|
1
|
Kim JE, Park KH, Park J, Kim BS, Kim GS, Hwang DG. Immunomodulatory Potential of 6-Gingerol and 6-Shogaol in Lactobacillus plantarum-Fermented Zingiber officinale Extract on Murine Macrophages. Int J Mol Sci 2025; 26:2159. [PMID: 40076780 PMCID: PMC11900057 DOI: 10.3390/ijms26052159] [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: 01/21/2025] [Revised: 02/21/2025] [Accepted: 02/24/2025] [Indexed: 03/14/2025] Open
Abstract
In this study, we aimed to investigate whether the physiological activity of ethanol extracts of Zingiber officinale was improved after fermentation with Lactobacillus plantarum strains KCTC 3108 (FLP8) and KCL005 (FLP9). Total polyphenol and flavonoid content was substantially increased after fermentation with FLP8 and FLP9 for 48 h and 24 h, respectively, compared with the unfermented control. The 6-gingerol content was significantly increased in FLP9 after 24 h of fermentation, whereas in FLP8, it remained comparable to pre-fermentation levels. The 6-shogaol content significantly increased in FLP8 and FLP9 at 48 h and 24 h, respectively, compared with the pre-fermentation levels. The anti-inflammatory effects were evaluated using RAW 264.7 cells stimulated with lipopolysaccharides. The fermented product of FLP8 at 48 h and FLP9 at 24 h maintained over 80% cell viability at a concentration of 200 µg/mL and significantly reduced nitric oxide production compared to the lipopolysaccharide-stimulated control. Moreover, each extract downregulated pro-inflammatory gene expression. Furthermore, the purified 6-gingerol and 6-shogaol, which were purchased as reference compounds, were included in the fermentation extracts of FLP8 at 48 h and FLP9 at 24 h, and both inhibited cell migration in a dose-dependent manner without any cytotoxicity. In conclusion, the fermentation of Z. officinale with these L. plantarum strains enhanced its antioxidant and anti-inflammatory activities, with significant increases in bioactive compound content.
Collapse
Affiliation(s)
- Ji Eun Kim
- Department of Companion and Laboratory Animal and Science, and Leaders in INdustryuniversity Cooperation 3.0 (LINC 3.0) Project by Ministry of Education, Kongju National University, Yesan 32439, Republic of Korea; (J.E.K.); (G.-S.K.)
| | - Kwang-Hyun Park
- Department of Emergency Medical Rescue, Nambu University, Gwangju 62271, Republic of Korea;
- BioMedical Science Graduate Program (BMSGP), Chonnam National University, Hwasun 58128, Republic of Korea
| | - Jinny Park
- Department of Medical Oncology and Hematology, Ansan Hospital, Korea University College of Medicine, Ansan 15355, Republic of Korea
| | - Byeong Soo Kim
- Department of Companion and Laboratory Animal and Science, and Leaders in INdustryuniversity Cooperation 3.0 (LINC 3.0) Project by Ministry of Education, Kongju National University, Yesan 32439, Republic of Korea; (J.E.K.); (G.-S.K.)
| | - Geun-Seop Kim
- Department of Companion and Laboratory Animal and Science, and Leaders in INdustryuniversity Cooperation 3.0 (LINC 3.0) Project by Ministry of Education, Kongju National University, Yesan 32439, Republic of Korea; (J.E.K.); (G.-S.K.)
| | - Dong Geon Hwang
- Department of Companion and Laboratory Animal and Science, and Leaders in INdustryuniversity Cooperation 3.0 (LINC 3.0) Project by Ministry of Education, Kongju National University, Yesan 32439, Republic of Korea; (J.E.K.); (G.-S.K.)
| |
Collapse
|
|
2
|
Li X, Qi X, Wang B, Fu L, Chen X, Luo X, Chen X, Lu Y. Efficacy of nintedanib as a host-directed therapy candidate in the treatment of tuberculosis. J Antimicrob Chemother 2025; 80:452-464. [PMID: 39656809 DOI: 10.1093/jac/dkae429] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2024] [Accepted: 11/12/2024] [Indexed: 12/17/2024] Open
Abstract
BACKGROUND The lengthy duration and high frequency of drug resistance associated with currently used antimycobacterial drug treatments have intensified the need for alternative therapies against Mycobacterium tuberculosis, the causative agent of TB. METHODS MICs and intracellular macrophage cfu counts were tested to evaluate the antibacterial activity of nintedanib and pirfenidone against drug-susceptible and -resistant M. tuberculosis. A chronic murine model of pulmonary infection was used to assay the therapeutic efficacy of nintedanib. Macrophage transcriptome deep sequencing, a confocal assay, siRNA knockdown, Western blotting, quantitative RT-PCR and a cfu assay were used to investigate the antibacterial mechanism of nintedanib. RESULTS The MIC90 of nintedanib against M. tuberculosis standard strain H37Rv was 23.56-40.51 mg/L. TB murine model studies showed that nintedanib, coadministered with isoniazid, rifampicin and pyrazinamide, shortened treatment duration, and ameliorated pulmonary inflammation and fibrosis. In mechanism studies, transcriptome sequencing analysis revealed that nintedanib may eliminate M. tuberculosis through up-regulating macrophage autophagy. Furthermore, inhibition of autophagy by using siRNA targeting ATG5 or the autophagy inhibitor 3-methyladenine almost completely abolished nintedanib-mediated suppression of M. tuberculosis. Nintedanib induced autophagy by the JAK2/STAT3/Beclin1 pathway. When JAK2 or Beclin1 were knocked down through siRNA, nintedanib no longer inhibited M. tuberculosis. JAK2 activator coumermycin A1 and STAT3 agonist colivelin also reversed this phenotype. CONCLUSIONS In vitro activity of nintedanib against drug-susceptible and -resistant M. tuberculosis and efficacy in murine infections warrant the continued clinical evaluation of nintedanib as a new adjuvant therapy for standard treatment of TB.
Collapse
Affiliation(s)
- Xinda Li
- Department of Pharmacology, Beijing Chest Hospital, Capital Medical University, Beijing, China
- Beijing Key Laboratory of Drug Resistance Tuberculosis Research, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, China
| | - Xueting Qi
- Department of Pharmacology, Beijing Chest Hospital, Capital Medical University, Beijing, China
- Beijing Key Laboratory of Drug Resistance Tuberculosis Research, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, China
| | - Bin Wang
- Department of Pharmacology, Beijing Chest Hospital, Capital Medical University, Beijing, China
- Beijing Key Laboratory of Drug Resistance Tuberculosis Research, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, China
| | - Lei Fu
- Department of Pharmacology, Beijing Chest Hospital, Capital Medical University, Beijing, China
- Beijing Key Laboratory of Drug Resistance Tuberculosis Research, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, China
| | - Xi Chen
- Department of Pharmacology, Beijing Chest Hospital, Capital Medical University, Beijing, China
- Beijing Key Laboratory of Drug Resistance Tuberculosis Research, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, China
| | - Xiaoyi Luo
- Department of Pharmacology, Beijing Chest Hospital, Capital Medical University, Beijing, China
- Beijing Key Laboratory of Drug Resistance Tuberculosis Research, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, China
| | - Xiaoyou Chen
- Infectious Diseases Department, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Yu Lu
- Department of Pharmacology, Beijing Chest Hospital, Capital Medical University, Beijing, China
- Beijing Key Laboratory of Drug Resistance Tuberculosis Research, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, China
| |
Collapse
|
|
3
|
Wei W, Gao X, Qian J, Li L, Zhao C, Xu L, Zhu Y, Liu Z, Liu N, Wang X, Jin Z, Liu B, Xu L, Dong J, Zhang S, Wang J, Zhang Y, Yu Y, Yan Z, Yang Y, Lu J, Fang Y, Yuan N, Wang J. Beclin 1 prevents ISG15-mediated cytokine storms to secure fetal hematopoiesis and survival. J Clin Invest 2025; 135:e177375. [PMID: 39589832 PMCID: PMC11785930 DOI: 10.1172/jci177375] [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: 11/16/2023] [Accepted: 11/22/2024] [Indexed: 11/28/2024] Open
Abstract
Proper control of inflammatory responses is essential for embryonic development, but the underlying mechanism is poorly understood. Here, we show that under physiological conditions, inactivation of ISG15, an inflammation amplifier, is associated with the interaction of Beclin 1 (Becn1), via its evolutionarily conserved domain, with STAT3 in the major fetal hematopoietic organ of mice. Conditional loss of Becn1 caused sequential dysfunction and exhaustion of fetal liver hematopoietic stem cells, leading to lethal inflammatory cell-biased hematopoiesis in the fetus. Molecularly, the absence of Becn1 resulted in the release of STAT3 from Becn1 tethering and subsequent phosphorylation and translocation to the nucleus, which in turn directly activated the transcription of ISG15 in fetal liver hematopoietic cells, coupled with increased ISGylation and production of inflammatory cytokines, whereas inactivating STAT3 reduced ISG15 transcription and inflammation but improved hematopoiesis potential, and further silencing ISG15 mitigated the above collapse in the Becn1-null hematopoietic lineage. The Becn1/STAT3/ISG15 axis remains functional in autophagy-disrupted fetal hematopoietic organs. These results suggest that Becn1, in an autophagy-independent manner, secures hematopoiesis and survival of the fetus by directly inhibiting STAT3/ISG15 activation to prevent cytokine storms. Our findings highlight a previously undocumented role of Becn1 in governing ISG15 to safeguard the fetus.
Collapse
Affiliation(s)
- Wen Wei
- Research Center for Blood Engineering and Manufacturing, Cyrus Tang Medical Institute, Soochow University, Suzhou, China
- National Clinical Research Center for Hematologic Diseases, Key Laboratory of Thrombosis and Hemostasis Ministry of Health, Collaborative Innovation Center of Hematology, Jiangsu Institute of Hematology, Institute of Blood and Marrow Transplantation, The First Affiliated Hospital of Soochow University, Suzhou, China
- State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou, China
- The Ninth Affiliated Suzhou Hospital of Soochow University, Suzhou, China
| | - Xueqin Gao
- Research Center for Blood Engineering and Manufacturing, Cyrus Tang Medical Institute, Soochow University, Suzhou, China
- National Clinical Research Center for Hematologic Diseases, Key Laboratory of Thrombosis and Hemostasis Ministry of Health, Collaborative Innovation Center of Hematology, Jiangsu Institute of Hematology, Institute of Blood and Marrow Transplantation, The First Affiliated Hospital of Soochow University, Suzhou, China
- State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou, China
| | - Jiawei Qian
- Research Center for Blood Engineering and Manufacturing, Cyrus Tang Medical Institute, Soochow University, Suzhou, China
| | - Lei Li
- Research Center for Blood Engineering and Manufacturing, Cyrus Tang Medical Institute, Soochow University, Suzhou, China
- The Ninth Affiliated Suzhou Hospital of Soochow University, Suzhou, China
| | - Chen Zhao
- Research Center for Blood Engineering and Manufacturing, Cyrus Tang Medical Institute, Soochow University, Suzhou, China
- The Ninth Affiliated Suzhou Hospital of Soochow University, Suzhou, China
| | - Li Xu
- Research Center for Blood Engineering and Manufacturing, Cyrus Tang Medical Institute, Soochow University, Suzhou, China
| | - Yanfei Zhu
- Research Center for Blood Engineering and Manufacturing, Cyrus Tang Medical Institute, Soochow University, Suzhou, China
| | - Zhenzhen Liu
- Research Center for Blood Engineering and Manufacturing, Cyrus Tang Medical Institute, Soochow University, Suzhou, China
| | - Nengrong Liu
- Research Center for Blood Engineering and Manufacturing, Cyrus Tang Medical Institute, Soochow University, Suzhou, China
| | - Xueqing Wang
- Research Center for Blood Engineering and Manufacturing, Cyrus Tang Medical Institute, Soochow University, Suzhou, China
| | - Zhicong Jin
- Research Center for Blood Engineering and Manufacturing, Cyrus Tang Medical Institute, Soochow University, Suzhou, China
| | - Bowen Liu
- Research Center for Blood Engineering and Manufacturing, Cyrus Tang Medical Institute, Soochow University, Suzhou, China
| | - Lan Xu
- Research Center for Blood Engineering and Manufacturing, Cyrus Tang Medical Institute, Soochow University, Suzhou, China
| | - Jin Dong
- Research Center for Blood Engineering and Manufacturing, Cyrus Tang Medical Institute, Soochow University, Suzhou, China
| | - Suping Zhang
- Research Center for Blood Engineering and Manufacturing, Cyrus Tang Medical Institute, Soochow University, Suzhou, China
- National Clinical Research Center for Hematologic Diseases, Key Laboratory of Thrombosis and Hemostasis Ministry of Health, Collaborative Innovation Center of Hematology, Jiangsu Institute of Hematology, Institute of Blood and Marrow Transplantation, The First Affiliated Hospital of Soochow University, Suzhou, China
- State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou, China
| | - Jiarong Wang
- Research Center for Blood Engineering and Manufacturing, Cyrus Tang Medical Institute, Soochow University, Suzhou, China
| | - Yumu Zhang
- Research Center for Blood Engineering and Manufacturing, Cyrus Tang Medical Institute, Soochow University, Suzhou, China
| | - Yao Yu
- Research Center for Blood Engineering and Manufacturing, Cyrus Tang Medical Institute, Soochow University, Suzhou, China
| | - Zhanjun Yan
- The Ninth Affiliated Suzhou Hospital of Soochow University, Suzhou, China
| | - Yanjun Yang
- The Ninth Affiliated Suzhou Hospital of Soochow University, Suzhou, China
| | - Jie Lu
- The Ninth Affiliated Suzhou Hospital of Soochow University, Suzhou, China
| | - Yixuan Fang
- Research Center for Blood Engineering and Manufacturing, Cyrus Tang Medical Institute, Soochow University, Suzhou, China
- National Clinical Research Center for Hematologic Diseases, Key Laboratory of Thrombosis and Hemostasis Ministry of Health, Collaborative Innovation Center of Hematology, Jiangsu Institute of Hematology, Institute of Blood and Marrow Transplantation, The First Affiliated Hospital of Soochow University, Suzhou, China
- State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou, China
- The Ninth Affiliated Suzhou Hospital of Soochow University, Suzhou, China
| | - Na Yuan
- Research Center for Blood Engineering and Manufacturing, Cyrus Tang Medical Institute, Soochow University, Suzhou, China
- National Clinical Research Center for Hematologic Diseases, Key Laboratory of Thrombosis and Hemostasis Ministry of Health, Collaborative Innovation Center of Hematology, Jiangsu Institute of Hematology, Institute of Blood and Marrow Transplantation, The First Affiliated Hospital of Soochow University, Suzhou, China
- State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou, China
- The Ninth Affiliated Suzhou Hospital of Soochow University, Suzhou, China
| | - Jianrong Wang
- Research Center for Blood Engineering and Manufacturing, Cyrus Tang Medical Institute, Soochow University, Suzhou, China
- National Clinical Research Center for Hematologic Diseases, Key Laboratory of Thrombosis and Hemostasis Ministry of Health, Collaborative Innovation Center of Hematology, Jiangsu Institute of Hematology, Institute of Blood and Marrow Transplantation, The First Affiliated Hospital of Soochow University, Suzhou, China
- State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou, China
- The Ninth Affiliated Suzhou Hospital of Soochow University, Suzhou, China
| |
Collapse
|
|
4
|
Zhang Y, Zhu M, Dai Y, Gao L, Cheng L. Research Progress in Ulcerative Colitis: The Role of Traditional Chinese Medicine on Gut Microbiota and Signaling Pathways. THE AMERICAN JOURNAL OF CHINESE MEDICINE 2024; 52:2277-2336. [PMID: 39756829 DOI: 10.1142/s0192415x24500885] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/07/2025]
Abstract
Ulcerative colitis (UC), one among other refractory diseases worldwide, has shown an increasing trend of progression to colorectal cancer in recent years. In the treatment of UC, traditional Chinese medicine has demonstrated good efficacy, with a high cure rate, fewer adverse effects, great improvement in the quality of patient survival, and reduction in the tendency of cancerous transformation. It shows promise as a complementary and alternative therapy. This review aims to evaluate and discuss the current research on UC, signaling pathways, and gut microbiota. We also summarized the mechanisms of action of various Chinese medicines (active ingredients or extracts) and herbal formulas, through signaling pathways and gut microbiota, with the expectation that they can provide references and evidence for treating UC and preventing inflammation-associated colorectal cancer by traditional Chinese medicine. We illustrate that multiple signaling pathways, such as TLR4, STAT3, PI3K/Akt, NF-[Formula: see text]B, and Keap1/Nrf2, can be inhibited by Chinese herbal treatments through the combined regulation of signaling pathways and gut microbiota, which can act individually or synergistically to inhibit intestinal inflammatory cell infiltration, attenuate gut oxidative responses, and repair the intestinal barrier.
Collapse
Affiliation(s)
- Yuyi Zhang
- Graduate School, Heilongjiang University of Chinese Medicine, Harbin, P. R. China
| | - Mingfang Zhu
- Graduate School, Zunyi Medical University Zunyi, P. R. China
| | - Yueying Dai
- Graduate School, Heilongjiang University of Chinese Medicine, Harbin, P. R. China
| | - Longying Gao
- Department of Anorectal, The First Affiliated Hospital of Heilongjiang, University of Chinese Medicine Harbin, P. R. China
| | - Limin Cheng
- Department of Anorectal, The First Affiliated Hospital of Heilongjiang, University of Chinese Medicine Harbin, P. R. China
| |
Collapse
|
|
5
|
Xiong B, Zhang X, Sangji D, Ni L, Fan M, Fan B. Mechanisms of breast cancer treatment using Gentiana robusta: evidence from comprehensive bioinformatics investigation. Sci Rep 2024; 14:31567. [PMID: 39738201 PMCID: PMC11686125 DOI: 10.1038/s41598-024-76063-z] [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: 05/10/2024] [Accepted: 10/10/2024] [Indexed: 01/01/2025] Open
Abstract
This study investigates the potential treatment of breast cancer utilizing Gentiana robusta King ex Hook. f. (QJ) through an integrated approach involving network pharmacology, molecular docking, and molecular dynamics simulation. Building upon prior research on QJ's chemical constituents, we conducted Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis using the DAVID database. Network interactions and core genes were identified using Cytoscape 3.9.1. Key target genes, including Interleukin-6 (IL-6), tumour suppressor gene P53 (TP53), and epidermal growth factor receptor (EGFR), were selected for molecular docking with QJ's active components, 2'-O-β-D-glucopyranosyl-gentiopicroside and macrophylloside D, employing Schrodinger Maestro 13.5. Molecular dynamics (MD) simulations were performed using the Desmond program. A total of 270 intersection targets of active ingredients and diseases were identified, with three core targets determined through network topology screening. Enrichment analysis highlighted the involvement of QJ in breast cancer treatment, primarily through the hsa05200 cancer signaling pathway and the hsa04066 HIF-1 signaling pathway. Molecular docking and dynamics simulations demonstrated the close interaction of 2'-O-β-D-glucopyranosyl-gentiopicroside (QJ17) and macrophylloside D (QJ25) with IL6, TP53, and EGFR, and other target genes, showcasing a stabilizing effect. In conclusion, this study unveils the effective components and potential mechanisms of 2'-O-β-D-glucopyranosyl-gentiopicroside and macrophylloside D in breast cancer prevention and treatment. The identified components act on target genes such as IL6, TP53, and EGFR, regulating crucial pathways including the cancer signaling and Hypoxia-inducible factor 1 (HIF-1) signaling pathways. These findings provide valuable insights into the therapeutic potential of QJ in breast cancer management. However, further experimental research are needed to validate the computational findings of QJ.
