedback loop between energy metabolic reprogramming and hypoxia, which is associated with the development and exacerbation of radioresistance in tumors. Simultaneous blockade of this feedback loop and other tumor-specific targets can be an effective approach to overcome radioresistance of cancer cells. This comprehensive overview provides new insights into the mechanisms underlying tumor radiosensitivity and progression.
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Affiliation(s)
- Zheng Shi
- Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, China
- Key Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences, Lanzhou, China
- Key Laboratory of Basic Research on Heavy Ion Radiation Application in Medicine, Lanzhou, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Cuilan Hu
- Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, China
- Key Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences, Lanzhou, China
- Key Laboratory of Basic Research on Heavy Ion Radiation Application in Medicine, Lanzhou, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Xiaogang Zheng
- Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, China
- Key Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences, Lanzhou, China
- Key Laboratory of Basic Research on Heavy Ion Radiation Application in Medicine, Lanzhou, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Chao Sun
- Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, China.
- Key Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences, Lanzhou, China.
- Key Laboratory of Basic Research on Heavy Ion Radiation Application in Medicine, Lanzhou, China.
- University of Chinese Academy of Sciences, Beijing, China.
| | - Qiang Li
- Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, China.
- Key Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences, Lanzhou, China.
- Key Laboratory of Basic Research on Heavy Ion Radiation Application in Medicine, Lanzhou, China.
- University of Chinese Academy of Sciences, Beijing, China.
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Sun M, Sun J, Sun W, Li X, Wang Z, Sun L, Wang Y. Unveiling the anticancer effects of SGLT-2i: mechanisms and therapeutic potential. Front Pharmacol 2024; 15:1369352. [PMID: 38595915 PMCID: PMC11002155 DOI: 10.3389/fphar.2024.1369352] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2024] [Accepted: 03/14/2024] [Indexed: 04/11/2024] Open
Abstract
Cancer and diabetes are significant diseases that pose a threat to human health. Their interconnection is complex, particularly when they coexist, often necessitating multiple therapeutic approaches to attain remission. Sodium-glucose cotransporter protein two inhibitors (SGLT-2i) emerged as a treatment for hyperglycemia, but subsequently exhibited noteworthy extra-glycemic properties, such as being registered for the treatment of heart failure and chronic kidney disease, especially with co-existing albuminuria, prompting its assessment as a potential treatment for various non-metabolic diseases. Considering its overall tolerability and established use in diabetes management, SGLT-2i may be a promising candidate for cancer therapy and as a supplementary component to conventional treatments. This narrative review aimed to examine the potential roles and mechanisms of SGLT-2i in the management of diverse types of cancer. Future investigations should focus on elucidating the antitumor efficacy of individual SGLT-2i in different cancer types and exploring the underlying mechanisms. Additionally, clinical trials to evaluate the safety and feasibility of incorporating SGLT-2i into the treatment regimen of specific cancer patients and determining appropriate dosage combinations with established antitumor agents would be of significant interest.
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Affiliation(s)
- Min Sun
- Department of Geriatrics, First Hospital, Jilin University, Changchun, China
| | - Jilei Sun
- Changchun Traditional Chinese Medicine Hospital, Changchun, China
| | - Wei Sun
- First Affiliated Hospital of Jilin University, Changchun, China
| | - Xiaonan Li
- Department of Geriatrics, First Hospital, Jilin University, Changchun, China
| | - Zhe Wang
- Department of Geriatrics, First Hospital, Jilin University, Changchun, China
| | - Liwei Sun
- Research Center of Traditional Chinese Medicine, The Affiliated Hospital to Changchun University of Chinese Medicine, Changchun, China
| | - Yuehui Wang
- Department of Geriatrics, First Hospital, Jilin University, Changchun, China
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20
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Hou Z, Wu C, Tang J, Liu S, Li L. CLSPN actives Wnt/β-catenin signaling to facilitate glycolysis and cell proliferation in oral squamous cell carcinoma. Exp Cell Res 2024; 435:113935. [PMID: 38237848 DOI: 10.1016/j.yexcr.2024.113935] [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: 10/19/2023] [Revised: 01/01/2024] [Accepted: 01/15/2024] [Indexed: 02/04/2024]
Abstract
OBJECTIVE Oral squamous cell carcinoma (OSCC) is a common malignancy with a poor prognosis. This study aimed to determine the influence and underlying mechanisms of CLSPN on OSCC. METHODS CLSPN expression was tested using quantitative real-time polymerase chain reaction, immunohistochemistry, and western blotting. Flow cytometry, cell counting kit, and colony formation assays were performed to determine OSCC cell apoptosis, viability, and proliferation, respectively. In OSCC cells, the extracellular acidification rate (ECAR), oxygen consumption rate (OCR), glucose uptake, and lactate production were determined using the corresponding kits. Changes in the protein levels of HK2, PKM2, LDHA, Wnt3a, and β-catenin were assessed using western blotting. RESULTS CLSPN expression was increased in OSCC tissues. Overexpression of CLSPN in HSC-2 cells promoted cell proliferation, increased the levels of ECAR, glucose uptake, and lactate production, and increased the protein levels of HK2, PKM2, LDHA, Wnt3a, and β-catenin, but inhibited OCR levels and apoptosis. The knockdown of CLSPN in CAL27 cells resulted in the opposite results. Moreover, the effects of CLSPN overexpression on glycolysis and OSCC cell proliferation were reversed by Wnt3a knockdown. In vivo, knockdown of CLSPN restrained tumor growth, glycolysis, and the activation of Wnt/β-catenin signaling. CONCLUSION CLSPN promoted glycolysis and OSCC cell proliferation, and reduced apoptosis, which was achieved by the activation of Wnt/β-catenin signaling pathway.
