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Zhang PP, Li L, Qu HY, Chen GY, Xie MZ, Chen YK. Traditional Chinese medicine in the treatment of Helicobacter pylori-related gastritis: The mechanisms of signalling pathway regulations. World J Gastroenterol 2025; 31:96582. [PMID: 39839895 PMCID: PMC11684169 DOI: 10.3748/wjg.v31.i3.96582] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2024] [Revised: 09/29/2024] [Accepted: 12/02/2024] [Indexed: 12/20/2024] Open
Abstract
Helicobacter pylori-associated gastritis (HPAG) is a common condition of the gastrointestinal tract. However, extensive and long-term antibiotic use has resulted in numerous adverse effects, including increased resistance, gastrointestinal dysfunction, and increased recurrence rates. When these concerns develop, traditional Chinese medicine (TCM) may have advantages. TCM is based on the concept of completeness and aims to eliminate pathogens and strengthen the body. It has the potential to prevent this condition while also boosting the rate of Helicobacter pylori eradication. This review elaborates on the mechanism of TCM treatment for HPAG based on cellular signalling pathways, which reflects the flexibility of TCM in treating diseases and the advantages of multi-level, multi-pathway, and multi-target treatments for HPAG.
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Affiliation(s)
- Pei-Pei Zhang
- School of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha 410200, Hunan Province, China
- Hunan Engineering Technology Research Center for Medicinal and Functional Food, Hunan University of Chinese Medicine, Changsha 410200, Hunan Province, China
- Key Laboratory of Traditional Chinese Medicine Heart and Lung Syndrome Differentiation and Medicated Diet and Dietotherapy, Hunan University of Chinese Medicine, Changsha 410200, Hunan Province, China
| | - Liang Li
- School of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha 410200, Hunan Province, China
- Hunan Engineering Technology Research Center for Medicinal and Functional Food, Hunan University of Chinese Medicine, Changsha 410200, Hunan Province, China
- Key Laboratory of Traditional Chinese Medicine Heart and Lung Syndrome Differentiation and Medicated Diet and Dietotherapy, Hunan University of Chinese Medicine, Changsha 410200, Hunan Province, China
| | - Hao-Yu Qu
- Hunan Engineering Technology Research Center for Medicinal and Functional Food, Hunan University of Chinese Medicine, Changsha 410200, Hunan Province, China
- School of Informatics, Hunan University of Chinese Medicine, Changsha 410208, Hunan Province, China
| | - Guang-Yu Chen
- School of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha 410200, Hunan Province, China
- Hunan Engineering Technology Research Center for Medicinal and Functional Food, Hunan University of Chinese Medicine, Changsha 410200, Hunan Province, China
- Key Laboratory of Traditional Chinese Medicine Heart and Lung Syndrome Differentiation and Medicated Diet and Dietotherapy, Hunan University of Chinese Medicine, Changsha 410200, Hunan Province, China
| | - Meng-Zhou Xie
- School of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha 410200, Hunan Province, China
- Hunan Engineering Technology Research Center for Medicinal and Functional Food, Hunan University of Chinese Medicine, Changsha 410200, Hunan Province, China
- Key Laboratory of Traditional Chinese Medicine Heart and Lung Syndrome Differentiation and Medicated Diet and Dietotherapy, Hunan University of Chinese Medicine, Changsha 410200, Hunan Province, China
| | - Yan-Kun Chen
- School of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha 410200, Hunan Province, China
- Precision Medicine Research and Development Center, Zhuhai Institute of Advanced Technology, Chinese Academy of Sciences, Zhuhai 519000, Guangdong Province, China
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YektaKooshali MH, SobhZahedi M, Razavi Tousi SMT, Hamidi M, Modiri L. Astaxanthin-loaded PLGA nanoparticles inhibit survival of MKN-45 gastric cancer cell line by modulating JAK2/STAT3/mTOR/PI3K pathway. BMC Cancer 2025; 25:44. [PMID: 39780129 PMCID: PMC11715247 DOI: 10.1186/s12885-024-13401-4] [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: 06/09/2024] [Accepted: 12/26/2024] [Indexed: 01/11/2025] Open
Abstract
BACKGROUND/AIMS Gastric cancer (GC) is a significant global health issue with high incidence rates and poor prognoses, ranking among the top prevalent cancers worldwide. Due to undesirable side effects and drug resistance, there is a pressing need for the development of novel therapeutic strategies. Understanding the interconnectedness of the JAK2/STAT3/mTOR/PI3K pathway in tumorigenesis and the role of Astaxanthin (ASX), a red ketocarotenoid member of xanthophylls and potent antioxidant and anti-tumor activity, can be effective for cancer treatments. This study aimed to investigate the effect of ASX-loaded nanoparticles on the survival of MKN-45 GC cells and the expression of JAK2/STAT3/mTOR/PI3K, offering insights into potential targeted therapies for GC. METHODS The growth status and survival rate of MKN-45 GC cell lines were determined using the 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide(MTT) assay, and the optimal IC50 concentration of ASX, PLGA, and ASX + PLGA was estimated. Also, the clonogenic assay was performed to determine the reproductive power and colony formation of under-treatment cells. Apoptosis and necroptosis of cells were evaluated using acridine orange (AO) staining. The western blot assessed the protein's level of expression and intensity (JAK2/STAT3/mTOR/PI3K). SPSS version 16 software was used for statistical analysis, P-value was considered lower than 0.05. RESULTS Based on the results, increasing concentrations of ASX and ASX + PLGA led to a decrease in the viability of MKN-45 cells compared to the control group (P < 0.001). This value was lower for cells treated with ASX + PLGA (P = 0.003). The IC50 values for each of the studied groups (ASX, ASX + PLGA, and PLGA) were 81.45 µg/ml, 51.45 µg/ml, and 3.383 mg/ml, respectively. The levels of expression and intensity of JAK2, STAT3, and mTOR proteins in the Western blotting analysis under ASX + PLGA treatment increased compared to the control group. Conversely, the levels of expression and intensity of P-JAK2, P-STAT3, and P-mTOR proteins in the ASX + PLGA treatment group decreased by 41%, 34%, 37%, and 43%, respectively, compared to the control group. Protein expression levels and intensities of JAK2, STAT3, and mTOR significantly increased when treated with PLGA, ASX, and ASX + PLGA compared to the control group (P < 0.001). CONCLUSIONS The encapsulation of ASX in PLGA nanoparticles enhances drug stability, enables targeted delivery, and allows for sustained release. This study highlights the therapeutic potential of ASX-loaded nanoparticles in targeting JAK2/STAT3/mTOR/PI3K pathways in GC treatment. Further research is needed to understand the mechanisms and clinical applications of this novel immunotherapy strategy.
