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Miao LF, Sun YY, Du XJ, Xu N, Shen JW, Hua H, Guo M, Yang HJ, Li JK, Zhu L. Combined detection of P53, Ki67, P504S, and IMP3: Diagnostic implications for gastric cancer and precursor lesions. World J Gastrointest Oncol 2025; 17:105604. [DOI: 10.4251/wjgo.v17.i5.105604] [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: 01/29/2025] [Revised: 03/11/2025] [Accepted: 04/18/2025] [Indexed: 05/15/2025] Open
Abstract
BACKGROUND Differential diagnosis among atypical hyperplasia (AH) (including reparative hyperplasia and intestinal metaplasia), low-grade dysplasia (LGD), high-grade dysplasia (HGD), and adenocarcinoma (AC) in gastric mucosal biopsies is challenging due to histomorphological overlaps, variability in pathological diagnosis consistency, and limited reproducibility.
AIM To evaluate the diagnostic utility of P53, Ki67, P504S, and IMP3 in gastric cancer and its precancerous lesions, focusing on their effectiveness in distinguishing AH, LGD, HGD, and AC.
METHODS From January 2018 to September 2020, a total of 185 gastric mucosal biopsy specimens were analyzed according to the pathological diagnostic criteria outlined in the World Health Organization Classification of Digestive System Tumors (2019). The specimens were categorized into four groups: AH, LGD, HGD, and AC. Immunohistochemistry was employed to assess the expression status of P53, Ki67, P504S, and IMP3. Intergroup comparisons were performed using the χ2 test or Fisher's exact probability test to compare the differences in immunohistochemical markers across the distinct lesion groups.
RESULTS The expression rate of P504S was highest in the LGD group (53.3%, 16/30), while IMP3 expression was highest in the AC group (41.9%, 26/62), followed by the HGD group (33.3%). Significant differences in P504S and IMP3 expression levels were observed among the four lesion groups (P < 0.001). Pairwise comparisons revealed statistically significant differences in P504S expression between the AH group and the LGD, HGD, and AC groups (P < 0.001), as well as significant variations in IMP3 expression between the AH group and the HGD and AC groups, and between the LGD group and the HGD and AC groups (P < 0.001). Additionally, significant correlations were found between P504S and the polarity expression pattern of Ki67, and between IMP3 and the mutation expression pattern of P53 (P < 0.001). The combined detection of P504S with Ki67 and IMP3 with P53 increased the diagnostic sensitivity for LGD and HGD/AC, respectively.
CONCLUSION P504S is highly expressed in LGD and is associated with the Ki67 “polarity” expression pattern. IMP3 is highly expressed in HGD/AC and is correlated with the P53 mutation expression pattern. The combined detection of P504S with Ki67 and IMP3 with P53 increased the diagnostic sensitivity for LGD and HGD/AC, respectively. The rational use of P504S, Ki67, IMP3, and p53 can help distinguish gastric cancer and precancerous lesions, improving the early cancer diagnosis rate.
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Affiliation(s)
- Lan-Fang Miao
- Department of Pathology, Anyang Tumor Hospital, Anyang 455000, Henan Province, China
- Department of Pathology, The Affiliated Anyang Tumor Hospital of Henan University of Science and Technology, Anyang 455000, Henan Province, China
| | - Yuan-Yuan Sun
- Department of Pathology, Anyang Tumor Hospital, Anyang 455000, Henan Province, China
- Department of Pathology, The Affiliated Anyang Tumor Hospital of Henan University of Science and Technology, Anyang 455000, Henan Province, China
| | - Xian-Juan Du
- Department of Pathology, Anyang Tumor Hospital, Anyang 455000, Henan Province, China
- Department of Pathology, The Affiliated Anyang Tumor Hospital of Henan University of Science and Technology, Anyang 455000, Henan Province, China
| | - Nan Xu
- Department of Pathology, Anyang Tumor Hospital, Anyang 455000, Henan Province, China
- Department of Pathology, The Affiliated Anyang Tumor Hospital of Henan University of Science and Technology, Anyang 455000, Henan Province, China
| | - Jing-Wei Shen
- Department of Pathology, Anyang Tumor Hospital, Anyang 455000, Henan Province, China
- Department of Pathology, The Affiliated Anyang Tumor Hospital of Henan University of Science and Technology, Anyang 455000, Henan Province, China
| | - Hui Hua
- Department of Pathology, Anyang Tumor Hospital, Anyang 455000, Henan Province, China
- Department of Pathology, The Affiliated Anyang Tumor Hospital of Henan University of Science and Technology, Anyang 455000, Henan Province, China
| | - Mei Guo
- Department of Pathology, Anyang Tumor Hospital, Anyang 455000, Henan Province, China
- Department of Pathology, The Affiliated Anyang Tumor Hospital of Henan University of Science and Technology, Anyang 455000, Henan Province, China
| | - Hai-Jun Yang
- Department of Pathology, Anyang Tumor Hospital, Anyang 455000, Henan Province, China
- Department of Pathology, The Affiliated Anyang Tumor Hospital of Henan University of Science and Technology, Anyang 455000, Henan Province, China
| | - Jun-Kuo Li
- Department of Pathology, Anyang Tumor Hospital, Anyang 455000, Henan Province, China
- Department of Pathology, The Affiliated Anyang Tumor Hospital of Henan University of Science and Technology, Anyang 455000, Henan Province, China
| | - Lei Zhu
- Department of Pathology, Anyang Sixth People's Hospital, Anyang 455000, Henan Province, China
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Ranjan G, Ranjan S, Sunita P, Pattanayak SP. Thiazolidinedione derivatives in cancer therapy: exploring novel mechanisms, therapeutic potentials, and future horizons in oncology. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025; 398:4705-4725. [PMID: 39621087 DOI: 10.1007/s00210-024-03661-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/16/2024] [Accepted: 11/20/2024] [Indexed: 04/11/2025]
Abstract
Thiazolidinedione derivatives have shown significant potential as targeted cancer therapies by leveraging their various mechanisms of action. These include suppressing cell proliferation, triggering apoptosis, and influencing signaling pathways associated with tumor development. Their multifaceted effects make them promising candidates for advancing cancer treatment strategies. They have shown significant promise as anti-cancer agents, particularly through their ability to inhibit lipogenesis pathways and apoptosis essential for cancer cell survival and proliferation. This review comprehensively examines the anti-cancer potential of thiazolidinedione derivatives by targeting key aspects of lipid metabolism, apoptosis, and various mechanistic pathways. This review provides an in-depth examination of the anti-cancer potential of TZD derivatives, focusing on their mechanisms of action, therapeutic applications, and future directions in oncology. The anti-tumor effects of TZDs primarily involve the stimulation of peroxisome proliferator-activated receptor gamma (PPAR-γ), suppressing cell proliferation, induction of apoptosis, and inhibition of angiogenesis. Moreover, recent evidence highlights their ability to modulate non-PPAR-γ pathways, such as PI3K/Akt, NF-κB, and MAPK, further expanding their role in overcoming drug resistance and enhancing therapeutic outcomes. This review explores the preclinical (in vitro and in vivo) and clinical research investigating TZD derivatives efficacy in various cancer types. The insights underscore the significance of targeting lipogenesis as a novel anti-cancer strategy, positioning thiazolidinedione derivatives as potent candidates for future cancer therapeutics. As the oncology landscape evolves, TZD derivatives (rosiglitazone, pioglitazone, inolitazone, troglitazone, and 2,4-thiazolidinedione derivatives) represent a promising class of agents with the potential to contribute meaningfully to cancer treatment. By integrating existing knowledge with recent advancements, this study provides valuable insights into the role of thiazolidinedione derivatives in cancer treatment, paving the way for further research and clinical applications.
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Affiliation(s)
- Gaurav Ranjan
- Department of Pharmacy, School of Health Sciences, Central University of South Bihar, Gaya, 824236, India
| | - Shashi Ranjan
- Department of Pharmacy, School of Health Sciences, Central University of South Bihar, Gaya, 824236, India
| | - Priyashree Sunita
- Department of Surgery, Case Comprehensive Cancer Centre, Case Western Reserve University, Wolstein Research Building 2103 Cornell Rd, Cleveland, OH, 44106, USA
| | - Shakti Prasad Pattanayak
- Department of Pharmacy, School of Health Sciences, Central University of South Bihar, Gaya, 824236, India.
- Department of Biochemistry, School of Medicine, Case Western Reserve University, Woods Building, W437, 2109 Adelbert Road, Cleaveland, OH, 44106, USA.
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Huang X, Zhang M, Gu L, Zhou Z, Shi S, Fan X, Tong W, Liu D, Fang J, Huang X, Fang Z, Lu M. Naringenin inhibits the microsomal triglyceridetransfer protein/apolipoprotein B axis to inhibit intestinal metaplasia progression. Phytother Res 2024; 38:4541-4554. [PMID: 39049610 DOI: 10.1002/ptr.8279] [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: 01/30/2024] [Revised: 05/21/2024] [Accepted: 06/11/2024] [Indexed: 07/27/2024]
Abstract
Intestinal metaplasia (IM) is a premalignant condition that increases the risk for subsequent gastric cancer (GC). Traditional Chinese medicine generally plays a role in the treatment of IM, and the phytochemical naringenin used in Chinese herbal medicine has shown therapeutic potential for the treatment of gastric diseases. However, naringenin's specific effect on IM is not yet clearly understood. Therefore, this study identified potential gene targets for the treatment of IM through bioinformatics analysis and experiment validation. Two genes (MTTP and APOB) were selected as potential targets after a comparison of RNA-seq results of clinical samples, the GEO dataset (GSE78523), and naringenin-related genes from the GeneCards database. The results of both cell and animal experiments suggested that naringenin can improve the changes in the intestinal epithelial metaplasia model via MTTP/APOB expression. In summary, naringenin likely inhibits the MTTP/APOB axis and therefore inhibits IM progression. These results support the development of naringenin as an anti-IM agent and may contribute to the discovery of novel IM therapeutic targets.
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Affiliation(s)
- Xiangming Huang
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
- Nanjing University of Chinese Medicine, Nanjing, China
| | - Mengqiu Zhang
- Nanjing University of Chinese Medicine, Nanjing, China
- Department of Gastroenterology, Suqian Hospital of Traditional Chinese Medicine, Suqian, China
| | - Lina Gu
- Nanjing University of Chinese Medicine, Nanjing, China
| | - Ziyan Zhou
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
- Nanjing University of Chinese Medicine, Nanjing, China
| | - Shengtong Shi
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
- Nanjing University of Chinese Medicine, Nanjing, China
| | - Xinyu Fan
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
- Jiangsu Province Hospital of Integration of Chinese and Western Medicine, Nanjing Lishui District Hospital of Traditional Chinese Medicine, Nanjing, China
- Clinical College, Jiangsu Health Vocational College, Nanjing, China
| | - Wei Tong
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
- Nanjing University of Chinese Medicine, Nanjing, China
| | - Dazhi Liu
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
- Nanjing University of Chinese Medicine, Nanjing, China
| | - Jihu Fang
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
- Nanjing University of Chinese Medicine, Nanjing, China
| | - Xinen Huang
- Department of Medical Oncology, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China
| | - Zhijun Fang
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
- Nanjing University of Chinese Medicine, Nanjing, China
| | - Min Lu
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
- Jiangsu Province Hospital of Integration of Chinese and Western Medicine, Nanjing Lishui District Hospital of Traditional Chinese Medicine, Nanjing, China
- Clinical College, Jiangsu Health Vocational College, Nanjing, China
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Skoczyńska A, Ołdakowska M, Dobosz A, Adamiec R, Gritskevich S, Jonkisz A, Lebioda A, Adamiec-Mroczek J, Małodobra-Mazur M, Dobosz T. PPARs in Clinical Experimental Medicine after 35 Years of Worldwide Scientific Investigations and Medical Experiments. Biomolecules 2024; 14:786. [PMID: 39062500 PMCID: PMC11275227 DOI: 10.3390/biom14070786] [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: 05/22/2024] [Revised: 06/27/2024] [Accepted: 06/28/2024] [Indexed: 07/28/2024] Open
Abstract
This year marks the 35th anniversary of Professor Walter Wahli's discovery of the PPARs (Peroxisome Proliferator-Activated Receptors) family of nuclear hormone receptors. To mark the occasion, the editors of the scientific periodical Biomolecules decided to publish a special issue in his honor. This paper summarizes what is known about PPARs and shows how trends have changed and how research on PPARs has evolved. The article also highlights the importance of PPARs and what role they play in various diseases and ailments. The paper is in a mixed form; essentially it is a review article, but it has been enriched with the results of our experiments. The selection of works was subjective, as there are more than 200,000 publications in the PubMed database alone. First, all papers done on an animal model were discarded at the outset. What remained was still far too large to describe directly. Therefore, only papers that were outstanding, groundbreaking, or simply interesting were described and briefly commented on.
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Affiliation(s)
- Anna Skoczyńska
- Department of Internal and Occupational Medicine and Hypertension, Wroclaw Medical University, Borowska 213, 50-556 Wroclaw, Poland;
| | - Monika Ołdakowska
- Department of Forensic Medicine, Division of Molecular Techniques, Wroclaw Medical University, M. Sklodowskiej-Curie 52, 50-369 Wroclaw, Poland; (M.O.); (A.J.); (A.L.); (M.M.-M.); (T.D.)
| | - Agnieszka Dobosz
- Department of Basic Medical Sciences and Immunology, Division of Basic Medical Sciences, Wroclaw Medical University, Borowska 211, 50-556 Wrocław, Poland
| | - Rajmund Adamiec
- Department of Diabetology and Internal Medicine, Wroclaw Medical University, Borowska 213, 50-556 Wroclaw, Poland;
- Department of Internal Medicine, Faculty of Medical and Technical Sciences, Karkonosze University of Applied Sciences, Lwówiecka 18, 58-506 Jelenia Góra, Poland
| | - Sofya Gritskevich
- Department of Forensic Medicine, Division of Molecular Techniques, Wroclaw Medical University, M. Sklodowskiej-Curie 52, 50-369 Wroclaw, Poland; (M.O.); (A.J.); (A.L.); (M.M.-M.); (T.D.)
| | - Anna Jonkisz
- Department of Forensic Medicine, Division of Molecular Techniques, Wroclaw Medical University, M. Sklodowskiej-Curie 52, 50-369 Wroclaw, Poland; (M.O.); (A.J.); (A.L.); (M.M.-M.); (T.D.)
| | - Arleta Lebioda
- Department of Forensic Medicine, Division of Molecular Techniques, Wroclaw Medical University, M. Sklodowskiej-Curie 52, 50-369 Wroclaw, Poland; (M.O.); (A.J.); (A.L.); (M.M.-M.); (T.D.)
| | - Joanna Adamiec-Mroczek
- Department of Ophthalmology, Wroclaw Medical University, Borowska 213, 50-556 Wroclaw, Poland;
| | - Małgorzata Małodobra-Mazur
- Department of Forensic Medicine, Division of Molecular Techniques, Wroclaw Medical University, M. Sklodowskiej-Curie 52, 50-369 Wroclaw, Poland; (M.O.); (A.J.); (A.L.); (M.M.-M.); (T.D.)
| | - Tadeusz Dobosz
- Department of Forensic Medicine, Division of Molecular Techniques, Wroclaw Medical University, M. Sklodowskiej-Curie 52, 50-369 Wroclaw, Poland; (M.O.); (A.J.); (A.L.); (M.M.-M.); (T.D.)
