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Gu W, Pan T, Wang X, Kang L, Liu N, Piao M, Feng C. Sevoflurane exposure triggers ferroptosis of neuronal cells initiated by the activation of ATM/p53 in the neonatal mouse brain via JNK/p38 MAPK-mediated oxidative DNA damage. Int Immunopharmacol 2025; 158:114866. [PMID: 40378436 DOI: 10.1016/j.intimp.2025.114866] [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: 03/06/2025] [Revised: 04/27/2025] [Accepted: 05/09/2025] [Indexed: 05/18/2025]
Abstract
Neuronal death has long been regarded as a pivotal pathological factor in the developmental neurotoxicity caused by the volatile anesthetic sevoflurane in the neonatal brain, but the detailed mechanism remains controversial. Ferroptosis is a novel type of regulated cell death driven by excess lipid peroxidation secondary to intracellular iron overload, and it is implicated in the pathogenesis of various neurological disorders. Acting as a death messenger, p53 is primarily activated by ATM during DNA damage and mediates various forms of cell death, including apoptosis, autophagy, and ferroptosis. JNK/p38 MAPK are important stress-responsive pathways that can exacerbate intracellular ROS production, thereby linking DNA damage to many pathological conditions such as neurodegeneration and ischemic injury. In our present study, we demonstrated that sevoflurane exposure-induced neuronal death was correlated with intracellular iron overload and lipid peroxidation in HT22 cells, primary hippocampal neurons, and the hippocampi of neonatal mice, consistent with the hallmarks of ferroptosis. Furthermore, we found that sevoflurane-induced neuronal ferroptosis was associated with ATM/p53 activation in response to DNA damage. Additionally, sevoflurane exposure caused JNK/p38 MAPK activation followed by intracellular ROS accumulation, ultimately leading to DNA damage. Mechanistically, ATM/p53 contributed to ferroptosis caused by sevoflurane via two pathways: (1) enhancing iron uptake (upregulating TFR and downregulating FPN) and (2) promoting lipid peroxidation through NOX4, ALOX12, ALOX15 activation and SLC7A11 suppression. Collectively, these findings demonstrated that sevoflurane exposure induced ferroptosis of neuronal cells in the neonatal brain, triggered by ATM/p53 activation via JNK/p38 MAPK-mediated ROS accumulation and subsequent DNA damage.
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Affiliation(s)
- Wanping Gu
- Department of Anesthesiology, The First Hospital of Jilin University, No. 1 Xinmin St., Changchun 130021, China
| | - Tingting Pan
- Department of Anesthesiology, The First Hospital of Jilin University, No. 1 Xinmin St., Changchun 130021, China
| | - Xuedong Wang
- Department of Anesthesiology, The First Hospital of Jilin University, No. 1 Xinmin St., Changchun 130021, China
| | - Liheng Kang
- Department of Anesthesiology, The First Hospital of Jilin University, No. 1 Xinmin St., Changchun 130021, China
| | - Nan Liu
- Department of Anesthesiology, The First Hospital of Jilin University, No. 1 Xinmin St., Changchun 130021, China
| | - Meihua Piao
- Department of Anesthesiology, The First Hospital of Jilin University, No. 1 Xinmin St., Changchun 130021, China.
| | - Chunsheng Feng
- Department of Anesthesiology, The First Hospital of Jilin University, No. 1 Xinmin St., Changchun 130021, China.
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2
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Mattos R, Fioretto MN, Dos Santos SAA, Ribeiro IT, Emílio-Silva MT, Portela LMF, Lima CAH, Seiva FRF, Justulin LA. Maternal malnutrition induces inflammatory pathways and oxidative stress in the dorsolateral prostate of male offspring rats. Biogerontology 2025; 26:109. [PMID: 40381043 DOI: 10.1007/s10522-025-10251-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2025] [Accepted: 05/02/2025] [Indexed: 05/19/2025]
Abstract
Maternal conditions during pregnancy can influence the long-term health of offspring. In particular, maternal malnutrition (MM), such as protein restriction, affects the development of several organs, including the male reproductive system. This study examined how a low-protein maternal diet impacts the structure and function of the dorsolateral prostate (DLP) in aging male rats. Male offspring were divided into two groups: A control group (CTR), whose mothers received a normal protein diet (17%) during pregnancy and lactation, and a low-protein group (GLLP), whose mothers received a low-protein diet (6%) during the same period. At 540 days of age, the offspring were euthanized, and the DLPs were collected for analysis. The GLLP group showed significant structural changes in the DLP, including increased epithelial and reduced stromal compartments. These rats also had lower levels of probasin (a prostate-specific protein), along with a higher number of mast cells, CD68 + macrophages, and IL-10 protein expression, indicating inflammation. Antioxidant balance was disrupted: Glutathione (GSH) levels increased, while catalase (CAT) and superoxide dismutase (SOD) decreased. The expression of SIRT1, a protein linked to aging and oxidative stress control, was reduced. In silico analysis using human prostate cancer data (PRAD-TCGA) revealed that biological pathways related to oxidative stress, immune response, and tissue remodeling were disrupted in both the rat model and human prostate cancer. In summary, maternal protein restriction leads to long-term changes in the dorsolateral prostate of aging male offspring, including inflammation, oxidative stress, and tissue remodeling. The reduced expression of SIRT1 may play a key role in these effects.