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Affiliation(s)
- Mohammad Hossein YektaKooshali
- Medical Biotechnology Research Center, School of Paramedicine, Guilan University of Medical Sciences, Rasht, Iran
- Department of Cellular and Molecular Biology, Lahijan Branch, Islamic Azad University, Lahijan, Iran
| | - Mahdieh SobhZahedi
- Department of Biology, Faculty of Science, University of Guilan, Rasht, Iran.
| | | | - Masoud Hamidi
- Université libre de Bruxelles (ULB), École polytechnique de Bruxelles - 3BIO-BioMatter, Avenue F.D. Roosevelt, 50 - CP 165/61, Brussels, 1050, Belgium
| | - Leila Modiri
- Department of Cellular and Molecular Biology, Lahijan Branch, Islamic Azad University, Lahijan, Iran.
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Blaheta RA, Han J, Oppermann E, Bechstein WO, Burkhard K, Haferkamp A, Rieger MA, Malkomes P. Transglutaminase 2 promotes epithelial-to-mesenchymal transition by regulating the expression of matrix metalloproteinase 7 in colorectal cancer cells via the MEK/ERK signaling pathway. Biochim Biophys Acta Mol Basis Dis 2025; 1871:167538. [PMID: 39389321 DOI: 10.1016/j.bbadis.2024.167538] [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: 05/06/2024] [Revised: 09/19/2024] [Accepted: 10/04/2024] [Indexed: 10/12/2024]
Abstract
Tissue transglutaminase 2 (TGM2) and matrix metalloproteinase 7 (MMP7) are suggested to be involved in cancer development and progression, however, their specific role in colon cancer remains elusive. The present study investigated whether TGM2 and MMP7 influence epithelial-mesenchymal-transition (EMT) processes of colon cancer cells. TGM2 was either overexpressed or knocked down in SW480 and HCT-116 cells, and MMP7 expression and activity analyzed. Conversely, MMP7 was silenced and its correlation with TGM2 expression and activity examined. Co-immunoprecipitation served to evaluate TGM2-MMP7-interaction. TGM2 and MMP7 expression were correlated with invasion, migration, EMT marker expression (E-cadherin, N-cadherin, Slug, Snail), and ERK/MEK signaling. TGM2 overexpression enhanced MMP7 expression and activity, promoted cell invasion, migration and EMT, characterized by increased N-cadherin and Snail/Slug expression. TGM2 knockdown resulted in the opposite effects. Knocking down MMP7 was associated with reduced TGM2 protein expression, cell invasion and migration. Down-regulation of MMP7 diminished ERK/MEK signaling, whereas its up-regulation activated this pathway. The ERK-inhibitor GDC-0994 blocked phosphorylation of MEK/ERK and suppressed TGM2 and MMP7. TGM2 communicates with MMP7 in colon cancer cells forces cell migration and invasion by the MEK/ERK signaling pathway and triggers EMT. Inhibiting TGM2 could thus offer new therapeutic options to treat patients with colon cancer, particularly to prevent metastatic progression.
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Affiliation(s)
- Roman A Blaheta
- University Medical Center Mainz, Dept. of Urology and Pediatric Urology, 55131 Mainz, Germany.
| | - Jiaoyan Han
- Department for General, Visceral, Transplant and Thoracic Surgery, Goethe University, 60590 Frankfurt am Main, Germany
| | - Elsie Oppermann
- Department for General, Visceral, Transplant and Thoracic Surgery, Goethe University, 60590 Frankfurt am Main, Germany
| | - Wolf Otto Bechstein
- Department for General, Visceral, Transplant and Thoracic Surgery, Goethe University, 60590 Frankfurt am Main, Germany
| | - Katrin Burkhard
- Department for General, Visceral, Transplant and Thoracic Surgery, Goethe University, 60590 Frankfurt am Main, Germany; Current affiliation: Department of Legal Medicine, University of Saarland Medical School, 66421 Homburg, Germany
| | - Axel Haferkamp
- University Medical Center Mainz, Dept. of Urology and Pediatric Urology, 55131 Mainz, Germany
| | - Michael A Rieger
- Department of Medicine II, Hematology/Oncology, Goethe University, 60590 Frankfurt am Main, Germany; Cardio-Pulmonary-Institute, 60590 Frankfurt am Main, Germany; Frankfurt Cancer Institute, 60590 Frankfurt am Main, Germany; German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
| | - Patrizia Malkomes
- Department for General, Visceral, Transplant and Thoracic Surgery, Goethe University, 60590 Frankfurt am Main, Germany; Frankfurt Cancer Institute, 60590 Frankfurt am Main, Germany; German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
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Utpal BK, Dehbia Z, Zidan BMRM, Sweilam SH, Singh LP, Arunkumar MS, Sona M, Panigrahy UP, Keerthana R, Mandadi SR, Rab SO, Alshehri MA, Koula D, Suliman M, Nafady MH, Emran TB. Carotenoids as modulators of the PI3K/Akt/mTOR pathway: innovative strategies in cancer therapy. Med Oncol 2024; 42:4. [PMID: 39549201 DOI: 10.1007/s12032-024-02551-x] [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: 09/20/2024] [Accepted: 10/29/2024] [Indexed: 11/18/2024]
Abstract
Cancer progression is primarily driven by the uncontrolled activation of cellular signaling pathways, with the PI3K/Akt/mTOR (PAMT) pathway playing a central role. This pathway significantly contributes to the proliferation and survival of cancer cells, and its hyperactivity is a major challenge in managing several types of malignancies. This article delves into the promising potential of carotenoids, natural pigments found in abundance in fruits and vegetables, as a novel therapeutic strategy for cancer treatment. By specifically targeting and inhibiting the PAMT pathway, carotenoids may effectively disrupt the growth and survival of cancer cells. The article examines the complex mechanisms underlying these interactions and highlights the obstacles faced in cancer treatment. It proposes a compelling approach to developing therapies that leverage natural products to target this critical pathway, offering a fresh perspective on cancer treatment. Further research is essential to enhance the therapeutic efficacy of these compounds.