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Eskandarion MR, Eskandarieh S, Shakoori Farahani A, Mahmoodzadeh H, Shahi F, Oghabian MA, Shirkoohi R. Prediction of novel biomarkers for gastric intestinal metaplasia and gastric adenocarcinoma using bioinformatics analysis. Heliyon 2024; 10:e30253. [PMID: 38737262 PMCID: PMC11088262 DOI: 10.1016/j.heliyon.2024.e30253] [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: 07/15/2023] [Revised: 04/22/2024] [Accepted: 04/23/2024] [Indexed: 05/14/2024] Open
Abstract
Background & aim The histologic and molecular changes from intestinal metaplasia (IM) to gastric cancer (GC) have not been fully characterized. The present study sought to identify potential alterations in signaling pathways in IM and GC to predict disease progression; these alterations can be considered therapeutic targets. Materials & methods Seven gene expression profiles were selected from the GEO database. Discriminate differentially expressed genes (DEGs) were analyzed by EnrichR. The STRING database, Cytoscape, Gene Expression Profiling Interactive Analysis (GEPIA), cBioPortal, NetworkAnalyst, MirWalk database, OncomiR, and bipartite miRNA‒mRNA correlation network was used for downstream analyses of selected module genes. Results Analyses revealed that extracellular matrix-receptor interactions (ITGB1, COL1A1, COL1A2, COL4A1, FN1, COL6A3, and THBS2) in GC and PPAR signaling pathway interactions (FABP1, APOC3, APOA1, HMGCS2, and PPARA and PCK1) in IM may play key roles in both the carcinogenesis and progression of underlying GC from intestinal metaplasia. IM enrichment indicated that this is closely related to digestion and absorption. The TF-hub gene regulatory network revealed that AR, TCF4, SALL4, and ESR1 were more important for hub gene expression. It was revealed that the development and prediction of GC may be affected by hsa-miR-29. It was found that PTGR1, C1orf115, CRYL1, ALDOB, and SULT1B1 were downregulated in GC and upregulated in IM. Therefore, they might have tumor suppressor activity in GC progression. Conclusion New potential biomarkers and pathways involved in GC and IM were identified that are important for the transformation of GC from IM to adenocarcinoma and can be therapeutic targets for GC.
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Affiliation(s)
| | - Sharareh Eskandarieh
- Multiple Sclerosis Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Abbas Shakoori Farahani
- Medical Genetics Ward, IKHC Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran
| | - Habibollah Mahmoodzadeh
- Department of Surgery, Cancer Research Center, Cancer Institute, IKHC, Tehran University of Medical Sciences, Tehran, Iran
| | - Farhad Shahi
- Department of Medical Oncology, Cancer Research Center, Cancer Institute, IKHC, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Ali Oghabian
- Medical Physics Department, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Reza Shirkoohi
- Cancer Research Center, Cancer Institute, IKHC, Tehran University of Medical Sciences, Tehran, Iran
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Jia Q, Li B, Wang X, Ma Y, Li G. Comprehensive analysis of peroxisome proliferator-activated receptors to predict the drug resistance, immune microenvironment, and prognosis in stomach adenocarcinomas. PeerJ 2024; 12:e17082. [PMID: 38529307 PMCID: PMC10962337 DOI: 10.7717/peerj.17082] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2023] [Accepted: 02/19/2024] [Indexed: 03/27/2024] Open
Abstract
Background Peroxisome proliferator-activated receptors (PPARs) exert multiple functions in the initiation and progression of stomach adenocarcinomas (STAD). This study analyzed the relationship between PPARs and the immune status, molecular mutations, and drug therapy in STAD. Methods The expression profiles of three PPAR genes (PPARA, PPARD and PPARG) were downloaded from The Cancer Genome Atlas (TCGA) dataset to analyze their expression patterns across pan-cancer. The associations between PPARs and clinicopathologic features, prognosis, tumor microenvironment, genome mutation and drug sensitivity were also explored. Co-expression between two PPAR genes was calculated using Pearson analysis. Regulatory pathways of PPARs were scored using gene set variation analysis (GSVA) package. Quantitative real-time polymerase chain reaction (qRT-PCR), Western blot, Cell Counting Kit-8 (CCK-8) assay and transwell assay were conducted to analyze the expression and function of the PPAR genes in STAD cell lines (AGS and SGC7901 cells). Results PPARA, PPARD and PPARG were more abnormally expressed in STAD samples and cell lines when compared to most of 32 type cancers in TCGA. In STAD, the expression of PPARD was higher in Grade 3+4 and male patients, while that of PPARG was higher in patient with Grade 3+4 and age > 60. Patients in high-PPARA expression group tended to have longer survival time. Co-expression analysis revealed 6 genes significantly correlated with the three PPAR genes in STAD. Single-sample GSEA (ssGSEA) showed that the three PPAR genes were enriched in 23 pathways, including MITOTIC_SPINDLE, MYC_TARGETS_V1, E2F_TARGETS and were closely correlated with immune cells, including NK_cells_resting, T_cells_CD4_memory_resting, and macrophages_M0. Immune checkpoint genes (CD274, SIGLEC15) were abnormally expressed between high-PPAR expression and low-PPAR expression groups. TTN, MUC16, FAT2 and ANK3 genes had a high mutation frequency in both high-PPARA/PPARG and low-PPARA/PPARG expression group. Fourteen and two PPARA/PPARD drugs were identified to be able to effectively treat patients in high-PPARA/PPARG and low-PPARA/PPARG expression groups, respectively. We also found that the chemotherapy drug Vinorelbine was positively correlated with the three PPAR genes, showing the potential of Vinorelbine to serve as a treatment drug for STAD. Furthermore, cell experiments demonstrated that PPARG had higher expression in AGS and SGC7901 cells, and that inhibiting PPARG suppressed the viability, migration and invasion of AGS and SGC7901 cells. Conclusions The current results confirmed that the three PPAR genes (PPARA, PPARD and PPARG) affected STAD development through mediating immune microenvironment and genome mutation.
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Affiliation(s)
- Qing Jia
- Department of Gastroenterology, Zibo Central Hospital, Zibo, China
| | - Baozhen Li
- Department of Gastroenterology, Zibo Central Hospital, Zibo, China
| | - Xiulian Wang
- Department of Gastroenterology, Zibo Central Hospital, Zibo, China
| | - Yongfen Ma
- Department of Gastroenterology, Zibo Central Hospital, Zibo, China
| | - Gaozhong Li
- Department of Gastroenterology, Zibo Central Hospital, Zibo, China
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Kim GY, Choi GT, Park J, Lee J, Do JT. Comparative Analysis of Porcine Adipose- and Wharton's Jelly-Derived Mesenchymal Stem Cells. Animals (Basel) 2023; 13:2947. [PMID: 37760347 PMCID: PMC10525484 DOI: 10.3390/ani13182947] [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: 08/17/2023] [Revised: 09/08/2023] [Accepted: 09/15/2023] [Indexed: 09/29/2023] Open
Abstract
Mesenchymal stem cells (MSCs) are promising candidates for tissue regeneration, cell therapy, and cultured meat research owing to their ability to differentiate into various lineages including adipocytes, chondrocytes, and osteocytes. As MSCs display different characteristics depending on the tissue of origin, the appropriate cells need to be selected according to the purpose of the research. However, little is known of the unique properties of MSCs in pigs. In this study, we compared two types of porcine mesenchymal stem cells (MSCs) isolated from the dorsal subcutaneous adipose tissue (adipose-derived stem cells (ADSCs)) and Wharton's jelly of the umbilical cord (Wharton's jelly-derived mesenchymal stem cells (WJ-MSCs)) of 1-day-old piglets. The ADSCs displayed a higher proliferation rate and more efficient differentiation potential into adipogenic and chondrogenic lineages than that of WJ-MSCs; conversely, WJ-MSCs showed superior differentiation capacity towards osteogenic lineages. In early passages, ADSCs displayed higher proliferation rates and mitochondrial energy metabolism (measured based on the oxygen consumption rate) compared with that of WJ-MSCs, although these distinctions diminished in late passages. This study broadens our understanding of porcine MSCs and provides insights into their potential applications in animal clinics and cultured meat science.
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Affiliation(s)
- Ga Yeon Kim
- Department of Stem Cell and Regenerative Biotechnology, KU Institute of Technology, Konkuk University, Seoul 05029, Republic of Korea; (G.Y.K.); (G.T.C.); (J.P.)
- 3D Tissue Culture Research Center, Konkuk University, Seoul 05029, Republic of Korea
| | - Gyu Tae Choi
- Department of Stem Cell and Regenerative Biotechnology, KU Institute of Technology, Konkuk University, Seoul 05029, Republic of Korea; (G.Y.K.); (G.T.C.); (J.P.)
- 3D Tissue Culture Research Center, Konkuk University, Seoul 05029, Republic of Korea
| | - Jinryong Park
- Department of Stem Cell and Regenerative Biotechnology, KU Institute of Technology, Konkuk University, Seoul 05029, Republic of Korea; (G.Y.K.); (G.T.C.); (J.P.)
- 3D Tissue Culture Research Center, Konkuk University, Seoul 05029, Republic of Korea
| | - Jeongeun Lee
- Department of Agricultural Convergency Technology, Jeonbuk National University, Jeonju 54896, Republic of Korea;
| | - Jeong Tae Do
- Department of Stem Cell and Regenerative Biotechnology, KU Institute of Technology, Konkuk University, Seoul 05029, Republic of Korea; (G.Y.K.); (G.T.C.); (J.P.)
- 3D Tissue Culture Research Center, Konkuk University, Seoul 05029, Republic of Korea
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A novel metabolism-related prognostic gene development and validation in gastric cancer. CLINICAL & TRANSLATIONAL ONCOLOGY : OFFICIAL PUBLICATION OF THE FEDERATION OF SPANISH ONCOLOGY SOCIETIES AND OF THE NATIONAL CANCER INSTITUTE OF MEXICO 2023; 25:447-459. [PMID: 36168087 DOI: 10.1007/s12094-022-02958-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Accepted: 09/15/2022] [Indexed: 01/29/2023]
Abstract
BACKGROUND The importance of metabolism-related alterations in the development of gastric cancer (GC) is increasingly recognized. The present study aimed to identify metabolism-related genes to facilitate prognosis of GC patients. METHODS Gene expression datasets and clinical information of GC patients were downloaded from TCGA and GEO databases. We scored the enrichment of human metabolism-related pathways (n = 86) in GC samples by GSV, constructed prognostic risk models using LASSO algorithm and multivariate Cox regression analysis, combined with clinical information to construct a nomogram, and finally cis score algorithm to analyze the abundance of immune-related cells in different subtypes. We used Weka software to screen for prognosis-related marker genes and finally validated the expression of the selected genes in clinical cancer patient tissues. RESULTS We identified that two GC metabolism-related signatures were strongly associated with OS and the levels of immune cell infiltration. Moreover, a survival prediction model for GC was established based on six GC metabolism-related genes. Time-dependent ROC analysis showed good stability of the risk prediction scoring model. The model was successfully validated in an independent ACRG cohort, and the expression trends of key genes were also verified in the GC tissues of patients. DLX1, LTBP2, FGFR1 and MMP2 were highly expressed in the cluster with poorer prognosis while SLC13A2 and SLCO1B3 were highly expressed in the cluster with better prognosis. CONCLUSIONS We identified a risk predictive score model based on six metabolism-related genes related to survival, which may serve as prognostic indicators and potential therapeutic targets for GC.
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Feng A, He L, Chen T, Xu M. A novel cuproptosis-related lncRNA nomogram to improve the prognosis prediction of gastric cancer. Front Oncol 2022; 12:957966. [PMID: 36106123 PMCID: PMC9465020 DOI: 10.3389/fonc.2022.957966] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Accepted: 07/29/2022] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Cuproptosis is a copper-triggered modality of mitochondrial cell death and cuproptosis process may play important roles in gastric cancer development. However, little is known about cuproptosis-related lncRNAs in gastric adenocarcinoma (STAD). This study is aimed to investigate the potential prognostic signatures of cuproptosis-related lncRNAs in STAD. METHODS The Cancer Genome Atlas (TCGA) database were used to obtain gene expression profiles, clinicopathological, and OS information for STAD. Cuproptosis-related genes were collected based on previous studies and cuproptosis-related lncRNAs were screened out by co-expression analysis. The nomogram constructed by Cox regression analysis with the minimum absolute contraction and selection operator (lasso) algorithm. In addition, the potential response of ICB therapy and immune evasion incidence were estimated with Tumor Immune Dysfunction and Exclusion (TIDE) algorithm. Immune checkpoint expressions associated with risk scores were also analyzed. The correlation of immune checkpoint CD209 and HAVCR2 expressions associated with risk scores were experimentally testified by RT-qPCR, Western Blot, and IHC. RESULTS Patients were classified into high-risk and low-risk groups based on the risk score calculated in this model. The Kaplan-Meier survival curve analysis revealed that the high-risk group was associated with poor prognosis. Multivariate Cox regression analysis suggested that this lncRNA prediction model was an independent risk factor affecting the OS rate. Furthermore, ROC curve indicates that the nomogram was superior to traditional clinicopathological features in predicting STAD prognosis. Finally, functional enrichment analysis and immune checkpoint investigation revealed that the nomogram is notably associated with cholesterol metabolism and immune functions, RT-qPCR and Western Blotting demonstrated the co-expression relationship of LINC01150 with CD209 and HAVCR2. CONCLUSION A novel cuproptosis-related lncRNAs signature impacts on the prognosis and immunological features of GC.