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Affiliation(s)
- Zeyu Hou
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases & Department of Head and Neck Oncology, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, 610041, China
| | - Chenzhou Wu
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases & Department of Head and Neck Oncology, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, 610041, China
| | - Jinru Tang
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases & Department of Head and Neck Oncology, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, 610041, China
| | - Shaohua Liu
- Department of Oral and Maxillofacial Surgery, Qilu Hospital of Shandong University, Jinan, Shandong, 250012, China.
| | - Longjiang Li
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases & Department of Head and Neck Oncology, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, 610041, China.
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21
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Huynh DJ, Renelus BD, Jamorabo DS. Reduced mortality and morbidity associated with metformin and SGLT2 inhibitor therapy in patients with type 2 diabetes mellitus and cirrhosis. BMC Gastroenterol 2023; 23:450. [PMID: 38114915 PMCID: PMC10731715 DOI: 10.1186/s12876-023-03085-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Accepted: 12/08/2023] [Indexed: 12/21/2023] Open
Abstract
INTRODUCTION Evidence for dual antidiabetic therapy in type 2 diabetes mellitus patients with cirrhosis is limited. This study compared 5-year mortality, composite hepatic decompensation risk, and hepatocellular carcinoma occurrence in patients with diabetes and cirrhosis who were either on metformin monotherapy or on dual metformin and sodium-glucose co-transporter-2 inhibitor (SGLT2-I) therapy. METHODS This retrospective study used the TriNetX Research Network to identify propensity score-matched patients treated with either metformin or dual metformin and SGLT2-I therapy. Our outcomes were all-cause mortality, a composite of hepatic decompensation events, and hepatocellular carcinoma (HCC) occurrence over 5 years. We estimated hazard ratios within each cohort with 95% confidence intervals (CI) and Kaplan-Meier estimates for time-to-event distributions with Log-rank tests. We were able to stratify our cohorts by age, sex, race, and ethnicity. We further investigated a subset of diabetic patients with cirrhosis due to MASH. RESULTS In our propensity score-matched cohorts of type 2 diabetes patients with cirrhosis, those on dual metformin and SGLT2-I therapy had decreased risk for mortality (HR 0.57, 95%CI 0.41-0.81), reduced composite risk of becoming decompensated (HR 0.63, 95%CI 0.43-0.93) and less than half the risk for developing HCC (HR 0.43, 95%CI 0.21-0.88) compared to those on mono metformin therapy. We did not find a difference between mono or dual therapy treatment for mortality, decompensation, or HCC risks in the subset of patients with MASH cirrhosis. CONCLUSION Dual metformin and SGLT2-I treatment in type 2 diabetes patients with cirrhosis are associated with improved mortality and hepatic complications.
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Affiliation(s)
- Daniel J Huynh
- Renaissance School of Medicine at Stony Brook University, Stony Brook, NY, USA
| | - Benjamin D Renelus
- Division of Gastroenterology and Hepatology, Morehouse School of Medicine, Atlanta, GA, USA
| | - Daniel S Jamorabo
- Division of Gastroenterology and Hepatology, Stony Brook Medicine, 101 Nicolls Road, Health Sciences Center, Stony Brook, NY, 11794-8167, USA.
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22
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Al-Kuraishy HM, Jabir MS, Albuhadily AK, Al-Gareeb AI, Rafeeq MF. The link between metabolic syndrome and Alzheimer disease: A mutual relationship and long rigorous investigation. Ageing Res Rev 2023; 91:102084. [PMID: 37802319 DOI: 10.1016/j.arr.2023.102084] [Citation(s) in RCA: 31] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2023] [Revised: 10/01/2023] [Accepted: 10/03/2023] [Indexed: 10/08/2023]
Abstract
It has been illustrated that metabolic syndrome (MetS) is associated with Alzheimer disease (AD) neuropathology. Components of MetS including central obesity, hypertension, insulin resistance (IR), and dyslipidemia adversely affect the pathogenesis of AD by different mechanisms including activation of renin-angiotensin system (RAS), inflammatory signaling pathways, neuroinflammation, brain IR, mitochondrial dysfunction, and oxidative stress. MetS exacerbates AD neuropathology, and targeting of molecular pathways in MetS by pharmacological approach could a novel therapeutic strategy in the management of AD in high risk group. However, the underlying mechanisms of these pathways in AD neuropathology are not completely clarified. Therefore, this review aims to elucidate the association between MetS and AD regarding the oxidative and inflammatory mechanistic pathways.
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Affiliation(s)
- Haydar M Al-Kuraishy
- Department of Clinical pharmacology and Medicine, College of Medicine, Mustansiriyah University, Baghdad, Iraq
| | - Majid S Jabir
- Department of Applied science, University of technology, Iraq.
| | - Ali K Albuhadily
- Department of Clinical pharmacology and Medicine, College of Medicine, Mustansiriyah University, Baghdad, Iraq
| | - Ali I Al-Gareeb
- Department of Clinical pharmacology and Medicine, College of Medicine, Mustansiriyah University, Baghdad, Iraq
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23
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Jalil AT, Abdulhadi MA, Alkubaisy SA, Thejeel SH, Essa IM, Merza MS, Zabibah RS, Al-Tamimi R. The role of endoplasmic reticulum stress in promoting aerobic glycolysis in cancer cells: An overview. Pathol Res Pract 2023; 251:154905. [PMID: 37925820 DOI: 10.1016/j.prp.2023.154905] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2023] [Revised: 10/19/2023] [Accepted: 10/24/2023] [Indexed: 11/07/2023]
Abstract
Aerobic glycolysis, also known as the Warburg effect, is a metabolic phenomenon frequently observed in cancer cells, characterized by the preferential utilization of glucose through glycolysis, even under normal oxygen conditions. This metabolic shift provides cancer cells with a proliferative advantage and supports their survival and growth. While the Warburg effect has been extensively studied, the underlying mechanisms driving this metabolic adaptation in cancer cells remain incompletely understood. In recent years, emerging evidence has suggested a potential link between endoplasmic reticulum (ER) stress and the promotion of aerobic glycolysis in cancer cells. The ER is a vital organelle involved in protein folding, calcium homeostasis, and lipid synthesis. Various cellular stresses, such as hypoxia, nutrient deprivation, and accumulation of misfolded proteins, can lead to ER stress. In response, cells activate the unfolded protein response (UPR) to restore ER homeostasis. However, prolonged or severe ER stress can activate alternative signaling pathways that modulate cellular metabolism, including the promotion of aerobic glycolysis. This review aims to provide an overview of the current understanding regarding the influence of ER stress on aerobic glycolysis in cancer cells to shed light on the complex interplay between ER stress and metabolic alterations in cancer cells. Understanding the intricate relationship between ER stress and the promotion of aerobic glycolysis in cancer cells may provide valuable insights for developing novel therapeutic strategies targeting metabolic vulnerabilities in cancer.