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Affiliation(s)
- Biswajit Kumar Utpal
- Department of Pharmacy, Faculty of Health and Life Sciences, Daffodil International University, Dhaka, 1207, Bangladesh
| | - Zerrouki Dehbia
- Laboratory of AgroBiotechnology and Nutrition in Semi Arid Zones, Faculty of Nature and Life Sciences, University of Ibn Khaldoun, Tiaret, Algeria
| | - B M Redwan Matin Zidan
- Department of Pharmacy, Faculty of Pharmacy, University of Dhaka, Dhaka, 1000, Bangladesh
| | - Sherouk Hussein Sweilam
- Department of Pharmacognosy, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj, 11942, Saudi Arabia
- Department of Pharmacognosy, Faculty of Pharmacy, Egyptian Russian University, Cairo-Suez Road, Badr City, Cairo, 11829, Egypt
| | - Laliteshwar Pratap Singh
- Department of Pharmaceutical Chemistry, Narayan Institute of Pharmacy, Gopal Narayan Singh University, Sasaram (Rohtas) Bihar, Jamuhar, 821305, India
| | - M S Arunkumar
- Faculty of Pharmacy, Karpagam Academy of Higher Education, Coimbatore, Tamil Nadu, 641021, India
| | - M Sona
- Faculty of Pharmacy, Karpagam Academy of Higher Education, Coimbatore, Tamil Nadu, 641021, India
| | - Uttam Prasad Panigrahy
- Faculty of Pharmaceutical Science, Assam Down Town University, Gandhi Nagar, Sankar Madhab Path, Panikhaiti, Guwahati, Assam, India
| | - R Keerthana
- Faculty of Pharmacy, Karpagam Academy of Higher Education, Coimbatore, Tamil Nadu, 641021, India
| | - Sandhya Rani Mandadi
- Department of Pharmaceutics, Vishnu Institute of Pharmaceutical Education and Research, Tuljaraopet, Telangana , 502313, India
| | - Safia Obaidur Rab
- Department of Clinical Laboratory Sciences, College of Applied Medical Science, King Khalid University, Abha, Saudi Arabia
| | - Mohammed Ali Alshehri
- Department of Biology, Faculty of Science, University of Tabuk, Tabuk, 71491, Saudi Arabia
| | - Doukani Koula
- Laboratory of AgroBiotechnology and Nutrition in Semi Arid Zones, Faculty of Nature and Life Sciences, University of Ibn Khaldoun, Tiaret, Algeria
- Laboratory of Animal Production Sciences and Techniques, University of Abdelhamid Ibn Badis, Mostaganem, Algeria
| | - Muath Suliman
- Department of Clinical Laboratory Sciences, College of Applied Medical Science, King Khalid University, Abha, Saudi Arabia
| | - Mohamed H Nafady
- Faculty of Applied Health Science Technology, Misr University for Science and Technology, Giza, 12568, Egypt.
| | - Talha Bin Emran
- Department of Pharmacy, Faculty of Health and Life Sciences, Daffodil International University, Dhaka, 1207, Bangladesh
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Katare PB, Dalmao-Fernandez A, Mengeste AM, Navabakbar F, Hamarsland H, Ellefsen S, Berge RK, Bakke HG, Nyman TA, Kase ET, Rustan AC, Thoresen GH. Krill oil supplementation in vivo promotes increased fuel metabolism and protein synthesis in cultured human skeletal muscle cells. Front Nutr 2024; 11:1452768. [PMID: 39555189 PMCID: PMC11565515 DOI: 10.3389/fnut.2024.1452768] [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: 06/21/2024] [Accepted: 10/07/2024] [Indexed: 11/19/2024] Open
Abstract
Introduction Krill oil is a dietary supplement derived from Antarctic krill; a small crustacean found in the ocean. Krill oil is a rich source of omega-3 fatty acids, specifically eicosapentaenoic acid and docosahexaenoic acid, as well as the antioxidant astaxanthin. The aim of this study was to investigate the effects of krill oil supplementation, compared to placebo oil (high oleic sunflower oil added astaxanthin), in vivo on energy metabolism and substrate turnover in human skeletal muscle cells. Methods Skeletal muscle cells (myotubes) were obtained before and after a 7-week krill oil or placebo oil intervention, and glucose and oleic acid metabolism and leucine accumulation, as well as effects of different stimuli in vitro, were studied in the myotubes. The functional data were combined with proteomic and transcriptomic analyses. Results In vivo intervention with krill oil increased oleic acid oxidation and leucine accumulation in skeletal muscle cells, however no effects were observed on glucose metabolism. The krill oil-intervention-induced increase in oleic acid oxidation correlated negatively with changes in serum low-density lipoprotein (LDL) concentration. In addition, myotubes were also exposed to krill oil in vitro. The in vitro study revealed that 24 h of krill oil treatment increased both glucose and oleic acid metabolism in myotubes, enhancing energy substrate utilization. Transcriptomic analysis comparing myotubes obtained before and after krill oil supplementation identified differentially expressed genes associated with e.g., glycolysis/gluconeogenesis, metabolic pathways and calcium signaling pathway, while proteomic analysis demonstrated upregulation of e.g., LDL-receptor in myotubes obtained after the krill oil intervention. Conclusion These findings suggest that krill oil intervention promotes increased fuel metabolism and protein synthesis in human skeletal muscle cells, with potential implications for metabolic health.