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Affiliation(s)
| | | | - Tao Chen
- Endoscopy Center, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Meidong Xu
- Endoscopy Center, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
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10
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Wagner N, Wagner KD. Peroxisome Proliferator-Activated Receptors and the Hallmarks of Cancer. Cells 2022; 11:cells11152432. [PMID: 35954274 PMCID: PMC9368267 DOI: 10.3390/cells11152432] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Revised: 08/02/2022] [Accepted: 08/04/2022] [Indexed: 12/11/2022] Open
Abstract
Peroxisome proliferator-activated receptors (PPARs) function as nuclear transcription factors upon the binding of physiological or pharmacological ligands and heterodimerization with retinoic X receptors. Physiological ligands include fatty acids and fatty-acid-derived compounds with low specificity for the different PPAR subtypes (alpha, beta/delta, and gamma). For each of the PPAR subtypes, specific pharmacological agonists and antagonists, as well as pan-agonists, are available. In agreement with their natural ligands, PPARs are mainly focused on as targets for the treatment of metabolic syndrome and its associated complications. Nevertheless, many publications are available that implicate PPARs in malignancies. In several instances, they are controversial for very similar models. Thus, to better predict the potential use of PPAR modulators for personalized medicine in therapies against malignancies, it seems necessary and timely to review the three PPARs in relation to the didactic concept of cancer hallmark capabilities. We previously described the functions of PPAR beta/delta with respect to the cancer hallmarks and reviewed the implications of all PPARs in angiogenesis. Thus, the current review updates our knowledge on PPAR beta and the hallmarks of cancer and extends the concept to PPAR alpha and PPAR gamma.
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Affiliation(s)
- Nicole Wagner
- Correspondence: (N.W.); (K.-D.W.); Tel.: +33-489-153-713 (K.-D.W.)
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11
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Morosi L, Matteo C, Meroni M, Ceruti T, Fuso Nerini I, Bello E, Frapolli R, D'Incalci M, Zucchetti M, Davoli E. Quantitative measurement of pioglitazone in neoplastic and normal tissues by AP-MALDI mass spectrometry imaging. Talanta 2022; 237:122918. [PMID: 34736656 DOI: 10.1016/j.talanta.2021.122918] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Revised: 09/24/2021] [Accepted: 09/29/2021] [Indexed: 11/26/2022]
Abstract
Pioglitazone is a Peroxisome Proliferator-Activated Receptor (PPAR) agonist of the thiazolidinedione class of compounds with promising anticancer activity. An innovative quantitative mass spectrometry imaging (MSI) method and a HPLC-UV method were developed and validated to investigate its distribution in tumor and liver tissues. The MSI method is based on stable isotope normalization and resulted highly specific and sensitive (0.2 pmol/spot). The correct identification of the drug ion signal is confirmed by MS/MS analysis on tissue. The method shows an optimal lateral resolution (25 μm) relying on the ionization efficiency and fine laser diameter of the atmospheric pressure MALDI source. The HPLC-UV method is simple and straightforward involving quick protein precipitation and shows good sensitivity (50ng/sample) using a small starting volume of biological sample. Thus, it is applicable to samples obtained from both preclinical models and clinical surgical procedures. MSI and HPLC-UV assays were validated assessing linearity, intra- and inter-day precision and accuracy, limit of quantification, selectivity and recovery. These are the first methods developed and validated for the analysis of pioglitazone in tissues, and they were applied successfully to myxoid liposarcoma xenograft-bearing mice, which received clinically relevant drug doses. Pioglitazone was measured by either method in sections of tumor and liver 2, 6 and 24 h post-treatment. Drug distribution was relatively homogeneous.
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Affiliation(s)
- Lavinia Morosi
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Department of Oncology, Via Mario Negri 2, Milan, Italy
| | - Cristina Matteo
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Department of Oncology, Via Mario Negri 2, Milan, Italy
| | - Marina Meroni
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Department of Oncology, Via Mario Negri 2, Milan, Italy
| | - Tommaso Ceruti
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Department of Oncology, Via Mario Negri 2, Milan, Italy
| | - Ilaria Fuso Nerini
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Department of Oncology, Via Mario Negri 2, Milan, Italy
| | - Ezia Bello
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Department of Oncology, Via Mario Negri 2, Milan, Italy
| | - Roberta Frapolli
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Department of Oncology, Via Mario Negri 2, Milan, Italy.
| | - Maurizio D'Incalci
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Department of Oncology, Via Mario Negri 2, Milan, Italy
| | - Massimo Zucchetti
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Department of Oncology, Via Mario Negri 2, Milan, Italy
| | - Enrico Davoli
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Mass Spectrometry Research Center for Health and Environment and Laboratory of Mass Spectrometry, Via Mario Negri 2, Milan, Italy
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12
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Synthesis, characterization and DFT calculated properties of electron-rich hydrazinylthiazoles: Experimental and computational synergy. J Mol Struct 2021. [DOI: 10.1016/j.molstruc.2021.131043] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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13
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Dixit G, Prabhu A. The pleiotropic peroxisome proliferator activated receptors: Regulation and therapeutics. Exp Mol Pathol 2021; 124:104723. [PMID: 34822814 DOI: 10.1016/j.yexmp.2021.104723] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Revised: 11/02/2021] [Accepted: 11/15/2021] [Indexed: 02/07/2023]
Abstract
The Peroxisome proliferator-activated receptors (PPARs) are key regulators of metabolic events in our body. Owing to their implication in maintenance of homeostasis, both PPAR agonists and antagonists assume therapeutic significance. Understanding the molecular mechanisms of each of the PPAR isotypes in the healthy body and during disease is crucial to exploiting their full therapeutic potential. This article is an attempt to present a rational analysis of the multifaceted therapeutic effects and underlying mechanisms of isotype-specific PPAR agonists, dual PPAR agonists, pan PPAR agonists as well as PPAR antagonists. A holistic understanding of the mechanistic dimensions of these key metabolic regulators will guide future efforts to identify novel molecules in the realm of metabolic, inflammatory and immunotherapeutic diseases.
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Affiliation(s)
- Gargi Dixit
- Department of Pharmaceutical Chemistry & Quality Assurance, SVKM's Dr. Bhanuben Nanavati College of Pharmacy, Mumbai, India
| | - Arati Prabhu
- Department of Pharmaceutical Chemistry & Quality Assurance, SVKM's Dr. Bhanuben Nanavati College of Pharmacy, Mumbai, India.
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Acharjee A, Agarwal P, Nash K, Bano S, Rahman T, Gkoutos GV. Immune infiltration and prognostic and diagnostic use of LGALS4 in colon adenocarcinoma and bladder urothelial carcinoma. Am J Transl Res 2021; 13:11353-11363. [PMID: 34786063 PMCID: PMC8581917] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2021] [Accepted: 06/03/2021] [Indexed: 06/13/2023]
Abstract
Colon adenocarcinoma (COAD) is a common tumor of the gastrointestinal tract with a high mortality rate. Current research has identified many genes associated with immune infiltration that play a vital role in the development of COAD. In this study, we analysed the prognostic and diagnostic features of such immune-related genes in the context of colonic adenocarcinoma (COAD). We analysed 17 overlapping gene expression profiles of COAD and healthy samples obtained from TCGA-COAD and public single-cell sequencing resources, to identify potential therapeutic COAD targets. We evaluated the abundance of immune infiltration with those genes using the TIMER (Tumor Immune Estimation Resource) deconvolution method. Subsequently, we developed predictive and survival models to assess the prognostic value of these genes. The LGALS4 (Galectin-4) gene was found to be significantly (P<0.05) downregulated in COAD and bladder urothelial carcinoma (BLCA) compared to healthy samples. We identified LGALS4 as a prognostic and diagnostic marker for multiple cancer types, including COAD and BLCA. Our analysis reveals a series of novel candidate drug targets, as well as candidate molecular markers, that may explain the pathogenesis of COAD and BLCA. LGALS4 gene is associated with multiple cancer types and is a possible prognostic, as well as diagnostic, marker of COAD and BLCA.
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Affiliation(s)
- Animesh Acharjee
- College of Medical and Dental Sciences, Institute of Cancer and Genomic Sciences, University of BirminghamB15 2TT, UK
- Institute of Translational Medicine, University Hospitals Birmingham NHS, Foundation TrustB15 2TT, UK
- NIHR Surgical Reconstruction and Microbiology Research Centre, University Hospital BirminghamBirmingham, B15 2WB, UK
| | - Prasoon Agarwal
- KTH Royal Institute of Technology, School of Electrical Engineering and Computer ScienceStockholm, Sweden
- Science for Life LaboratorySolna, Sweden
| | - Katrina Nash
- College of Medical and Dental Sciences, University of BirminghamBirmingham, B15 2TT, UK
| | - Subia Bano
- Elvesys Microfluidic Innovation CentreParis 75011, France
| | - Taufiq Rahman
- Department of Pharmacology, Tennis Court Road, University of CambridgeCambridge, CB2 1PD
| | - Georgios V Gkoutos
- College of Medical and Dental Sciences, Institute of Cancer and Genomic Sciences, University of BirminghamB15 2TT, UK
- Institute of Translational Medicine, University Hospitals Birmingham NHS, Foundation TrustB15 2TT, UK
- NIHR Surgical Reconstruction and Microbiology Research Centre, University Hospital BirminghamBirmingham, B15 2WB, UK
- MRC Health Data Research UK (HDR UK)
- NIHR Experimental Cancer Medicine CentreBirmingham, B15 2TT, UK
- NIHR Biomedical Research Centre, University Hospital BirminghamBirmingham, B15 2TT, UK
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15
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Esmaeili S, Salari S, Kaveh V, Ghaffari SH, Bashash D. Alteration of PPAR-GAMMA (PPARG; PPARγ) and PTEN gene expression in acute myeloid leukemia patients and the promising anticancer effects of PPARγ stimulation using pioglitazone on AML cells. Mol Genet Genomic Med 2021; 9:e1818. [PMID: 34549887 PMCID: PMC8606220 DOI: 10.1002/mgg3.1818] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2021] [Revised: 05/10/2021] [Accepted: 09/07/2021] [Indexed: 12/22/2022] Open
Abstract
Background In the new era of tailored cancer treatment strategies, finding a molecule to regulate a wide range of intracellular functions is valuable. The unique property of nuclear receptor peroxisome proliferator‐activated receptor‐γ (PPARγ; PPARG) in transmitting the anti‐survival signals of the chemotherapeutic drugs has fired the enthusiasm into the application of this receptor in cancer treatment. Objectives We aimed to investigate the expression of PPARγ and one of its downstream targets PTEN in non‐M3 acute myeloid leukemia (AML) patients. We also investigated the therapeutic value of PPARγ stimulation using pioglitazone in the AML‐derived U937 cell line. Methods The blood samples from 30 patients diagnosed with non‐M3 AML as well as 10 healthy individuals were collected and the mRNA expression levels of PPARγ and PTEN were evaluated. Additionally, we used trypan blue assay, MTT assay, and flow cytometry analysis to evaluate the anti‐leukemic effects of pioglitazone on U937 cells. Results While PTEN was significantly downregulated in AML patients as compared to the control group, the expression of PPARγ was increased in the patients’ group. The expression level of PPARγ was also negatively correlated with PTEN; however, it was not statistically significant. Besides, PPARγ stimulation using pioglitazone reduced survival and proliferative capacity of U937 cells through inducing apoptosis and suppression of cell transition from the G1 phase of the cell cycle. Conclusion The results of the present study shed more light on the importance of PPARγ and its stimulation in the therapeutic strategies of AML.
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Affiliation(s)
- Shadi Esmaeili
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Sina Salari
- Department of Medical Oncology, Hematology and Bone Marrow Transplantation, Taleghani Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Vahid Kaveh
- Department of Medical Oncology and Hematology, Iran University of Medical Sciences, Tehran, Iran
| | - Seyed H Ghaffari
- Hematology, Oncology and Stem Cell Transplantation Research Center, Shariati Hospital, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Davood Bashash
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Bednarz-Misa I, Fleszar MG, Fortuna P, Lewandowski Ł, Mierzchała-Pasierb M, Diakowska D, Krzystek-Korpacka M. Altered L-Arginine Metabolic Pathways in Gastric Cancer: Potential Therapeutic Targets and Biomarkers. Biomolecules 2021; 11:biom11081086. [PMID: 34439753 PMCID: PMC8395015 DOI: 10.3390/biom11081086] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Revised: 07/20/2021] [Accepted: 07/22/2021] [Indexed: 12/11/2022] Open
Abstract
There is a pressing need for molecular targets and biomarkers in gastric cancer (GC). We aimed at identifying aberrations in L-arginine metabolism with therapeutic and diagnostic potential. Systemic metabolites were quantified using mass spectrometry in 293 individuals and enzymes’ gene expression was quantified in 29 paired tumor-normal samples using qPCR and referred to cancer pathology and molecular landscape. Patients with cancer or benign disorders had reduced systemic arginine, citrulline, and ornithine and elevated symmetric dimethylarginine and dimethylamine. Citrulline and ornithine depletion was accentuated in metastasizing cancers. Metabolite diagnostic panel had 91% accuracy in detecting cancer and 70% accuracy in differentiating cancer from benign disorders. Gastric tumors had upregulated NOS2 and downregulated ASL, PRMT2, ORNT1, and DDAH1 expression. NOS2 upregulation was less and ASL downregulation was more pronounced in metastatic cancers. Tumor ASL and PRMT2 expression was inversely related to local advancement. Enzyme up- or downregulation was greater or significant solely in cardia subtype. Metabolic reprogramming in GC includes aberrant L-arginine metabolism, reflecting GC subtype and pathology, and is manifested by altered interplay of its intermediates and enzymes. Exploiting L-arginine metabolic pathways for diagnostic and therapeutic purposes is warranted. Functional studies on ASL, PRMT2, and ORNT1 in GC are needed.