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Affiliation(s)
| | - Mohanad Ali Abdulhadi
- Department of Medical Laboratory Techniques, Al-Maarif University College, Al-Anbar, Iraq
| | | | - Sara Hamed Thejeel
- National University of Science and Technology, Al-Nasiriyah, Thi-Qar, Iraq
| | - Israa M Essa
- Department of Veterinary Parasitology, College of Veterinary Medicine, University of Basrah, Basrah, Iraq
| | - Muna S Merza
- Prosthetic Dental Techniques Department, Al-Mustaqbal, University College, Hillah, Babylon, Iraq
| | - Rahman S Zabibah
- Medical Laboratory Technology Department, College of Medical Technology, The Islamic University of Najaf, Najaf, Iraq
| | - Raad Al-Tamimi
- Medical Technical College, Al-Farahidi University, Baghdad, Iraq
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24
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Shao H, Chen J, Li A, Ma L, Tang Y, Chen H, Chen Y, Liu J. Salvigenin Suppresses Hepatocellular Carcinoma Glycolysis and Chemoresistance Through Inactivating the PI3K/AKT/GSK-3β Pathway. Appl Biochem Biotechnol 2023; 195:5217-5237. [PMID: 37129745 PMCID: PMC10354167 DOI: 10.1007/s12010-023-04511-z] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/11/2023] [Indexed: 05/03/2023]
Abstract
Salvigenin is a Trimethoxylated Flavone enriched in Scutellariae Barbatae Herba and Scutellariae Radix and is demonstrated to have anti-tumor properties in colon cancer. Notwithstanding, the function and mechanism of Salvigenin in hepatocellular carcinoma (HCC) are less well studied. Different doses of Salvigenin were taken to treat HCC cells. Cell viability, colony formation ability, cell migration, invasion, apoptosis, glucose uptake, and lactate production levels were detected. As shown by the data, Salvigenin concentration dependently dampened HCC cell proliferation, migration, and invasion, weakened glycolysis by abating glucose uptake and lactate generation, and suppressed the profiles of glycolytic enzymes. Moreover, Salvigenin strengthened HCC cells' sensitivity to 5-fluorouracil (5-FU) and attenuated HCC 5-FU-resistant cells' resistance to 5-FU. Through network pharmacological analysis, we found Salvigenin potentially regulates PI3K/AKT pathway. As shown by the data, Salvigenin repressed the phosphorylated levels of PI3K, AKT, and GSK-3β. The PI3K activator 740Y-P induced PI3K/AKT/GSK-3β pathway activation and promotive effects in HCC cells. However, Salvigenin substantially weakened 740Y-P-mediated effects. In-vivo assay revealed that Salvigenin hampered the growth and promoted apoptosis of HCC cells in nude mice. Collectively, Salvigenin impedes the aerobic glycolysis and 5-FU chemoresistance of HCC cells by dampening the PI3K/AKT/GSK-3β pathway.
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Affiliation(s)
- Hui Shao
- Department of Infection, Zhejiang Taizhou Hospital Affiliated to Wenzhou Medical University, Linhai City, 317000, Zhejiang Province, China
| | - Jingyan Chen
- Department of Infection, Zhejiang Taizhou Hospital Affiliated to Wenzhou Medical University, Linhai City, 317000, Zhejiang Province, China
| | - Ali Li
- Department of Infection, Zhejiang Taizhou Hospital Affiliated to Wenzhou Medical University, Linhai City, 317000, Zhejiang Province, China
| | - Lili Ma
- Department of Infection, Zhejiang Taizhou Hospital Affiliated to Wenzhou Medical University, Linhai City, 317000, Zhejiang Province, China
| | - Yongzhi Tang
- Department of Infection, Zhejiang Taizhou Hospital Affiliated to Wenzhou Medical University, Linhai City, 317000, Zhejiang Province, China
| | - Huazhong Chen
- Department of Infection, Zhejiang Taizhou Hospital Affiliated to Wenzhou Medical University, Linhai City, 317000, Zhejiang Province, China
| | - Yongping Chen
- Department of Infectious and Liver Diseases, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang Province, China.
| | - Junyan Liu
- Department of Infection, Zhejiang Taizhou Hospital Affiliated to Wenzhou Medical University, Linhai City, 317000, Zhejiang Province, China.
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25
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Basak D, Gamez D, Deb S. SGLT2 Inhibitors as Potential Anticancer Agents. Biomedicines 2023; 11:1867. [PMID: 37509506 PMCID: PMC10376602 DOI: 10.3390/biomedicines11071867] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2023] [Revised: 06/22/2023] [Accepted: 06/26/2023] [Indexed: 07/30/2023] Open
Abstract
Sodium-glucose cotransporter 2 (SGLT2) serves as a critical glucose transporter that has been reported to be overexpressed in cancer models, followed by increased glucose uptake in both mice and humans. Inhibition of its expression can robustly thwart tumor development in vitro and in vivo. SGLT2 inhibitors are a comparatively new class of antidiabetic drugs that have demonstrated anticancer effects in several malignancies, including breast, liver, pancreatic, thyroid, prostate, and lung cancers. This review aims to assess the extent of SGLT involvement in different cancer cell lines and discuss the pharmacology, mechanisms of action, and potential applications of SGLT2 inhibitors to reduce tumorigenesis and its progression. Although these agents display a common mechanism of action, they exhibit distinct affinity towards the SGLT type 2 transporter compared to the SGLT type 1 transporter and varying extents of bioavailability and half-lives. While suppression of glucose uptake has been attributed to their primary mode of antidiabetic action, SGLT2 inhibitors have demonstrated several mechanistic ways to combat cancer, including mitochondrial membrane instability, suppression of β-catenin, and PI3K-Akt pathways, increase in cell cycle arrest and apoptosis, and downregulation of oxidative phosphorylation. Growing evidence and ongoing clinical trials suggest a potential benefit of combination therapy using an SGLT2 inhibitor with the standard chemotherapeutic regimen. Nevertheless, further experimental and clinical evidence is required to characterize the expression and role of SGLTs in different cancer types, the activity of different SGLT subtypes, and their role in tumor development and progression.