Collapse
Affiliation(s)
- Bo Xiong
- Department of Clinical Pharmacy, Baoshan Hospital Affiliated to, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Xinxin Zhang
- Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Dongzhi Sangji
- Tibetan Medical Hospital of Xizang Autonomous Region, Lhasa, China
| | - Lianghong Ni
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Mingjie Fan
- Department of Pharmacy, Shanghai Fourth Rehabilitation Hospital, Shanghai, China.
| | - Beibei Fan
- Department of Clinical Pharmacy, Baoshan Hospital Affiliated to, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
| |
Collapse
|
|
6
|
Su Y, Liu S, Long C, Zhou Z, Zhou Y, Tang J. The cross-talk between B cells and macrophages. Int Immunopharmacol 2024; 143:113463. [PMID: 39467344 DOI: 10.1016/j.intimp.2024.113463] [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: 05/26/2024] [Revised: 10/18/2024] [Accepted: 10/18/2024] [Indexed: 10/30/2024]
Abstract
B cells and macrophages are significant immune cells that maintain the immune balance of the body. B cells are involved in humoral immunity, producing immune effects mainly by secreting antibodies. Macrophages participate in non-specific and specific immune responses. To gain a further understanding of macrophages and B cells, researchers have not only paid attention to the unidirectional influence between B cells and macrophages, but also have focused on the cross-talk between them, and the effect of this cross talk on diseases. Therefore, this review summarizes the influence of macrophages on B cells, the ways and mechanisms by which B cells affect macrophages, and their cross-talk, leading to a more comprehensive understanding of the mechanism of the interaction between macrophages and B cells.
Collapse
Affiliation(s)
- Yahui Su
- Department of Geriatrics, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China; Cancer Research Institute, Basic School of Medicine, Central South University, Changsha, Hunan 410078, China
| | - Siyi Liu
- Cancer Research Institute, Basic School of Medicine, Central South University, Changsha, Hunan 410078, China
| | - Chen Long
- Department of General Surgery, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China
| | - Zihua Zhou
- Department of Oncology, Loudi Central Hospital, Loudi 417000, China
| | - Yanhong Zhou
- Cancer Research Institute, Basic School of Medicine, Central South University, Changsha, Hunan 410078, China.
| | - Jingqiong Tang
- Department of Geriatrics, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China.
| |
Collapse
|
|
7
|
Cui G, Yuan A, Sørbye SW, Florholmen J. Th9 and Th17 Cells in Human Ulcerative Colitis-Associated Dysplastic Lesions. Clin Med Insights Oncol 2024; 18:11795549241301358. [PMID: 39651422 PMCID: PMC11624539 DOI: 10.1177/11795549241301358] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2024] [Accepted: 11/04/2024] [Indexed: 12/11/2024] Open
Abstract
Background Inflammation is the most important deriving force for the development of colitis-associated colorectal cancer (CAC) through the Inflammation-Pretumor dysplasia-CAC sequence. T helper (Th) subsets Th9 and Th17 cells can potentially stimulate inflammation in the ulcerative colitis (UC). Therefore, Th9 and Th17 cells may play a promoting role in the colitis-associated dysplasia (CAD). Methods Using immunohistochemistry (IHC), we evaluated the presentation patterns and densities of T lymphocytes, Th9 and Th17 cells in human UC and CAD tissues. Results A general increasing trend of CD3-positive T lymphocytes, P.U.1-positive Th9 and interleukin (IL)-17A-positive Th17 cells was illustrated throughout the normal-UC-CAD sequence, IHC images showed that these cells were very prominent in the lamina propria, and some cells were also observed in the epithelium in the CAD tissues. Density analysis revealed that numbers of Th9 and Th17 cells were progressively increased in the CAD tissues as compared with the UC and control tissues. In general, densities of Th9 and Th17 cells in the lamina propria were slightly higher in the non-adenoma-like dysplasia (NALD) tissues than that in the adenoma-like dysplasia (ALD) tissues. However, densities of neither Th9 nor Th17 cells in both the ALD and NALD subgroups were associated with the degree of dysplasia in CAD lesions. Conclusion Accumulated Th9 and Th17 cells contribute to the immune cellular composition in the CAD tissues and may represent the early conditional change for the Dysplasia-CAC transition.
Collapse
Affiliation(s)
- Guanglin Cui
- Research Group of Gastrointestinal Diseases, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Faculty of Health Science, Nord University, Campus Levanger, Norway
| | - Aping Yuan
- Research Group of Gastrointestinal Diseases, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Sveinung W Sørbye
- Department of Pathology, University Hospital of North Norway, University of Tromsø, Tromsø, Norway
| | - Jon Florholmen
- Department of Gastroenterology & Nutrition, University Hospital of North Norway, University of Tromsø, Tromsø, Norway
| |
Collapse
|
|
8
|
DeJesus J, Wang X, Gu Y, Mao RM, Zhou J, Radhakrishnan R. Novel Compound HJC0416 Attenuates Hepatic Fibrosis via HSP90/NF-κB-Associated Mechanism. J Surg Res 2024; 304:305-314. [PMID: 39579470 DOI: 10.1016/j.jss.2024.09.038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Revised: 08/19/2024] [Accepted: 09/14/2024] [Indexed: 11/25/2024]
Abstract
INTRODUCTION Chronic liver disease is driven by a prolonged wound healing response leading to fibrogenesis, potentially progressing to cirrhosis. Hepatic stellate cells (HSCs) are the primary cells driving hepatic fibrosis because they are major producers of extracellular matrix. The nuclear factor kappa-light-chain-enhancer of activated B cells (NF-ΚB) pathway is a key regulator of inflammatory signaling, and survival of activated HSCs has been found to be NF-KB dependent. Our team previously synthesized HJC0416-a signal transducer and activator of transcription three inhibitor with potent anti-inflammatory effects. In HSCs, HJC0416 reduced cell viability, extracellular matrix production, and-notably-NF-KB activation. However, HJC0416's antifibrogenetic mechanism remains unknown. This study examined the effects of HJC0416 on NF-KB and its associate factor HSP-90 in HSCs. METHODS The activated human HSC line LX-2 was treated with either HJC0416 or 17-AAG, then exposed to TNFα as indicated. Nuclear and cytosolic proteins were isolated for Western blot or immunofluorescence assay. RESULTS HJC0416 significantly attenuated TNFα-induced IκBα phosphorylation, NF-KBp65 nuclear translocation, and DNA binding activity. Endogenous and TNFα-induced p65 phosphorylation of S536 was suppressed by HJC0416. Notably, HJC0416 dose-dependently attenuated the expression of FAK, IKKα, and signal transducer and activator of transcription three which are Heat Shock Protein 90 (HSP90) interacting proteins. The expression of other HSP90 interacting proteins-RIP1, AKT, FAK, and cyclin-dependent kinase nine-were decreased. HSP90-specific inhibitor 17-AAG significantly attenuated TNFα-induced IκBα phosphorylation and degradation, p65 nuclear translocation, DNA binding, and production of collagen type I and fibronectin. CONCLUSIONS The HSP90 chaperone protein may be a key intermediary linking HJC0416's ability to inhibit NF-κB activity. HJC0416 may be a promising drug candidate for liver fibrosis.
Collapse
Affiliation(s)
- Jana DeJesus
- Department of Surgery, University of Texas Medical Branch, Galveston, Texas
| | - Xiaofu Wang
- Department of Surgery, University of Texas Medical Branch, Galveston, Texas
| | - Yanping Gu
- Department of Neurobiology, University of Texas Medical Branch, Galveston, Texas
| | - Rui-Min Mao
- Department of Surgery, University of Texas Medical Branch, Galveston, Texas
| | - Jia Zhou
- Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas
| | - Ravi Radhakrishnan
- Department of Surgery, University of Texas Medical Branch, Galveston, Texas.
| |
Collapse
|
|
9
|
Wang D, Zhu L, Liu H, Feng X, Zhang C, Li T, Liu B, Liu L, Sun J, Chang H, Chen S, Guo S, Yang W. Huangqin tang alleviates colitis-associated colorectal cancer via amino acids homeostasisand PI3K/AKT/mtor pathway modulation. JOURNAL OF ETHNOPHARMACOLOGY 2024; 334:118597. [PMID: 39034016 DOI: 10.1016/j.jep.2024.118597] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/19/2024] [Revised: 04/29/2024] [Accepted: 07/17/2024] [Indexed: 07/23/2024]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Huangqin Tang (HQT), a traditional Chinese medicine formula, is commonly used in clinical practice for the treatment of inflammatory bowel diseases. It has been reported that HQT exerts antitumor effects on colitis-associated colorectal cancer (CAC). However, the mechanism by which HQT interferes with the inflammation-to-cancer transformation remains unclear. AIMS OF THE STUDY The purpose of this study was to dynamically evaluate the efficacy of HQT in alleviating or delaying CAC and to reveal the underlying mechanism. METHODS We established a mouse model of CAC using azoxymethane combined with 1.5% dextran sodium sulphate. The efficacy of HQT was evaluated based on pathological sections and serum biochemical indices. Subsequently, amino acids (AAs) metabolism analyses were performed using ultra-performance liquid chromatography-tandem mass spectrometry, and the phosphatidylinositol 3 kinase/protein kinase B/mechanistic target of rapamycin (PI3K/AKT/mTOR) pathway was detected by western blotting. RESULTS The data demonstrated that HQT could alleviate the development of CAC in the animal model. HQT effectively reduced the inflammatory response, particularly interleukin-6 (IL-6), in the inflammation induction stage, as well as in the stages of proliferation initiation and tumorigenesis. During the proliferation initiation and tumorigenesis stages, immunohistochemistry staining showed that the expression of the proliferation marker Ki67 was reduced, while apoptosis was increased in the HQT group. Accordingly, HQT substantially decreased the levels of specific AAs in the colon with CAC, including glutamic acid, glutamine, arginine, and isoleucine. Furthermore, HQT significantly inhibited the activated PI3K/AKT/mTOR pathway, which may contribute to suppression of cell proliferation and enhancement of apoptosis. CONCLUSION HQT is effective in alleviating and delaying the colon "inflammation-to-cancer". The mechanism of action may involve HQT maintained AAs metabolism homeostasis and regulated PI3K/AKT/mTOR pathway, so as to maintain the balance between proliferation and apoptosis, and then interfere in the occurrence and development of CAC.
Collapse
Affiliation(s)
- Dunfang Wang
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China.
| | - Lin Zhu
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China.
| | - Haifan Liu
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China.
| | - Xue Feng
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China.
| | - Caijuan Zhang
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China.
| | - Tao Li
- Experimental Research Center, China Academy of Chinese Medical Sciences, Beijing, 100700, China.
| | - Bin Liu
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China.
| | - Li Liu
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China.
| | - Jingwei Sun
- Beijing University of Chinese Medicine, Beijing, 100700, China.
| | - Hao Chang
- Experimental Research Center, China Academy of Chinese Medical Sciences, Beijing, 100700, China.
| | - Siyuan Chen
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China.
| | - Shanshan Guo
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China.
| | - Weipeng Yang
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China.
| |
Collapse
|
|
10
|
Wakisaka R, Kumai T, Komatsuda H, Yamaki H, Kono M, Sato R, Ohara K, Kishibe K, Hayashi T, Okizaki A, Takahara M. Prognostic Value of the 18F-FDG PET/CT and Haematological Parameters in Head and Neck Cancer. Clin Otolaryngol 2024; 49:733-741. [PMID: 38950901 DOI: 10.1111/coa.14195] [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: 08/23/2023] [Revised: 06/10/2024] [Accepted: 06/15/2024] [Indexed: 07/03/2024]
Abstract
INTRODUCTION Fluorine 18-fluoro-glucose positron emission tomography/computed tomography (18F-FDG PET/CT) is commonly used for the staging of head and neck cancer. This study aimed to evaluate the correlation between 18F-FDG PET/CT, haematological parameters and prognosis in patients with advanced head and neck cancer. METHODS This was a single-institutional retrospective study of 83 patients with advanced head and neck squamous cell carcinoma (HNSCC) who underwent 18F-FDG PET/CT imaging before initial treatment between 2014 and 2018. 18F-FDG PET/CT after treatment was performed in 57 patients. The prognostic parameters of the pre- and post-treatment maximum standardised uptake value (SUVmax), metabolic tumour volume (MTV), total lesion glycolysis (TLG) of primary tumours and haematological parameters were analysed to evaluate the association between overall survival (OS) and progression-free survival (PFS). RESULTS Pre-MTV, pre-TLG and post-SUVmax were significantly associated with poor OS and PFS (p < 0.05). Haematological parameters, including pretreatment neutrophil/lymphocyte ratio and C-reactive protein/albumin ratio, were associated with 18F-FDG PET/CT parameters. In multivariate analysis, post-SUVmax was an independent prognostic factor for OS and PFS. CONCLUSION A correlation between PET/CT metabolic and haematological parameters was observed. The volume and intensity of 18F-FDG uptake region, in addition to haematological parameters, are feasible markers for predicting the progression of HNSCC in daily practice. Further, post-SUVmax could be an independent parameter for predicting poor survival.
Collapse
Affiliation(s)
- Risa Wakisaka
- Department of Otolaryngology - Head and Neck Surgery, Asahikawa Medical University, Asahikawa, Japan
| | - Takumi Kumai
- Department of Otolaryngology - Head and Neck Surgery, Asahikawa Medical University, Asahikawa, Japan
- Department of Innovative Head & Neck Cancer Research and Treatment (IHNCRT), Asahikawa Medical University, Asahikawa, Japan
| | - Hiroki Komatsuda
- Department of Otolaryngology - Head and Neck Surgery, Asahikawa Medical University, Asahikawa, Japan
| | - Hidekiyo Yamaki
- Department of Otolaryngology - Head and Neck Surgery, Asahikawa Medical University, Asahikawa, Japan
| | - Michihisa Kono
- Department of Otolaryngology - Head and Neck Surgery, Asahikawa Medical University, Asahikawa, Japan
| | - Ryosuke Sato
- Department of Otolaryngology - Head and Neck Surgery, Asahikawa Medical University, Asahikawa, Japan
| | - Kenzo Ohara
- Department of Otolaryngology - Head and Neck Surgery, Asahikawa Medical University, Asahikawa, Japan
| | - Kan Kishibe
- Department of Otolaryngology - Head and Neck Surgery, Asahikawa Medical University, Asahikawa, Japan
| | - Tatsuya Hayashi
- Department of Otolaryngology - Head and Neck Surgery, Asahikawa Medical University, Asahikawa, Japan
| | - Atsutaka Okizaki
- Department of Radiology, Asahikawa Medical University, Asahikawa, Japan
| | - Miki Takahara
- Department of Otolaryngology - Head and Neck Surgery, Asahikawa Medical University, Asahikawa, Japan
- Department of Innovative Head & Neck Cancer Research and Treatment (IHNCRT), Asahikawa Medical University, Asahikawa, Japan
| |
Collapse
|
|
11
|
Wang D, Zhu L, Liu H, Feng X, Zhang C, Liu B, Li T, Liu L, Chang H, Sun J, Yang L, Yang W. Altered gut metabolites and metabolic reprogramming involved in the pathogenesis of colitis-associated colorectal cancer and the transition of colon "inflammation to cancer". J Pharm Biomed Anal 2024; 253:116553. [PMID: 39486392 DOI: 10.1016/j.jpba.2024.116553] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2024] [Revised: 10/27/2024] [Accepted: 10/27/2024] [Indexed: 11/04/2024]
Abstract
Colitis-associated colorectal cancer (CAC) is fatal and can develop spontaneously or as a complication of inflammatory bowel diseases. Although co-administration of azoxymethane/dextran sulfate sodium (AOM/DSS) is a classic method for CAC modeling, its limitations need to be addressed. Accordingly, we aimed to optimize the AOM/DSS model to study CAC extensively and further investigate its pathogenic mechanisms relative to microbiota and metabolism. We optimized the CAC model via a single or enhanced injection of AOM combined with different administration modes and varying DSS concentrations. Subsequently, the fecal-microbiota composition was examined using 16S RNA sequencing, and fecal-colon-metabolome profiles were evaluated via ultra-high performance liquid chromatography-mass spectrometry. Two interval injections of AOM combined with 1.5 % DSS-free drinking resulted in a high tumor formation rate, uniform tumor formation, and low mortality. Based on this model, we innovatively divided the pathogenesis of CAC into three stages, namely inflammation induction, proliferation initiation, and tumorigenesis, and examined the pathological characteristics in each stage. Gut microbial dysbiosis and metabolic alteration drove colorectal tumorigenesis by aggravating inflammation while promoting cell proliferation and carcinogenesis in mice. For the first time, we dynamically demonstrated the process of colon "inflammation to cancer" transformation and provided novel insights to clarify the role of amino acid metabolism in the formation of CAC.