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Affiliation(s)
- Parmeshwar B. Katare
- Section for Pharmacology and Pharmaceutical Biosciences, Department of Pharmacy, University of Oslo, Oslo, Norway
| | - Andrea Dalmao-Fernandez
- Section for Pharmacology and Pharmaceutical Biosciences, Department of Pharmacy, University of Oslo, Oslo, Norway
| | - Abel M. Mengeste
- Section for Pharmacology and Pharmaceutical Biosciences, Department of Pharmacy, University of Oslo, Oslo, Norway
| | - Farnaz Navabakbar
- Section for Pharmacology and Pharmaceutical Biosciences, Department of Pharmacy, University of Oslo, Oslo, Norway
| | - Håvard Hamarsland
- Section for Health and Exercise Physiology, Faculty of Social and Health Sciences, Inland Norway University of Applied Sciences, Lillehammer, Norway
| | - Stian Ellefsen
- Section for Health and Exercise Physiology, Faculty of Social and Health Sciences, Inland Norway University of Applied Sciences, Lillehammer, Norway
- Innlandet Hospital Trust, Lillehammer, Norway
| | - Rolf K. Berge
- Department of Heart Disease, Haukeland University Hospital, Bergen, Norway
- Department of Clinical Sciences, University of Bergen, Bergen, Norway
| | - Hege G. Bakke
- Section for Pharmacology and Pharmaceutical Biosciences, Department of Pharmacy, University of Oslo, Oslo, Norway
| | - Tuula Anneli Nyman
- Department of Immunology, Institute of Clinical Medicine, Oslo University Hospital, University of Oslo, Oslo, Norway
| | - Eili Tranheim Kase
- Section for Pharmacology and Pharmaceutical Biosciences, Department of Pharmacy, University of Oslo, Oslo, Norway
| | - Arild C. Rustan
- Section for Pharmacology and Pharmaceutical Biosciences, Department of Pharmacy, University of Oslo, Oslo, Norway
| | - G. Hege Thoresen
- Section for Pharmacology and Pharmaceutical Biosciences, Department of Pharmacy, University of Oslo, Oslo, Norway
- Department of Pharmacology, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
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An TY, Hu QM, Ni P, Hua YQ, Wang D, Duan GC, Chen SY, Jia B. N6-methyladenosine modification of hypoxia-inducible factor-1α regulates Helicobacter pylori-associated gastric cancer via the PI3K/AKT pathway. World J Gastrointest Oncol 2024; 16:3270-3283. [PMID: 39072157 PMCID: PMC11271789 DOI: 10.4251/wjgo.v16.i7.3270] [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: 03/10/2024] [Revised: 05/09/2024] [Accepted: 05/20/2024] [Indexed: 07/12/2024] Open
Abstract
BACKGROUND Helicobacter pylori (H. pylori) colonizes the human gastric mucosa and is implicated in the development of gastric cancer (GC). The tumor microenvironment is characterized by hypoxia, where hypoxia-inducible factor-1α (HIF-1α) plays a key role as a transcription factor, but the mechanisms underlying H. pylori-induced HIF-1α expression and carcinogenesis remain unclear. AIM To explore the underlying mechanism of H. pylori-induced HIF-1α expression in promoting the malignant biological behavior of gastric epithelial cells (GES-1). METHODS The study was conducted with human GES-1 cells in vitro. Relative protein levels of methyltransferase-like protein 14 (METTL14), HIF-1α, main proteins of the PI3K/AKT pathway, epithelial-mesenchymal transition (EMT) biomarkers, and invasion indicators were detected by Western blot. Relative mRNA levels of METTL14 and HIF-1α were detected by quantitative reverse transcription-polymerase chain reaction. mRNA stability was evaluated using actinomycin D, and the interaction between METTL14 and HIF-1α was confirmed by immunofluorescence staining. Cell proliferation and migration were evaluated by cell counting kit-8 assay and wound healing assay, respectively. RESULTS H. pylori promoted HIF-1α expression and activated the PI3K/AKT pathway. Notably, METTL14 was downregulated in H. pylori-infected gastric mucosal epithelial cells and positively regulated HIF-1α expression. Functional experiments showed that the overexpression of HIF-1α or knockdown of METTL14 enhanced the activity of the PI3K/AKT pathway, thereby driving a series of malignant transformation, such as EMT and cell proliferation, migration, and invasion. By contrast, the knockdown of HIF-1α or overexpression of METTL14 had an opposite effect. CONCLUSION H. pylori-induced underexpression of METTL14 promotes the translation of HIF-1α and accelerates tumor progression by activating the PI3K/AKT pathway. These results provide novel insights into the carcinogenesis of GC.