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Affiliation(s)
- Iwona Bednarz-Misa
- Department of Biochemistry and Immunochemistry, Wroclaw Medical University, 50-368 Wroclaw, Poland; (I.B.-M.); (M.G.F.); (P.F.); (Ł.L.); (M.M.-P.)
| | - Mariusz G. Fleszar
- Department of Biochemistry and Immunochemistry, Wroclaw Medical University, 50-368 Wroclaw, Poland; (I.B.-M.); (M.G.F.); (P.F.); (Ł.L.); (M.M.-P.)
| | - Paulina Fortuna
- Department of Biochemistry and Immunochemistry, Wroclaw Medical University, 50-368 Wroclaw, Poland; (I.B.-M.); (M.G.F.); (P.F.); (Ł.L.); (M.M.-P.)
| | - Łukasz Lewandowski
- Department of Biochemistry and Immunochemistry, Wroclaw Medical University, 50-368 Wroclaw, Poland; (I.B.-M.); (M.G.F.); (P.F.); (Ł.L.); (M.M.-P.)
| | - Magdalena Mierzchała-Pasierb
- Department of Biochemistry and Immunochemistry, Wroclaw Medical University, 50-368 Wroclaw, Poland; (I.B.-M.); (M.G.F.); (P.F.); (Ł.L.); (M.M.-P.)
| | - Dorota Diakowska
- Department of Gastrointestinal and General Surgery, Wroclaw Medical University, 50-368 Wroclaw, Poland;
- Department of Nervous System Diseases, Wroclaw Medical University, 51-618 Wroclaw, Poland
| | - Małgorzata Krzystek-Korpacka
- Department of Biochemistry and Immunochemistry, Wroclaw Medical University, 50-368 Wroclaw, Poland; (I.B.-M.); (M.G.F.); (P.F.); (Ł.L.); (M.M.-P.)
- Correspondence:
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Lee BR, Paing MH, Sharma-Walia N. Cyclopentenone Prostaglandins: Biologically Active Lipid Mediators Targeting Inflammation. Front Physiol 2021; 12:640374. [PMID: 34335286 PMCID: PMC8320392 DOI: 10.3389/fphys.2021.640374] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Accepted: 05/10/2021] [Indexed: 12/13/2022] Open
Abstract
Cyclopentenone prostaglandins (cyPGs) are biologically active lipid mediators, including PGA2, PGA1, PGJ2, and its metabolites. cyPGs are essential regulators of inflammation, cell proliferation, apoptosis, angiogenesis, cell migration, and stem cell activity. cyPGs biologically act on multiple cellular targets, including transcription factors and signal transduction pathways. cyPGs regulate the inflammatory response by interfering with NF-κB, AP-1, MAPK, and JAK/STAT signaling pathways via both a group of nuclear receptor peroxisome proliferator-activated receptor-gamma (PPAR-γ) dependent and PPAR-γ independent mechanisms. cyPGs promote the resolution of chronic inflammation associated with cancers and pathogen (bacterial, viral, and parasitic) infection. cyPGs exhibit potent effects on viral infections by repressing viral protein synthesis, altering viral protein glycosylation, inhibiting virus transmission, and reducing virus-induced inflammation. We summarize their anti-proliferative, pro-apoptotic, cytoprotective, antioxidant, anti-angiogenic, anti-inflammatory, pro-resolution, and anti-metastatic potential. These properties render them unique therapeutic value, especially in resolving inflammation and could be used in adjunct with other existing therapies. We also discuss other α, β -unsaturated carbonyl lipids and cyPGs like isoprostanes (IsoPs) compounds.
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Toppo E, Al-Dhabi NA, Sankar C, Kumar SN, Buvanesvaragurunathan K, Darvin SS, Stalin A, Balakrishna K, Ceasar SA, Pandikumar P, Ignacimuthu S, Sivasankaran K, Agastian P. Hepatoprotective effect of selected isoandrographolide derivatives on steatotic HepG2 cells and High Fat Diet fed rats. Eur J Pharmacol 2021; 899:174056. [PMID: 33753108 DOI: 10.1016/j.ejphar.2021.174056] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Revised: 03/06/2021] [Accepted: 03/17/2021] [Indexed: 02/07/2023]
Abstract
Non-alcoholic Fatty Liver Disease (NAFLD) is one of the growing epidemics of the globe. This study was aimed to evaluate the anti-NAFLD effect of selected IAN derivatives using in silico, in vitro and in vivo models. In silico tools viz., DataWarrior, SwissADME and Gaussian 09 were used to predict the pharmacokinetic properties and electronic distribution patterns of the derivatives; docking analysis was done with Autodock against PPARα. Toxicities of the derivatives were assessed in HepG2 cells using MTT assay. Anti-NAFLD efficacies of the derivatives were assessed in free fatty acid induced steatotic HepG2 cells. In vivo anti-NAFLD effect of active isoandrographolide (IAN) derivative, 19-propionyl isoandrographolide (IAN-19P) was assessed in High Fat Diet fed rats. In silico and in vitro studies indicated that IAN-19P showed improved drug-likeness and drug score. The toxicity of IAN-19P to HepG2 cells was comparatively less than IAN and other derivatives. In free fatty acid induced steatotic HepG2 cells, treatment with IAN-19P significantly lowered intracellular triglyceride content and leakage of LDH and transaminases. Treating High Fat Diet fed animals with IAN-19P significantly lowered plasma lipids, transaminases, LDH and GGT levels. The treatment with IAN-19P upregulated the expressions of PPARα and CPT-1. IAN-19P did not produce any noticeable adverse effect till 2 g/kg concentration in acute and 250 mg/kg concentration in subacute toxicity studies. This study indicated the beneficial effect of IAN-19P for the treatment of NAFLD; however robust investigations are needed to establish the potential of IAN-19P to treat NAFLD.
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Affiliation(s)
- Erenius Toppo
- Xavier Research Foundation, St Xavier's College, Palayamkottai, Tamil Nadu, 627002, India; St Xavier's College, Tejpur, Sonabheel Solabsti, Bokajan, Assam, 784105, India
| | - Naif Abdullah Al-Dhabi
- Addiriyah Chair for Environmental Studies, Department of Botany and Microbiology, College of Science, King Saud University, Riyadh, 11451, Saudi Arabia
| | - Chinnakulandai Sankar
- Xavier Research Foundation, St Xavier's College, Palayamkottai, Tamil Nadu, 627002, India
| | | | | | | | - Antony Stalin
- State Key Laboratory of Subtropical Silviculture, Department of Traditional Chinese Medicine, Zhejiang A&F University, Hangzhou, 311300, China
| | - Kedeke Balakrishna
- Xavier Research Foundation, St Xavier's College, Palayamkottai, Tamil Nadu, 627002, India
| | - Stanislaus Antony Ceasar
- Division of Plant Molecular Biology and Biotechnology, Biosciences Department, Rajagiri College of Social Sciences, Cochin, Kerala, 683104, India
| | - Perumal Pandikumar
- Xavier Research Foundation, St Xavier's College, Palayamkottai, Tamil Nadu, 627002, India.
| | - Savarimuthu Ignacimuthu
- Xavier Research Foundation, St Xavier's College, Palayamkottai, Tamil Nadu, 627002, India; Bharath Institute of Higher Education and Research, Selaiyur, Tambaram, Chennai, Tamil Nadu, 600073, India.
| | - Kuppusamy Sivasankaran
- Xavier Research Foundation, St Xavier's College, Palayamkottai, Tamil Nadu, 627002, India
| | - Paul Agastian
- Department of Plant Biology & Biotechnology, Loyola College, Chennai, Tamil Nadu, 600034, India
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Visceral-to-subcutaneous fat ratio independently predicts the prognosis of locally advanced gastric cancer----- highlighting the role of adiponectin receptors and PPARα, β/ δ, ɤ. Eur J Surg Oncol 2021; 47:3064-3073. [PMID: 33941417 DOI: 10.1016/j.ejso.2021.04.028] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Revised: 03/23/2021] [Accepted: 04/20/2021] [Indexed: 11/24/2022] Open
Abstract
BACKGROUND Results of computed tomography body composition (CTBC) predicting long-term outcomes of gastric cancer have been mixed and the plausible mechanism remains elusive. METHODS We retrospectively enrolled a cohort of stage III gastric cancer who had undergone curative-intent gastrectomy. Clinicopathological variables, preoperative CTBC including abdominal muscle, subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT), and nutritional and inflammatory index were taken together to construct prognostic analysis. In vitro tests using co-culture system of gastric cancer cell lines and visceral adipocytes were conducted. RESULTS A total of 191 eligible patients were enrolled. By multivariate analysis, SAT and VAT/ SAT ratio were prognostic factors of disease-free survival, while sarcopenia was not. SAT remained as a prognostic factor of overall survival. SAT index was positively correlated with prognostic nutritional index, while VAT HU was positively correlated with platelet-to-lymphocyte ratio. Expression of adiponectin receptor 1 and 2 (AdipoR1, R2), and peroxisome proliferator-activated receptor (PPAR) α, β/δ, ɤ of patients with higher VAT/SAT ratio were decreased as compared to those with lower VAT/SAT ratio. Proliferation of gastric cancer cells co-cultured with adipocytes was increased by 50-100% and accompanied by down-regulation of mRNAs of AdipoR1, 2, PPARα, β/δ, ɤ, and pro-apoptotic genes, as compared to their controls. CONCLUSION SAT and VAT played exactly opposite prognostic roles of locally advanced gastric cancers, which might work through modulation of AdipoR1, 2 and PPARα, β/δ, ɤ. Preoperative CTBC, supplementary to classic TNM system, helps clinicians tailor individualized adjuvant therapy and/or nutritional support.
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Haq MEU, Akash MSH, Rehman K, Khurshid M. Therapeutic role of metformin and troglitazone to prevent cancer risk in diabetic patients: evidences from experimental studies. TURKISH JOURNAL OF BIOCHEMISTRY 2020; 45:229-239. [DOI: 10.1515/tjb-2019-0318] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
Abstract
Abstract
Objectives
It is evident from literature that individual with diabetes mellitus is more prone to develop cancer as compared to non-diabetic one. We aimed to highlight the risk factors that trigger the tumor formation in diabetic individuals and collect evidences regarding the preventive role of anti-diabetics in cancer.
Content
A comprehensive literature was searched in English language using electronic databases including PubMed, ScienceDirect, Medline, Scopus and Embase.
Summary and outlook
Antidiabetic drugs notably metformin and troglitazone, exhibit anticancer effects. Metformin targets energy sensor pathway i. e., AMPK/mTOR which is controlled by LKB1. Whereas. troglitazone activates PPARϒ that modulate the transcription of insulin responsive gene which is essential for lipid and glucose metabolism. Adipocytes are highly expressed with PPARɣ which induce differentiation and regulate adipogenesis. Ligand-driven expression of PPARɣ in myoblast and fibroblast cell lines produces adipocyte differentiation in breast cancer. Prostate cancer that expresses PPARɣ may be suppressed by troglitazone and retinoid which inhibit their proliferation and initiate differentiation. The findings summarized here show that metformin and troglitazone may have the ability to inhibit the cancer cell proliferation via involvement of molecular pathways. This therapeutic intervention will help to control the progression of cancer in diabetic patients.
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Affiliation(s)
- Muhammad Ejaz ul Haq
- Department of Pharmaceutical Chemistry , Government College University , Faisalabad , Pakistan
| | | | - Kanwal Rehman
- Department of Pharmacy , University of Agriculture , Faisalabad , Pakistan
| | - Mohsin Khurshid
- Department of Microbiology , Government College University , Faisalabad , Pakistan
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Hall JA, Rusten M, Abughazaleh RD, Wuertz B, Souksavong V, Escher P, Ondrey F. Effects of PPAR-γ agonists on oral cancer cell lines: Potential horizons for chemopreventives and adjunctive therapies. Head Neck 2020; 42:2542-2554. [PMID: 32519370 DOI: 10.1002/hed.26286] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2020] [Revised: 04/17/2020] [Accepted: 05/12/2020] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Peroxisome proliferator-activated receptor-gamma (PPAR-γ) activators have anti-cancer effects. Our objective was to determine the effect of PPAR-γ ligands 15-deoxy-D12,14 -Prostaglandin J2 (15-PGJ2 ) and ciglitazone on proliferation, apoptosis, and NF-κB in human oral squamous cell carcinoma cell lines. METHODS NA and CA9-22 cells were treated in vitro with 15-PGJ2 and ciglitazone. Proliferation was measured by MTT colorimetric assay and cell cycle analysis performed via flow cytometry, apoptosis by caspase-3 colorimetric assay and poly-(ADP-ribose) polymerase cleavage on Western blot, and NF-κB activation by luciferase assays. RESULTS MTT assays demonstrated dose-dependent decreases after 15-PGJ2 treatment in both cell lines, and S-phase cell cycle arrest was also demonstrated. NF-κB luciferase reporter gene activity decreased seven- and eightfold in NA and CA9-22 cells, respectively. Caspase-3 activity increased two- and eightfold in NA and CA9-22 cells, respectively. CONCLUSIONS Our results suggest these agents, in addition to activating PPAR-γ, can downregulate NF-κB and potentiate apoptosis in oral cancer cells.
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Affiliation(s)
| | - Mark Rusten
- SoutheastHEALTH, Cape Girardeau, Missouri, USA
| | - Raed D Abughazaleh
- Department of Otolaryngology-Head and Neck Surgery, University of Minnesota, Minneapolis, Minnesota, USA
| | - Beverly Wuertz
- Department of Otolaryngology-Head and Neck Surgery, University of Minnesota, Minneapolis, Minnesota, USA
| | - Vannesa Souksavong
- University of Minnesota Medical School, University of Minnesota, Minneapolis, Minnesota, USA
| | - Paul Escher
- University of Minnesota Medical School, University of Minnesota, Minneapolis, Minnesota, USA
| | - Frank Ondrey
- Department of Otolaryngology-Head and Neck Surgery, University of Minnesota, Minneapolis, Minnesota, USA
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22
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George S, Lucero Y, Torres JP, Lagomarcino AJ, O'Ryan M. Gastric Damage and Cancer-Associated Biomarkers in Helicobacter pylori-Infected Children. Front Microbiol 2020; 11:90. [PMID: 32117120 PMCID: PMC7029740 DOI: 10.3389/fmicb.2020.00090] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2019] [Accepted: 01/15/2020] [Indexed: 12/11/2022] Open
Abstract
Helicobacter pylori (H. pylori) is well-known to be involved in gastric carcinogenesis, associated with deregulation of cell proliferation and epigenetic changes in cancer-related genes. H. pylori infection is largely acquired during childhood, persisting long-term in about half of infected individuals, a subset of whom will go on to develop peptic ulcer disease and eventually gastric cancer, however, the sequence of events leading to disease is not completely understood. Knowledge on carcinogenesis and gastric damage-related biomarkers is abundant in adult populations, but scarce in children. We performed an extensive literature review focusing on gastric cancer related biomarkers identified in adult populations, which have been detected in children infected with H. pylori. Biomarkers were related to expression levels (RNA or protein) and/or methylation levels (DNA) in gastric tissue or blood of infected children as compared to non-infected controls. In this review, we identified 37 biomarkers of which 24 are over expressed, three are under expressed, and ten genes are significantly hypermethylated in H. pylori-infected children compared to healthy controls in at least 1 study. Only four of these biomarkers (pepsinogen I, pepsinogen II, gastrin, and SLC5A8) have been studied in asymptomatically infected children. Importantly, 13 of these biomarkers (β-catenin, C-MYC, GATA-4, DAPK1, CXCL13, DC-SIGN, TIMP3, EGFR, GRIN2B, PIM2, SLC5A8, CDH1, and VCAM-1.) are consistently deregulated in infected children and in adults with gastric cancer. Future studies should be designed to determine the clinical significance of these changes in infection-associated biomarkers in children and their persistence over time. The effect of eradication therapy over these biomarkers in children if proven significant, could lead to modifications in treatment guidelines for younger populations, and eventually promote the development of preventive strategies, such as vaccination, in the near future.