Collapse
Affiliation(s)
- Dunfang Wang
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Lin Zhu
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Haifan Liu
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Xue Feng
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Caijuan Zhang
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Bin Liu
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Tao Li
- Experimental Research Center, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Li Liu
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Hao Chang
- Experimental Research Center, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Jingwei Sun
- Beijing University of Chinese Medicine, Beijing 100700, China
| | - Lei Yang
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China.
| | - Weipeng Yang
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China.
| |
Collapse
|
|
12
|
He TS, Cai K, Lai W, Yu J, Qing F, Shen A, Sui L, He W, Wang W, Xiao Q, Lei X, Guo T, Liu Z. E3 ubiquitin ligase RNF128 attenuates colitis and colorectal tumorigenesis by triggering the degradation of IL-6 receptors. J Adv Res 2024:S2090-1232(24)00262-5. [PMID: 38964734 DOI: 10.1016/j.jare.2024.06.025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2024] [Revised: 06/07/2024] [Accepted: 06/27/2024] [Indexed: 07/06/2024] Open
Abstract
INTRODUCTION Intestinal immune dysregulation is strongly linked to the occurrence and formation of tumors. RING finger protein 128 (RNF128) has been identified to play distinct immunoregulatory functions in innate and adaptive systems. However, the physiological roles of RNF128 in intestinal inflammatory conditions such as colitis and colorectal cancer (CRC) remain controversial. OBJECTIVES To elucidate the function and mechanism of RNF128 in colitis and CRC. METHODS Animal models of dextran sodium sulfate (DSS)-induced colitis and azoxymethane (AOM)/DSS-induced CRC were established in WT and Rnf128-deficient mice and evaluated by histopathology. Co-immunoprecipitation and ubiquitination analyses were employed to investigate the role of RNF128 in IL-6-STAT3 signaling. RESULTS RNF128 was significantly downregulated in clinical CRC tissues compared with paired peritumoral tissues. Rnf128-deficient mice were hypersusceptible to both colitis induced by DSS and CRC induced by AOM/DSS or APC mutation. Loss of RNF128 promoted the proliferation of CRC cells and STAT3 activation during the early transformative stage of carcinogenesis in vivo and in vitro when stimulated by IL-6. Mechanistically, RNF128 interacted with the IL-6 receptor α subunit (IL-6Rα) and membrane glycoprotein gp130 and mediated their lysosomal degradation in ligase activity-dependent manner. Through a series of point mutations in the IL-6 receptor, we identified that RNF128 promoted K48-linked polyubiquitination of IL-6Rα at K398/K401 and gp130 at K718/K816/K866. Additionally, blocking STAT3 activation effectively eradicated the inflammatory damage of Rnf128-deficient mice during the transformative stage of carcinogenesis. CONCLUSION RNF128 attenuates colitis and colorectal tumorigenesis by inhibiting IL-6-STAT3 signaling, which sheds novel insights into the modulation of IL-6 receptors and the inflammation-to-cancer transition.
Collapse
Affiliation(s)
- Tian-Sheng He
- Center for Immunology, Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Gannan Medical University, Ganzhou, Jiangxi, China; School of Basic Medicine, Gannan Medical University, Ganzhou, Jiangxi, China
| | - Kuntai Cai
- Center for Immunology, Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Gannan Medical University, Ganzhou, Jiangxi, China; Graduate School, Gannan Medical University, Ganzhou, Jiangxi, China
| | - Weiling Lai
- Department of Oncology, The First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China
| | - Jingge Yu
- Center for Immunology, Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Gannan Medical University, Ganzhou, Jiangxi, China; Graduate School, Gannan Medical University, Ganzhou, Jiangxi, China
| | - Furong Qing
- Center for Immunology, Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Gannan Medical University, Ganzhou, Jiangxi, China; Graduate School, Gannan Medical University, Ganzhou, Jiangxi, China
| | - Ao Shen
- Center for Immunology, Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Gannan Medical University, Ganzhou, Jiangxi, China; Graduate School, Gannan Medical University, Ganzhou, Jiangxi, China
| | - Lina Sui
- Center for Immunology, Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Gannan Medical University, Ganzhou, Jiangxi, China; Graduate School, Gannan Medical University, Ganzhou, Jiangxi, China
| | - Wenji He
- School of Basic Medicine, Gannan Medical University, Ganzhou, Jiangxi, China; Graduate School, China Medical University, Shenyang, Liaoning, China
| | - Weihua Wang
- Graduate School, China Medical University, Shenyang, Liaoning, China; Department of Clinical Laboratory, The First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China
| | - Qiuxiang Xiao
- Graduate School, China Medical University, Shenyang, Liaoning, China; Department of Pathology, The First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China
| | - Xiong Lei
- Department of General Surgery, The First Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi, China
| | - Tianfu Guo
- School of Basic Medicine, Gannan Medical University, Ganzhou, Jiangxi, China.
| | - Zhiping Liu
- Center for Immunology, Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Gannan Medical University, Ganzhou, Jiangxi, China; School of Basic Medicine, Gannan Medical University, Ganzhou, Jiangxi, China.
| |
Collapse
|
|
13
|
Glasgow TE, Burch JB, Arcan C, Reading JM, Theal M, Cyrus JW, Fuemmeler BF. A Scoping Review of Firefighters' Health Behaviors and Chronic Diseases. Am J Health Behav 2024; 48:746-765. [DOI: 10.5993/ajhb.48.3.16] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
Objectives:Due to exposure to carcinogenic agents, firefighters are at increased risk for chronic diseases (e. g., cancer). It is unclear how much research has focused on firefighters' health behaviors that also could also contribute to firefighters' disease risk. In this scoping review, we aimed to (1) determine how much research has examined firefighters' health behaviors and (2) determine how many studies have assessed the association between health behaviors and chronic diseases.Methods:We searched electronic databases (e. g., PubMed/MEDLINE). We included studies if they measured at least one health behavior (diet, tobacco use, physical activity, sleep, alcohol consumption), regardless of assessing chronic diseases. We noted if the study included chronic diseases and if it examined an association between health behavior and chronic disease.Results:Overall, 126 articles were included that measured at least one health behavior. Physical activity and diet were the most studied health behaviors. About half of the studies included a chronic disease. Of those studies, 26 examined associations between the health behavior(s) and chronic diseases.Conclusions:There is a growing literature examining health behaviors among firefighters. This information can inform intervention development.
Collapse
Affiliation(s)
- Trevin E. Glasgow
- University of Virginia, Department of Public Health Sciences, Charlottesville, VA, United States
| | - James B. Burch
- Virginia Commonwealth University School of Medicine, Department of Family Medicine and Population Health, Richmond, VA, United States
| | - Chrisa Arcan
- Virginia Commonwealth University School of Medicine, Department of Family Medicine and Population Health, Richmond, VA, United States
| | - Jean M. Reading
- Northwestern University Feinberg School of Medicine, Department of Preventive Medicine, Chicago, IL, United States
| | - Maddy Theal
- Virginia Commonwealth University School of Medicine, Department of Family Medicine and Population Health, Richmond, VA, United States
| | - John W. Cyrus
- Virginia Commonwealth University, VCU Libraries, Research and Education Department, Richmond, VA, United States
| | - Bernard F. Fuemmeler
- Virginia Commonwealth University School of Medicine, Department of Family Medicine and Population Health, Richmond, VA, United States
| |
Collapse
|
|
14
|
Swaroop AK, Negi P, Kar A, Mariappan E, Natarajan J, Namboori P K K, Selvaraj J. Navigating IL-6: From molecular mechanisms to therapeutic breakthroughs. Cytokine Growth Factor Rev 2024; 76:48-76. [PMID: 38220583 DOI: 10.1016/j.cytogfr.2023.12.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2023] [Accepted: 12/28/2023] [Indexed: 01/16/2024]
Abstract
This concise review navigates the intricate realm of Interleukin-6 (IL-6), an important member of the cytokine family. Beginning with an introduction to cytokines, this narrative review unfolds with the historical journey of IL-6, illuminating its evolving significance. A crucial section unravels the three distinct signaling modes employed by IL-6, providing a foundational understanding of its versatile interactions within cellular landscapes. Moving deeper, the review meticulously dissects IL-6's signaling mechanisms, unraveling the complexities of its pleiotropic effects in both physiological responses and pathological conditions. A significant focus is dedicated to the essential role IL-6 plays in inflammatory diseases, offering insights into its associations and implications for various health conditions. The review also takes a therapeutic turn by exploring the emergence of anti-IL-6 monoclonal inhibitors, marking a profound stride in treatment modalities. Diving into the molecular realm, the review explores small molecules as agents for IL-6 inhibition, providing a nuanced perspective on diverse intervention strategies. As the review embarks on the final chapters, it contemplates future aspects, offering glimpses into potential research trajectories and the evolving landscape of IL-6-related studies.
Collapse
Affiliation(s)
- Akey Krishna Swaroop
- Department of Pharmaceutical Chemistry, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Ooty, Tamil Nadu, India
| | - Preeya Negi
- Department of Pharmaceutical Chemistry, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Ooty, Tamil Nadu, India
| | - Ayushi Kar
- Department of Pharmaceutical Chemistry, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Ooty, Tamil Nadu, India
| | - Esakkimuthukumar Mariappan
- Department of Pharmaceutical Chemistry, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Ooty, Tamil Nadu, India
| | - Jawahar Natarajan
- Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Ooty, Tamil Nadu, India
| | - Krishnan Namboori P K
- Amrita Molecular Modeling and Synthesis (AMMAS) Research lab, Amrita Vishwavidyapeetham, Amrita Nagar, Ettimadai, Coimbatore, Tamil Nadu, India
| | - Jubie Selvaraj
- Department of Pharmaceutical Chemistry, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Ooty, Tamil Nadu, India.
| |
Collapse
|
|
15
|
Liu J, Zhao F, Zhang Y, Lin Z, Chen JL, Diao H. C6 Ceramide Inhibits Canine Mammary Cancer Growth and Metastasis by Targeting EGR3 through JAK1/STAT3 Signaling. Animals (Basel) 2024; 14:422. [PMID: 38338065 PMCID: PMC10854580 DOI: 10.3390/ani14030422] [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: 11/24/2023] [Revised: 01/18/2024] [Accepted: 01/24/2024] [Indexed: 02/12/2024] Open
Abstract
Cancer is the leading cause of death in both humans and companion animals. Canine mammary tumor is an important disease with a high incidence and metastasis rate, and its poor prognosis remains a serious clinical challenge. C6 ceramide is a short-chain sphingolipid metabolite with powerful potential as a tumor suppressor. However, the specific impact of C6 ceramide on canine mammary cancer remains unclear. However, the effects of C6 ceramide in canine mammary cancer are still unclear. Therefore, we investigated the role of C6 ceramide in the progress of canine mammary cancer and explored its potential mechanism. C6 ceramide inhibited cell growth by regulating the cell cycle without involving apoptosis. Additionally, C6 ceramide inhibited the migration and invasion of CHMp cells. In vivo, C6 ceramide decreased tumor growth and metastasis in the lungs without side effects. Further investigation found that the knockdown of EGR3 expression led to a noticeable increase in proliferation and migration by upregulating the expressions of pJAK1 and pSTAT3, thus activating the JAK1/STAT3 signaling pathway. In conclusion, C6 ceramide inhibits canine mammary cancer growth and metastasis by targeting EGR3 through the regulation of the JAK1/STAT3 signaling pathway. This study implicates the mechanisms underlying the anti-tumor activity of C6 ceramide and demonstrates the potential of EGR3 as a novel target for treating canine mammary cancer.
Collapse
Affiliation(s)
- Jiayue Liu
- Joint Laboratory of Animal Pathogen Prevention and Control of Fujian-Nepal, College of Animal Sciences, Fujian Agriculture and Forestry University, Fuzhou 350002, China; (J.L.); (Y.Z.); (J.-L.C.)
| | - Fangying Zhao
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China;
| | - Yan Zhang
- Joint Laboratory of Animal Pathogen Prevention and Control of Fujian-Nepal, College of Animal Sciences, Fujian Agriculture and Forestry University, Fuzhou 350002, China; (J.L.); (Y.Z.); (J.-L.C.)
| | - Zhaoyan Lin
- Key Lab for Integrated Chinese Traditional Veterinary Medicine and Animal Healthcare in Fujian Province, College of Animal Sciences, Fujian Agriculture and Forestry University, Fuzhou 350002, China;
| | - Ji-Long Chen
- Joint Laboratory of Animal Pathogen Prevention and Control of Fujian-Nepal, College of Animal Sciences, Fujian Agriculture and Forestry University, Fuzhou 350002, China; (J.L.); (Y.Z.); (J.-L.C.)
| | - Hongxiu Diao
- Joint Laboratory of Animal Pathogen Prevention and Control of Fujian-Nepal, College of Animal Sciences, Fujian Agriculture and Forestry University, Fuzhou 350002, China; (J.L.); (Y.Z.); (J.-L.C.)
| |
Collapse
|
|
16
|
Berger K, Persson E, Gregersson P, Ruiz-Martínez S, Jonasson E, Ståhlberg A, Rhost S, Landberg G. Interleukin-6 Induces Stem Cell Propagation through Liaison with the Sortilin-Progranulin Axis in Breast Cancer. Cancers (Basel) 2023; 15:5757. [PMID: 38136303 PMCID: PMC10741783 DOI: 10.3390/cancers15245757] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2023] [Revised: 10/25/2023] [Accepted: 12/06/2023] [Indexed: 12/24/2023] Open
Abstract
Unraveling the complex network between cancer cells and their tumor microenvironment is of clinical importance, as it might allow for the identification of new targets for cancer treatment. Cytokines and growth factors secreted by various cell types present in the tumor microenvironment have the potential to affect the challenging subpopulation of cancer stem cells showing treatment-resistant properties as well as aggressive features. By using various model systems, we investigated how the breast cancer stem cell-initiating growth factor progranulin influenced the secretion of cancer-associated proteins. In monolayer cultures, progranulin induced secretion of several inflammatory-related cytokines, such as interleukin (IL)-6 and -8, in a sortilin-dependent manner. Further, IL-6 increased the cancer stem fraction similarly to progranulin in the breast cancer cell lines MCF7 and MDA-MB-231 monitored by the surrogate mammosphere-forming assay. In a cohort of 63 patient-derived scaffold cultures cultured with breast cancer cells, we observed significant correlations between IL-6 and progranulin secretion, clearly validating the association between IL-6 and progranulin also in human-based microenvironments. In conclusion, the interplay between progranulin and IL-6 highlights a dual breast cancer stem cell-promoting function via sortilin, further supporting sortilin as a highly relevant therapeutic target for aggressive breast cancer.
Collapse
Affiliation(s)
- Karoline Berger
- Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, 40530 Gothenburg, Sweden; (K.B.); (E.P.); (P.G.); (S.R.-M.); (E.J.); (A.S.); (S.R.)
| | - Emma Persson
- Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, 40530 Gothenburg, Sweden; (K.B.); (E.P.); (P.G.); (S.R.-M.); (E.J.); (A.S.); (S.R.)
| | - Pernilla Gregersson
- Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, 40530 Gothenburg, Sweden; (K.B.); (E.P.); (P.G.); (S.R.-M.); (E.J.); (A.S.); (S.R.)
| | - Santiago Ruiz-Martínez
- Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, 40530 Gothenburg, Sweden; (K.B.); (E.P.); (P.G.); (S.R.-M.); (E.J.); (A.S.); (S.R.)
| | - Emma Jonasson
- Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, 40530 Gothenburg, Sweden; (K.B.); (E.P.); (P.G.); (S.R.-M.); (E.J.); (A.S.); (S.R.)
| | - Anders Ståhlberg
- Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, 40530 Gothenburg, Sweden; (K.B.); (E.P.); (P.G.); (S.R.-M.); (E.J.); (A.S.); (S.R.)
- Wallenberg Center for Molecular and Translational Medicine, University of Gothenburg, 41390 Gothenburg, Sweden
- Department of Clinical Genetics and Genomics, Sahlgrenska University Hospital, 41346 Gothenburg, Sweden
| | - Sara Rhost
- Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, 40530 Gothenburg, Sweden; (K.B.); (E.P.); (P.G.); (S.R.-M.); (E.J.); (A.S.); (S.R.)
| | - Göran Landberg
- Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, 40530 Gothenburg, Sweden; (K.B.); (E.P.); (P.G.); (S.R.-M.); (E.J.); (A.S.); (S.R.)
| |
Collapse
|
|
17
|
Xi Y, Wen R, Zhang R, Dong Q, Hou S, Zhang S. Genetic evidence supporting a causal role of Janus kinase 2 in prostate cancer: a Mendelian randomization study. Aging Male 2023; 26:2257300. [PMID: 37706641 DOI: 10.1080/13685538.2023.2257300] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Revised: 09/04/2023] [Accepted: 09/06/2023] [Indexed: 09/15/2023] Open
Abstract
BACKGROUND Janus kinase-2 (JAK2) inhibitors are now being tried in basic research and clinical practice in prostate cancer (PCa). However, the causal relationship between JAK2 and PCa has not been uniformly described. Here, we examined the cause-effect relation between JAK2 and PCa. METHODS Two-sample Mendelian randomization (MR) analysis of genetic variation data of JAK2, PCa from IEU OpenGWAS Project was performed by inverse variance weighted, MR-Egger, and weighted median. Cochran's Q heterogeneity test and MR-Egger multiplicity analysis were performed to normalize the MR analysis results to reduce the effect of bias on the results. RESULTS Five instrumental variables were identified for further MR analysis. Specifically, combining the inverse variance-weighted (OR: 1.0009, 95% CI: 1.0001-1.0015, p = 0.02) and weighted median (OR: 1.0009, 95% CI: 1.0000-1.0017, p = 0.03). Sensitivity analysis showed that there was no heterogeneity (p = 0.448) and horizontal multiplicity (p = 0.770) among the instrumental variables. CONCLUSIONS We found JAK2 was associated with the development of PCa and was a risk factor for PCa, which might be instructive for the use of JAK2 inhibitors in PCa patients.