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Affiliation(s)
- Debasish Basak
- Department of Pharmaceutical Sciences, College of Pharmacy, Larkin University, Miami, FL 33169, USA
| | - David Gamez
- Department of Pharmaceutical Sciences, College of Pharmacy, Larkin University, Miami, FL 33169, USA
| | - Subrata Deb
- Department of Pharmaceutical Sciences, College of Pharmacy, Larkin University, Miami, FL 33169, USA
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26
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Hashemi M, Nadafzadeh N, Imani MH, Rajabi R, Ziaolhagh S, Bayanzadeh SD, Norouzi R, Rafiei R, Koohpar ZK, Raei B, Zandieh MA, Salimimoghadam S, Entezari M, Taheriazam A, Alexiou A, Papadakis M, Tan SC. Targeting and regulation of autophagy in hepatocellular carcinoma: revisiting the molecular interactions and mechanisms for new therapy approaches. Cell Commun Signal 2023; 21:32. [PMID: 36759819 PMCID: PMC9912665 DOI: 10.1186/s12964-023-01053-z] [Citation(s) in RCA: 30] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2022] [Accepted: 01/15/2023] [Indexed: 02/11/2023] Open
Abstract
Autophagy is an evolutionarily conserved process that plays a role in regulating homeostasis under physiological conditions. However, dysregulation of autophagy is observed in the development of human diseases, especially cancer. Autophagy has reciprocal functions in cancer and may be responsible for either survival or death. Hepatocellular carcinoma (HCC) is one of the most lethal and common malignancies of the liver, and smoking, infection, and alcohol consumption can lead to its development. Genetic mutations and alterations in molecular processes can exacerbate the progression of HCC. The function of autophagy in HCC is controversial and may be both tumor suppressive and tumor promoting. Activation of autophagy may affect apoptosis in HCC and is a regulator of proliferation and glucose metabolism. Induction of autophagy may promote tumor metastasis via induction of EMT. In addition, autophagy is a regulator of stem cell formation in HCC, and pro-survival autophagy leads to cancer cell resistance to chemotherapy and radiotherapy. Targeting autophagy impairs growth and metastasis in HCC and improves tumor cell response to therapy. Of note, a large number of signaling pathways such as STAT3, Wnt, miRNAs, lncRNAs, and circRNAs regulate autophagy in HCC. Moreover, regulation of autophagy (induction or inhibition) by antitumor agents could be suggested for effective treatment of HCC. In this paper, we comprehensively review the role and mechanisms of autophagy in HCC and discuss the potential benefit of targeting this process in the treatment of the cancer. Video Abstract.
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Affiliation(s)
- Mehrdad Hashemi
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Niloufar Nadafzadeh
- Faculty of Veterinary Medicine, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Mohammad Hassan Imani
- Department of Clinical Science, Faculty of Veterinary Medicine, Shahr-E Kord Branch, Islamic Azad University, Tehran, Chaharmahal and Bakhtiari, Iran
| | - Romina Rajabi
- Faculty of Veterinary Medicine, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Setayesh Ziaolhagh
- Faculty of Veterinary Medicine, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | | | - Raheleh Norouzi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Reihaneh Rafiei
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Zeinab Khazaei Koohpar
- Department of Cell and Molecular Biology, Faculty of Biological Sciences, Tonekabon Branch, Islamic Azad University, Tonekabon, Iran
| | - Behnaz Raei
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Mohammad Arad Zandieh
- Department of Food Hygiene and Quality Control, Division of Epidemiology, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran.
| | - Shokooh Salimimoghadam
- Department of Biochemistry and Molecular Biology, Faculty of Veterinary Medicine, Shahid Chamran University of Ahvaz, Ahvaz, Iran
| | - Maliheh Entezari
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
| | - Afshin Taheriazam
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
- Department of Orthopedics, Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
| | - Athanasios Alexiou
- Department of Science and Engineering, Novel Global Community Educational Foundation, Hebersham, Australia
- AFNP Med Austria, Vienna, Austria
| | - Marios Papadakis
- Department of Surgery II, University Hospital Witten-Herdecke, University of Witten-Herdecke, Heusnerstrasse 40, 42283, Wuppertal, Germany.