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Affiliation(s)
- Sergio George
- Host-Pathogen Interaction Laboratory, Microbiology and Mycology Program, ICBM, Faculty of Medicine, University of Chile, Santiago, Chile
| | - Yalda Lucero
- Host-Pathogen Interaction Laboratory, Microbiology and Mycology Program, ICBM, Faculty of Medicine, University of Chile, Santiago, Chile.,Department of Pediatrics and Pediatric Surgery, Dr. Roberto del Río Hospital, Faculty of Medicine, Universidad de Chile, Santiago, Chile
| | - Juan Pablo Torres
- Host-Pathogen Interaction Laboratory, Microbiology and Mycology Program, ICBM, Faculty of Medicine, University of Chile, Santiago, Chile.,Department of Pediatrics and Pediatric Surgery, Dr. Luis Calvo Mackenna Hospital, Faculty of Medicine, Universidad de Chile, Santiago, Chile
| | - Anne J Lagomarcino
- Host-Pathogen Interaction Laboratory, Microbiology and Mycology Program, ICBM, Faculty of Medicine, University of Chile, Santiago, Chile
| | - Miguel O'Ryan
- Host-Pathogen Interaction Laboratory, Microbiology and Mycology Program, ICBM, Faculty of Medicine, University of Chile, Santiago, Chile.,Millennium Institute on Immunology and Immunotherapy (IMII), Faculty of Medicine, Universidad de Chile, Santiago, Chile
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Wu L, Guo C, Wu J. Therapeutic potential of PPARγ natural agonists in liver diseases. J Cell Mol Med 2020; 24:2736-2748. [PMID: 32031298 PMCID: PMC7077554 DOI: 10.1111/jcmm.15028] [Citation(s) in RCA: 82] [Impact Index Per Article: 16.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2019] [Revised: 11/17/2019] [Accepted: 01/13/2020] [Indexed: 12/11/2022] Open
Abstract
Peroxisome proliferator‐activated receptor gamma (PPARγ) is a vital subtype of the PPAR family. The biological functions are complex and diverse. PPARγ plays a significant role in protecting the liver from inflammation, oxidation, fibrosis, fatty liver and tumours. Natural products are a promising pool for drug discovery, and enormous research effort has been invested in exploring the PPARγ‐activating potential of natural products. In this manuscript, we will review the research progress of PPARγ agonists from natural products in recent years and probe into the application potential and prospects of PPARγ natural agonists in the therapy of various liver diseases, including inflammation, hepatic fibrosis, non‐alcoholic fatty liver and liver cancer.
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Affiliation(s)
- Liwei Wu
- Department of Gastroenterology, Putuo People's Hospital, Tongji University School of Medicine, Shanghai, China.,Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Chuanyong Guo
- Department of Gastroenterology, Putuo People's Hospital, Tongji University School of Medicine, Shanghai, China.,Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Jianye Wu
- Department of Gastroenterology, Putuo People's Hospital, Tongji University School of Medicine, Shanghai, China
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24
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Costantini L, Molinari R, Farinon B, Merendino N. Retinoic Acids in the Treatment of Most Lethal Solid Cancers. J Clin Med 2020; 9:E360. [PMID: 32012980 PMCID: PMC7073976 DOI: 10.3390/jcm9020360] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2020] [Revised: 01/21/2020] [Accepted: 01/24/2020] [Indexed: 12/14/2022] Open
Abstract
Although the use of oral administration of pharmacological all-trans retinoic acid (ATRA) concentration in acute promyelocytic leukaemia (APL) patients was approved for over 20 years and used as standard therapy still to date, the same use in solid cancers is still controversial. In the present review the literature about the top five lethal solid cancers (lung, stomach, liver, breast, and colon cancer), as defined by The Global Cancer Observatory of World Health Organization, and retinoic acids (ATRA, 9-cis retinoic acid, and 13-cis retinoic acid, RA) was compared. The action of retinoic acids in inhibiting the cell proliferation was found in several cell pathways and compartments: from membrane and cytoplasmic signaling, to metabolic enzymes, to gene expression. However, in parallel in the most aggressive phenotypes several escape routes have evolved conferring retinoic acids-resistance. The comparison between different solid cancer types pointed out that for some cancer types several information are still lacking. Moreover, even though some pathways and escape routes are the same between the cancer types, sometimes they can differently respond to retinoic acid therapy, so that generalization cannot be made. Further studies on molecular pathways are needed to perform combinatorial trials that allow overcoming retinoic acids resistance.
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Affiliation(s)
- Lara Costantini
- Department of Ecological and Biological Sciences (DEB), Tuscia University, Largo dell’Università snc, 01100 Viterbo, Italy
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25
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Frapolli R, Bello E, Ponzo M, Craparotta I, Mannarino L, Ballabio S, Marchini S, Carrassa L, Ubezio P, Porcu L, Brich S, Sanfilippo R, Casali PG, Gronchi A, Pilotti S, D'Incalci M. Combination of PPARγ Agonist Pioglitazone and Trabectedin Induce Adipocyte Differentiation to Overcome Trabectedin Resistance in Myxoid Liposarcomas. Clin Cancer Res 2019; 25:7565-7575. [PMID: 31481505 DOI: 10.1158/1078-0432.ccr-19-0976] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2019] [Revised: 07/01/2019] [Accepted: 08/28/2019] [Indexed: 11/16/2022]
Abstract
PURPOSE This study was aimed at investigating whether the PPARγ agonist pioglitazone-given in combination with trabectedin-is able to reactivate adipocytic differentiation in myxoid liposarcoma (MLS) patient-derived xenografts, overcoming resistance to trabectedin. EXPERIMENTAL DESIGN The antitumor and biological effects of trabectedin, pioglitazone, and the combination of the two drugs were investigated in nude mice bearing well-characterized MLS xenografts representative of innate or acquired resistance against trabectedin. Pioglitazone and trabectedin were given by daily oral and weekly i.v. administrations, respectively. Molecular studies were performed by using microarrays approach, real-time PCR, and Western blotting. RESULTS We found that the resistance of MLS against trabectedin is associated with the lack of activation of adipogenesis. The PPARγ agonist pioglitazone reactivated adipogenesis, assessed by histologic and gene pathway analyses. Pioglitazone was well tolerated and did not increase the toxicity of trabectedin. The ability of pioglitazone to reactivate adipocytic differentiation was observed by morphologic examination, and it is consistent with the increased expression of genes such as ADIPOQ implicated in the adipogenesis process. The determination of adiponectin by Western blotting constitutes a good and reliable biomarker related to MLS adipocytic differentiation. CONCLUSIONS The finding that the combination of pioglitazone and trabectedin induces terminal adipocytic differentiation of some MLSs with the complete pathologic response and cure of tumor-bearing mice provides a strong rationale to test the combination of trabectedin and pioglitazone in patients with MLS.
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Affiliation(s)
- Roberta Frapolli
- Unit of Preclinical Experimental Therapeutics, Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy
| | - Ezia Bello
- Unit of Preclinical Experimental Therapeutics, Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy
| | - Marianna Ponzo
- Unit of Preclinical Experimental Therapeutics, Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy
| | - Ilaria Craparotta
- Unit of Translational Genomic, Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy
| | - Laura Mannarino
- Unit of Translational Genomic, Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy
| | - Sara Ballabio
- Unit of Translational Genomic, Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy
| | - Sergio Marchini
- Unit of Translational Genomic, Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy
| | - Laura Carrassa
- Unit of DNA repair, Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy
| | - Paolo Ubezio
- Unit of Biophysics, Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy
| | - Luca Porcu
- Unit of Methodological Research, Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy
| | - Silvia Brich
- Laboratory of Molecular Pathology, Department of Pathology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Roberta Sanfilippo
- Medical Oncology Unit 2, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Paolo Giovanni Casali
- Medical Oncology Unit 2, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Alessandro Gronchi
- Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Silvana Pilotti
- Laboratory of Molecular Pathology, Department of Pathology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Maurizio D'Incalci
- Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy.
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15-Deoxy-∆- 12,14-Prostaglandin J2 (15d-PGJ2), an Endogenous Ligand of PPAR- γ: Function and Mechanism. PPAR Res 2019; 2019:7242030. [PMID: 31467514 PMCID: PMC6699332 DOI: 10.1155/2019/7242030] [Citation(s) in RCA: 65] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2019] [Accepted: 07/14/2019] [Indexed: 02/06/2023] Open
Abstract
15-Deoxy-∆-12,14-prostaglandin J2 (15d-PGJ2), a natural peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist, has been explored in some detail over the last 20 years. By triggering the PPAR-γ signalling pathway, it plays many roles and exerts antitumour, anti-inflammatory, antioxidation, antifibrosis, and antiangiogenesis effects. Although many synthetic PPAR-γ receptor agonists have been developed, as an endogenous product of PPAR-γ receptors, 15d-PGJ2 has beneficial characteristics including rapid expression and the ability to contribute to a natural defence mechanism. In this review, we discuss the latest advances in our knowledge of the biological role of 15d-PGJ2 mediated through PPAR-γ. It is important to understand its structure, synthesis, and functional mechanisms to develop preventive agents and limit the progression of associated diseases.
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27
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Bie Q, Dong H, Jin C, Zhang H, Zhang B. 15d-PGJ2 is a new hope for controlling tumor growth. Am J Transl Res 2018; 10:648-658. [PMID: 29636856 PMCID: PMC5883107] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2017] [Accepted: 12/23/2017] [Indexed: 06/08/2023]
Abstract
15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2), a natural PPARγ agonist, has been investigated for over a decade. Studies have revealed that it has proapoptotic, anti-inflammatory, antiangiogenic, and anti-metastatic abilities, as well as a significant anticancer effect. However, the mechanisms underlying the actions of 15d-PGJ2 on various tumors are only partially known. In this review, we discuss the recent progress in elucidating these mechanisms. Understanding the various functions and mechanisms of 15d-PGJ2 are crucial for the development of new therapies for controlling tumor growth and providing the basis for further research.
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Affiliation(s)
- Qingli Bie
- Department of Laboratory Medicine, Affiliated Hospital of Jining Medical UniversityJining, Shandong, P. R. China
- Institute of Forensic Medicine and Laboratory Medicine, Jining Medical UniversityJining, Shandong, P. R. China
| | - Haixin Dong
- Department of Laboratory Medicine, Affiliated Hospital of Jining Medical UniversityJining, Shandong, P. R. China
| | - Chengqiang Jin
- Department of Laboratory Medicine, Affiliated Hospital of Jining Medical UniversityJining, Shandong, P. R. China
| | - Hao Zhang
- Department of Laboratory Medicine, Affiliated Hospital of Jining Medical UniversityJining, Shandong, P. R. China
- Department of Hematology, Affiliated Hospital of Jining Medical UniversityJining, Shandong, P. R. China
| | - Bin Zhang
- Department of Laboratory Medicine, Affiliated Hospital of Jining Medical UniversityJining, Shandong, P. R. China
- Institute of Forensic Medicine and Laboratory Medicine, Jining Medical UniversityJining, Shandong, P. R. China
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28
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Liu L, Si N, Ma Y, Ge D, Yu X, Fan A, Wang X, Hu J, Wei P, Chen Z, Zhang Q, Feng C. Hydroxysafflor-Yellow A Induces Human Gastric Carcinoma BGC-823 Cell Apoptosis by Activating Peroxisome Proliferator-Activated Receptor Gamma (PPARγ). Med Sci Monit 2018; 24:803-811. [PMID: 29417935 PMCID: PMC5813879 DOI: 10.12659/msm.905587] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2017] [Accepted: 07/03/2017] [Indexed: 11/17/2022] Open
Abstract
BACKGROUND Anti-tumor properties of hydroxysafflor-yellow A (HSYA) have been recently revealed, as a series of apoptotic factors were confirmed to be regulated by HSYA and associated with peroxisome proliferator-activated receptor Gamma (PPARγ). In this study, we investigated the cell apoptosis mechanism of HSYA via activated PPARγ signal in human gastric carcinoma cells. MATERIAL AND METHODS BGC-823 cells were cultured and divided into 5 independent groups: Tumor, HSYA, HSYA+PPARγ inhibitor (GW9662), and PPARg agonist (RGZ), RGZ+GW9662. Cell proliferative activity was measured by MTT. Apoptosis and cell cycle were detected by flow cytometry. The nuclear translocation of PPARγ was detected by immunofluorescence staining chemistry, and mRNA levels of PPARγ and caspase-3 were measured by real-time qPCR. RESULTS Compared to the RGZ group, the HSYA group (100 µM) showed a similar inhibitory effect on the proliferation process of BGC-823 cells, inducing their apoptosis. As a result, the transition of BGC-823 cells from G0/G1 phase to S phase was blocked. HSYA was also found to promote the nuclear translocation of PPARγ, leading to increased expression of PPARγ and caspase-3. The regulatory effect of HSYA on BGC-823 cells could be further inhibited by PPARγ inhibitor in group GW9662. CONCLUSIONS We report the inhibitory effect of HSYA on the proliferation of BGC-823 cells, which results in activating PPARg-dependent cell cycle blocking and cell apoptosis, suggesting that PPARg is a specific type of HSYA that can induce apoptosis of BGC-823 cells.