Collapse
Affiliation(s)
- Yujia Xi
- Department of Urology, The Second Hospital of Shanxi Medical University, Shanxi Medical University, Taiyuan, China
- Shanxi Provincial Key Laboratory of Rheumatism Immune Microecology, Taiyuan, PR China
- Key Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, Taiyuan, PR China
| | - Rui Wen
- Shanxi Provincial Key Laboratory of Rheumatism Immune Microecology, Taiyuan, PR China
- Key Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, Taiyuan, PR China
| | - Ran Zhang
- Shanxi Provincial Key Laboratory of Rheumatism Immune Microecology, Taiyuan, PR China
- Key Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, Taiyuan, PR China
| | - Qirui Dong
- Shanxi Provincial Key Laboratory of Rheumatism Immune Microecology, Taiyuan, PR China
- Key Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, Taiyuan, PR China
| | - Sijia Hou
- Shanxi Provincial Key Laboratory of Rheumatism Immune Microecology, Taiyuan, PR China
- Key Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, Taiyuan, PR China
- Department of Neurology, The First Hospital of Shanxi Medical University, Shanxi Medical University, Taiyuan, China
| | - Shengxiao Zhang
- Shanxi Provincial Key Laboratory of Rheumatism Immune Microecology, Taiyuan, PR China
- Key Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, Taiyuan, PR China
- Department of Rheumatology, The Second Hospital of Shanxi Medical University, Shanxi Medical University, Taiyuan, China
| |
Collapse
|
|
18
|
WEN JY, PENG HX, WANG D, WEN ZM, LIU YT, QU J, CUI HX, WANG YY, DU YL, WANG T, GENG C, XU B. Lipopolysaccharides protect mesenchymal stem cell against cardiac ischemia-reperfusion injury by HMGB1/STAT3 signaling. J Geriatr Cardiol 2023; 20:801-812. [PMID: 38098470 PMCID: PMC10716610 DOI: 10.26599/1671-5411.2023.11.007] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2023] Open
Abstract
BACKGROUND Myocardial ischemia-reperfusion (I/R) is a serious and irreversible injury. Bone marrow-derived mesenchymal stem cells (MSCs) is considered to be a potential therapy for I/R injury due to the paracrine effects. High-mobility group box 1 (HMGB1) is a novel mediator in MSC and regulates the response of inflammation injury. Signal Transduction and Transcription Activator 3 (STAT3) is a critical transcription factor and important for release of paracrine factors. However, the relationship between HMGB1 and STAT3 in paracrine effect of MSC remains unknown. METHODS In vitro, hypoxia/reoxygenation injury model was established by AnaeroPack System and examined by Annexin V flow cytometry, CCK8 assay and morphology observation. Detection of apoptotic proteins and protein expression of HMGB1 and STAT3 by Western blot. RESULTS The conditioned medium of MSCs with or without LPS pretreatment was cocultured with H9C2 cells for 24 h before hypoxia treatment and MSC showed obvious cardiomyocytes protect role, as evidence by decreased apoptosis rate and improved cells viability, and LPS pretreated MSC exhibited better protect role than untreated MSC. However, such effect was abolished in HMGB1 deficiency group, silencing HMGB1 decreased the secretion of vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), insulin growth factor (IGF), cell viability, and the expression of STAT3. Furthermore, STAT3 silence attenuated the protective effect of LPS in MSC. CONCLUSIONS These findings suggested that LPS improved MSC-mediated cardiomyocytes protection by HMGB1/STAT3 signaling.
Collapse
Affiliation(s)
- Jing-Yi WEN
- Department of Clinical Pharmacy, the Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
- Department of Pharmacy, the Second Affiliated Hospital of Inner Mongolia Medical University, Hohhot, Inner Mongolia, China
| | - Hui-Xi PENG
- Department of Clinical Pharmacy, the Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
| | - Dan WANG
- Department of Pharmacy, Ordos Central Hospital, Ordos, Inner Mongolia, China
| | - Zhi-Min WEN
- Department of Clinical Laboratory, the Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
| | - Yu-Tong LIU
- Department of Clinical Laboratory, the Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
| | - Jian QU
- Department of Clinical Laboratory, the Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
| | - Hong-Xuan CUI
- Department of Clinical Pharmacy, the Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
| | - Yu-Ying WANG
- Department of Clinical Pharmacy, the Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
| | - Yan-Lin DU
- Department of Clinical Pharmacy, the Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
| | - Ting WANG
- Department of Clinical Laboratory, the Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
| | - Cong GENG
- Department of Clinical Laboratory, the Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
| | - Bing XU
- Department of Clinical Pharmacy, the Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
| |
Collapse
|
|
19
|
Ben-Mordechai T, Lawrence YR, Symon Z, Shimoni-Sebag A, Amit U. CX3CR1-Expressing Immune Cells Infiltrate the Tumor Microenvironment and Promote Radiation Resistance in a Mouse Model of Lung Cancer. Cancers (Basel) 2023; 15:5472. [PMID: 38001732 PMCID: PMC10669975 DOI: 10.3390/cancers15225472] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2023] [Revised: 11/09/2023] [Accepted: 11/13/2023] [Indexed: 11/26/2023] Open
Abstract
INTRODUCTION Chemokine (C-X3-C Motif) Receptor 1 (CX3CR1) is present in a subset of the immune cells in the tumor microenvironment (TME) and plays an essential and diverse role in cancer progression. However, its potential function in the irradiated TME remains unknown. MATERIALS AND METHODS A mouse lung cancer model was performed by subcutaneously inoculating Lewis Lung Carcinoma (LLC) cells expressing luciferase (Luc-2) and mCherry cells in CX3CR1GFP/GFP, CX3CR1DTR/+, and wild-type (WT) mice. Bioluminescence imaging, clonogenic assay, and flow cytometry were used to assess tumor progression, proliferation, and cell composition after radiation. RESULTS Radiation provoked a significant influx of CX3CR1-expressing immune cells, notably monocytes and macrophages, into the TME. Co-culturing irradiated LLC cells with CX3CR1-deficient monocytes, and macrophages resulted in reduced clonogenic survival and increased apoptosis of the cancer cells. Interestingly, deficiency of CX3CR1 in macrophages led to a redistribution of the irradiated LLC cells in the S-phase, parallel to increased expression of cyclin E1, required for cell cycle G1/S transition. In addition, the deficiency of CX3CR1 expression in macrophages altered the cytokine secretion with a decrease in interleukin 6, a crucial mediator of cancer cell survival and proliferation. Next, LLC cells were injected subcutaneously into CX3CR1DTR/+ mice, sensitive to diphtheria toxin (DT), and WT mice. After injection, tumors were irradiated with 8 Gy, and mice were treated with DT, leading to conditional ablation of CX3CR1-expressing cells. After three weeks, CX3CR1-depleted mice displayed reduced tumor progression. Furthermore, combining the S-phase-specific chemotherapeutic gemcitabine with CX3CR1 cell ablation resulted in additional attenuation of tumor progression. CONCLUSIONS CX3CR1-expressing mononuclear cells invade the TME after radiation therapy in a mouse lung cancer model. CX3CR1 cell depletion attenuates tumor progression following radiation and sensitizes the tumor to S-phase-specific chemotherapy. Thus, we propose a novel strategy to improve radiation sensitivity by targeting the CX3CR1-expressing immune cells.
Collapse
Affiliation(s)
- Tamar Ben-Mordechai
- Radiation Oncology Department, Chaim Sheba Medical Center, Ramat Gan 52621, Israel; (T.B.-M.); (Y.R.L.); (Z.S.); (A.S.-S.)
| | - Yaacov R. Lawrence
- Radiation Oncology Department, Chaim Sheba Medical Center, Ramat Gan 52621, Israel; (T.B.-M.); (Y.R.L.); (Z.S.); (A.S.-S.)
- Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel
| | - Zvi Symon
- Radiation Oncology Department, Chaim Sheba Medical Center, Ramat Gan 52621, Israel; (T.B.-M.); (Y.R.L.); (Z.S.); (A.S.-S.)
- Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel
| | - Ariel Shimoni-Sebag
- Radiation Oncology Department, Chaim Sheba Medical Center, Ramat Gan 52621, Israel; (T.B.-M.); (Y.R.L.); (Z.S.); (A.S.-S.)
| | - Uri Amit
- Radiation Oncology Department, Tel Aviv Medical Center, Tel Aviv 64239, Israel
- Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, 3400 Civic Center Boulevard, TRC 2 West Philadelphia, Philadelphia, PA 19104, USA
| |
Collapse
|
|
20
|
Bershawy R, Hafez HS, El-Sakka SS, Hammad A, Soliman MH. The anticancer and anti-inflammatory activity screening of pyridazinone-based analogs against human epidermoid skin cancer with detailed mechanistic analyses. J Biomol Struct Dyn 2023; 42:12885-12899. [PMID: 37916672 DOI: 10.1080/07391102.2023.2273985] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Accepted: 09/07/2023] [Indexed: 11/03/2023]
Abstract
3(2H)-Pyridazinone derivatives based on 4-biphenyl, naphtha-2-yl, pyridine, or piperidine moiety were synthesized and characterized using I-R and 1HNMR spectra. The activity and cytotoxicity of some synthesized compounds on the skin epidermoid cancer cell proliferation and progression were investigated. The pyridazine isomer with pyridine revealed a significant decrease in the level of nitric oxide p < 0.01 than the activity of caffeine phenecyl ester. The activity of the three active isomers recorded significant activity for their total antioxidant content that triggers their ability for the scavenging the oxygen free radicals significantly p < 0.01. Moreover, revealing the pharmaceutical activity of the isomers as anti-inflammatory agents, IL-6, IL10, and IL12 have been decreased by variable significant values. Additionally, the active isomers revealed variable actions on the skin cancer cell to induce apoptosis using annexin V-FITC/PI. Pyridine was the highest isomer to induce late apoptosis and necrosis for the skin cancer cells against the use of cisplatin. Importantly, Molecular modeling experiments including docking and dynamic simulations were done for the most active 3 analogs to explore the ligand binding and stability leading to exploring the structure-activity relationship with biological target PARP1 which showed a good binding propensity to pyridazine binding site which supports the in vitro data. In conclusion, the pyridazine moieties with piperdine, naphthayl, and pyridine have pharmacological activities against skin cancer epidermoid by triggering action in inhibition of the proliferation and progression with an up-regulated apoptotic mechanism that evades the emergence of cisplatin resistance among different cancer cells.Communicated by Ramaswamy H. Sarma.
Collapse
Affiliation(s)
- Rana Bershawy
- Department of Chemistry, Faculty of Science, Suez University, Suez, Egypt
| | - Hani S Hafez
- Department of Zoology, Faculty of Science, Suez University, Suez, Egypt
| | - Sahar S El-Sakka
- Department of Chemistry, Faculty of Science, Suez University, Suez, Egypt
| | - Ali Hammad
- Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt
| | - Mohammed H Soliman
- Department of Chemistry, Faculty of Science, Suez University, Suez, Egypt
| |
Collapse
|
|
21
|
Wang R, Ye H, Yang B, Ao M, Yu X, Wu Y, Xi M, Hou M. m6A-modified circNFIX promotes ovarian cancer progression and immune escape via activating IL-6R/JAK1/STAT3 signaling by sponging miR-647. Int Immunopharmacol 2023; 124:110879. [PMID: 37713785 DOI: 10.1016/j.intimp.2023.110879] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Revised: 08/21/2023] [Accepted: 08/28/2023] [Indexed: 09/17/2023]
Abstract
BACKGROUND Ovarian cancer (OC) is one of the most common gynecological malignant cancers. Our previous work confirmed that circNFIX acted as an oncogene in OC, which could promote malignant proliferation, metastasis and angiogenesis. However, the role and mechanism of circNFIX in OC immune escape remain unclear. METHODS The RNA and protein levels were determined by qRT-PCR and western blot assays. The malignant phenotypes were tested by cell count kit-8, EdU staining, flow cytometry and transwell assays. The immune cytokines levels were measured by ELISA analysis. Molecular interactions were verified employing RNA immunoprecipitation, meRIP and dual luciferase methods. In vivo validation was performed by xenograft tumor and lung metastasis model. Hematoxylin & eosin and immunohistochemistry staining were used to observe the pathological changes. RESULTS The levels of circNFIX, PD-L1, and IL-6R were upregulated in OC tissues and cell lines, while miR-647 was downregulated. Functional assays showed that loss of circNFIX suppressed the growth, metastasis and immune escape of OC cells both in vitro and in vivo. On the molecular level, the m6A modification of circNFIX was elevated in OC cells, and its expression was positively correlated to m6A modification and depended on IGF2BP1 ∼ 3 recognition. Moreover, circNFIX acted as a competing endogenous RNA for miR-647 to upregulate IL-6R expression, thereby activating JAK/STAT3 signaling and elevating PD-L1 expression. Rescue assays revealed that co-silencing of miR-647 reversed the antitumor effects of circNFIX knockdown on cell proliferation, metastasis and immune escape of OC cells. CONCLUSION This study provided a comprehensive understanding of the molecular mechanism about circNFIX in OC, demonstrating m6A activated-circNFIX accelerated OC development and immune escape via regulating miR-647/IL-6R/PD-L1 pathway.
Collapse
Affiliation(s)
- Ruiyu Wang
- Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University & Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Ministry of Education, Chengdu 610041, Sichuan, PR China
| | - Hui Ye
- Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University & Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Ministry of Education, Chengdu 610041, Sichuan, PR China
| | - Bowen Yang
- Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University & Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Ministry of Education, Chengdu 610041, Sichuan, PR China
| | - Mengyin Ao
- Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University & Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Ministry of Education, Chengdu 610041, Sichuan, PR China
| | - Xiuzhang Yu
- Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University & Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Ministry of Education, Chengdu 610041, Sichuan, PR China
| | - Yuke Wu
- Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University & Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Ministry of Education, Chengdu 610041, Sichuan, PR China
| | - Mingrong Xi
- Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University & Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Ministry of Education, Chengdu 610041, Sichuan, PR China
| | - Minmin Hou
- Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University & Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Ministry of Education, Chengdu 610041, Sichuan, PR China.
| |
Collapse
|
|
22
|
Zogorean R, Wirtz S. The yin and yang of B cells in a constant state of battle: intestinal inflammation and inflammatory bowel disease. Front Immunol 2023; 14:1260266. [PMID: 37849749 PMCID: PMC10577428 DOI: 10.3389/fimmu.2023.1260266] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Accepted: 09/18/2023] [Indexed: 10/19/2023] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the gastrointestinal tract, defined by a clinical relapse-remitting course. Affecting people worldwide, the origin of IBD is still undefined, arising as a consequence of the interaction between genes, environment, and microbiota. Although the root cause is difficult to identify, data clearly indicate that dysbiosis and pathogenic microbial taxa are connected with the establishment and clinical course of IBD. The composition of the microbiota is shaped by plasma cell IgA secretion and binding, while cytokines such as IL10 or IFN-γ are important fine-tuners of the immune response in the gastrointestinal environment. B cells may also influence the course of inflammation by promoting either an anti-inflammatory or a pro-inflammatory milieu. Here, we discuss IgA-producing B regulatory cells as an anti-inflammatory factor in intestinal inflammation. Moreover, we specify the context of IgA and IgG as players that can potentially participate in mucosal inflammation. Finally, we discuss the role of B cells in mouse infection models where IL10, IgA, or IgG contribute to the outcome of the infection.
Collapse
Affiliation(s)
- Roxana Zogorean
- Medizinische Klinik 1, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Stefan Wirtz
- Medizinische Klinik 1, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
- Medical Immunology Campus Erlangen, FAU Erlangen-Nürnberg, Erlangen, Bavaria, Germany
| |
Collapse
|
|
23
|
Liu L, Xu W, Li K, Hu Y, Shen L, Zhang H, Wang Y. Kv1.3 mediates ox-LDL-induced vascular smooth muscle cell proliferation through JAK2/STAT3 signaling pathway. Arch Biochem Biophys 2023; 746:109719. [PMID: 37591369 DOI: 10.1016/j.abb.2023.109719] [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: 05/26/2023] [Revised: 08/10/2023] [Accepted: 08/13/2023] [Indexed: 08/19/2023]
Abstract
Kv1.3 channel has been shown to participate in regulating inflammatory activation, proliferation and apoptosis in several cell types. However, most of those existing studies focused on the ion-conducting properties of Kv1.3 in maintaining the resting potential and regulating Ca2+ influx. The aim of our study was to explore whether the Kv1.3-JAK2/STAT3 signaling pathway was involved in oxidized low density lipoprotein (ox-LDL) induced vascular smooth muscle cell (VSMC) proliferation. VSMCs from mouse aorta were cultured and treated with ox-LDL (25 μg/mL). The cell counting kit-8 was used to assess cell proliferation, and western blotting was performed to detect expression levels of Kv1.3, JAK2/STAT3, phosphorylated JAK2/STAT3, cyclin B1 and cyclin D1 in treated VSMCs. VSMCs were transfected with Kv1.3 small interfering RNA (Kv1.3-siRNA) or infected with a Kv1.3 lentiviral expression vector (Lv-Kv1.3) and treated with a JAK2 inhibitor LY2784544 to assess the role of Kv1.3 and JAK2/STAT3 signaling in mediating VSMC proliferation induced by ox-LDL. Ox-LDL induced cell proliferation and upregulated the expression of Kv1.3 in mouse VSMCs. In VSMCs transfected with Kv1.3-siRNA, ox-LDL was not efficient in inducing cell proliferation or the levels of proliferation associated proteins, cyclin B1 and cyclin D1. However, cell proliferation, cyclin B1 and cyclin D1 levels increased in VSMCs infected with Lv-Kv1.3. Levels of phosphorylated JAK2 and STAT3 were increased in ox-LDL-treated VSMCs, and this increase was prevented in VSMCs transfected with Kv1.3-siRNA. Treatment with the JAK2 inhibitor LY2784544 also prevented the increase in VSMCs proliferation treated with ox-LDL. Our findings demonstrated that Kv1.3 promoted proliferation of VSMCs treated with ox-LDL, and that this effect might be mediated through activation of the JAK2/STAT3 signaling pathway.