| | - Shing Cheng Tan
- UKM Medical Molecular Biology Institute, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
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27
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Paskeh MDA, Ghadyani F, Hashemi M, Abbaspour A, Zabolian A, Javanshir S, Razzazan M, Mirzaei S, Entezari M, Goharrizi MASB, Salimimoghadam S, Aref AR, Kalbasi A, Rajabi R, Rashidi M, Taheriazam A, Sethi G. Biological impact and therapeutic perspective of targeting PI3K/Akt signaling in hepatocellular carcinoma: Promises and Challenges. Pharmacol Res 2023; 187:106553. [PMID: 36400343 DOI: 10.1016/j.phrs.2022.106553] [Citation(s) in RCA: 71] [Impact Index Per Article: 35.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Revised: 11/09/2022] [Accepted: 11/10/2022] [Indexed: 11/17/2022]
Abstract
Cancer progression results from activation of various signaling networks. Among these, PI3K/Akt signaling contributes to proliferation, invasion, and inhibition of apoptosis. Hepatocellular carcinoma (HCC) is a primary liver cancer with high incidence rate, especially in regions with high prevalence of viral hepatitis infection. Autoimmune disorders, diabetes mellitus, obesity, alcohol consumption, and inflammation can also lead to initiation and development of HCC. The treatment of HCC depends on the identification of oncogenic factors that lead tumor cells to develop resistance to therapy. The present review article focuses on the role of PI3K/Akt signaling in HCC progression. Activation of PI3K/Akt signaling promotes glucose uptake, favors glycolysis and increases tumor cell proliferation. It inhibits both apoptosis and autophagy while promoting HCC cell survival. PI3K/Akt stimulates epithelial-to-mesenchymal transition (EMT) and increases matrix-metalloproteinase (MMP) expression during HCC metastasis. In addition to increasing colony formation capacity and facilitating the spread of tumor cells, PI3K/Akt signaling stimulates angiogenesis. Therefore, silencing PI3K/Akt signaling prevents aggressive HCC cell behavior. Activation of PI3K/Akt signaling can confer drug resistance, particularly to sorafenib, and decreases the radio-sensitivity of HCC cells. Anti-cancer agents, like phytochemicals and small molecules can suppress PI3K/Akt signaling by limiting HCC progression. Being upregulated in tumor tissues and clinical samples, PI3K/Akt can also be used as a biomarker to predict patients' response to therapy.
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Affiliation(s)
- Mahshid Deldar Abad Paskeh
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Farhikhtegan Medical Convergence sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Fatemeh Ghadyani
- Farhikhtegan Medical Convergence sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Mehrdad Hashemi
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Farhikhtegan Medical Convergence sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Alireza Abbaspour
- Cellular and Molecular Research Center,Qazvin University of Medical Sciences, Qazvin, Iran
| | - Amirhossein Zabolian
- Resident of department of Orthopedics, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Salar Javanshir
- Young Researchers and Elite Club, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Mehrnaz Razzazan
- Medical Student, Student Research Committee, Golestan University of Medical Sciences, Gorgan, Iran
| | - Sepideh Mirzaei
- Department of Biology, Faculty of Science, Islamic Azad University, Science and Research Branch, Tehran, Iran
| | - Maliheh Entezari
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Farhikhtegan Medical Convergence sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | | | - Shokooh Salimimoghadam
- Department of Biochemistry and Molecular Biology, Faculty of Veterinary Medicine, Shahid Chamran University of Ahvaz, Ahvaz, Iran
| | - Amir Reza Aref
- Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; Translational Sciences, Xsphera Biosciences Inc. 6, Tide Street, Boston, MA 02210, USA
| | - Alireza Kalbasi
- Department of Pharmacy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Romina Rajabi
- Faculty of Veterinary Medicine, Islamic Azad University, Science and Research Branch, Tehran, Iran.
| | - Mohsen Rashidi
- Department Pharmacology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran; The Health of Plant and Livestock Products Research Center, Mazandaran University of Medical Sciences, Sari, Iran.
| | - Afshin Taheriazam
- Farhikhtegan Medical Convergence sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Orthopedics, Faculty of medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore; NUS Centre for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117599, Singapore.
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28
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Thabet NM, Abdel-Rafei MK, Askar MA, Abdelmohsen SA, Ahmed OM, Elbakry MM. Nanocomposite zinc oxide@ γ-linolenic acid-canagliflozin-fucoxanthin and/or γ-radiation perturbs key metabolic effectors and suppresses the proliferation of breast cancer cells in vitro. J Drug Deliv Sci Technol 2023. [DOI: 10.1016/j.jddst.2023.104161] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
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29
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Deng H, Chen Y, Li P, Hang Q, Zhang P, Jin Y, Chen M. PI3K/AKT/mTOR pathway, hypoxia, and glucose metabolism: Potential targets to overcome radioresistance in small cell lung cancer. CANCER PATHOGENESIS AND THERAPY 2023; 1:56-66. [PMID: 38328610 PMCID: PMC10846321 DOI: 10.1016/j.cpt.2022.09.001] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Revised: 09/02/2022] [Accepted: 09/25/2022] [Indexed: 02/09/2024]
Abstract
Small cell lung cancer (SCLC) is a highly aggressive tumor type for which limited therapeutic progress has been made. Platinum-based chemotherapy with or without thoracic radiotherapy remains the backbone of treatment, but most patients with SCLC acquire therapeutic resistance. Given the need for more effective therapies, better elucidation of the molecular pathogenesis of SCLC is imperative. The phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway is frequently activated in SCLC and strongly associated with resistance to ionizing radiation in many solid tumors. This pathway is an important regulator of cancer cell glucose metabolism, and its activation probably effects radioresistance by influencing bioenergetic processes in SCLC. Glucose metabolism has three main branches-aerobic glycolysis, oxidative phosphorylation, and the pentose phosphate pathway-involved in radioresistance. The interaction between the PI3K/AKT/mTOR pathway and glucose metabolism is largely mediated by hypoxia-inducible factor 1 (HIF-1) signaling. The PI3K/AKT/mTOR pathway also influences glucose metabolism through other mechanisms to participate in radioresistance, including inhibiting the ubiquitination of rate-limiting enzymes of the pentose phosphate pathway. This review summarizes our understanding of links among the PI3K/AKT/mTOR pathway, hypoxia, and glucose metabolism in SCLC radioresistance and highlights promising research directions to promote cancer cell death and improve the clinical outcome of patients with this devastating disease.