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Affiliation(s)
- Tong-Yan An
- Department of Epidemiology, College of Public Health, Zhengzhou University, Zhengzhou 450001, Henan Province, China
| | - Quan-Man Hu
- Department of Epidemiology, College of Public Health, Zhengzhou University, Zhengzhou 450001, Henan Province, China
| | - Peng Ni
- Department of Epidemiology, College of Public Health, Zhengzhou University, Zhengzhou 450001, Henan Province, China
| | - Yan-Qiao Hua
- Department of Epidemiology, College of Public Health, Zhengzhou University, Zhengzhou 450001, Henan Province, China
| | - Di Wang
- Department of Epidemiology, College of Public Health, Zhengzhou University, Zhengzhou 450001, Henan Province, China
| | - Guang-Cai Duan
- Department of Epidemiology, College of Public Health, Zhengzhou University, Zhengzhou 450001, Henan Province, China
| | - Shuai-Yin Chen
- Department of Epidemiology, College of Public Health, Zhengzhou University, Zhengzhou 450001, Henan Province, China
| | - Bin Jia
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
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Cunha FFMD, Tonon AP, Machado F, Travassos LR, Grazzia N, Possatto JF, Sant'ana AKCD, Lopes RDM, Rodrigues T, Miguel DC, Gadelha FR, Arruda DC. Astaxanthin induces autophagy and apoptosis in murine melanoma B16F10-Nex2 cells and exhibits antitumor activity in vivo. J Chemother 2024; 36:222-237. [PMID: 37800867 DOI: 10.1080/1120009x.2023.2264585] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Accepted: 09/22/2023] [Indexed: 10/07/2023]
Abstract
Countless efforts have been made to prevent and suppress the formation and spread of melanoma. Natural astaxanthin (AST; extracted from the alga Haematococcus pluvialis) showed an antitumor effect on various cancer cell lines due to its interaction with the cell membrane. This study aimed to characterize the antitumor effect of AST against B16F10-Nex2 murine melanoma cells using cell viability assay and evaluate its mechanism of action using electron microscopy, western blotting analysis, terminal deoxynucleotidyl transferase dUTP nick-end labelling (TUNEL) assay, and mitochondrial membrane potential determination. Astaxanthin exhibited a significant cytotoxic effect in murine melanoma cells with features of apoptosis and autophagy. Astaxanthin also decreased cell migration and invasion in vitro assays at subtoxic concentrations. In addition, assays were conducted in metastatic cancer models in mice where AST significantly decreased the development of pulmonary nodules. In conclusion, AST has cytotoxic effect in melanoma cells and inhibits cell migration and invasion, indicating a promising use in cancer treatment.
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Affiliation(s)
| | - Angela Pedroso Tonon
- Instituto de Física e Biotecnologia, Universidade de São Paulo, São Carlos, Brazil
- Institute of Environmental Science and Technology, Autonomous University of Barcelona, Barcelona, Spain
| | - Fabricio Machado
- Departamento de Microbiologia, Imunologia e Parasitologia, Universidade Federal de São Paulo (UNIFESP), São Paulo, Brazil
| | - Luis Rodolpho Travassos
- Departamento de Microbiologia, Imunologia e Parasitologia, Universidade Federal de São Paulo (UNIFESP), São Paulo, Brazil
| | - Nathalia Grazzia
- Instituto de Biologia, Universidade Estadual de Campinas (UNICAMP), Campinas, Brazil
| | | | | | - Rayssa de Mello Lopes
- Centro de Ciências Naturais e Humanas (CCNH), Universidade Federal do ABC, UFABC, Santo André, Brazil
| | - Tiago Rodrigues
- Centro de Ciências Naturais e Humanas (CCNH), Universidade Federal do ABC, UFABC, Santo André, Brazil
| | - Danilo Ciccone Miguel
- Instituto de Biologia, Universidade Estadual de Campinas (UNICAMP), Campinas, Brazil
| | | | - Denise Costa Arruda
- Núcleo Integrado de Biotecnologia (NIB), Universidade de Mogi das Cruzes, UMC, Mogi das Cruzes, Brazil
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8
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Zhang Y, Zhao H, Fu X, Wang K, Yang J, Zhang X, Wang H. The role of hydrogen sulfide regulation of pyroptosis in different pathological processes. Eur J Med Chem 2024; 268:116254. [PMID: 38377826 DOI: 10.1016/j.ejmech.2024.116254] [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: 10/03/2023] [Revised: 01/31/2024] [Accepted: 02/15/2024] [Indexed: 02/22/2024]
Abstract
Pyroptosis is one kind of programmed cell death in which the cell membrane ruptures and subsequently releases cell contents and pro-inflammatory cytokines including IL-1β and IL-18. Pyroptosis is caused by many types of pathological stimuli, such as hyperglycemia (HG), oxidative stress, and inflammation, and is mediated by gasdermin (GSDM) protein family. Increasing evidence indicates that pyroptosis plays an important role in multiple diseases, such as cancer, kidney diseases, inflammatory diseases, and cardiovascular diseases. Therefore, the regulation of pyroptosis is crucial for the occurrence, development, and treatment of many diseases. Hydrogen sulfide (H2S) is a biologically active gasotransmitter following carbon monoxide (CO) and nitrogen oxide (NO) in mammalian tissues. So far, three enzymes, including 3-mercaptopyruvate sulphurtransferase (3-MST), cystathionine γ- Lyase (CSE), and Cystine β-synthesis enzyme (CBS), have been found to catalyze the production of endogenous H2S in mammals. H2S has been reported to have multiple biological functions including anti-inflammation, anti-oxidative stress, anti-apoptosis and so on. Hence, H2S is involved in various physiological and pathological processes. In recent years, many studies have demonstrated that H2S plays a critical role by regulating pyroptosis in various pathological processes, such as ischemia-reperfusion injury, alcoholic liver disease, and diabetes cardiomyopathy. However, the relevant mechanism has not been completely understood. Therefore, elucidating the mechanism by which H2S regulates pyroptosis in diseases will help understand the pathogenesis of multiple diseases and provide important new avenues for the treatment of many diseases. Here, we reviewed the progress of H2S regulation of pyroptosis in different pathological processes, and analyzed the molecular mechanism in detail to provide a theoretical reference for future related research.
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Affiliation(s)
- Yanting Zhang
- School of Basic Medical Sciences, Henan University, Kaifeng, Henan, 475004, China; School of Clinical Medicine, Henan University, Kaifeng, Henan, 475004, China
| | - Huijie Zhao
- Institute of Chronic Disease Risks Assessment, Henan University, Jinming Avenue, Kaifeng, 475004, China
| | - Xiaodi Fu
- School of Basic Medical Sciences, Henan University, Kaifeng, Henan, 475004, China
| | - Kexiao Wang
- School of Clinical Medicine, Henan University, Kaifeng, Henan, 475004, China
| | - Jiahao Yang
- School of Clinical Medicine, Henan University, Kaifeng, Henan, 475004, China
| | | | - Honggang Wang
- School of Basic Medical Sciences, Henan University, Kaifeng, Henan, 475004, China.