Collapse
Affiliation(s)
- Lin Liu
- Department of Geriatric Medicine, Qilu Hospital of Shandong University, Ji'nan, 250012, China; Key Laboratory of Cardiovascular Proteomics of Shandong Province, Qilu Hospital of Shandong University, Ji'nan, 250012, China
| | - Wei Xu
- Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Qilu Hospital of Shandong University, Ji'nan, 250012, China
| | - Kaiwen Li
- Department of Geriatric Medicine, Qilu Hospital of Shandong University, Ji'nan, 250012, China; Key Laboratory of Cardiovascular Proteomics of Shandong Province, Qilu Hospital of Shandong University, Ji'nan, 250012, China
| | - Yanyan Hu
- Department of Geriatric Medicine, Qilu Hospital of Shandong University, Ji'nan, 250012, China; Key Laboratory of Cardiovascular Proteomics of Shandong Province, Qilu Hospital of Shandong University, Ji'nan, 250012, China
| | - Lin Shen
- Department of Geriatric Medicine, Qilu Hospital of Shandong University, Ji'nan, 250012, China; Key Laboratory of Cardiovascular Proteomics of Shandong Province, Qilu Hospital of Shandong University, Ji'nan, 250012, China
| | - Hongyu Zhang
- Department of Geriatric Medicine, Qilu Hospital of Shandong University, Ji'nan, 250012, China; Key Laboratory of Cardiovascular Proteomics of Shandong Province, Qilu Hospital of Shandong University, Ji'nan, 250012, China
| | - Yuanyuan Wang
- Department of Geriatric Medicine, Qilu Hospital of Shandong University, Ji'nan, 250012, China; Key Laboratory of Cardiovascular Proteomics of Shandong Province, Qilu Hospital of Shandong University, Ji'nan, 250012, China.
| |
Collapse
|
|
24
|
Mao H, Yang F. Prognostic significance of albumin-to-globulin ratio in patients with renal cell carcinoma: a meta-analysis. Front Oncol 2023; 13:1210451. [PMID: 37538115 PMCID: PMC10394642 DOI: 10.3389/fonc.2023.1210451] [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: 04/22/2023] [Accepted: 07/03/2023] [Indexed: 08/05/2023] Open
Abstract
Background Whether the albumin-to-globulin ratio (AGR) predicts the prognosis of renal cell carcinoma (RCC) remains controversial. Herein, we performed a meta-analysis to critically evaluate the relationship between the AGR and RCC prognosis, as well as the association between the AGR and the clinicopathological characteristics of RCC. Methods The PubMed, Web of Science, Embase, and Cochrane Library databases were thoroughly and comprehensively searched from their inception until 24 June 2023. To determine the predictive significance of the AGR, hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) were calculated from the pooled data. The relationship between the AGR and the clinicopathological features of RCC was evaluated by estimating odds ratios (ORs) and 95% CIs in subgroup analyses. Results The meta-analysis included nine articles involving 5,671 RCC cases. A low AGR significantly correlated with worse overall survival (OS) (HR = 1.82, 95% CI = 1.37-2.41, p <0.001) and progression-free survival (PFS) (HR = 2.44, 95% CI = 1.61-3.70, p <0.001). Analysis of the pooled data also revealed significant associations between a low AGR and the following: female sex (OR = 1.48, 95% CI = 1.31-1.67, p <0.001), pT stage T3-T4 (OR = 4.12, 95% CI = 2.93-5.79, p <0.001), pN stage N1 (OR = 3.99, 95% CI = 2.40-6.64, p <0.001), tumor necrosis (OR = 3.83, 95% CI = 2.23-6.59, p <0.001), and Fuhrman grade 3-4 (OR = 1.82, 95% CI = 1.34-2.42, p <0.001). The AGR was not related to histology (OR = 0.83, 95% CI = 0.60-1.15, p = 0.267). Conclusion In patients with RCC, a low AGR strongly predicted poor OS and PFS and significantly correlated with clinicopathological features indicative of disease progression.
Collapse
Affiliation(s)
- Huaying Mao
- Clinical Laboratory, Huzhou Central Hospital, Affiliated Central Hospital of Huzhou University, Huzhou, Zhejiang, China
| | - Fan Yang
- Clinical Laboratory, Huzhou Maternity and Child Health Care Hospital, Huzhou, Zhejiang, China
| |
Collapse
|
|
25
|
Gombos G, Németh N, Pös O, Styk J, Buglyó G, Szemes T, Danihel L, Nagy B, Balogh I, Soltész B. New Possible Ways to Use Exosomes in Diagnostics and Therapy via JAK/STAT Pathways. Pharmaceutics 2023; 15:1904. [PMID: 37514090 PMCID: PMC10386711 DOI: 10.3390/pharmaceutics15071904] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Revised: 06/27/2023] [Accepted: 07/04/2023] [Indexed: 07/30/2023] Open
Abstract
Exosomes have the potential to be the future of personalized diagnostics and therapy. They are nano-sized particles between 30 and 100 nm flowing in the extracellular milieu, where they mediate cell-cell communication and participate in immune system regulation. Tumor-derived exosomes (TDEs) secreted from different types of cancer cells are the key regulators of the tumor microenvironment. With their immune suppressive cargo, TDEs prevent the antitumor immune response, leading to reduced effectiveness of cancer treatment by promoting a pro-tumorigenic microenvironment. Involved signaling pathways take part in the regulation of tumor proliferation, differentiation, apoptosis, and angiogenesis. Signal transducers and activators of transcription factors (STATs) and Janus kinase (JAK) signaling pathways are crucial in malignancies and autoimmune diseases alike, and their potential to be manipulated is currently the focus of interest. In this review, we aim to discuss exosomes, TDEs, and the JAK/STAT pathways, along with mediators like interleukins, tripartite motif proteins, and interferons.
Collapse
Affiliation(s)
- Gréta Gombos
- Department of Human Genetics, Faculty of Medicine, University of Debrecen, Egyetem Tér 1, H-4032 Debrecen, Hungary
| | - Nikolett Németh
- Department of Human Genetics, Faculty of Medicine, University of Debrecen, Egyetem Tér 1, H-4032 Debrecen, Hungary
| | - Ondrej Pös
- Comenius University Science Park, 841 04 Bratislava, Slovakia
- Geneton Ltd., 841 04 Bratislava, Slovakia
| | - Jakub Styk
- Comenius University Science Park, 841 04 Bratislava, Slovakia
- Geneton Ltd., 841 04 Bratislava, Slovakia
- Institute of Medical Biology, Genetics and Clinical Genetics, Faculty of Medicine, Comenius University, 811 08 Bratislava, Slovakia
| | - Gergely Buglyó
- Department of Human Genetics, Faculty of Medicine, University of Debrecen, Egyetem Tér 1, H-4032 Debrecen, Hungary
| | - Tomas Szemes
- Comenius University Science Park, 841 04 Bratislava, Slovakia
- Geneton Ltd., 841 04 Bratislava, Slovakia
- Department of Molecular Biology, Faculty of Natural Sciences, Comenius University, 841 01 Bratislava, Slovakia
| | - Ludovit Danihel
- 3rd Surgical Clinic, Faculty of Medicine, Comenius University and Merciful Brothers University Hospital, 811 08 Bratislava, Slovakia
| | - Bálint Nagy
- Department of Human Genetics, Faculty of Medicine, University of Debrecen, Egyetem Tér 1, H-4032 Debrecen, Hungary
- Comenius University Science Park, 841 04 Bratislava, Slovakia
| | - István Balogh
- Department of Human Genetics, Faculty of Medicine, University of Debrecen, Egyetem Tér 1, H-4032 Debrecen, Hungary
- Division of Clinical Genetics, Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary
| | - Beáta Soltész
- Department of Human Genetics, Faculty of Medicine, University of Debrecen, Egyetem Tér 1, H-4032 Debrecen, Hungary
| |
Collapse
|
|
26
|
El-Far M, Essam A, El-Senduny FF, El-Azim AO, Yahia S, El-Sherbiny IM. Novel highly effective combination of naturally-derived quercetin and ascorbyl palmitate and their nanoformulations as an advancement therapy of cancer. J Drug Deliv Sci Technol 2023. [DOI: 10.1016/j.jddst.2023.104405] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/03/2023]
|
|
27
|
Ng MJ, Kong BH, Teoh KH, Yap YHY, Ng ST, Tan CS, Mohamad Razif MF, Fung SY. In vivo anti-tumor activity of Lignosus rhinocerus TM02® using a MCF7-xenograft NCr nude mice model. JOURNAL OF ETHNOPHARMACOLOGY 2023; 304:115957. [PMID: 36509254 DOI: 10.1016/j.jep.2022.115957] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Revised: 11/07/2022] [Accepted: 11/18/2022] [Indexed: 06/17/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Lignosus rhinocerus (Cooke) Ryvarden (also known as Tiger Milk mushroom, TMM), is a basidiomycete belonging to the Polyporaceae family. It has been documented to be used by traditional Chinese physicians and indigenous people in Southeast Asia to treat a variety of illnesses, such as gastritis, arthritis, and respiratory conditions, as well as to restore patients' physical well-being. TMM has also been used in folk medicine to treat cancer. For example, people from the indigenous Kensiu tribe of northeast Kedah (Malaysia) apply shredded TMM sclerotium mixed with water directly onto breast skin to treat breast cancer, while Chinese practitioners from Hong Kong, China prescribe TMM sclerotium as a treatment for liver cancer. L. rhinocerus has previously been demonstrated to possess selective anti-proliferative properties in vitro, however pre-clinical in vivo research has not yet been conducted. AIM OF STUDY This study aimed to examine the anti-tumor activities of L. rhinocerus TM02®, using two different sample preparations [cold water extract (CWE) and fraction] via various routes of administration (oral and intraperitoneal) on an MCF7-xenograft nude mouse model. This study also investigated the inhibitory effect of TM02® CWE and its fractions against COX-2 in vitro using LPS-induced RAW264.7 macrophages, on the basis of the relationship between COX-2 and metastasis, apoptosis resistance, as well as the proliferation of cancer cells. MATERIALS AND METHODS The first preparation, L. rhinocerus TM02® sclerotium powder (TSP) was dissolved in cold water to obtain the cold water extract (CWE). It was further fractionated based on its molecular weight to obtain the high (HMW), medium (MMW) and low (LMW) molecular weight fractions. The second preparation, known as the TM02® rhinoprolycan fraction (TRF), was obtained by combining the HMW and MMW fractions. TSP was given orally to mimic the daily consumption of a supplement; TRF was administered intraperitoneally to mimic typical tumorous cancer treatment with a rapid and more thorough absorption through the peritoneal cavity. Another experiment was conducted to examine changes in COX-2 activity in LPS-induced RAW264.7 macrophages after a 1-h pre-treatment with CWE, HMW, and MMW. RESULTS Our results revealed that intraperitoneal TRF-injection (90 μg/g BW) for 20 days reduced initial tumor volume by ∼64.3% (n = 5). The percentage of apoptotic cells was marginally higher in TRF-treated mice vs. control, suggesting that induction of apoptosis as one of the factors that led to tumor shrinkage. TSP (500 μg/g BW) oral treatment (n = 5) for 63 days (inclusive of pre-treatment prior to tumor inoculation) effectively inhibited tumor growth. Four of the five tumors totally regressed, demonstrating the effectiveness of TSP ingestion in suppressing tumor growth. Although no significant changes were found in mouse serum cytokines (TNF-α, IL-5, IL-6 and CCL2), some increasing and decreasing trends were observed. This may suggest the immunomodulatory potential of these treatments that can directly or indirectly affect tumor growth. Pre-treatment with CWE, HMW and MMW significantly reduced COX-2 activity in RAW264.7 macrophages upon 24 h LPS-stimulation, suggesting the potential of L. rhinocerus TM02® extract and fractions in regulating M1/M2 polarization. CONCLUSION Based on the findings of our investigation, both the rhinoprolycan fraction and crude sclerotial powder from L. rhinocerus TM02® demonstrated tumor suppressive effects, indicating that they contain substances with strong anticancer potential. The antitumor effects of L. rhinocerus TM02® in our study highlights the potential for further explorations into its mechanism of action and future development as a prophylactic or adjunct therapeutic against tumorous cancer.
Collapse
Affiliation(s)
- Min Jia Ng
- Medicinal Mushroom Research Group (MMRG), Department of Molecular Medicine, Faculty of Medicine, Universiti Malaya, 50603, Kuala Lumpur, Malaysia.
| | - Boon Hong Kong
- Medicinal Mushroom Research Group (MMRG), Department of Molecular Medicine, Faculty of Medicine, Universiti Malaya, 50603, Kuala Lumpur, Malaysia; Centre of Excellence for Research in AIDS (CERiA), Department of Medicine, Faculty of Medicine, Universiti Malaya, 50603, Kuala Lumpur, Malaysia
| | - Kean Hooi Teoh
- Department of Pathology, Faculty of Medicine, Universiti Malaya, 50603, Kuala Lumpur, Malaysia; Department of Laboratory, Sunway Medical Center, Bandar Sunway, 47500, Petaling Jaya, Selangor, Malaysia
| | - Yeannie Hui-Yeng Yap
- Department of Oral Biology and Biomedical Sciences, Faculty of Dentistry, MAHSA University, Bandar Saujana Putra, 42610, Jenjarom, Selangor, Malaysia
| | - Szu Ting Ng
- LiGNO Biotech Sdn. Bhd, 43300, Balakong Jaya, Selangor, Malaysia
| | - Chon Seng Tan
- LiGNO Biotech Sdn. Bhd, 43300, Balakong Jaya, Selangor, Malaysia
| | - Muhammad Fazril Mohamad Razif
- Medicinal Mushroom Research Group (MMRG), Department of Molecular Medicine, Faculty of Medicine, Universiti Malaya, 50603, Kuala Lumpur, Malaysia.
| | - Shin Yee Fung
- Medicinal Mushroom Research Group (MMRG), Department of Molecular Medicine, Faculty of Medicine, Universiti Malaya, 50603, Kuala Lumpur, Malaysia; Center for Natural Products Research and Drug Discovery (CENAR), Universiti Malaya, 50603, Kuala Lumpur, Malaysia; University of Malaya Centre for Proteomics Research (UMCPR), Universiti Malaya, 50603, Kuala Lumpur, Malaysia.
| |
Collapse
|
|
28
|
Liu Y, Zhang B, Zhou Y, Xing Y, Wang Y, Jia Y, Liu D. Targeting Hippo pathway: A novel strategy for Helicobacter pylori-induced gastric cancer treatment. Biomed Pharmacother 2023; 161:114549. [PMID: 36958190 DOI: 10.1016/j.biopha.2023.114549] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2023] [Accepted: 03/15/2023] [Indexed: 03/25/2023] Open
Abstract
The Hippo pathway plays an important role in cell proliferation, apoptosis, and differentiation; it is a crucial regulatory pathway in organ development and tumor growth. Infection with Helicobacter pylori (H. pylori) increases the risk of developing gastric cancer. In recent years, significant progress has been made in understanding the mechanisms by which H. pylori infection promotes the development and progression of gastric cancer via the Hippo pathway. Exploring the Hippo pathway molecules may yield new diagnostic and therapeutic targets for H. pylori-induced gastric cancer. The current article reviews the composition and regulatory mechanism of the Hippo pathway, as well as the research progress of the Hippo pathway in the occurrence and development of H. pylori-related gastric cancer, in order to provide a broader perspective for the study and prevention of gastric cancer.
Collapse
Affiliation(s)
- Yunyun Liu
- Research Center of Basic Medicine, Jinan Central Hospital, Shandong University, Jinan, People's Republic of China; Research Center of Basic Medicine, Jinan Central Hospital, Shandong First Medical University, Jinan, People's Republic of China
| | - Bingkai Zhang
- Department of Anorectal Surgery, Qingzhou People's Hospital, Qingzhou, People's Republic of China
| | - Yimin Zhou
- School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, People's Republic of China
| | - Yuanxin Xing
- Research Center of Basic Medicine, Jinan Central Hospital, Shandong University, Jinan, People's Republic of China; Research Center of Basic Medicine, Jinan Central Hospital, Shandong First Medical University, Jinan, People's Republic of China
| | - Yunshan Wang
- Research Center of Basic Medicine, Jinan Central Hospital, Shandong University, Jinan, People's Republic of China; Research Center of Basic Medicine, Jinan Central Hospital, Shandong First Medical University, Jinan, People's Republic of China
| | - Yanfei Jia
- Research Center of Basic Medicine, Jinan Central Hospital, Shandong University, Jinan, People's Republic of China; Research Center of Basic Medicine, Jinan Central Hospital, Shandong First Medical University, Jinan, People's Republic of China.
| | - Duanrui Liu
- Department of Clinical Laboratory, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, People's Republic of China; Department of Clinical Laboratory, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, People's Republic of China.
| |
Collapse
|
|
29
|
Jochum SB, Engen PA, Shaikh M, Naqib A, Wilber S, Raeisi S, Zhang L, Song S, Sanzo G, Chouhan V, Ko F, Post Z, Tran L, Ramirez V, Green SJ, Khazaie K, Hayden DM, Brown MJ, Voigt RM, Forsyth CB, Keshavarzian A, Swanson GR. Colonic Epithelial Circadian Disruption Worsens Dextran Sulfate Sodium-Induced Colitis. Inflamm Bowel Dis 2023; 29:444-457. [PMID: 36287037 PMCID: PMC9977234 DOI: 10.1093/ibd/izac219] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Indexed: 12/09/2022]
Abstract
BACKGROUND Disruption of central circadian rhythms likely mediated by changes in microbiota and a decrease in gut-derived metabolites like short chain fatty acids (SCFAs) negatively impacts colonic barrier homeostasis. We aimed to explore the effects of isolated peripheral colonic circadian disruption on the colonic barrier in a mouse model of colitis and explore the mechanisms, including intestinal microbiota community structure and function. METHODS Colon epithelial cell circadian rhythms were conditionally genetically disrupted in mice: TS4Cre-BMAL1lox (cBMAL1KO) with TS4Cre as control animals. Colitis was induced through 5 days of 2% dextran sulfate sodium (DSS). Disease activity index and intestinal barrier were assessed, as were fecal microbiota and metabolites. RESULTS Colitis symptoms were worse in mice with peripheral circadian disruption (cBMAL1KO). Specifically, the disease activity index and intestinal permeability were significantly higher in circadian-disrupted mice compared with control animals (TS4Cre) (P < .05). The worsening of colitis appears to be mediated, in part, through JAK (Janus kinase)-mediated STAT3 (signal transducer and activator of transcription 3), which was significantly elevated in circadian-disrupted (cBMAL1KO) mice treated with DSS (P < .05). Circadian-disrupted (cBMAL1KO) mice also had decreased SCFA metabolite concentrations and decreased relative abundances of SCFA-producing bacteria in their stool when compared with control animals (TS4Cre). CONCLUSIONS Disruption of intestinal circadian rhythms in colonic epithelial cells promoted more severe colitis, increased inflammatory mediators (STAT3 [signal transducer and activator of transcription 3]), and decreased gut microbiota-derived SCFAs compared with DSS alone. Further investigation elucidating the molecular mechanisms behind these findings could provide novel circadian directed targets and strategies in the treatment of inflammatory bowel disease.