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Affiliation(s)
- Huan Deng
- Department of Medical Oncology, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, Zhejiang 310022, China
- Department of Radiation Oncology, Zhejiang Key Laboratory of Radiation Oncology, Hangzhou, Zhejiang 310022, China
- Department of Radiation Oncology, Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, China
- College of Life Sciences, University of the Chinese Academy of Sciences, Beijing 100049, China
| | - Yamei Chen
- Department of Medical Oncology, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, Zhejiang 310022, China
- Department of Radiation Oncology, Zhejiang Key Laboratory of Radiation Oncology, Hangzhou, Zhejiang 310022, China
- Department of Radiation Oncology, Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, China
| | - Peijing Li
- Department of Medical Oncology, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, Zhejiang 310022, China
- Department of Radiation Oncology, Zhejiang Key Laboratory of Radiation Oncology, Hangzhou, Zhejiang 310022, China
- Department of Radiation Oncology, Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, China
| | - Qingqing Hang
- Department of Medical Oncology, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, Zhejiang 310022, China
- Department of Radiation Oncology, Zhejiang Key Laboratory of Radiation Oncology, Hangzhou, Zhejiang 310022, China
- Department of Radiation Oncology, Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, China
| | - Peng Zhang
- Department of Medical Oncology, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, Zhejiang 310022, China
- Department of Radiation Oncology, Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, China
| | - Ying Jin
- Department of Medical Oncology, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, Zhejiang 310022, China
- Department of Radiation Oncology, Zhejiang Key Laboratory of Radiation Oncology, Hangzhou, Zhejiang 310022, China
- Department of Radiation Oncology, Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, China
| | - Ming Chen
- Department of Radiation Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510060, China
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Systems Pharmacology-Based Strategy to Investigate the Mechanism of Ruangan Lidan Decoction for Treatment of Hepatocellular Carcinoma. COMPUTATIONAL AND MATHEMATICAL METHODS IN MEDICINE 2022; 2022:2940654. [PMID: 36578460 PMCID: PMC9791079 DOI: 10.1155/2022/2940654] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Revised: 10/12/2022] [Accepted: 10/13/2022] [Indexed: 12/23/2022]
Abstract
epatocellular carcinoma (HCC) is one of the leading contributors to cancer mortality worldwide. Currently, the prevention and treatment of HCC remains a major challenge. As a traditional Chinese medicine (TCM) formula, Ruangan Lidan decoction (RGLD) has been proved to own the effect of relieving HCC symptoms. However, due to its biological effects and complex compositions, its underlying mechanism of actions (MOAs) have not been fully clarified yet. In this study, we proposed a pharmacological framework to systematically explore the MOAs of RGLD against HCC. We firstly integrated the active ingredients and potential targets of RGLD. We next highlighted 25 key targets that played vital roles in both RGLD and HCC disease via a protein-protein interaction (PPI) network and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. Furthermore, an ingredient-target network of RGLD consisting of 216 ingredients with 306 targets was constructed, and multilevel systems pharmacology analyses indicated that RGLD could act on multiple biological processes related to the pathogenesis of HCC, such as cellular response to hypoxia and cell proliferation. Additionally, integrated pathway analysis of RGLD uncovered that RGLD might treat HCC through regulating various pathways, including MAPK signaling pathway, PI3K/Akt signaling pathway, TNF signaling pathway, and ERBB signaling pathway. Survival analysis results showed that HCC patients with low expression of VEGFA, HIF1A, CASP8, and TOP2A were related with a higher survival rate than those with high expression, indicating the potential clinical significance for HCC. Finally, molecular docking results of core ingredients and targets further proved the feasibility of RGLD in the treatment of HCC. Overall, this study indicates that RGLD may treat HCC through multiple mechanisms, which also provides a potential paradigm to investigate the MOAs of TCM prescription.
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Oura K, Morishita A, Tani J, Masaki T. Antitumor Effects and Mechanisms of Metabolic Syndrome Medications on Hepatocellular Carcinoma. J Hepatocell Carcinoma 2022; 9:1279-1298. [PMID: 36545268 PMCID: PMC9760577 DOI: 10.2147/jhc.s392051] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Accepted: 12/04/2022] [Indexed: 12/15/2022] Open
Abstract
Liver cancer has a high incidence and mortality rate worldwide, with hepatocellular carcinoma (HCC) being the most common histological type. With the decrease in the number of newly infected patients and the spread of antiviral therapy, hepatitis virus-negative chronic liver diseases including steatohepatitis are increasingly accounting for a large proportion of HCC, and an important clinical characteristic is the high prevalence of metabolic syndrome including hypertension, type 2 diabetes (T2D), dyslipidemia, and obesity. Since patients with steatohepatitis are less likely to undergo surveillance for early detection of HCC, they may be diagnosed at an advanced stage and have worse prognosis. Therefore, treatment strategies for patients with HCC caused by steatohepatitis, especially in advanced stages, become increasingly important. Further, hypertension, T2D, and dyslipidemia may occur as side effects during systemic treatment, and there will be increasing opportunities to prescribe metabolic syndrome medications, not only for originally comorbid diseases, but also for adverse events during HCC treatment. Interestingly, epidemiological studies have shown that patients taking some metabolic syndrome medications are less likely to develop various types of cancers, including HCC. Basic studies have also shown that these drugs have direct antitumor effects on HCC. In particular, angiotensin II receptor blockers (a drug group for treating hypertension), biguanides (a drug group for treating T2D), and statins (a drug group for treating dyslipidemia) have shown to elucidate antitumor effects against HCC. In this review, we focus on the antitumor effects of metabolic syndrome medications on HCC and their mechanisms based on recent literature. New therapeutic agents are also increasingly being reported. Analysis of the antitumor effects of metabolic syndrome medications on HCC and their mechanisms will be doubly beneficial for HCC patients with metabolic syndrome, and the use of these medications may be a potential strategy against HCC.