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Morgos DT, Stefani C, Miricescu D, Greabu M, Stanciu S, Nica S, Stanescu-Spinu II, Balan DG, Balcangiu-Stroescu AE, Coculescu EC, Georgescu DE, Nica RI. Targeting PI3K/AKT/mTOR and MAPK Signaling Pathways in Gastric Cancer. Int J Mol Sci 2024; 25:1848. [PMID: 38339127 PMCID: PMC10856016 DOI: 10.3390/ijms25031848] [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: 12/21/2023] [Revised: 01/26/2024] [Accepted: 01/31/2024] [Indexed: 02/12/2024] Open
Abstract
Gastric cancer (GC) is the fourth leading cause of death worldwide, with more than 1 million cases diagnosed every year. Helicobacter pylori represents the main risk factor, being responsible for 78% of the cases. Increased amounts of salt, pickled food, red meat, alcohol, smoked food, and refined sugars negatively affect the stomach wall, contributing to GC development. Several gene mutations, including PIK3CA, TP53, ARID1A, CDH1, Ras, Raf, and ERBB3 are encountered in GC pathogenesis, leading to phosphatidylinositol 3-kinase (PI3K) protein kinase B (AKT)/mammalian target of rapamycin (mTOR)-PI3K/AKT/mTOR-and mitogen-activated protein kinase (MAPK) signaling pathway activation and promoting tumoral activity. Helicobacter pylori, growth factors, cytokines, hormones, and oxidative stress also activate both pathways, enhancing GC development. In clinical trials, promising results have come from monoclonal antibodies such as trastuzumab and ramucirumab. Dual inhibitors targeting the PI3K/AKT/mTOR and MAPK signaling pathways were used in vitro studies, also with promising results. The main aim of this review is to present GC incidence and risk factors and the dysregulations of the two protein kinase complexes together with their specific inhibitors.
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Affiliation(s)
- Diana-Theodora Morgos
- Discipline of Anatomy, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania;
| | - Constantin Stefani
- Department I of Family Medicine and Clinical Base, “Dr. Carol Davila” Central Military Emergency University Hospital, 010825 Bucharest, Romania
| | - Daniela Miricescu
- Discipline of Biochemistry, Faculty of Dentistry, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania;
| | - Maria Greabu
- Discipline of Biochemistry, Faculty of Dentistry, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania;
| | - Silviu Stanciu
- Department of Internal Medicine and Gastroenterology, Carol Davila University of Medicine and Pharmacy, Central Military Emergency University Hospital, 010825 Bucharest, Romania;
| | - Silvia Nica
- Emergency Discipline, University Hospital of Bucharest, 050098 Bucharest, Romania;
| | - Iulia-Ioana Stanescu-Spinu
- Discipline of Physiology, Faculty of Dentistry, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania; (I.-I.S.-S.); (D.G.B.); (A.-E.B.-S.)
| | - Daniela Gabriela Balan
- Discipline of Physiology, Faculty of Dentistry, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania; (I.-I.S.-S.); (D.G.B.); (A.-E.B.-S.)
| | - Andra-Elena Balcangiu-Stroescu
- Discipline of Physiology, Faculty of Dentistry, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania; (I.-I.S.-S.); (D.G.B.); (A.-E.B.-S.)
| | - Elena-Claudia Coculescu
- Discipline of Oral Pathology, Faculty of Dentistry, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania;
| | - Dragos-Eugen Georgescu
- Department of General Surgery, Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, 50474 Bucharest, Romania;
- Department of General Surgery, “Dr. Ion Cantacuzino” Clinical Hospital, 020475 Bucharest, Romania
| | - Remus Iulian Nica
- Central Military Emergency University Hospital “Dr. Carol Davila”, 010825 Bucharest, Romania;
- Discipline of General Surgery, Faculty of Midwifery and Nursing, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania
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10
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Gonzalez-Avila G, Sommer B, Flores-Soto E, Aquino-Galvez A. Hypoxic Effects on Matrix Metalloproteinases' Expression in the Tumor Microenvironment and Therapeutic Perspectives. Int J Mol Sci 2023; 24:16887. [PMID: 38069210 PMCID: PMC10707261 DOI: 10.3390/ijms242316887] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2023] [Revised: 11/14/2023] [Accepted: 11/18/2023] [Indexed: 12/18/2023] Open
Abstract
The tumor microenvironment (TME) is characterized by an acidic pH and low oxygen concentrations. Hypoxia induces neoplastic cell evasion of the immune surveillance, rapid DNA repair, metabolic reprogramming, and metastasis, mainly as a response to the hypoxic inducible factors (HIFs). Likewise, cancer cells increase matrix metalloproteinases' (MMPs) expression in response to TME conditions, allowing them to migrate from the primary tumor to different tissues. Since HIFs and MMPs are augmented in the hypoxic TME, it is easy to consider that HIFs participate directly in their expression regulation. However, not all MMPs have a hypoxia response element (HRE)-HIF binding site. Moreover, different transcription factors and signaling pathways activated in hypoxia conditions through HIFs or in a HIF-independent manner participate in MMPs' transcription. The present review focuses on MMPs' expression in normal and hypoxic conditions, considering HIFs and a HIF-independent transcription control. In addition, since the hypoxic TME causes resistance to anticancer conventional therapy, treatment approaches using MMPs as a target alone, or in combination with other therapies, are also discussed.