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Affiliation(s)
- Li Liu
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, P.R. China
| | - Na Si
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, P.R. China
| | - YiCong Ma
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, P.R. China
| | - DongYu Ge
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, P.R. China
| | - Xue Yu
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, P.R. China
| | - AngRan Fan
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, P.R. China
| | - Xu Wang
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, P.R. China
| | - JingHong Hu
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, P.R. China
| | - Peng Wei
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, P.R. China
| | - ZiWei Chen
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, P.R. China
| | - Qian Zhang
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, P.R. China
| | - CuiLing Feng
- Department of Traditional Chinese Medicine, Peking University People’s Hospital, Beijing, P.R. China
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Wu K, Yang Y, Liu D, Qi Y, Zhang C, Zhao J, Zhao S. Activation of PPARγ suppresses proliferation and induces apoptosis of esophageal cancer cells by inhibiting TLR4-dependent MAPK pathway. Oncotarget 2018; 7:44572-44582. [PMID: 27323819 PMCID: PMC5190119 DOI: 10.18632/oncotarget.10067] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2016] [Accepted: 05/29/2016] [Indexed: 01/07/2023] Open
Abstract
Although substantial studies on peroxisome proliferator-activated receptor γ (PPARγ) have focused on the mechanisms by which PPARγ regulates glucose and lipid metabolism, recent reports have suggested that PPARγ shows tumorigenic or antitumorigenic effects. The roles and mechanisms of PPARγ activation in esophageal cancer remain unclarified. EC109 and TE10 esophageal cancer cells were treated with 0, 10, 20 and 40 mM of PPARγ agonist rosiglitazone (RGZ) for 24, 48, and 72 h, and the cell viability and apoptosis were detected using methyl thiazolyl tetrazolium (MTT) assay and Flow cytometric (FCM) analysis, respectively. Moreover, the effects of inhibition of PPARγ by antagonist or specific RNA interference on cell viability, apoptosis, the Toll-like receptor 4 (TLR4) and mitogen-activated protein kinase (MAPK) pathways were evaluated. Additionally, the effect of TLR4 signaling on the MAPK pathway, cell viability and apoptosis was assessed. The results showed that RGZ suppressed proliferation and induced apoptosis of esophageal cancer cells, which could be partly restored by inactivation of PPARγ. RGZ suppressed the MAPK and TLR4 pathways, and the inhibitory effect could be counteracted by PPARγ antagonist or specific RNA interference. We also suggested that MAPK activation was regulated by the TLR4 pathway and that blocking the TLR4 and MAPK pathways significantly suppressed proliferation and induced apoptosis of esophageal cancer cells. In conclusion, our data suggested that activation of PPARγ suppressed proliferation and induced apoptosis of esophageal cancer cells by inhibiting TLR4-dependent MAPK pathway.
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Affiliation(s)
- Kai Wu
- Department of Thoracic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Yang Yang
- Department of Thoracic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Donglei Liu
- Department of Thoracic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Yu Qi
- Department of Thoracic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Chunyang Zhang
- Department of Thoracic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Jia Zhao
- Department of Thoracic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Song Zhao
- Department of Thoracic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
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30
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Channar PA, Saeed A, Larik FA, Rafiq M, Ashraf Z, Jabeen F, Fattah TA. Synthesis, computational studies and enzyme inhibitory kinetics of substituted methyl[2-(4-dimethylamino-benzylidene)-hydrazono)-4-oxo-thiazolidin-5-ylidene]acetates as mushroom tyrosinase inhibitors. Bioorg Med Chem 2017; 25:5929-5938. [DOI: 10.1016/j.bmc.2017.09.009] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2017] [Revised: 08/02/2017] [Accepted: 09/06/2017] [Indexed: 11/26/2022]
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Xu X, Wang J, Jiang H, Meng L, Lang B. Rosiglitazone induces apoptosis on human bladder cancer 5637 and T24 cell lines. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2017; 10:10197-10204. [PMID: 31966353 PMCID: PMC6965772] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 04/08/2016] [Accepted: 06/13/2016] [Indexed: 06/10/2023]
Abstract
Rosiglitazone is a synthetic ligand of peroxisome proliferator-activated receptor γ (PPARγ), and it can induce apoptosis and autophagy in a variety of cancer cells. In the present study, we aimed to investigate the influence of rosiglitazone on the proliferation and apoptosis of the 5637 and T24 human bladder cancer cell lines. The results demonstrated that the level of growth inhibition rate was gradually increased by treating the 5637 and T24 cells with higher doses of rosiglitazone and longer incubation time. Rosiglitazone exerted a potent inhibiting effect on migration of the 5637 and T24 cell lines. Moreover, rosiglitazone exerted a antineoplastic activity by inducing apoptosis and cell cycle arrest. Furthermore, treatment with rosiglitazone led to decrease the anti-apoptotic protein Bcl-2 level and increase the pro-apoptotic protein caspase 3 level in 5637 and T24 cells. Importantly, the protein expression of PPAR γ was significantly increased in the present of rosiglitazone in 5637 and T24 cells as compared to control group. In conclusion, the present study demonstrates that rosiglitazone has a potential antineoplastic activity in human bladder cancer cell lines, and the underlying mechanism was mediated, at least partially, through regulation of apoptosis-related protein and PPAR γ expression.
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Affiliation(s)
- Xiaoyuan Xu
- Key Laboratory of System Bio-medicine of Jiangxi Province, Jiujiang UniversityJiujiang, China
| | - Jianjun Wang
- Department of Orthopedic Surgery, People Hospital of Zhuhai, The Third Affiliated Hospital of Jinan UniversityZhuhai, China
| | - He Jiang
- Key Laboratory of System Bio-medicine of Jiangxi Province, Jiujiang UniversityJiujiang, China
| | - Lirong Meng
- School of Health Sciences, Macao Polytechnic InstituteMacao, China
| | - Bin Lang
- School of Health Sciences, Macao Polytechnic InstituteMacao, China
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32
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Thermodynamics in cancers: opposing interactions between PPAR gamma and the canonical WNT/beta-catenin pathway. Clin Transl Med 2017; 6:14. [PMID: 28405929 PMCID: PMC5389954 DOI: 10.1186/s40169-017-0144-7] [Citation(s) in RCA: 51] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2016] [Accepted: 03/20/2017] [Indexed: 01/03/2023] Open
Abstract
Cancer cells are the site of numerous metabolic and thermodynamic abnormalities. We focus this review on the interactions between the canonical WNT/beta-catenin pathway and peroxisome proliferator-activated receptor gamma (PPAR gamma) in cancers and their implications from an energetic and metabolic point of view. In numerous tissues, PPAR gamma activation induces inhibition of beta-catenin pathway, while the activation of the canonical WNT/beta-catenin pathway inactivates PPAR gamma. In most cancers but not all, PPAR gamma is downregulated while the WNT/beta-catenin pathway is upregulated. In cancer cells, upregulation of the WNT/beta-catenin signaling induces dramatic changes in key metabolic enzymes that modify their thermodynamic behavior. This leads to activation of pyruvate dehydrogenase kinase1 (PDK-1) and monocarboxylate lactate transporter. Consequently, phosphorylation of PDK-1 inhibits the pyruvate dehydrogenase complex (PDH). Thus, a large part of pyruvate cannot be converted into acetyl-coenzyme A (acetyl-CoA) in mitochondria and only a part of acetyl-CoA can enter the tricarboxylic acid cycle. This leads to aerobic glycolysis in spite of the availability of oxygen. This phenomenon is referred to as the Warburg effect. Cytoplasmic pyruvate is converted into lactate. The WNT/beta-catenin pathway induces the transcription of genes involved in cell proliferation, i.e., MYC and CYCLIN D1. This ultimately promotes the nucleotide, protein and lipid synthesis necessary for cell growth and multiplication. In cancer, activation of the PI3K-AKT pathway induces an increase of the aerobic glycolysis. Moreover, prostaglandin E2 by activating the canonical WNT pathway plays also a role in cancer. In addition in many cancer cells, PPAR gamma is downregulated. Moreover, PPAR gamma contributes to regulate some key circadian genes. In cancers, abnormalities in the regulation of circadian rhythms (CRs) are observed. CRs are dissipative structures which play a key-role in far-from-equilibrium thermodynamics. In cancers, metabolism, thermodynamics and CRs are intimately interrelated.
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Quantitative targeted metabolomics for 15d-deoxy-Δ12, 14-PGJ2 (15d-PGJ2) by MALDI-MS. BIOTECHNOL BIOPROC E 2017. [DOI: 10.1007/s12257-016-0558-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
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Hu Y, Tao X, Han X, Xu L, Yin L, Qi Y, Zhao Y, Xu Y, Wang C, Peng J. Dioscin attenuates gastric ischemia/reperfusion injury through the down-regulation of PKC/ERK1/2 signaling via PKCα and PKCβ2 inhibition. Chem Biol Interact 2016; 258:234-244. [PMID: 27649624 DOI: 10.1016/j.cbi.2016.09.014] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2016] [Revised: 08/18/2016] [Accepted: 09/16/2016] [Indexed: 02/07/2023]
Abstract
BACKGROUND We previously reported the promising effects of dioscin against cerebral and renal ischemia-reperfusion (I/R) injury. However, its role against gastric I/R injury has not yet been reported. Thus, the aim of the present work was to investigate the protective effect and possible mechanisms of dioscin against gastric I/R. MATERIALS AND METHODS The hypoxia-reoxygenation (H/R) model in GES-1 cells and the celiac artery occlusion model in rats were carried out in the study. RESULTS Dioscin markedly attenuated H/R insult in GES-1 cells and gastric I/R injury in rats. Mechanistic studies demonstrated that dioscin-induced gastric protection was accompanied by inhibiting the levels of PKCα, PKCβ2 and phosphorylation via decreasing Raf-1 level. Blockade of PKC/ERK1/2 signaling pathway by dioscin decreased MEK1/2 level, ERK1/2 phosphorylation and the nuclear translocation, NF-κB and AP-1 transcriptional activities, pro-inflammatory cytokine responses, and up-regulated PPAR-γ level. Moreover, the results of small interfering RNA (siRNA) and overexpression of PKCα and PKCβ2 confirmed that dioscin attenuated gastric I/R injury through inhibiting PKC/ERK1/2 signaling by down-regulating PKCα and PKCβ2. CONCLUSION These data confirmed the protective effect of dioscin against gastric I/R injury, which should be developed as a therapeutic agent for the treatment of acute gastric mucosal lesions in the future.
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Affiliation(s)
- Yupeng Hu
- College of Pharmacy, Dalian Medical University, Western 9 Lvshunnan Road, Dalian 116044, China
| | - Xufeng Tao
- College of Pharmacy, Dalian Medical University, Western 9 Lvshunnan Road, Dalian 116044, China
| | - Xu Han
- College of Pharmacy, Dalian Medical University, Western 9 Lvshunnan Road, Dalian 116044, China
| | - Lina Xu
- College of Pharmacy, Dalian Medical University, Western 9 Lvshunnan Road, Dalian 116044, China
| | - Lianhong Yin
- College of Pharmacy, Dalian Medical University, Western 9 Lvshunnan Road, Dalian 116044, China
| | - Yan Qi
- College of Pharmacy, Dalian Medical University, Western 9 Lvshunnan Road, Dalian 116044, China
| | - Yanyan Zhao
- College of Pharmacy, Dalian Medical University, Western 9 Lvshunnan Road, Dalian 116044, China
| | - Youwei Xu
- College of Pharmacy, Dalian Medical University, Western 9 Lvshunnan Road, Dalian 116044, China
| | - Changyuan Wang
- College of Pharmacy, Dalian Medical University, Western 9 Lvshunnan Road, Dalian 116044, China
| | - Jinyong Peng
- College of Pharmacy, Dalian Medical University, Western 9 Lvshunnan Road, Dalian 116044, China.
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PPAR Gamma in Neuroblastoma: The Translational Perspectives of Hypoglycemic Drugs. PPAR Res 2016; 2016:3038164. [PMID: 27799938 PMCID: PMC5069360 DOI: 10.1155/2016/3038164] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2016] [Accepted: 09/14/2016] [Indexed: 12/15/2022] Open
Abstract
Neuroblastoma (NB) is the most common and aggressive pediatric cancer, characterized by a remarkable phenotypic diversity and high malignancy. The heterogeneous clinical behavior, ranging from spontaneous remission to fatal metastatic disease, is attributable to NB biology and genetics. Despite major advances in therapies, NB is still associated with a high morbidity and mortality. Thus, novel diagnostic, prognostic, and therapeutic approaches are required, mainly to improve treatment outcomes of high-risk NB patients. Among neuroepithelial cancers, NB is the most studied tumor as far as PPAR ligands are concerned. PPAR ligands are endowed with antitumoral effects, mainly acting on cancer stem cells, and constitute a possible add-on therapy to antiblastic drugs, in particular for NB with unfavourable prognosis. While discussing clinical background, this review will provide a synopsis of the major studies about PPAR expression in NB, focusing on the potential beneficial effects of hypoglycemic drugs, thiazolidinediones and metformin, to reduce the occurrence of relapses as well as tumor regrowth in NB patients.
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Ji HG, Piao JY, Kim SJ, Kim DH, Lee HN, Na HK, Surh YJ. Docosahexaenoic acid inhibits Helicobacter pylori-induced STAT3 phosphorylation through activation of PPARγ. Mol Nutr Food Res 2016; 60:1448-57. [PMID: 27079734 DOI: 10.1002/mnfr.201600009] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2016] [Revised: 03/08/2016] [Accepted: 03/09/2016] [Indexed: 01/09/2023]
Abstract
SCOPE The health beneficial effects of docosahexaenoic acid (DHA) have been attributed to its anti-inflammatory properties. However, the molecular mechanism underlying anti-inflammatory effects of DHA remains largely elusive. METHODS AND RESULTS In the present study, DHA was found to suppress the phosphorylation and nuclear translocation of signal transducer and activator of transcription 3 (STAT3) induced by Helicobacter pylori infection in human gastric cancer AGS cells. Notably, DHA induced expression of suppressor of cytokine signaling 3 (SOCS3), a negative regulator of STAT3. Knockdown of SOCS3 abolished the suppressive effect of DHA on STAT3(Tyr705) phosphorylation induced by H. pylori infection. DHA also induced nuclear translocation, DNA binding, and transcriptional activities of peroxisome proliferator-activated receptor gamma (PPARγ) in AGS cells. Knockdown of PPARγ inhibited the transcription of SOCS3 and attenuated the suppressive effect of DHA on phosphorylation of STAT3(Tyr705) induced by H. pylori. The PPARγ antagonist bisphenol A diglycidyl ether also mitigated the suppressive effect of DHA on H. pylori-induced phosphorylation of STAT3(Tyr705) . In addition, DHA inhibited the expression of c-Myc, which was attenuated in the AGS cells harboring SOCS3 specific siRNA. DHA also markedly decreased anchorage-independent growth of AGS cells infected by H. pylori. CONCLUSION DHA inhibits H. pylori-induced STAT3 phosphorylation in a PPARγ/SOCS3-dependent manner.