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Affiliation(s)
- Kyoko Oura
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa, Japan,Correspondence: Kyoko Oura, Department of Gastroenterology and Neurology, Kagawa University, 1750-1 Ikenobe, Miki, Kida, Kagawa, Japan, Tel +81-87-891-2156, Fax +81-87-891-2158, Email
| | - Asahiro Morishita
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa, Japan
| | - Joji Tani
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa, Japan
| | - Tsutomu Masaki
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa, Japan
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Qiang W, Lei Y, Yuan L, Yuan J, Zhang J, Shan Y, Tian H, Shi B, Guo H. SGLT-2 as a potential target in pancreatic cancer: the preliminary clue from The Cancer Genome Atlas data. J Gastrointest Oncol 2022; 13:2539-2552. [PMID: 36388652 PMCID: PMC9660074 DOI: 10.21037/jgo-22-900] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Accepted: 10/17/2022] [Indexed: 01/25/2023] Open
Abstract
BACKGROUND Sodium-glucose co-transporters-2 (SGLT-2) has been reported as overexpressed in tumors including pancreatic cancer (PC). The aim of this study was to investigate the clinicopathological and prognostic significance, as well as the potential role of SGLT-2 in PC development and progression. METHODS The expression of SGLT-2 was assessed using The Cancer Genome Atlas (TCGA) PC dataset (179 cases). The overall survival (OS) and disease-free survival (DFS) of PC patients with high and low SLC5A2 expression were compared using the online database Gene Expression Profiling Interactive Analysis (GEPIA). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed using The Database for Annotation Visualization and Integrated Discovery (DAVID) online tool. The genetic correlations of SLC5A2 genes in different subtypes of PC were analyzed by using cBioPortal and LinkedOmics online databases. RESULTS No relationship between SGLT-2 expression and PC risk factors, tumor location, histology grade, or tumor-node-metastasis (TNM) stage was identified. Further, SGLT-2 could not be used as prognosis predictor. The KEGG analyses demonstrated that high SGLT-2 expression is correlated with activation of pathways related with chemical carcinogenesis, energy metabolism and drug metabolism, and the suppression of nucleotide excision repair, messenger RNA (mRNA) surveillance, and cell cycle regulation. Specifically, high SGLT-2 level also coexisted with upregulation of gene symbols for pancreatic progenitor subtype for PC. CONCLUSIONS There is potential for SGLT-2 as a potential target for PC treatment, and SGLT-2 inhibitors should be further evaluated as a novel therapy in PC.
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Affiliation(s)
- Wei Qiang
- Department of Endocrinology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Yuyang Lei
- Department of Cardiovascular Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Liyue Yuan
- Department of Endocrinology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.,Department of Internal Medicine, Xi'an Baqiao District People's Hospital, Xi'an, China
| | - Jia Yuan
- Department of Endocrinology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.,Emergency Department, Xi'an Hospital of Civil Aviation, Xi'an, China
| | - Jiaojiao Zhang
- Department of Pathology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Yuanyuan Shan
- Department of Pharmacy, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Hong Tian
- Research Center of Reproductive Medicine, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, China.,Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, China
| | - Bingyin Shi
- Department of Endocrinology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Hui Guo
- Department of Endocrinology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
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Xie H, Shi Y, Zhou Y, Liu H. TMBIM6 promotes diabetic tubular epithelial cell survival and albumin endocytosis by inhibiting the endoplasmic reticulum stress sensor, IRE1α. Mol Biol Rep 2022; 49:9181-9194. [PMID: 35857174 DOI: 10.1007/s11033-022-07744-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Revised: 06/21/2022] [Accepted: 06/22/2022] [Indexed: 11/25/2022]
Abstract
AIM Reduced albumin reabsorption in proximal tubular epithelial cells (PTECs), resulting from decreased megalin plasma membrane (PM) localization due to prolonged endoplasmic reticulum (ER) stress, potentially contributes to albuminuria in early diabetic kidney disease (DKD). To examine this possibility, we investigated the cytoprotective effect of TMBIM6 in promoting diabetic PTEC survival and albumin endocytosis by attenuating ER stress with an IRE1α inhibitor, KIRA6. METHODS AND RESULTS Renal TMBIM6 distribution and expression were determined by immunohistochemistry, western blotting, and qPCR, whereas tubular injury was evaluated in db/db mice. High-glucose (HG)-treated HK-2 cells were either treated with KIRA6 or transduced with a lentiviral vector for TMBIM6 overexpression. ER stress was measured by western blotting and ER-Tracker Red staining, whereas apoptosis was determined by performing TUNEL assays. Megalin expression was measured by immunofluorescence, and albumin endocytosis was evaluated after incubating cells with FITC-labeled albumin. Tubular injury and TMBIM6 downregulation occurred in db/db mouse renal cortical tissues. Both KIRA6 treatment and TMBIM6 overexpression inhibited ER stress by decreasing the levels of phosphorylated IRE1α, XBP1s, GRP78, and CHOP, and stabilizing ER expansion in HG-treated HK-2 cells. TUNEL assays performed with KIRA6-treated or TMBIM6-overexpressing cells showed a significant decrease in apoptosis, consistent with the significant downregulation of BAX and upregulation of BCL-2, as measured by immunoblotting. Both KIRA6 and TMBIM6 overexpression promoted megalin PM localization and restored albumin endocytosis in HG-treated HK-2 cells. CONCLUSION TMBIM6 promoted diabetic PTEC survival and albumin endocytosis by negatively regulating the IRE1α branch of ER stress.
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Affiliation(s)
- Huidi Xie
- Department of Nephrology and Endocrinology (A), Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Yang Shi
- Department of Nephrology and Endocrinology (A), Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Ying Zhou
- Department of Nephrology and Endocrinology (A), Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Hongfang Liu
- Department of Nephrology and Endocrinology (A), Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China.
- Dongzhimen Hospital, Renal Research Institute of Beijing University of Chinese Medicine, Beijing University of Chinese Medicine, No. 5, Haiyuncang Alley, Dongcheng District, 100700, Beijing, China.