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Affiliation(s)
- Georgina Gonzalez-Avila
- Laboratorio de Oncología Biomédica, Instituto Nacional de Enfermedades Respiratorias “Ismael Cosío Villegas”, Calzada de Tlalpan 4502, Col. Sección XVI, Tlalpan, Ciudad de México 14080, Mexico
| | - Bettina Sommer
- Departamento de Investigación en Hiperreactividad Bronquial, Instituto Nacional de Enfermedades Respiratorias “Ismael Cosío Villegas”, Calzada de Tlalpan 4502, Col. Sección XVI, Tlalpan, Ciudad de México 14080, Mexico;
| | - Edgar Flores-Soto
- Departamento de Farmacología, Facultad de Medicina, Universidad Nacional Autónoma de México, Coyoacán, Ciudad de México 04510, Mexico;
| | - Arnoldo Aquino-Galvez
- Laboratorio de Biología Molecular, Departamento de Fibrosis Pulmonar, Instituto Nacional de Enfermedades Respiratorias “Ismael Cosío Villegas”, Calzada de Tlalpan 4502, Col. Sección XVI, Tlalpan, Ciudad de México 14080, Mexico;
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11
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Sah DK, Arjunan A, Lee B, Jung YD. Reactive Oxygen Species and H. pylori Infection: A Comprehensive Review of Their Roles in Gastric Cancer Development. Antioxidants (Basel) 2023; 12:1712. [PMID: 37760015 PMCID: PMC10525271 DOI: 10.3390/antiox12091712] [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: 07/05/2023] [Revised: 08/14/2023] [Accepted: 08/30/2023] [Indexed: 09/29/2023] Open
Abstract
Gastric cancer (GC) is the fifth most common cancer worldwide and makes up a significant component of the global cancer burden. Helicobacter pylori (H. pylori) is the most influential risk factor for GC, with the International Agency for Research on Cancer classifying it as a Class I carcinogen for GC. H. pylori has been shown to persist in stomach acid for decades, causing damage to the stomach's mucosal lining, altering gastric hormone release patterns, and potentially altering gastric function. Epidemiological studies have shown that eliminating H. pylori reduces metachronous cancer. Evidence shows that various molecular alterations are present in gastric cancer and precancerous lesions associated with an H. pylori infection. However, although H. pylori can cause oxidative stress-induced gastric cancer, with antioxidants potentially being a treatment for GC, the exact mechanism underlying GC etiology is not fully understood. This review provides an overview of recent research exploring the pathophysiology of H. pylori-induced oxidative stress that can cause cancer and the antioxidant supplements that can reduce or even eliminate GC occurrence.
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Affiliation(s)
| | | | - Bora Lee
- Department of Biochemistry, Chonnam National University Medical School, Seoyang Ro 264, Jeonnam, Hwasun 58128, Republic of Korea; (D.K.S.); (A.A.)
| | - Young Do Jung
- Department of Biochemistry, Chonnam National University Medical School, Seoyang Ro 264, Jeonnam, Hwasun 58128, Republic of Korea; (D.K.S.); (A.A.)
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12
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Paramakrishnan N, Lim KG, Paramaswaran Y, Ali N, Waseem M, Shazly GA, Bin Jardan YA, Muthuraman A. Astaxanthin: A Marine Drug That Ameliorates Cerebrovascular-Damage-Associated Alzheimer's Disease in a Zebrafish Model via the Inhibition of Matrix Metalloprotease-13. Mar Drugs 2023; 21:433. [PMID: 37623714 PMCID: PMC10455645 DOI: 10.3390/md21080433] [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: 06/14/2023] [Revised: 07/19/2023] [Accepted: 07/26/2023] [Indexed: 08/26/2023] Open
Abstract
Alzheimer's disease (AD) is a major type of dementia disorder. Common cognitive changes occur as a result of cerebrovascular damage (CVD) via the disruption of matrix metalloproteinase-13 (MMP-13). In diabetic cases, the progress of vascular dementia is faster and the AD rate is higher. Patients with type 2 diabetes are known to have a higher risk of the factor for AD progression. Hence, this study is designed to investigate the role of astaxanthin (AST) in CVD-associated AD in zebrafish via the inhibition of MMP-13 activity. CVD was developed through the intraperitoneal and intracerebral injection of streptozotocin (STZ). The AST (10 and 20 mg/L), donepezil (1 mg/L), and MMP-13 inhibitor (i.e., CL-82198; 10 μM) were exposed for 21 consecutive days in CVD animals. The cognitive changes in zebrafish were evaluated through light and dark chamber tests, a color recognition test, and a T-maze test. The biomarkers of AD pathology were assessed via the estimation of the cerebral extravasation of Evans blue, tissue nitrite, amyloid beta-peptide aggregation, MMP-13 activity, and acetylcholinesterase activity. The results revealed that exposure to AST leads to ameliorative behavioral and biochemical changes. Hence, AST can be used for the management of AD due to its multi-targeted actions, including MMP-13 inhibition.
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Affiliation(s)
| | - Khian Giap Lim
- Pharmacology Unit, Faculty of Pharmacy, AIMST University, Semeling, Bedong 08100, Kedah, Malaysia
| | - Yamunna Paramaswaran
- Pharmacology Unit, Faculty of Pharmacy, AIMST University, Semeling, Bedong 08100, Kedah, Malaysia
| | - Nemat Ali
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia
| | - Mohammad Waseem
- School of Pharmacy, University of Maryland Eastern Shore, Princess Anne, MD 21853, USA
| | - Gamal A. Shazly
- Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
| | - Yousef A. Bin Jardan
- Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
| | - Arunachalam Muthuraman
- Pharmacology Unit, Faculty of Pharmacy, AIMST University, Semeling, Bedong 08100, Kedah, Malaysia
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13
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Zhang S, Wang L, Kang Y, Wu J, Zhang Z. Nanomaterial-based Reactive Oxygen Species Scavengers for Osteoarthritis Therapy. Acta Biomater 2023; 162:1-19. [PMID: 36967052 DOI: 10.1016/j.actbio.2023.03.030] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Revised: 02/17/2023] [Accepted: 03/20/2023] [Indexed: 03/29/2023]
Abstract
Reactive oxygen species (ROS) play distinct but important roles in physiological and pathophysiological processes. Recent studies on osteoarthritis (OA) have suggested that ROS plays a crucial role in its development and progression, serving as key mediators in the degradation of the extracellular matrix, mitochondrial dysfunction, chondrocyte apoptosis, and OA progression. With the continuous development of nanomaterial technology, the ROS-scavenging ability and antioxidant effects of nanomaterials are being explored, with promising results already achieved in OA treatment. However, current research on nanomaterials as ROS scavengers for OA is relatively non-uniform and includes both inorganic and functionalized organic nanomaterials. Although the therapeutic efficacy of nanomaterials has been reported to be conclusive, there is still no uniformity in the timing and potential of their use in clinical practice. This paper reviews the nanomaterials currently used as ROS scavengers for OA treatment, along with their mechanisms of action, with the aim of providing a reference and direction for similar studies, and ultimately promoting the early clinical use of nanomaterials for OA treatment. STATEMENT OF SIGNIFICANCE: Reactive oxygen species (ROS) play an important role in the pathogenesis of osteoarthritis (OA). Nanomaterials serving as promising ROS scavengers have gained increasing attention in recent years. This review provides a comprehensive overview of ROS production and regulation, as well as their role in OA pathogenesis. Furthermore, this review highlights the applications of various types of nanomaterials as ROS scavengers in OA treatment and their mechanisms of action. Finally, the challenges and future prospects of nanomaterial-based ROS scavengers in OA therapy are discussed.