Collapse
Affiliation(s)
- Sarah B Jochum
- Department of Surgery, Rush University Medical Center, Chicago, IL, USA
| | - Phillip A Engen
- Rush Center for Integrated Microbiome and Chronobiology Research, Rush Medical College, Rush University Medical Center, Chicago, IL, USA
| | - Maliha Shaikh
- Rush Center for Integrated Microbiome and Chronobiology Research, Rush Medical College, Rush University Medical Center, Chicago, IL, USA
| | - Ankur Naqib
- Rush Center for Integrated Microbiome and Chronobiology Research, Rush Medical College, Rush University Medical Center, Chicago, IL, USA
| | - Sherry Wilber
- Rush Center for Integrated Microbiome and Chronobiology Research, Rush Medical College, Rush University Medical Center, Chicago, IL, USA
| | - Shohreh Raeisi
- Rush Center for Integrated Microbiome and Chronobiology Research, Rush Medical College, Rush University Medical Center, Chicago, IL, USA
| | - Lijuan Zhang
- Rush Center for Integrated Microbiome and Chronobiology Research, Rush Medical College, Rush University Medical Center, Chicago, IL, USA
| | - Shiwen Song
- Department of Pathology, GoPath Global Pathology Service, Buffalo Grove, IL, USA
| | - Gabriella Sanzo
- Rush Center for Integrated Microbiome and Chronobiology Research, Rush Medical College, Rush University Medical Center, Chicago, IL, USA
| | - Vijit Chouhan
- Rush Center for Integrated Microbiome and Chronobiology Research, Rush Medical College, Rush University Medical Center, Chicago, IL, USA
| | - Frank Ko
- Department of Cell and Molecular Medicine, Rush University Medical Center, Chicago, IL, USA
| | - Zoe Post
- Rush Center for Integrated Microbiome and Chronobiology Research, Rush Medical College, Rush University Medical Center, Chicago, IL, USA
- Department of Medicine, Rush University Medical Center, Chicago, IL, USA
| | - Laura Tran
- Rush Center for Integrated Microbiome and Chronobiology Research, Rush Medical College, Rush University Medical Center, Chicago, IL, USA
| | - Vivian Ramirez
- Rush Center for Integrated Microbiome and Chronobiology Research, Rush Medical College, Rush University Medical Center, Chicago, IL, USA
| | - Stefan J Green
- Genomics and Microbiome Core Facility, Rush University Medical Center, Chicago, IL, USA
| | | | - Dana M Hayden
- Division of Colon and Rectal Surgery, Department of Surgery, Rush University Medical Center, Chicago, IL, USA
| | - Mark J Brown
- Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, OH, USA
| | - Robin M Voigt
- Rush Center for Integrated Microbiome and Chronobiology Research, Rush Medical College, Rush University Medical Center, Chicago, IL, USA
- Department of Medicine, Rush University Medical Center, Chicago, IL, USA
| | - Christopher B Forsyth
- Rush Center for Integrated Microbiome and Chronobiology Research, Rush Medical College, Rush University Medical Center, Chicago, IL, USA
- Department of Medicine, Rush University Medical Center, Chicago, IL, USA
| | - Ali Keshavarzian
- Rush Center for Integrated Microbiome and Chronobiology Research, Rush Medical College, Rush University Medical Center, Chicago, IL, USA
- Department of Medicine, Rush University Medical Center, Chicago, IL, USA
- Department of Physiology, Rush University Medical Center, Chicago, IL, USA
| | - Garth R Swanson
- Rush Center for Integrated Microbiome and Chronobiology Research, Rush Medical College, Rush University Medical Center, Chicago, IL, USA
- Department of Medicine, Rush University Medical Center, Chicago, IL, USA
| |
Collapse
|
|
30
|
Chen J, Ke K, Liu Z, Yang L, Wang L, Zhou J, Dong Q. Body Mass Index and Cancer Risk: An Umbrella Review of Meta-Analyses of Observational Studies. Nutr Cancer 2023; 75:1051-1064. [PMID: 37139871 DOI: 10.1080/01635581.2023.2180824] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Revised: 01/05/2023] [Accepted: 02/09/2023] [Indexed: 02/24/2023]
Abstract
Increasing evidence indicates that obesity is a risk factor for various tumors. We aimed to clarify the evidence for an association between body mass index (BMI) and cancer risk based on existing systematic reviews and meta-analyses. Eighteen studies were included in this umbrella review after searching PubMed, Embase and Web of science. The results revealed that underweight was inversely associated with the incidence of brain tumors and positively related to the risk of esophageal and lung cancer. Overweight enhances the incidence of brain tumors, kidney cancer, endometrial cancer, ovarian cancer, multiple myeloma, bladder cancer and liver cancer. Obesity was related to the increased incidence of brain tumors, cervical cancer, kidney cancer, endometrial cancer, esophageal cancer, gastric cancer, ovarian cancer, multiple myeloma, gallbladder cancer, bladder cancer, colorectal cancer, liver cancer, thyroid cancer and Hodgkin's lymphoma. Moreover, dose-response analysis was conducted by 10 studies, and the results demonstrated that each 5 Kg/m2 increase in BMI was associated with a 1.01- to 1.13-fold increased risk of general brain tumors, multiple myeloma, bladder cancer, pancreatic cancer, breast cancer, and non-Hodgkin's lymphoma. Every 1 Kg/m2 increase in BMI was linked to 6% and 4% increases in the risk of kidney cancer and gallbladder cancer, respectively.
Collapse
Affiliation(s)
- Junhao Chen
- West China School of Medicine, Sichuan University, Chengdu, Sichuan, China
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Kaimin Ke
- Department of General Surgery, Nanchang First Hospital, Nanchang University, Nanchang, Jiangxi, China
| | - Zhenghuan Liu
- West China School of Medicine, Sichuan University, Chengdu, Sichuan, China
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Luchen Yang
- West China School of Medicine, Sichuan University, Chengdu, Sichuan, China
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Linchun Wang
- West China School of Medicine, Sichuan University, Chengdu, Sichuan, China
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Jing Zhou
- West China School of Medicine, Sichuan University, Chengdu, Sichuan, China
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Qiang Dong
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| |
Collapse
|
|
31
|
Habanjar O, Bingula R, Decombat C, Diab-Assaf M, Caldefie-Chezet F, Delort L. Crosstalk of Inflammatory Cytokines within the Breast Tumor Microenvironment. Int J Mol Sci 2023; 24:4002. [PMID: 36835413 PMCID: PMC9964711 DOI: 10.3390/ijms24044002] [Citation(s) in RCA: 80] [Impact Index Per Article: 40.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Revised: 02/10/2023] [Accepted: 02/14/2023] [Indexed: 02/18/2023] Open
Abstract
Several immune and immunocompetent cells, including dendritic cells, macrophages, adipocytes, natural killer cells, T cells, and B cells, are significantly correlated with the complex discipline of oncology. Cytotoxic innate and adaptive immune cells can block tumor proliferation, and others can prevent the immune system from rejecting malignant cells and provide a favorable environment for tumor progression. These cells communicate with the microenvironment through cytokines, a chemical messenger, in an endocrine, paracrine, or autocrine manner. These cytokines play an important role in health and disease, particularly in host immune responses to infection and inflammation. They include chemokines, interleukins (ILs), adipokines, interferons, colony-stimulating factors (CSFs), and tumor necrosis factor (TNF), which are produced by a wide range of cells, including immune cells, such as macrophages, B-cells, T-cells, and mast cells, as well as endothelial cells, fibroblasts, a variety of stromal cells, and some cancer cells. Cytokines play a crucial role in cancer and cancer-related inflammation, with direct and indirect effects on tumor antagonistic or tumor promoting functions. They have been extensively researched as immunostimulatory mediators to promote the generation, migration and recruitment of immune cells that contribute to an effective antitumor immune response or pro-tumor microenvironment. Thus, in many cancers such as breast cancer, cytokines including leptin, IL-1B, IL-6, IL-8, IL-23, IL-17, and IL-10 stimulate while others including IL-2, IL-12, and IFN-γ, inhibit cancer proliferation and/or invasion and enhance the body's anti-tumor defense. Indeed, the multifactorial functions of cytokines in tumorigenesis will advance our understanding of cytokine crosstalk pathways in the tumor microenvironment, such as JAK/STAT, PI3K, AKT, Rac, MAPK, NF-κB, JunB, cFos, and mTOR, which are involved in angiogenesis, cancer proliferation and metastasis. Accordingly, targeting and blocking tumor-promoting cytokines or activating and amplifying tumor-inhibiting cytokines are considered cancer-directed therapies. Here, we focus on the role of the inflammatory cytokine system in pro- and anti-tumor immune responses, discuss cytokine pathways involved in immune responses to cancer and some anti-cancer therapeutic applications.
Collapse
Affiliation(s)
- Ola Habanjar
- Université Clermont-Auvergne, INRAE, UNH, Unité de Nutrition Humaine, CRNH-Auvergne, 63000 Clermont-Ferrand, France
| | - Rea Bingula
- Université Clermont-Auvergne, INRAE, UNH, Unité de Nutrition Humaine, CRNH-Auvergne, 63000 Clermont-Ferrand, France
| | - Caroline Decombat
- Université Clermont-Auvergne, INRAE, UNH, Unité de Nutrition Humaine, CRNH-Auvergne, 63000 Clermont-Ferrand, France
| | - Mona Diab-Assaf
- Equipe Tumorigénèse Pharmacologie Moléculaire et Anticancéreuse, Faculté des Sciences II, Université Libanaise Fanar, Beyrouth 1500, Lebanon
| | - Florence Caldefie-Chezet
- Université Clermont-Auvergne, INRAE, UNH, Unité de Nutrition Humaine, CRNH-Auvergne, 63000 Clermont-Ferrand, France
| | - Laetitia Delort
- Université Clermont-Auvergne, INRAE, UNH, Unité de Nutrition Humaine, CRNH-Auvergne, 63000 Clermont-Ferrand, France
| |
Collapse
|
|
32
|
Cuevas-Cianca SI, Romero-Castillo C, Gálvez-Romero JL, Juárez ZN, Hernández LR. Antioxidant and Anti-Inflammatory Compounds from Edible Plants with Anti-Cancer Activity and Their Potential Use as Drugs. Molecules 2023; 28:molecules28031488. [PMID: 36771154 PMCID: PMC9920972 DOI: 10.3390/molecules28031488] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Revised: 01/28/2023] [Accepted: 01/28/2023] [Indexed: 02/05/2023] Open
Abstract
Food is our daily companion, performing numerous beneficial functions for our bodies. Many of them can help to alleviate or prevent ailments and diseases. In this review, an extensive bibliographic search is conducted in various databases to update information on unprocessed foods with anti-inflammatory and antioxidant properties that can aid in treating diseases such as cancer. The current state of knowledge on inflammatory processes involving some interleukins and tumor necrosis factor-alpha (TNF-α) is reviewed. As well as unprocessed foods, which may help reduce inflammation and oxidative stress, both of which are important factors in cancer development. Many studies are still needed to take full advantage of the food products we use daily.
Collapse
Affiliation(s)
- Sofía Isabel Cuevas-Cianca
- Department of Chemical Biological Sciences, Universidad de las Américas Puebla, Ex Hacienda Sta. Catarina Mártir S/N, San Andrés Cholula 72810, Mexico
| | - Cristian Romero-Castillo
- Biotechnology Faculty, Deanship of Biological Sciences, Universidad Popular Autónoma del Estado de Puebla, 21 Sur 1103 Barrio Santiago, Puebla 72410, Mexico
- Chemistry Area, Deanship of Biological Sciences, Universidad Popular Autónoma del Estado de Puebla, 21 Sur 1103 Barrio Santiago, Puebla 72410, Mexico
| | - José Luis Gálvez-Romero
- ISSTE Puebla Hospital Regional, Boulevard 14 Sur 4336, Colonia Jardines de San Manuel, Puebla 72570, Mexico
| | - Zaida Nelly Juárez
- Chemistry Area, Deanship of Biological Sciences, Universidad Popular Autónoma del Estado de Puebla, 21 Sur 1103 Barrio Santiago, Puebla 72410, Mexico
- Correspondence: (Z.N.J.); (L.R.H.)
| | - Luis Ricardo Hernández
- Department of Chemical Biological Sciences, Universidad de las Américas Puebla, Ex Hacienda Sta. Catarina Mártir S/N, San Andrés Cholula 72810, Mexico
- Correspondence: (Z.N.J.); (L.R.H.)
| |
Collapse
|
|
33
|
Extracellular Vesicles: New Classification and Tumor Immunosuppression. BIOLOGY 2023; 12:biology12010110. [PMID: 36671802 PMCID: PMC9856004 DOI: 10.3390/biology12010110] [Citation(s) in RCA: 79] [Impact Index Per Article: 39.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Revised: 01/05/2023] [Accepted: 01/05/2023] [Indexed: 01/13/2023]
Abstract
Extracellular vesicles (EVs) are cell-derived membrane-surrounded vesicles carrying various types of molecules. These EV cargoes are often used as pathophysiological biomarkers and delivered to recipient cells whose fates are often altered in local and distant tissues. Classical EVs are exosomes, microvesicles, and apoptotic bodies, while recent studies discovered autophagic EVs, stressed EVs, and matrix vesicles. Here, we classify classical and new EVs and non-EV nanoparticles. We also review EVs-mediated intercellular communication between cancer cells and various types of tumor-associated cells, such as cancer-associated fibroblasts, adipocytes, blood vessels, lymphatic vessels, and immune cells. Of note, cancer EVs play crucial roles in immunosuppression, immune evasion, and immunotherapy resistance. Thus, cancer EVs change hot tumors into cold ones. Moreover, cancer EVs affect nonimmune cells to promote cellular transformation, including epithelial-to-mesenchymal transition (EMT), chemoresistance, tumor matrix production, destruction of biological barriers, angiogenesis, lymphangiogenesis, and metastatic niche formation.
Collapse
|
|
34
|
Tourkochristou E, Mouzaki A, Triantos C. Unveiling the biological role of sphingosine-1-phosphate receptor modulators in inflammatory bowel diseases. World J Gastroenterol 2023; 29:110-125. [PMID: 36683721 PMCID: PMC9850947 DOI: 10.3748/wjg.v29.i1.110] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Revised: 11/16/2022] [Accepted: 12/14/2022] [Indexed: 01/04/2023] Open
Abstract
Inflammatory bowel disease (IBD) is chronic inflammation of the gastrointestinal tract that has a high epidemiological prevalence worldwide. The increasing disease burden worldwide, lack of response to current biologic therapeutics, and treatment-related immunogenicity have led to major concerns regarding the clinical management of IBD patients and treatment efficacy. Understanding disease pathogenesis and disease-related molecular mechanisms is the most important goal in developing new and effective therapeutics. Sphingosine-1-phosphate (S1P) receptor (S1PR) modulators form a class of oral small molecule drugs currently in clinical development for IBD have shown promising effects on disease improvement. S1P is a sphingosine-derived phospholipid that acts by binding to its receptor S1PR and is involved in the regulation of several biological processes including cell survival, differentiation, migration, proliferation, immune response, and lymphocyte trafficking. T lymphocytes play an important role in regulating inflammatory responses. In inflamed IBD tissue, an imbalance between T helper (Th) and regulatory T lymphocytes and Th cytokine levels was found. The S1P/S1PR signaling axis and metabolism have been linked to inflammatory responses in IBD. S1P modulators targeting S1PRs and S1P metabolism have been developed and shown to regulate inflammatory responses by affecting lymphocyte trafficking, lymphocyte number, lymphocyte activity, cytokine production, and contributing to gut barrier function.
Collapse
Affiliation(s)
- Evanthia Tourkochristou
- Division of Gastroenterology, Department of Internal Medicine, Medical School, University of Patras, Patras 26504, Greece
| | - Athanasia Mouzaki
- Division of Hematology, Department of Internal Medicine, Medical School, University of Patras, Patras 26504, Greece
| | - Christos Triantos
- Division of Gastroenterology, Department of Internal Medicine, Medical School, University of Patras, Patras 26504, Greece
| |
Collapse
|
|
35
|
Zhang R, Hu C, Zhang J, Zhang Y, Yuan L, Yu P, Wang Y, Bao Z, Cao M, Ruan R, Cheng X, Xu Z. Prognostic significance of inflammatory and nutritional markers in perioperative period for patients with advanced gastric cancer. BMC Cancer 2023; 23:5. [PMID: 36597055 PMCID: PMC9808945 DOI: 10.1186/s12885-022-10479-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2022] [Accepted: 12/23/2022] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND It has been reported that inflammatory and nutritional markers are related to prognosis in numerous malignancies. The present study analyzed the significance of these markers' alterations during neoadjuvant chemotherapy in the long-term outcomes in patients with advanced gastric cancer. METHODS A retrospective review was performed of 437 advanced gastric cancer patients who underwent a neoadjuvant chemotherapy (NACT) regimen followed by surgical treatment. Inflammatory and nutritional markers measured from the blood samples collected from the patients before the first neoadjuvant chemotherapy and after the last neoadjuvant chemotherapy were used for analysis. Statistical analysis, including Mann-Whitney U or chi-square tests, the Kaplan-Meier method and Cox multivariate analysis, were performed to analyze the predictive value of these markers for overall survival outcomes (OS). RESULTS Most biomarkers, including lymphocyte, leucocyte, neutrophil, monocyte, platelet, LMR, PLR, SII, CRP, CAR, hemoglobulin and albumin levels, changed during NACT (P < 0.05). After separately grouping the patients based on the normal range of hematologic indexes and the change rate (α) of systemic inflammatory and nutritional markers by the cutoff value derived from X-tile (P < 0.05), we found that differentiation, TRG, pre-NACT BMI, pre-NACT platelet counts, post-NACT lymphocyte counts, the change in lymphocyte counts, change in platelet counts and LMR(α), PLR(α), SII(α), and CAR(α) were associated with OS. Multivariate analysis revealed that PLR (α) > - 19% was correlated with a 3.193-fold (95% CI: 2.194-4.649) higher risk of death (P < 0.001) than others. CONCLUSION NACT could significantly change several inflammatory and nutritional markers in the perioperative period; the platelet counts before NACT, and the change in lymphocytes during NACT truly correlated with long-term outcomes among patients with advanced gastric cancer. The systemic inflammatory marker PLR may be a reliable marker for the prediction of prognosis.