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Arvanitakis K, Koufakis T, Kotsa K, Germanidis G. The effects of sodium-glucose cotransporter 2 inhibitors on hepatocellular carcinoma: From molecular mechanisms to potential clinical implications. Pharmacol Res 2022; 181:106261. [PMID: 35588918 DOI: 10.1016/j.phrs.2022.106261] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2022] [Revised: 05/11/2022] [Accepted: 05/12/2022] [Indexed: 02/08/2023]
Abstract
Hepatocellular carcinoma (HCC) occurs in the setting of prolonged liver inflammation, hepatocyte necrosis and regeneration in patients with cirrhosis. Despite the progress made in the medical management of the disorder during the past decades, the available pharmacological options remain limited, leading to poor survival rates and quality of life for patients with HCC. Sodium-glucose cotransporter 2 inhibitors (SGLT2) originally emerged as drugs for the treatment of hyperglycemia; however, they soon demonstrated important extra-glycemic properties, which led to their evaluation as potential treatments for a wide range of non-metabolic disorders. Evidence from animal studies suggests that SGLT2i have the potential to modulate molecular pathways that affect hallmarks of HCC, including inflammatory responses, cell proliferation, and oxidative stress. The impressive benefits of neurohormonal modulation observed with SGLT2i in congestive heart failure set the stage for human trials in cirrhotic ascites. However, future studies need to evaluate several aspects of the benefit to risk ratio of such a therapeutic strategy, including the co-administration with antineoplastic agents and diuretics, infections, use in hospitalized individuals, renal safety and hypovolemia. In this narrative review, we discuss the putative role of SGLT2i in the treatment of patients with HCC, starting with the mechanisms that could justify a possible benefit and ending with potential clinical implications and areas for future research.
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Affiliation(s)
- Konstantinos Arvanitakis
- First Department of Internal Medicine, AHEPA University Hospital, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece; Basic and Translational Research Unit, Special Unit for Biomedical Research and Education, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece
| | - Theocharis Koufakis
- Division of Endocrinology and Metabolism and Diabetes Centre, First Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, AHEPA University Hospital, 54636 Thessaloniki, Greece
| | - Kalliopi Kotsa
- Division of Endocrinology and Metabolism and Diabetes Centre, First Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, AHEPA University Hospital, 54636 Thessaloniki, Greece
| | - Georgios Germanidis
- First Department of Internal Medicine, AHEPA University Hospital, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece; Basic and Translational Research Unit, Special Unit for Biomedical Research and Education, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece.
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Role of Sodium-Glucose Co-Transporter 2 Inhibitors in the Regulation of Inflammatory Processes in Animal Models. Int J Mol Sci 2022; 23:ijms23105634. [PMID: 35628443 PMCID: PMC9144929 DOI: 10.3390/ijms23105634] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Revised: 05/14/2022] [Accepted: 05/16/2022] [Indexed: 12/12/2022] Open
Abstract
Sodium-glucose co-transporter 2 inhibitors, also known as gliflozins, were developed as a novel class of anti-diabetic agents that promote glycosuria through the prevention of glucose reabsorption in the proximal tubule by sodium-glucose co-transporter 2. Beyond the regulation of glucose homeostasis, they resulted as being effective in different clinical trials in patients with heart failure, showing a strong cardio-renal protective effect in diabetic, but also in non-diabetic patients, which highlights the possible existence of other mechanisms through which gliflozins could be exerting their action. So far, different gliflozins have been approved for their therapeutic use in T2DM, heart failure, and diabetic kidney disease in different countries, all of them being diseases that have in common a deregulation of the inflammatory process associated with the pathology, which perpetuates and worsens the disease. This inflammatory deregulation has been observed in many other diseases, which led the scientific community to have a growing interest in the understanding of the biological processes that lead to or control inflammation deregulation in order to be able to identify potential therapeutic targets that could revert this situation and contribute to the amelioration of the disease. In this line, recent studies showed that gliflozins also act as an anti-inflammatory drug, and have been proposed as a useful strategy to treat other diseases linked to inflammation in addition to cardio-renal diseases, such as diabetes, obesity, atherosclerosis, or non-alcoholic fatty liver disease. In this work, we will review recent studies regarding the role of the main sodium-glucose co-transporter 2 inhibitors in the control of inflammation.
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RXRα agonist bexarotene attenuates radiation-induced skin injury by relieving oxidative stress. RADIATION MEDICINE AND PROTECTION 2022. [DOI: 10.1016/j.radmp.2022.04.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
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SGLT-2 Inhibitors in NAFLD: Expanding Their Role beyond Diabetes and Cardioprotection. Int J Mol Sci 2022; 23:ijms23063107. [PMID: 35328527 PMCID: PMC8953901 DOI: 10.3390/ijms23063107] [Citation(s) in RCA: 86] [Impact Index Per Article: 28.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Revised: 03/03/2022] [Accepted: 03/09/2022] [Indexed: 12/16/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is an ‘umbrella’ term, comprising a spectrum ranging from benign, liver steatosis to non-alcoholic steatohepatitis, liver fibrosis and eventually cirrhosis and hepatocellular carcinoma. NAFLD has evolved as a major health problem in recent years. Discovering ways to prevent or delay the progression of NAFLD has become a global focus. Lifestyle modifications remain the cornerstone of NAFLD treatment, even though various pharmaceutical interventions are currently under clinical trial. Among them, sodium-glucose co-transporter type-2 inhibitors (SGLT-2i) are emerging as promising agents. Processes regulated by SGLT-2i, such as endoplasmic reticulum (ER) and oxidative stress, low-grade inflammation, autophagy and apoptosis are all implicated in NAFLD pathogenesis. In this review, we summarize the current understanding of the NAFLD pathophysiology, and specifically focus on the potential impact of SGLT-2i in NAFLD development and progression, providing current evidence from in vitro, animal and human studies. Given this evidence, further mechanistic studies would advance our understanding of the exact mechanisms underlying the pathogenesis of NAFLD and the potential beneficial actions of SGLT-2i in the context of NAFLD treatment.
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Yang H, Su G, Chen X. Pantoprazole promotes the sensitivity of cervical cancer cells to cisplatin by inhibiting cisplatin-induced autophagy. J Cancer Res Ther 2022; 18:362-369. [DOI: 10.4103/jcrt.jcrt_968_21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
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