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Affiliation(s)
- Hyeon-Geun Ji
- Cancer Research Institute, Seoul National University, Seoul, South Korea.,Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, South Korea
| | - Juan-Yu Piao
- Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, South Korea
| | - Su-Jung Kim
- Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Sciences, Seoul, South Korea
| | - Do-Hee Kim
- Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, South Korea
| | - Ha-Na Lee
- Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, South Korea
| | - Hye-Kyung Na
- Department of Food and Nutrition, College of Human Ecology, Sungshin Women's University, Seoul, South Korea
| | - Young-Joon Surh
- Cancer Research Institute, Seoul National University, Seoul, South Korea.,Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, South Korea.,Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Sciences, Seoul, South Korea
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ZHANG SHIMENG, LIU FEI, MAO XINRU, HUANG JINLAN, YANG JUNYAO, YIN XIAOMAO, WU LIJUAN, ZHENG LEI, WANG QIAN. Elevation of miR-27b by HPV16 E7 inhibits PPARγ expression and promotes proliferation and invasion in cervical carcinoma cells. Int J Oncol 2015; 47:1759-66. [DOI: 10.3892/ijo.2015.3162] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2015] [Accepted: 08/06/2015] [Indexed: 11/06/2022] Open
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Keap1/Nrf2 pathway in the frontiers of cancer and non-cancer cell metabolism. Biochem Soc Trans 2015; 43:639-44. [PMID: 26551705 PMCID: PMC4613493 DOI: 10.1042/bst20150049] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2015] [Indexed: 12/13/2022]
Abstract
Cancer cells adapt their metabolism to their increased needs for energy and substrates for protein, lipid and nucleic acid synthesis. Nuclear erythroid factor 2-like 2 (Nrf2) pathway is usually activated in cancers and has been suggested to promote cancer cell survival mainly by inducing a large battery of cytoprotective genes. This mini review focuses on metabolic pathways, beyond cytoprotection, which can be directly or indirectly regulated by Nrf2 in cancer cells to affect their survival. The pentose phosphate pathway (PPP) is enhanced by Nrf2 in cancers and aids their growth. PPP has also been found to be up-regulated in non-cancer tissues and other pathways, such as de novo lipogenesis, have been found to be repressed after activation of the Nrf2 pathway. The importance of these Nrf2-regulated metabolic pathways in cancer compared with non-cancer state remains to be determined. Last but not least, the importance of context about Nrf2 and cancer is highlighted as the Nrf2 pathway may be activated in cancers but its pharmacological activators are useful in chemoprevention.
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Henique C, Bollee G, Lenoir O, Dhaun N, Camus M, Chipont A, Flosseau K, Mandet C, Yamamoto M, Karras A, Thervet E, Bruneval P, Nochy D, Mesnard L, Tharaux PL. Nuclear Factor Erythroid 2-Related Factor 2 Drives Podocyte-Specific Expression of Peroxisome Proliferator-Activated Receptor γ Essential for Resistance to Crescentic GN. J Am Soc Nephrol 2015; 27:172-88. [PMID: 25999406 DOI: 10.1681/asn.2014111080] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2014] [Accepted: 03/29/2015] [Indexed: 01/10/2023] Open
Abstract
Necrotizing and crescentic rapidly progressive GN (RPGN) is a life-threatening syndrome characterized by a rapid loss of renal function. Evidence suggests that podocyte expression of the transcription factor peroxisome proliferator-activated receptor γ (PPARγ) may prevent podocyte injury, but the function of glomerular PPARγ in acute, severe inflammatory GN is unknown. Here, we observed marked loss of PPARγ abundance and transcriptional activity in glomerular podocytes in experimental RPGN. Blunted expression of PPARγ in podocyte nuclei was also found in kidneys from patients diagnosed with crescentic GN. Podocyte-specific Pparγ gene targeting accentuated glomerular damage, with increased urinary loss of albumin and severe kidney failure. Furthermore, a PPARγ gain-of-function approach achieved by systemic administration of thiazolidinedione (TZD) failed to prevent severe RPGN in mice with podocyte-specific Pparγ gene deficiency. In nuclear factor erythroid 2-related factor 2 (NRF2)-deficient mice, loss of podocyte PPARγ was observed at baseline. NRF2 deficiency markedly aggravated the course of RPGN, an effect that was partially prevented by TZD administration. Furthermore, delayed administration of TZD, initiated after the onset of RPGN, still alleviated the severity of experimental RPGN. These findings establish a requirement for the NRF2-PPARγ cascade in podocytes, and we suggest that these transcription factors have a role in augmenting the tolerance of glomeruli to severe immune-complex mediated injury. The NRF2-PPARγ pathway may be a therapeutic target for RPGN.
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Affiliation(s)
- Carole Henique
- Paris Cardiovascular Centre (PARCC), Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France;
| | - Guillaume Bollee
- Paris Cardiovascular Centre (PARCC), Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France; Centre de Recherche, Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada
| | - Olivia Lenoir
- Paris Cardiovascular Centre (PARCC), Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France
| | - Neeraj Dhaun
- Paris Cardiovascular Centre (PARCC), Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France; British Heart Foundation Centre of Research Excellence (BHF CoRE), Edinburgh, United Kingdom
| | - Marine Camus
- Paris Cardiovascular Centre (PARCC), Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France
| | - Anna Chipont
- Paris Cardiovascular Centre (PARCC), Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France
| | - Kathleen Flosseau
- Paris Cardiovascular Centre (PARCC), Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France
| | - Chantal Mandet
- Paris Cardiovascular Centre (PARCC), Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France
| | - Masayuki Yamamoto
- Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Alexandre Karras
- Paris Cardiovascular Centre (PARCC), Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France; Department of Nephrology and
| | - Eric Thervet
- Paris Cardiovascular Centre (PARCC), Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France; Department of Nephrology and
| | - Patrick Bruneval
- Paris Cardiovascular Centre (PARCC), Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France; Department of Pathology, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France; and
| | - Dominique Nochy
- Paris Cardiovascular Centre (PARCC), Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France; Department of Pathology, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France; and
| | - Laurent Mesnard
- Unité Mixte de Recherche (UMR) 702, Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France
| | - Pierre-Louis Tharaux
- Paris Cardiovascular Centre (PARCC), Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France; Department of Nephrology and
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Zhao J, Zhi Z, Song G, Wang J, Wang C, Ma H, Yu X, Sui A, Zhang H. Peroxisome Proliferator-Activated Receptor-Gamma Pro12Ala Polymorphism Could be a Risk Factor for Gastric Cancer. Asian Pac J Cancer Prev 2015; 16:2333-40. [DOI: 10.7314/apjcp.2015.16.6.2333] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
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Arif IS, Hooper CL, Greco F, Williams AC, Boateng SY. Increasing doxorubicin activity against breast cancer cells using PPARγ-ligands and by exploiting circadian rhythms. Br J Pharmacol 2015; 169:1178-88. [PMID: 23578093 DOI: 10.1111/bph.12202] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2012] [Revised: 01/25/2013] [Accepted: 04/09/2013] [Indexed: 01/09/2023] Open
Abstract
BACKGROUND AND PURPOSE Doxorubicin is effective against breast cancer, but its major side effect is cardiotoxicity. The aim of this study was to determine whether the efficacy of doxorubicin on cancer cells could be increased in combination with PPARγ agonists or chrono-optimization by exploiting the diurnal cycle. EXPERIMENTAL APPROACH We determined cell toxicity using MCF-7 cancer cells, neonatal rat cardiac myocytes and fibroblasts in this study. KEY RESULTS Doxorubicin damages the contractile filaments of cardiac myocytes and affects cardiac fibroblasts by significantly inhibiting collagen production and proliferation at the level of the cell cycle. Cyclin D1 protein levels decreased significantly following doxorubicin treatment indicative of a G1/S arrest. PPARγ agonists with doxorubicin increased the toxicity to MCF-7 cancer cells without affecting cardiac cells. Rosiglitazone and ciglitazone both enhanced anti-cancer activity when combined with doxorubicin (e.g. 50% cell death for doxorubicin at 0.1 μM compared to 80% cell death when combined with rosiglitazone). Thus, the therapeutic dose of doxorubicin could be reduced by 20-fold through combination with the PPARγ agonists, thereby reducing adverse effects on the heart. The presence of melatonin also significantly increased doxorubicin toxicity, in cardiac fibroblasts (1 μM melatonin) but not in MCF-7 cells. CONCLUSIONS AND IMPLICATIONS Our data show, for the first time, that circadian rhythms play an important role in doxorubicin toxicity in the myocardium; doxorubicin should be administered mid-morning, when circulating levels of melatonin are low, and in combination with rosiglitazone to increase therapeutic efficacy in cancer cells while reducing the toxic effects on the heart.
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Affiliation(s)
- I S Arif
- School of Pharmacy, University of Reading, Reading, UK
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Zhang Y, Luo HY, Liu GL, Wang DS, Wang ZQ, Zeng ZL, Xu RH. Prognostic significance and therapeutic implications of peroxisome proliferator-activated receptor γ overexpression in human pancreatic carcinoma. Int J Oncol 2015; 46:175-84. [PMID: 25333644 DOI: 10.3892/ijo.2014.2709] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2014] [Accepted: 09/23/2014] [Indexed: 12/18/2022] Open
Abstract
Peroxisome proliferator-activated receptor γ (PPARγ) is a ligand-activated nuclear receptor which has been implicated in carcinogenesis and angiogenesis in a wide range of cancers, including pancreatic carcinoma (PC). We aimed to characterize the prognosis and potential therapeutic implications of PPARγ in PC. Real-time RT-PCR and western blotting were used to quantify PPARγ expression in immortalized pancreatic epithelial cells, PC cell lines and freshly isolated matched tumor and non-tumor tissues. PPARγ protein expression was analyzed by immunohistochemistry (IHC) in archived tumor tissues from 101 PC patients. Furthermore, the effect of PPARγ on the cytotoxic action of gemcitabine (Gem) and 5-fluorouracil (5-FU) in PC cell lines was investigated in vitro using RNA interference techniques. Both PPARγ protein and mRNA were expressed at markedly higher levels in all of the PC cell lines and freshly isolated PC tissues, compared to normal immortalized pancreatic epithelial cells and the matched adjacent non-tumor tissues. High levels of PPARγ expression correlated significantly with tumor-node-metastasis (TNM) staging (P<0.001) and poor overall survival (P<0.001), especially in patients with advanced disease who received postoperative chemotherapy. While silencing of PPARγ significantly inhibit the cytotoxic effects of both gemcitabine and 5-fluorouracil in PC cells in vitro. This study suggests that high levels of PPARγ expression are associated with poor overall survival in PC. Additionally, PPARγ promotes chemoresistance in PC cells, indicating that PPARγ may represent a novel therapeutic target for PC.
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Affiliation(s)
- Yan Zhang
- State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou 510060, P.R. China
| | - Hui-Yan Luo
- State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou 510060, P.R. China
| | - Guang-Lin Liu
- Department of Radiation Oncology, The First Affiliated Hospital of Guangzhou Medical College, Guangzhou 510120, P.R. China
| | - De-Shen Wang
- State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou 510060, P.R. China
| | - Zhi-Qiang Wang
- State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou 510060, P.R. China
| | - Zhao-Lei Zeng
- State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou 510060, P.R. China
| | - Rui-Hua Xu
- State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou 510060, P.R. China
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Thiazolidine-2,4-diones as multi-targeted scaffold in medicinal chemistry: Potential anticancer agents. Eur J Med Chem 2014; 87:814-33. [DOI: 10.1016/j.ejmech.2014.10.025] [Citation(s) in RCA: 83] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2014] [Revised: 08/22/2014] [Accepted: 10/10/2014] [Indexed: 12/17/2022]
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Hosseinzadeh B, Chermahini AN, Beni AS, Teimouri A. Theoretical studies on the reactivity of thiazole derivatives. MONATSHEFTE FUR CHEMIE 2014. [DOI: 10.1007/s00706-014-1258-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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Cho SJ, Kook MC, Lee JH, Shin JY, Park J, Bae YK, Choi IJ, Ryu KW, Kim YW. Peroxisome proliferator-activated receptor γ upregulates galectin-9 and predicts prognosis in intestinal-type gastric cancer. Int J Cancer 2014; 136:810-20. [PMID: 24976296 DOI: 10.1002/ijc.29056] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2014] [Accepted: 06/13/2014] [Indexed: 12/23/2022]
Abstract
The importance of PPARγ (peroxisome proliferator-activated receptor γ) in gastric cancer (GC) is unclear. We investigated the role of PPARγ in GC cell lines and an animal model, and its prognostic significance of PPARγ in GC patients. We controlled PPARγ and galectin-9 expression by using siRNAs and lentiviral constructs. Interaction between PPARγ and galectin-9 was evaluated using luciferase and chromatin immunoprecipitation assays. PPARγ expression in GCs was determined by immunohistochemical staining of tissue microarrays and survival analysis was done. Overexpression of PPARγ was accompanied by increased galectin-9. Enhanced PPARγ or galectin-9 expression increased E-cadherin expression; decreased expression of N-cadherin, fibronectin, snail, twist and slug and reduced cell invasion and migration. PPARγ bound to the galectin-9 promoter region. Galectin-9 activity increased in PPARγ-overexpressing cells but decreased in PPARγ siRNA-treated cells. In a zebrafish xenograft model, the number of migrated cancer cells and number of fish with AGS cells in the tail vein were reduced in PPARγ-overexpressing GC cells. PPARγ was expressed in 462 of the 688 patients (69.2%) with GC. In 306 patients with intestinal-type GC, those with PPARγ-positive tumors had lower overall and cancer-specific mortalities than those with PPARγ-negative tumors. PPARγ expression was an independent prognostic factor for overall and GC-specific mortality in patients with intestinal-type GC (adjusted hazard ratio, 0.42; 95% CI, 0.22-0.81). PPARγ inhibits cell invasion, migration and epithelial-mesenchymal transition through upregulation of galectin-9 in vitro and in vivo.