Collapse
Affiliation(s)
- Ruolan Zhang
- The Second School of Clinical Medicine of Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Can Hu
- The Second School of Clinical Medicine of Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Jiaqing Zhang
- The Second School of Clinical Medicine of Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Yanqiang Zhang
- The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institutes of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, 310022, China
| | - Li Yuan
- The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institutes of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, 310022, China
| | - Pengcheng Yu
- The First School of Clinical Medicine of Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Yi Wang
- The First School of Clinical Medicine of Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Zhehan Bao
- The First School of Clinical Medicine of Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Mengxuan Cao
- Wenzhou Medical University, Wenzhou, 325035, China
| | - Rongwei Ruan
- The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institutes of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, 310022, China.
| | - Xiangdong Cheng
- The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institutes of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, 310022, China.
| | - Zhiyuan Xu
- The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institutes of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, 310022, China.
| |
Collapse
|
|
36
|
Downregulation of SLC9A8 Promotes Epithelial-Mesenchymal Transition and Metastasis in Colorectal Cancer Cells via the IL6-JAK1/STAT3 Signaling Pathway. Dig Dis Sci 2022; 68:1873-1884. [PMID: 36583805 DOI: 10.1007/s10620-022-07805-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Accepted: 12/17/2022] [Indexed: 12/31/2022]
Abstract
BACKGROUND SLC9A8 has been shown to be involved in mucus layer formation, intestinal mucosal integrity, and hyperproliferation of colitis-associated tumor development. However, its effects on the epithelial-mesenchymal transition (EMT) and the metastasis of colorectal cancer (CRC) remain unknown. AIMS To explore whether SLC9A8 participates in EMT and the metastasis of CRC. METHODS Western blotting and immunohistochemistry were performed to evaluate the expression of SLC9A8 in CRC patients. At the cellular level, the effect of SLC9A8 on proliferation, migration, and invasion was measured using cell viability analysis, flow cytometry analysis, and Transwell assays. Mouse tumor xenograft and metastasis models were established to analyze whether knockdown of SLC9A8 increased tumor volume, tumor weight, and metastasis. Moreover, whether downregulated expression of SLC9A8 promotes EMT via activation of the IL6-JAK1-STAT3 signaling pathway was investigated. RESULTS SLC9A8 protein was downregulated in CRC tissues, and this downregulation was significantly associated with tumor size, lymph node status, pTNM stage, and poor prognosis. SLC9A8 overexpression markedly suppressed cell proliferation, migration, and invasion. Downregulation of SLC9A8 promoted CRC cell proliferation, migration, and invasion. Moreover, knockdown of SLC9A8 also increased tumor volume, tumor weight, and metastasis in vivo. Meanwhile, downregulation of SLC9A8 significantly promoted the in vitro migration of CRC cells via EMT by activating the IL6-JAK1/STAT3 signaling pathway. CONCLUSIONS Downregulation of SLC9A8 plays an important role in EMT and metastasis of CRC progression and may become a new potential therapeutic target for the treatment of CRC.
Collapse
|
|
37
|
Huang B, Lang X, Li X. The role of IL-6/JAK2/STAT3 signaling pathway in cancers. Front Oncol 2022; 12:1023177. [PMID: 36591515 PMCID: PMC9800921 DOI: 10.3389/fonc.2022.1023177] [Citation(s) in RCA: 126] [Impact Index Per Article: 42.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Accepted: 12/06/2022] [Indexed: 12/23/2022] Open
Abstract
Interleukin-6 (IL-6) is a pleiotropic cytokine involved in immune regulation. It can activate janus kinase 2 (JAK2)-signal transducer and activator of transcription 3 (STAT3) signaling pathway. As one of the important signal transduction pathways in cells, JAK2/STAT3 signaling pathway plays a critical role in cell proliferation and differentiation by affecting the activation state of downstream effector molecules. The activation of JAK2/STAT3 signaling pathway is involved in tumorigenesis and development. It contributes to the formation of tumor inflammatory microenvironment and is closely related to the occurrence and development of many human tumors. This article focuses on the relationship between IL-6/JAK2/STAT3 signaling pathway and liver cancer, breast cancer, colorectal cancer, gastric cancer, lung cancer, pancreatic cancer and ovarian cancer, hoping to provide references for the research of cancer treatment targeting key molecules in IL-6/JAK2/STAT3 signaling pathway.
Collapse
Affiliation(s)
- Bei Huang
- Operational Management Office, West China Second University Hospital, Sichuan University, Chengdu, China,Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China
| | - Xiaoling Lang
- Operational Management Office, West China Second University Hospital, Sichuan University, Chengdu, China,Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China,*Correspondence: Xiaoling Lang, ; Xihong Li,
| | - Xihong Li
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China,Emergency Department, West China Second University Hospital, Sichuan University, Chengdu, China,*Correspondence: Xiaoling Lang, ; Xihong Li,
| |
Collapse
|
|
38
|
Nassar A, Zekri ARN, Elberry MH, Lymona AM, Lotfy MM, Abouelhoda M, Youssef ASED. Somatic Mutations Alter Interleukin Signaling Pathways in Grade II Invasive Breast Cancer Patients: An Egyptian Experience. Curr Issues Mol Biol 2022; 44:5890-5901. [PMID: 36547062 PMCID: PMC9777163 DOI: 10.3390/cimb44120401] [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: 07/21/2022] [Revised: 09/30/2022] [Accepted: 10/11/2022] [Indexed: 11/30/2022] Open
Abstract
This study aimed to investigate the impact of somatic mutations on various interleukin signaling pathways associated with grade II invasive breast cancer (BC) in Egyptian patients to broaden our understanding of their role in promoting carcinogenesis. Fifty-five grade II invasive BC patients were included in this study. Data for somatic mutations in 45 BC patients were already available from a previous study. Data for somatic mutations of 10 new BC patients were included in the current study. Somatic mutations were identified using targeted next-generation sequencing (NGS) to study their involvement in interleukin signaling pathways. For pathway analysis, we used ingenuity variant analysis (IVA) to identify the most significantly altered pathways. We identified somatic mutations in components of the interleukin-2, interleukin-6, and inter-leukin-7 signaling pathways, including mutations in JAK1, JAK2, JAK3, SOCS1, IL7R, MCL1, BCL2, MTOR, and IL6ST genes. Interestingly, six mutations which were likely to be novel deleterious were identified: two in the SCH1 gene, two in the IL2 gene, and one in each of the IL7R and JUN genes. According to IVA analysis, interleukin 2, interleukin 6, and interleukin 7 signaling pathways were the most altered in 34.5%, 29%, and 23.6% of our BC group, respectively. Our multigene panel sequencing analysis reveals that our BC patients have altered interleukin signaling pathways. So, these results highlight the prominent role of interleukins in the carcinogenesis process and suggest its potential role as promising candidates for personalized therapy in Egyptian patients.
Collapse
Affiliation(s)
- Auhood Nassar
- Cancer Biology Department, Virology and Immunology Unit, National Cancer Institute, Cairo University, Cairo 11796, Egypt
- Correspondence: (A.N.); (A.R.N.Z.); Tel.: +20-222-742-607 (A.N.)
| | - Abdel Rahman N. Zekri
- Cancer Biology Department, Virology and Immunology Unit, National Cancer Institute, Cairo University, Cairo 11796, Egypt
- Correspondence: (A.N.); (A.R.N.Z.); Tel.: +20-222-742-607 (A.N.)
| | - Mostafa H. Elberry
- Cancer Biology Department, Virology and Immunology Unit, National Cancer Institute, Cairo University, Cairo 11796, Egypt
| | - Ahmed M. Lymona
- Surgical Oncology Department, National Cancer Institute, Cairo University, Cairo 11796, Egypt
| | - Mai M. Lotfy
- Cancer Biology Department, Virology and Immunology Unit, National Cancer Institute, Cairo University, Cairo 11796, Egypt
| | | | - Amira Salah El-Din Youssef
- Cancer Biology Department, Virology and Immunology Unit, National Cancer Institute, Cairo University, Cairo 11796, Egypt
| |
Collapse
|
|
39
|
Li Y, Tan Y, Li X, Chen X, Wang L, Zhang L, Xu S, Huang K, Shu W, Liang H, Chen M. Loss of LXN promotes macrophage M2 polarization and PD-L2 expression contributing cancer immune-escape in mice. Cell Death Dis 2022; 8:440. [PMID: 36323670 PMCID: PMC9630456 DOI: 10.1038/s41420-022-01227-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Revised: 10/17/2022] [Accepted: 10/18/2022] [Indexed: 11/06/2022]
Abstract
Latexin (LXN) plays an important role in tumorigenesis and inflammatory response and as a tumor suppressor in many tumors. However, whether LXN regulates tumorigenesis through immune regulation remains uncertain. Here, we demonstrate that LXN deficiency increases hematopoietic stem cells, as well as affects the proportion of immune cells in the peripheral system. Animal studies show that mice loss of LXN promotes tumor growth in subcutaneous tumor model and AOM/DSS-induced colorectal cancer model. We found that loss of LXN promotes macrophage M2 polarization and PD-L2 expression in macrophage, thus, inhibits the function of T cells. Adoptive transfer of wild-type macrophage rescues the function of T cells in LXN-deficient mice. LXN deficiency in hematopoietic lineage exacerbates colorectal carcinogenesis, and targeted inhibition of PD-L2 ameliorates cancer growth in LXN-deficient mice. Mechanistically, we demonstrate that LXN inhibits STAT3 transcriptional activity by targeting inhibition of JAK1 in macrophages. LXN deficiency enhances PD-L2 expression rather than PD-L1 in macrophages, which lead to inhibition of T cells in tumor microenvironment. Collectively, we define a critical role of LXN/JAK1/STAT3 signal in macrophage and highlights the potential role of LXN in tumor immune-escape by regulating macrophage polarization, as well as the expression of immune checkpoint PD-L2.
Collapse
Affiliation(s)
- Yaping Li
- grid.459584.10000 0001 2196 0260State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), Collaborative Innovation Center for Guangxi Ethnic Medicine, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin, 541004 P.R. China
| | - Yanhui Tan
- grid.459584.10000 0001 2196 0260State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), Collaborative Innovation Center for Guangxi Ethnic Medicine, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin, 541004 P.R. China
| | - XiuZhen Li
- grid.459584.10000 0001 2196 0260State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), Collaborative Innovation Center for Guangxi Ethnic Medicine, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin, 541004 P.R. China
| | - Xuanming Chen
- grid.459584.10000 0001 2196 0260State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), Collaborative Innovation Center for Guangxi Ethnic Medicine, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin, 541004 P.R. China
| | - Lingzhu Wang
- grid.459584.10000 0001 2196 0260State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), Collaborative Innovation Center for Guangxi Ethnic Medicine, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin, 541004 P.R. China
| | - Lijun Zhang
- grid.459584.10000 0001 2196 0260State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), Collaborative Innovation Center for Guangxi Ethnic Medicine, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin, 541004 P.R. China
| | - Shaohua Xu
- grid.459584.10000 0001 2196 0260State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), Collaborative Innovation Center for Guangxi Ethnic Medicine, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin, 541004 P.R. China
| | - Kebing Huang
- grid.459584.10000 0001 2196 0260State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), Collaborative Innovation Center for Guangxi Ethnic Medicine, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin, 541004 P.R. China
| | - Wei Shu
- grid.443385.d0000 0004 1798 9548College of Biotechnology, Guilin Medical University, Guilin, 541199 P.R. China
| | - Hong Liang
- grid.459584.10000 0001 2196 0260State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), Collaborative Innovation Center for Guangxi Ethnic Medicine, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin, 541004 P.R. China
| | - Ming Chen
- grid.459584.10000 0001 2196 0260State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), Collaborative Innovation Center for Guangxi Ethnic Medicine, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin, 541004 P.R. China
| |
Collapse
|
|
40
|
Yang H, Karl MN, Wang W, Starich B, Tan H, Kiemen A, Pucsek AB, Kuo YH, Russo GC, Pan T, Jaffee EM, Fertig EJ, Wirtz D, Spangler JB. Engineered bispecific antibodies targeting the interleukin-6 and -8 receptors potently inhibit cancer cell migration and tumor metastasis. Mol Ther 2022; 30:3430-3449. [PMID: 35841152 PMCID: PMC9637575 DOI: 10.1016/j.ymthe.2022.07.008] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2022] [Revised: 06/12/2022] [Accepted: 07/09/2022] [Indexed: 12/15/2022] Open
Abstract
Simultaneous inhibition of interleukin-6 (IL-6) and interleukin-8 (IL-8) signaling diminishes cancer cell migration, and combination therapy has recently been shown to synergistically reduce metastatic burden in a preclinical model of triple-negative breast cancer. Here, we have engineered two novel bispecific antibodies that target the IL-6 and IL-8 receptors to concurrently block the signaling activity of both ligands. We demonstrate that a first-in-class bispecific antibody design has promising therapeutic potential, with enhanced selectivity and potency compared with monoclonal antibody and small-molecule drug combinations in both cellular and animal models of metastatic triple-negative breast cancer. Mechanistic characterization revealed that our engineered bispecific antibodies have no impact on cell viability, but profoundly reduce the migratory potential of cancer cells; hence they constitute a true anti-metastatic treatment. Moreover, we demonstrate that our antibodies can be readily combined with standard-of-care anti-proliferative drugs to develop effective anti-cancer regimens. Collectively, our work establishes an innovative metastasis-focused direction for cancer drug development.
Collapse
Affiliation(s)
- Huilin Yang
- Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218, USA; Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
| | - Michelle N Karl
- Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218, USA; Institute for Nano Biotechnology (INBT), the Johns Hopkins University, Baltimore, MD 21218, USA
| | - Wentao Wang
- Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
| | - Bartholomew Starich
- Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218, USA; Institute for Nano Biotechnology (INBT), the Johns Hopkins University, Baltimore, MD 21218, USA
| | - Haotian Tan
- Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218, USA; Institute for Nano Biotechnology (INBT), the Johns Hopkins University, Baltimore, MD 21218, USA
| | - Ashley Kiemen
- Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218, USA; Institute for Nano Biotechnology (INBT), the Johns Hopkins University, Baltimore, MD 21218, USA
| | - Alexandra B Pucsek
- Department of Oncology, the Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
| | - Yun-Huai Kuo
- Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218, USA; Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
| | - Gabriella C Russo
- Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218, USA; Institute for Nano Biotechnology (INBT), the Johns Hopkins University, Baltimore, MD 21218, USA
| | - Tim Pan
- Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218, USA; Institute for Nano Biotechnology (INBT), the Johns Hopkins University, Baltimore, MD 21218, USA
| | - Elizabeth M Jaffee
- Department of Oncology, the Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; Department of Pathology, the Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; Sidney Kimmel Cancer Center, the Johns Hopkins University, Baltimore, MD 21231, USA
| | - Elana J Fertig
- Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; Department of Oncology, the Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; Sidney Kimmel Cancer Center, the Johns Hopkins University, Baltimore, MD 21231, USA; Department of Applied Mathematics and Statistics, Johns Hopkins University, Baltimore, MD 21218, USA; Convergence Institute, Johns Hopkins University, Baltimore, MD 21231, USA
| | - Denis Wirtz
- Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218, USA; Institute for Nano Biotechnology (INBT), the Johns Hopkins University, Baltimore, MD 21218, USA; Department of Oncology, the Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; Department of Pathology, the Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; Sidney Kimmel Cancer Center, the Johns Hopkins University, Baltimore, MD 21231, USA
| | - Jamie B Spangler
- Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218, USA; Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; Department of Oncology, the Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; Sidney Kimmel Cancer Center, the Johns Hopkins University, Baltimore, MD 21231, USA; Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, MD 21231, USA; Department of Ophthalmology, Johns Hopkins School of Medicine, Baltimore, MD 21231, USA.
| |
Collapse
|
|
41
|
Seo E, Jang H, Kwon S, Kwon Y, Kim S, Lee S, Jeong AJ, Shin HM, Kim Y, Ma S, Kim H, Lee Y, Suh P, Ye S. Loss of phospholipase Cγ1 suppresses hepatocellular carcinogenesis through blockade of STAT3-mediated cancer development. Hepatol Commun 2022; 6:3234-3246. [PMID: 36153805 PMCID: PMC9592768 DOI: 10.1002/hep4.2077] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Revised: 07/11/2022] [Accepted: 08/08/2022] [Indexed: 12/14/2022] Open
Abstract
Phospholipase C gamma 1 (PLCγ1) plays an oncogenic role in several cancers, alongside its usual physiological roles. Despite studies aimed at identifying the effect of PLCγ1 on tumors, the pathogenic role of PLCγ1 in the tumorigenesis and development of hepatocellular carcinoma (HCC) remains unknown. To investigate the function of PLCγ1 in HCC, we generated hepatocyte-specific PLCγ1 conditional knockout (PLCγ1f/f ; Alb-Cre) mice and induced HCC with diethylnitrosamine (DEN). Here, we identified that hepatocyte-specific PLCγ1 deletion effectively prevented DEN-induced HCC in mice. PLCγ1f/f ; Alb-Cre mice showed reduced tumor burden and tumor progression, as well as a decreased incidence of HCC and less marked proliferative and inflammatory responses. We also showed that oncogenic phenotypes such as repressed apoptosis, and promoted proliferation, cell cycle progression and migration, were induced by PLCγ1. In terms of molecular mechanism, PLCγ1 regulated the activation of signal transducer and activator of transcription 3 (STAT3) signaling. Moreover, PLCγ1 expression is elevated in human HCC and correlates with a poor prognosis in patients with HCC. Our results suggest that PLCγ1 promotes the pathogenic progression of HCC, and PLCγ1/STAT3 axis was identified as a potential therapeutic target pathway for HCC.