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14
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Nahar L, Al-Groshi A, Kumar A, Sarker SD. Arbutin: Occurrence in Plants, and Its Potential as an Anticancer Agent. MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27248786. [PMID: 36557918 PMCID: PMC9787540 DOI: 10.3390/molecules27248786] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/05/2022] [Revised: 12/07/2022] [Accepted: 12/08/2022] [Indexed: 12/14/2022]
Abstract
Arbutin, a hydroquinone glucoside, has been detected in ca. 50 plant families, especially in the plants of the Asteraceae, Ericaceae, Proteaceae and Rosaceae families. It is one of the most widely used natural skin-whitening agents. In addition to its skin whitening property, arbutin possesses other therapeutically relevant biological properties, e.g., antioxidant, antimicrobial and anti-inflammatory, as well as anticancer potential. This review presents, for the first time, a comprehensive overview of the distribution of arbutin in the plant kingdom and critically appraises its therapeutic potential as an anticancer agent based on the literature published until the end of August 2022, accessed via several databases, e.g., Web of Science, Science Direct, Dictionary of Natural Products, PubMed and Google Scholar. The keywords used in the search were arbutin, cancer, anticancer, distribution and hydroquinone. Published outputs suggest that arbutin has potential anticancer properties against bladder, bone, brain, breast, cervix, colon, liver, prostate and skin cancers and a low level of acute or chronic toxicity.
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Affiliation(s)
- Lutfun Nahar
- Laboratory of Growth Regulators, Palacký University and Institute of Experimental Botany, The Czech Academy of Sciences, Šlechtitelů 27, 78371 Olomouc, Czech Republic
- Correspondence: or (L.N.); (S.D.S.)
| | - Afaf Al-Groshi
- Centre for Natural Products Discovery, School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, James Parsons Building, Byrom Street, Liverpool L3 3AF, UK
- Faculty of Pharmacy, Tripoli University, Tripoli 42300, Libya
| | - Anil Kumar
- Department of Biotechnology, Government V. Y. T. PG Autonomous College, Durg 491001, Chhattisgarh, India
| | - Satyajit D. Sarker
- Centre for Natural Products Discovery, School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, James Parsons Building, Byrom Street, Liverpool L3 3AF, UK
- Correspondence: or (L.N.); (S.D.S.)
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15
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Lee J, Lim JW, Kim H. Astaxanthin Inhibits Oxidative Stress-Induced Ku Protein Degradation and Apoptosis in Gastric Epithelial Cells. Nutrients 2022; 14:nu14193939. [PMID: 36235593 PMCID: PMC9570747 DOI: 10.3390/nu14193939] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Revised: 09/13/2022] [Accepted: 09/20/2022] [Indexed: 11/16/2022] Open
Abstract
Oxidative stress induces DNA damage which can be repaired by DNA repair proteins, such as Ku70/80. Excess reactive oxygen species (ROS) stimulate the activation of caspase-3, which degrades Ku 70/80. Cells with decreased Ku protein levels undergo apoptosis. Astaxanthin exerts antioxidant activity by inducing the expression of catalase, an antioxidant enzyme, in gastric epithelial cells. Therefore, astaxanthin may inhibit oxidative stress-induced DNA damage by preventing Ku protein degradation and thereby suppressing apoptosis. Ku proteins can be degraded via ubiquitination and neddylation which adds ubiquitin-like protein to substrate proteins. We aimed to determine whether oxidative stress decreases Ku70/80 expression through the ubiquitin–proteasome pathway to induce apoptosis and whether astaxanthin inhibits oxidative stress-induced changes in gastric epithelial AGS cells. We induced oxidative stress caused by the treatment of β-D-glucose (G) and glucose oxidase (GO) in the cells. As a result, the G/GO treatment increased ROS levels, decreased nuclear Ku protein levels and Ku-DNA-binding activity, and induced the ubiquitination of Ku80. G/GO increased the DNA damage marker levels (γ-H2AX; DNA fragmentation) and apoptosis marker annexin V-positive cells and cell death. Astaxanthin inhibited G/GO-induced alterations, including Ku degradation in AGS cells. MLN4924, a neddylation inhibitor, and MG132, a proteasome inhibitor, suppressed G/GO-mediated DNA fragmentation and decreased cell viability. These results indicated that G/GO-induced oxidative stress causes Ku protein loss through the ubiquitin–proteasome pathway, resulting in DNA fragmentation and apoptotic cell death. Astaxanthin inhibited oxidative stress-mediated apoptosis via the reduction of ROS levels and inhibition of Ku protein degradation. In conclusion, dietary astaxanthin supplementation or astaxanthin-rich food consumption may be effective for preventing or delaying oxidative stress-mediated cell damage by suppressing Ku protein loss and apoptosis in gastric epithelial cells.
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Affiliation(s)
| | | | - Hyeyoung Kim
- Correspondence: ; Tel.: +82-2-2123-3125; Fax: +82-2-364-5781
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