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Affiliation(s)
- Soo-Jeong Cho
- Center for Gastric Cancer, National Cancer Center, Gyeonggi, Republic of Korea
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Rinella ME, Loomba R, Caldwell SH, Kowdley K, Charlton M, Tetri B, Harrison SA. Controversies in the Diagnosis and Management of NAFLD and NASH. Gastroenterol Hepatol (N Y) 2014; 10:219-227. [PMID: 24976805 PMCID: PMC4073533] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/03/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is recognized as the most common cause of chronic liver disease in the United States. Nonalcoholic steatohepatitis (NASH) occurs in a subset of patients with NAFLD and is characterized by the presence of hepa-tocellular injury, which is progressive in a substantial proportion of cases and can lead to cirrhosis and all of its complications. Although the diagnosis of NAFLD can be made through imaging studies or liver biopsy, the diagnosis of NASH still requires histologic confirmation. Liver biopsy should be performed in the presence of risk factors for advanced disease. Measures aimed at promoting weight loss, a healthier lifestyle, and optimization of metabolic risk factors remain the cornerstone of management of NAFLD. Therapeutic agents that are presently considered the most promising in NAFLD are effective in less than 50% of patients. Among patients with biopsy-proven NASH, treatment with pharmacologic agents should be considered; however, the role of specific agents in NASH still needs further study. Despite a wealth of research over the past 15 years, many controversies remain with respect to the diagnosis and management of NAFLD and NASH as well as the influence of alcohol on liver disease progression in these patients.
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Affiliation(s)
- Mary E Rinella
- Dr Rinella is an associate professor of medicine in the Division of Gastroenterology and Hepatology at Northwestern University Feinberg School of Medicine in Chicago, Illinois. Dr Loomba is an associate professor of clinical medicine at the University of California, San Diego in La Jolla, California. Dr Caldwell is a professor of medicine in gastroenterology and hepatology and the director of hepatology at the University of Virginia in Charlottesville, Virginia. Dr Kowdley is the director of the Liver Center of Excellence at the Digestive Disease Institute at Virginia Mason Medical Center in Seattle, Washington. Dr Charlton is the medical director of the Liver Transplant Program at Intermountain Medical Center in Salt Lake City, Utah. Dr Tetri is a professor of medicine in the Division of Gastroenterology and Hepatology at St. Louis University in St. Louis, Missouri. Dr Harrison is associate dean of San Antonio Uniformed Services Health Education Consortium, professor of medicine at Uniformed Services University of the Health Sciences, and director of medical education at Brooke Army Medical Center in San Antonio, Texas
| | - Rohit Loomba
- Dr Rinella is an associate professor of medicine in the Division of Gastroenterology and Hepatology at Northwestern University Feinberg School of Medicine in Chicago, Illinois. Dr Loomba is an associate professor of clinical medicine at the University of California, San Diego in La Jolla, California. Dr Caldwell is a professor of medicine in gastroenterology and hepatology and the director of hepatology at the University of Virginia in Charlottesville, Virginia. Dr Kowdley is the director of the Liver Center of Excellence at the Digestive Disease Institute at Virginia Mason Medical Center in Seattle, Washington. Dr Charlton is the medical director of the Liver Transplant Program at Intermountain Medical Center in Salt Lake City, Utah. Dr Tetri is a professor of medicine in the Division of Gastroenterology and Hepatology at St. Louis University in St. Louis, Missouri. Dr Harrison is associate dean of San Antonio Uniformed Services Health Education Consortium, professor of medicine at Uniformed Services University of the Health Sciences, and director of medical education at Brooke Army Medical Center in San Antonio, Texas
| | - Stephen H Caldwell
- Dr Rinella is an associate professor of medicine in the Division of Gastroenterology and Hepatology at Northwestern University Feinberg School of Medicine in Chicago, Illinois. Dr Loomba is an associate professor of clinical medicine at the University of California, San Diego in La Jolla, California. Dr Caldwell is a professor of medicine in gastroenterology and hepatology and the director of hepatology at the University of Virginia in Charlottesville, Virginia. Dr Kowdley is the director of the Liver Center of Excellence at the Digestive Disease Institute at Virginia Mason Medical Center in Seattle, Washington. Dr Charlton is the medical director of the Liver Transplant Program at Intermountain Medical Center in Salt Lake City, Utah. Dr Tetri is a professor of medicine in the Division of Gastroenterology and Hepatology at St. Louis University in St. Louis, Missouri. Dr Harrison is associate dean of San Antonio Uniformed Services Health Education Consortium, professor of medicine at Uniformed Services University of the Health Sciences, and director of medical education at Brooke Army Medical Center in San Antonio, Texas
| | - Kris Kowdley
- Dr Rinella is an associate professor of medicine in the Division of Gastroenterology and Hepatology at Northwestern University Feinberg School of Medicine in Chicago, Illinois. Dr Loomba is an associate professor of clinical medicine at the University of California, San Diego in La Jolla, California. Dr Caldwell is a professor of medicine in gastroenterology and hepatology and the director of hepatology at the University of Virginia in Charlottesville, Virginia. Dr Kowdley is the director of the Liver Center of Excellence at the Digestive Disease Institute at Virginia Mason Medical Center in Seattle, Washington. Dr Charlton is the medical director of the Liver Transplant Program at Intermountain Medical Center in Salt Lake City, Utah. Dr Tetri is a professor of medicine in the Division of Gastroenterology and Hepatology at St. Louis University in St. Louis, Missouri. Dr Harrison is associate dean of San Antonio Uniformed Services Health Education Consortium, professor of medicine at Uniformed Services University of the Health Sciences, and director of medical education at Brooke Army Medical Center in San Antonio, Texas
| | - Michael Charlton
- Dr Rinella is an associate professor of medicine in the Division of Gastroenterology and Hepatology at Northwestern University Feinberg School of Medicine in Chicago, Illinois. Dr Loomba is an associate professor of clinical medicine at the University of California, San Diego in La Jolla, California. Dr Caldwell is a professor of medicine in gastroenterology and hepatology and the director of hepatology at the University of Virginia in Charlottesville, Virginia. Dr Kowdley is the director of the Liver Center of Excellence at the Digestive Disease Institute at Virginia Mason Medical Center in Seattle, Washington. Dr Charlton is the medical director of the Liver Transplant Program at Intermountain Medical Center in Salt Lake City, Utah. Dr Tetri is a professor of medicine in the Division of Gastroenterology and Hepatology at St. Louis University in St. Louis, Missouri. Dr Harrison is associate dean of San Antonio Uniformed Services Health Education Consortium, professor of medicine at Uniformed Services University of the Health Sciences, and director of medical education at Brooke Army Medical Center in San Antonio, Texas
| | - Brent Tetri
- Dr Rinella is an associate professor of medicine in the Division of Gastroenterology and Hepatology at Northwestern University Feinberg School of Medicine in Chicago, Illinois. Dr Loomba is an associate professor of clinical medicine at the University of California, San Diego in La Jolla, California. Dr Caldwell is a professor of medicine in gastroenterology and hepatology and the director of hepatology at the University of Virginia in Charlottesville, Virginia. Dr Kowdley is the director of the Liver Center of Excellence at the Digestive Disease Institute at Virginia Mason Medical Center in Seattle, Washington. Dr Charlton is the medical director of the Liver Transplant Program at Intermountain Medical Center in Salt Lake City, Utah. Dr Tetri is a professor of medicine in the Division of Gastroenterology and Hepatology at St. Louis University in St. Louis, Missouri. Dr Harrison is associate dean of San Antonio Uniformed Services Health Education Consortium, professor of medicine at Uniformed Services University of the Health Sciences, and director of medical education at Brooke Army Medical Center in San Antonio, Texas
| | - Stephen A Harrison
- Dr Rinella is an associate professor of medicine in the Division of Gastroenterology and Hepatology at Northwestern University Feinberg School of Medicine in Chicago, Illinois. Dr Loomba is an associate professor of clinical medicine at the University of California, San Diego in La Jolla, California. Dr Caldwell is a professor of medicine in gastroenterology and hepatology and the director of hepatology at the University of Virginia in Charlottesville, Virginia. Dr Kowdley is the director of the Liver Center of Excellence at the Digestive Disease Institute at Virginia Mason Medical Center in Seattle, Washington. Dr Charlton is the medical director of the Liver Transplant Program at Intermountain Medical Center in Salt Lake City, Utah. Dr Tetri is a professor of medicine in the Division of Gastroenterology and Hepatology at St. Louis University in St. Louis, Missouri. Dr Harrison is associate dean of San Antonio Uniformed Services Health Education Consortium, professor of medicine at Uniformed Services University of the Health Sciences, and director of medical education at Brooke Army Medical Center in San Antonio, Texas
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The role of inflammation in gastric cancer. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2014; 816:235-57. [PMID: 24818726 DOI: 10.1007/978-3-0348-0837-8_10] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Gastric cancer, despite its declining incidence rate, is still the second cause of cancer-related death worldwide, killing 750,000 people each year and remaining the second common type of cancer. The best examples of inflammation-associated cancer in human beings may be gastric cancer. Understanding the molecular mechanism of the inflammation in gastric carcinogenesis is important for developing new strategies against gastric cancer.
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Chen FZ, Mo XM, Wang QP, Li J, Zhang L. Effects of rosiglitazone on the growth and lymphangiogenesis of human gastric cancer transplanted in nude mice. Oncol Rep 2013; 30:2705-12. [PMID: 24002492 DOI: 10.3892/or.2013.2704] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2013] [Accepted: 07/19/2013] [Indexed: 11/05/2022] Open
Abstract
Gastric cancer mainly metastasizes via lymphatic vessels. Thus, it is critical to identify efficacious chemopreventive agents for lymphangiogenesis. The present study was undertaken to explore the effects of rosiglitazone (ROSI) on the growth and lymphangiogenesis of human gastric cancer. We established a model of gastric cancer by subcutaneously inoculating the human gastric cancer cell line SGC-7901 into nude mice. Mice were randomly divided into 4 groups and each group received a different agent by oral gavage. The control group received normal saline and treatment groups received different doses of ROSI once every 2 days. The growth of the tumor in vivo was assessed by measuring tumor volume. After 42 days, the mice were sacrificed and the tumors were removed. H&E staining was used to observe the histomorphological features; immunohistochemistry staining for lymphatic vessel density (LVD) was used to evaluate tumor lymphangiogenesis, RT-PCR was performed to determine the mRNA expression of vascular endothelial growth factor C (VEGF-C) and VEGF receptor-3 (VEGFR-3), and western blotting was used to detect the protein expression of VEGF-C and VEGFR-3. Compared with the control group, all treatment groups had smaller tumor volume and higher tumor growth inhibitory rate every day. The number of typical tumor cells in the control group was higher compared to that in the treatment groups, and the highest level of LVD was found in the control group. Furthermore, both the expression of VEGF-C and VEGFR-3 mRNA and proteins in the control group were significantly higher compared to those in the treatment groups. Markedly, these changes were correlated in a dose-dependent manner with ROSI. These results demonstrated that, through simultaneously blocking the expression of VEGF-C and VEGFR-3, ROSI suppresses lymphangiogenesis. This may represent a powerful therapeutic approach for controlling gastric cancer cell growth and metastasis.
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Affiliation(s)
- Fang-Zhi Chen
- Department of Gastroenterology, The Second Affiliated Hospital of University of South China, Hengyang, Hunan 421001, P.R. China
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Hassan WMI, Badawy MA, Mohamed GG, Moustafa H, Elramly S. Synthesis, spectroscopic, thermal and DFT calculations of 2-(3-amino-2-hydrazono-4-oxothiazolidin-5-yl) acetic acid binuclear metal complexes. SPECTROCHIMICA ACTA. PART A, MOLECULAR AND BIOMOLECULAR SPECTROSCOPY 2013; 111:169-177. [PMID: 23624211 DOI: 10.1016/j.saa.2013.03.085] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/01/2013] [Revised: 03/14/2013] [Accepted: 03/16/2013] [Indexed: 06/02/2023]
Abstract
The binuclear complexes of 2-(3-amino-2-hydrazono-4-oxothiazolidin-5-yl) acetic acid ligand (HL) with Fe(III), Co(II), Ni(II), Cu(II) and Zn(II) ions were prepared and their stoichiometry was determined by elemental analysis. The stereochemistry of the studied series of metal complexes was established by analyzing their infrared, (1)H NMR spectra and the magnetic moment measurements. According to the elemental analysis data, the complexes were found to have the formulae [Fe2L(H2O)8]Cl5 and [M2L(H2O)8]Cl3 (M=Co(II), Ni(II), Cu(II) and Zn(II)). The present analyses demonstrate that all metal ions coordinated to the ligand via O(9), O(11), N(16) and N(18) atoms. Thermal decomposition studies of the ligand-metal complexes have been performed to verify the status of water molecules present in these metal complexes and their general decomposition pattern. Density Functional Theory (DFT) calculations at the B3LYP/6-31G(*) level of theory have been carried out to investigate the equilibrium geometry of the ligand and complexes. Moreover, charge density distribution, extent of distortion from regular geometry, dipole moment and orientation have been performed and discussed.
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Affiliation(s)
- Walid M I Hassan
- Chemistry Department, Faculty of Science, Cairo University, 12613 Giza, Egypt
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50
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Tsukahara T, Haniu H, Matsuda Y. PTB-associated splicing factor (PSF) is a PPARγ-binding protein and growth regulator of colon cancer cells. PLoS One 2013; 8:e58749. [PMID: 23516550 PMCID: PMC3596311 DOI: 10.1371/journal.pone.0058749] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2012] [Accepted: 02/05/2013] [Indexed: 11/19/2022] Open
Abstract
Peroxisome proliferator-activated receptor gamma (PPARγ) is a nuclear receptor that plays an essential role in cell proliferation, apoptosis, and inflammation. It is over-expressed in many types of cancer, including colon, stomach, breast, and lung cancer, suggesting that regulation of PPARγ might affect cancer pathogenesis. Here, using a proteomic approach, we identify PTB-associated splicing factor (PSF) as a novel PPARγ-interacting protein and demonstrate that PSF is involved in several important regulatory steps of colon cancer cell proliferation. To investigate the relationship between PSF and PPARγ in colon cancer, we evaluated the effects of PSF expression in DLD-1 and HT-29 colon cancer cell lines, which express low and high levels of PPARγ, respectively PSF affected the ability of PPARγ to bind, and expression of PSF siRNA significantly suppressed the proliferation of colon cancer cells. Furthermore, PSF knockdown induced apoptosis via activation of caspase-3. Interestingly, DLD-1 cells were more susceptible to PSF knockdown-induced cell death than HT-29 cells. Our data suggest that PSF is an important regulator of cell death that plays critical roles in the survival and growth of colon cancer cells. The PSF-PPARγ axis may play a role in the control of colorectal carcinogenesis. Taken together, this study is the first to describe the effects of PSF on cell proliferation, tumor growth, and cell signaling associated with PPARγ.
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Affiliation(s)
- Tamotsu Tsukahara
- Department of Integrative Physiology and Bio-System Control, Shinshu University School of Medicine, Asahi, Matsumoto, Nagano, Japan.
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