Collapse
Affiliation(s)
- Eun‐Bi Seo
- Department of Pharmacology and Biomedical SciencesSeoul National University College of MedicineSeoulRepublic of Korea
- Biomedical Science Project (BK21PLUS)Seoul National University College of MedicineSeoulRepublic of Korea
| | - Hyun‐Jun Jang
- School of Life SciencesUlsan National Institute of Science and TechnologyUlsanRepublic of Korea
| | - Sun‐Ho Kwon
- Department of Pharmacology and Biomedical SciencesSeoul National University College of MedicineSeoulRepublic of Korea
| | - Yong‐Jin Kwon
- Department of Pharmacology and Biomedical SciencesSeoul National University College of MedicineSeoulRepublic of Korea
- Biomedical Science Project (BK21PLUS)Seoul National University College of MedicineSeoulRepublic of Korea
| | - Seul‐Ki Kim
- Department of Pharmacology and Biomedical SciencesSeoul National University College of MedicineSeoulRepublic of Korea
| | - Song‐Hee Lee
- Department of Pharmacology and Biomedical SciencesSeoul National University College of MedicineSeoulRepublic of Korea
| | - Ae Jin Jeong
- Department of Pharmacology and Biomedical SciencesSeoul National University College of MedicineSeoulRepublic of Korea
| | - Hyun Mu Shin
- Wide River Institute of ImmunologySeoul National UniversityHongcheonRepublic of Korea
| | - Yong‐Nyun Kim
- Division of Translational ScienceNational Cancer CenterGoyangRepublic of Korea
| | - Stephanie Ma
- State Key Laboratory of Liver ResearchLi Ka Shing Faculty of Medicine, The University of Hong KongHong Kong
| | - Haeryoung Kim
- Department of PathologySeoul National University College of MedicineSeoulRepublic of Korea
| | - Yun‐Han Lee
- Department of Molecular MedicineKeimyung University School of MedicineDaeguRepublic of Korea
| | - Pann‐Ghill Suh
- School of Life SciencesUlsan National Institute of Science and TechnologyUlsanRepublic of Korea
- Korea Brain Research Institute (KBRI)DaeguRepublic of Korea
| | - Sang‐Kyu Ye
- Department of Pharmacology and Biomedical SciencesSeoul National University College of MedicineSeoulRepublic of Korea
- Biomedical Science Project (BK21PLUS)Seoul National University College of MedicineSeoulRepublic of Korea
- Wide River Institute of ImmunologySeoul National UniversityHongcheonRepublic of Korea
- Ischemic/Hypoxic Disease InstituteSeoul National University College of MedicineSeoulRepublic of Korea
- Neuro‐Immune Information Storage Network Research CenterSeoul National University College of MedicineSeoulRepublic of Korea
| |
Collapse
|
|
42
|
Cytokine chemokine network in tumor microenvironment: Impact on CSC properties and therapeutic applications. Cytokine 2022; 156:155916. [DOI: 10.1016/j.cyto.2022.155916] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Revised: 04/27/2022] [Accepted: 05/16/2022] [Indexed: 12/21/2022]
|
|
43
|
Study on the Mechanism of Action of STAT3 in the Drug Resistance of Gastric Cancer Cells. CONTRAST MEDIA & MOLECULAR IMAGING 2022; 2022:1426343. [PMID: 35992548 PMCID: PMC9356858 DOI: 10.1155/2022/1426343] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Revised: 05/24/2022] [Accepted: 05/31/2022] [Indexed: 11/21/2022]
Abstract
Gastric cancer is the most common digestive tract malignancy in China and has a poor prognosis, with a 5-year overall survival rate of only 35.1%. Because its early symptoms are not obvious and early diagnosis is complicated, there is an urgent need to find biological targets for diagnosis and treatment. This research detected the expression of STAT3 in gastric cancer tissues and adjacent tissues by Western blot and immunohistochemical experiments and conducted corresponding basic experiments to explore the role of STAT3 in inhibiting the proliferation of cisplatin-resistant gastric cancer cells and promoting their apoptosis, including the construction of cisplatin-resistant gastric cancer cell line, the knock-out STAT3 in drug-resistant gastric cancer cells by CRISPR-Cas9, and the comparison of the proliferation and apoptosis of drug-resistant cells and drug-resistant cells STAT3(-). The mechanism provides a possible intervention target for clinically improving the prognosis of patients with cisplatin-resistant gastric cancer.
Collapse
|
|
44
|
Yamato K, Ikeda A, Endo M, Filomeno R, Kiyohara K, Inada K, Nishimura K, Tanigawa T. An association between cancer type and delirium incidence in Japanese elderly patients: A retrospective longitudinal study. Cancer Med 2022; 12:2407-2416. [PMID: 35880545 PMCID: PMC9939101 DOI: 10.1002/cam4.5069] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Revised: 05/03/2022] [Accepted: 07/12/2022] [Indexed: 11/12/2022] Open
Abstract
OBJECTIVE There is not a known elevated prevalence of delirium in older adult cancer patients. However, it is unknown if the incidence of delirium varies by cancer type among older adult patients. Therefore, this study aimed to examine the association between the incidence of delirium and cancer type among older adult patients using a Japanese hospital-based administrative claims database. METHODS A total of 76,868 patients over 65 years of age or older, first diagnosed with cancer on an initial date of hospitalization between April 2008 and December 2019, were included in this retrospective longitudinal study. Delirium was defined by the World Health Organization's International Statistical Classification of Diseases and Related Health Problems (ICD-10) codes or antipsychotic medication use. Cox proportional hazard models were performed to estimate the risk of delirium incidence according to 22 cancer types during the one-year hospitalization period. RESULTS The incidence rates of delirium were 17.1% for men and 15.3% for women. Compared to gastric cancer, the risk of delirium was significantly higher for pancreatic cancer (HR: 1.26, 95% CI: 1.11-1.42 for men; HR: 1.27, 95% CI: 1.11-1.45 for women), leukemia (HR: 1.24, 95% CI: 1.09-1.41 for men; HR: 1.20, 95% CI: 1.03-1.41 for women), and oropharyngeal cancer (HR: 1.30, 95% CI: 1.10-1.54 for men; HR: 1.32; 95% CI: 1.02-1.72 for women) after adjusting for age, initial hospitalization year, antipsychotic medications, and surgery. CONCLUSIONS As compared to gastric cancer, patients with pancreatic cancer, leukemia, oropharyngeal cancer were found to have a higher risk of developing delirium. Our study findings suggested that the risk of delirium incidence may vary by cancer type.
Collapse
Affiliation(s)
- Kentaro Yamato
- Department of Public Health, Graduate School of MedicineJuntendo UniversityTokyoJapan
| | - Ai Ikeda
- Department of Public Health, Graduate School of MedicineJuntendo UniversityTokyoJapan,Faculty of International Liberal ArtsJuntendo UniversityTokyoJapan
| | - Motoki Endo
- Department of Public Health, Graduate School of MedicineJuntendo UniversityTokyoJapan
| | - Ronald Filomeno
- Department of Public Health, Graduate School of MedicineJuntendo UniversityTokyoJapan
| | - Kosuke Kiyohara
- Department of Food ScienceOtsuma Women's UniversityTokyoJapan
| | - Ken Inada
- Department of PsychiatryTokyo Women's Medical UniversityTokyoJapan
| | | | - Takeshi Tanigawa
- Department of Public Health, Graduate School of MedicineJuntendo UniversityTokyoJapan
| |
Collapse
|
|
45
|
Maresin 1 alleviates sevoflurane-induced neuroinflammation in neonatal rats via JAK2/STAT3/IL-6 pathways. Int Immunopharmacol 2022; 108:108912. [DOI: 10.1016/j.intimp.2022.108912] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2022] [Revised: 05/23/2022] [Accepted: 05/27/2022] [Indexed: 11/17/2022]
|
|
46
|
Sharma S, Malhotra L, Yadav P, Mishra V, Sharma RS, Abdul Samath E. Genistein: A novel inhibitor of IL-6/IL-6R interface of the Interleukin-6–mediated STAT3 dependent pathway of carcinogenesis. J Mol Struct 2022. [DOI: 10.1016/j.molstruc.2022.132668] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
|
|
47
|
Kostka L, Sivák L, Šubr V, Kovářová J, Šírová M, Říhová B, Sedlacek R, Etrych T, Kovář M. Simultaneous Delivery of Doxorubicin and Protease Inhibitor Derivative to Solid Tumors via Star-Shaped Polymer Nanomedicines Overcomes P-gp- and STAT3-Mediated Chemoresistance. Biomacromolecules 2022; 23:2522-2535. [PMID: 35584053 DOI: 10.1021/acs.biomac.2c00256] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
The derivative of protease inhibitor ritonavir (5-methyl-4-oxohexanoic acid ritonavir ester; RD) was recently recognized as a potent P-gp inhibitor and cancerostatic drug inhibiting the proteasome and STAT3 signaling. Therefore, we designed high-molecular-weight HPMA copolymer conjugates with a PAMAM dendrimer core bearing both doxorubicin (Dox) and RD (Star-RD + Dox) to increase the circulation half-life to maximize simultaneous delivery of Dox and RD into the tumor. Star-RD inhibited P-gp activity, potently sensitizing both low- and high-P-gp-expressing cancer cells to the cytostatic and proapoptotic activity of Dox in vitro. Star-RD + Dox possessed higher cytostatic and proapoptotic activities compared to Star-Dox and the equivalent mixture of Star-Dox and Star-RD in vitro. Star-RD + Dox efficiently inhibited STAT3 signaling and induced caspase-3 activation and DNA fragmentation in cancer cells in vivo. Importantly, Star-RD + Dox was found to have superior antitumor activity in terms of tumor growth inhibition and increased survival of mice bearing P-gp-expressing tumors.
Collapse
Affiliation(s)
- Libor Kostka
- Institute of Macromolecular Chemistry, Czech Academy of Sciences, Heyrovského nám. 2, 16206 Prague, Czech Republic
| | - Ladislav Sivák
- Institute of Microbiology, Czech Academy of Sciences, Vídeňská 1083, 14220 Prague, Czech Republic
| | - Vladimír Šubr
- Institute of Macromolecular Chemistry, Czech Academy of Sciences, Heyrovského nám. 2, 16206 Prague, Czech Republic
| | - Jiřina Kovářová
- Institute of Microbiology, Czech Academy of Sciences, Vídeňská 1083, 14220 Prague, Czech Republic
| | - Milada Šírová
- Institute of Microbiology, Czech Academy of Sciences, Vídeňská 1083, 14220 Prague, Czech Republic
| | - Blanka Říhová
- Institute of Microbiology, Czech Academy of Sciences, Vídeňská 1083, 14220 Prague, Czech Republic
| | - Radislav Sedlacek
- Czech Center of Phenogenomics, Institute of Molecular Genetics, Czech Academy of Sciences, Průmyslová 595, 25250 Vestec, Czech Republic
| | - Tomáš Etrych
- Institute of Macromolecular Chemistry, Czech Academy of Sciences, Heyrovského nám. 2, 16206 Prague, Czech Republic
| | - Marek Kovář
- Institute of Microbiology, Czech Academy of Sciences, Vídeňská 1083, 14220 Prague, Czech Republic
| |
Collapse
|
|
48
|
Systematic analysis of IL-6 as a predictive biomarker and desensitizer of immunotherapy responses in patients with non-small cell lung cancer. BMC Med 2022; 20:187. [PMID: 35550592 PMCID: PMC9102328 DOI: 10.1186/s12916-022-02356-7] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Accepted: 03/28/2022] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Cytokines have been reported to alter the response to immune checkpoint inhibitors (ICIs) in patients with the tumor in accordance with their plasma concentrations. Here, we aimed to identify the key cytokines which influenced the responses and stimulated resistance to ICIs and tried to improve immunological response and develop novel clinical treatments in non-small cell lung cancer (NSCLC). METHODS The promising predictive cytokines were analyzed via the multi-analyte flow assay. Next, we explored the correlation baseline level of plasma cytokines and clinical outcomes in 45 NSCLC patients treated with ICIs. The mechanism of the potential candidate cytokine in predicting response and inducing resistance to ICIs was then investigated. RESULTS We found NSCLC with a low baseline concentration of IL-6 in plasma specimens or tumor tissues could derive more benefit from ICIs based on the patient cohort. Further analyses revealed that a favorable relationship between PD-L1 and IL-6 expression was seen in NSCLC specimens. Results in vitro showed that PD-L1 expression in the tumor was enhanced by IL-6 via the JAK1/Stat3 pathway, which induced immune evasion. Notably, an adverse correlation was found between IL-6 levels and CD8+ T cells. And a positive association between IL-6 levels and myeloid-derived suppressor cells, M2 macrophages and regulator T cells was also seen in tumor samples, which may result in an inferior response to ICIs. Results of murine models of NSCLC suggested that the dual blockade of IL-6 and PD-L1 attenuated tumor growth. Further analyses detected that the inhibitor of IL-6 stimulated the infiltration of CD8+ T cells and yielded the inflammatory phenotype. CONCLUSIONS This study elucidated the role of baseline IL-6 levels in predicting the responses and promoting resistance to immunotherapy in patients with NSCLC. Our results indicated that the treatment targeting IL-6 may be beneficial for ICIs in NSCLC.
Collapse
|
|
49
|
Lipocalin 2 potentially contributes to tumorigenesis from colitis via IL-6/STAT3/NF-kB signaling pathway. Biosci Rep 2022; 42:231201. [PMID: 35470375 PMCID: PMC9109459 DOI: 10.1042/bsr20212418] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Revised: 03/29/2022] [Accepted: 04/25/2022] [Indexed: 11/17/2022] Open
Abstract
Lipocalin 2 (LCN2), a member of the lipocalin superfamily, plays an important role in oncogenesis and progression in various types of cancer. However, the role of LCN2 in inflammation-associated cancer remains unknown. Here, we explored the functional role and mechanisms of LCN2 in tumorigenesis using murine colitis-associated cancer (CAC) models and human colorectal cancer (CRC) cells. Using murine CAC models, we found that LCN2 was preferentially expressed in colonic tissues from CAC models compared to tissues from normal mice. In vitro results demonstrated that the levels of LCN2 mRNA and protein were markedly up-regulated by Interleukin-6 (IL-6) in human CRC cells. Interestingly, we found LCN2 up-regulation by IL-6 is diminished by NF-kB and STAT3 inhibition using specific inhibitors and siRNA. Reporter assay results determined that IL-6 induces LCN2 gene promoter activity under control of NF-kB/STAT3 activation. IL-6-induced LCN2 regulated cell survival and susceptibility of developmental factors to the NF-kB/STAT3 pathway. Taken together, our results highlight the unknown role of LCN2 in CAC progression and suggest that increased LCN2 may serve as an indicator of CRC development in the setting of chronic inflammation.
Collapse
|
|
50
|
Badraoui R, Saeed M, Bouali N, Hamadou WS, Elkahoui S, Alam MJ, Siddiqui AJ, Adnan M, Saoudi M, Rebai T. Expression Profiling of Selected Immune Genes and Trabecular Microarchitecture in Breast Cancer Skeletal Metastases Model: Effect of α-Tocopherol Acetate Supplementation. Calcif Tissue Int 2022; 110:475-488. [PMID: 34988595 DOI: 10.1007/s00223-021-00931-3] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Accepted: 11/18/2021] [Indexed: 01/26/2023]
Abstract
Breast cancer bone metastases (BCBM) result in serious skeletal morbidity. Although there have been important advances in cancer treatment methods such as surgery and chemotherapy, the complementary treatments, such as α-tocopherol acetate (ATA), still remain of key role via complementary and/or synergistic effects. The aim of this work was to study immune response in a rat model of BCBM due to Walker 256/B cells inoculation and the effect of ATA alone. Compared to the control group (CTRL), rat injected with Walker 256/B cells (5 × 104) in the medullar cavity (W256 group) showed osteolytic damages with marked tumor osteolysis of both cancellous and trabecular bone as assessed by X-ray radiology, micro-computed tomography, and histology. Rats inoculated with Walker 256/B cells and treated with ATA (45 mg/kg BW, W256ATA group) presented marked less tumor osteolysis, less disturbance of Tb.Th and Tb.Sp associated with conversion of rods into plates, and increased structure model index and trabecular pattern factor (Tb.Pf). Elsewhere, 3D frequency distributions of Tb.Th and Tb.Sp were highly disturbed in metastatic W256 rats. Overexpression of some genes commonly associated with cancer and metastatic proliferation: COX-2, TNF-α, and pro-inflammatory interleukins 1 and 6 was outlined. ATA alleviated most of the Walker 256/B cells-induced microarchitectural changes in the target parameters without turning back to normal levels. Likewise, it alleviates the BCSM-induced overexpression of COX-2, TNF-α, IL-1, and IL-6. In silico approach showed that ATA bound these proteins with high affinities, which satisfactory explain its beneficial effects. In conclusion, BCBM is associated with bone microarchitectural disorders and an immune response characterized by an overexpression of some key role genes in cancer proliferation and invasion. ATA exerted favorable effects on trabecular bone distribution and morphology, which may involve the COX-2, TNF-α, and ILs pathways.
Collapse
Affiliation(s)
- Riadh Badraoui
- Laboratory of General Biology, Department of Biology, University of Ha'il, Ha'il, 81451, Saudi Arabia.
- Section of Histology-Cytology, Medicine Faculty of Tunis, University of Tunis El Manar, La Rabta, 1007, Tunis, Tunisia.
- Laboratory of Histo-Embryology and Cytogenetics, Medicine Faculty of Sfax, University of Sfax, 3029, Sfax, Tunisia.
| | - Mohd Saeed
- Laboratory of General Biology, Department of Biology, University of Ha'il, Ha'il, 81451, Saudi Arabia
| | - Nouha Bouali
- Laboratory of General Biology, Department of Biology, University of Ha'il, Ha'il, 81451, Saudi Arabia
- Research Unit "Biologie Moléculaire Des Leucémies Et Lymphomes", Laboratory of Biochemistry, Medicine Faculty of Sousse University, 4002, Sousse, Tunisia
| | - Walid S Hamadou
- Laboratory of General Biology, Department of Biology, University of Ha'il, Ha'il, 81451, Saudi Arabia
- Research Unit "Biologie Moléculaire Des Leucémies Et Lymphomes", Laboratory of Biochemistry, Medicine Faculty of Sousse University, 4002, Sousse, Tunisia
| | - Salem Elkahoui
- Laboratory of General Biology, Department of Biology, University of Ha'il, Ha'il, 81451, Saudi Arabia
- Laboratory of Bioactive Substances, Center of Biotechnology of Borj Cedria (CBBC), 2050, Hammam-Lif, Tunisia
| | - Mohammad J Alam
- Laboratory of General Biology, Department of Biology, University of Ha'il, Ha'il, 81451, Saudi Arabia
| | - Arif J Siddiqui
- Laboratory of General Biology, Department of Biology, University of Ha'il, Ha'il, 81451, Saudi Arabia
| | - Mohd Adnan
- Laboratory of General Biology, Department of Biology, University of Ha'il, Ha'il, 81451, Saudi Arabia
| | - Mongi Saoudi
- Laboratory Animal Physiology, Department of Biology, College of Science, University of Sfax, 3045, Sfax, Tunisia
| | - Tarek Rebai
- Laboratory of Histo-Embryology and Cytogenetics, Medicine Faculty of Sfax, University of Sfax, 3029, Sfax, Tunisia
| |
Collapse
|