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Affiliation(s)
- Renato Mattos
- Department of Structural and Functional Biology (UNESP), Institute of Biosciences, Botucatu, SP, 18618-68, Brazil
| | - Matheus Naia Fioretto
- Department of Structural and Functional Biology (UNESP), Institute of Biosciences, Botucatu, SP, 18618-68, Brazil
| | | | - Isabelle Tenori Ribeiro
- Department of Structural and Functional Biology (UNESP), Institute of Biosciences, Botucatu, SP, 18618-68, Brazil
| | - Maycon Tavares Emílio-Silva
- Department of Structural and Functional Biology (UNESP), Institute of Biosciences, Botucatu, SP, 18618-68, Brazil
| | - Luiz Marcos Frediani Portela
- Department of Structural and Functional Biology (UNESP), Institute of Biosciences, Botucatu, SP, 18618-68, Brazil
| | - Clélia Akiko Hiruma Lima
- Department of Structural and Functional Biology (UNESP), Institute of Biosciences, Botucatu, SP, 18618-68, Brazil
| | | | - Luis A Justulin
- Department of Structural and Functional Biology (UNESP), Institute of Biosciences, Botucatu, SP, 18618-68, Brazil.
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3
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Toprani SM, Mordukhovich I, McNeely E, Nagel ZD. Suppressed DNA repair capacity in flight attendants after air travel. Sci Rep 2025; 15:16513. [PMID: 40360675 PMCID: PMC12075667 DOI: 10.1038/s41598-025-98934-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2025] [Accepted: 04/15/2025] [Indexed: 05/15/2025] Open
Abstract
Elevated cancer risk and compromised reproductive health have been well documented in flight attendants (FA), but the etiology remains unknown. Many studies using cell and animal models suggest that air travel related exposures might plausibly explain the adverse health outcomes observed in flight crew, but our understanding of the underlying biological mechanisms is incomplete. During air travel, FA are constantly exposed to complex mixtures of mutagens in the flight cabin that may contribute to genomic instability by inducing DNA damage and interfering with DNA repair. Defects in DNA repair capacity (DRC) have been associated with risk of cancer and other diseases. To explore our hypothesis that alterations in DNA damage and repair in FA are related to flight travel, we conducted a pilot study of FA's DNA damage and assess global DNA repair efficiency pre and post flight. We collected venous blood samples from nine FA before and after flight. Differential blood cell counts were carried out to assess immune responses and functional assays were performed to assess the DNA damage response. The CometChip assay was employed to quantify baseline DNA damage and repair kinetics for DNA damage induced by X-rays. Fluorescence multiplex based host cell reactivation (FM-HCR) assays were utilized to assess DRC in five major DNA repair pathways. Our findings revealed a significant increase in lymphocyte counts as well as diminished repair of ionizing radiation induced DNA damage and excision of 8oxoG:C lesions in after flight samples. Our results illustrate the potential for using biological samples to identify molecular mechanisms that may implicate impaired genomic stability and altered immune responses in the etiology of excess cancer in FAs.
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Affiliation(s)
- Sneh M Toprani
- John B. Little Center of Radiation Sciences, Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, USA
- Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Irina Mordukhovich
- Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, USA
- SHINE, Human Flourishing Program Institute for Quantitative Science, Harvard University, Cambridge, MA, USA
| | - Eileen McNeely
- Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, USA
- SHINE, Human Flourishing Program Institute for Quantitative Science, Harvard University, Cambridge, MA, USA
| | - Zachary D Nagel
- John B. Little Center of Radiation Sciences, Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
- Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
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Hsu CY, Jasim SA, Rasool KH, H M, Kaur J, Jabir MS, Alhajlah S, Kumar A, Jawad SF, Husseen B. Divergent functions of TLRs in gastrointestinal (GI) cancer: Overview of their diagnostic, prognostic and therapeutic value. Semin Oncol 2025; 52:152344. [PMID: 40347779 DOI: 10.1016/j.seminoncol.2025.152344] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2025] [Revised: 03/10/2025] [Accepted: 03/15/2025] [Indexed: 05/14/2025]
Abstract
The relationship between the innate immune signal and the start of the adaptive immune response is the central idea of this theory. By controlling the inflammatory and tissue-repair reactions to damage, the Toll-like receptors (TLRs), as a family of PRRs, have attracted increasing attention for its function in protecting the host against infection and preserving tissue homeostasis. Microbial infection, damage, inflammation, and tissue healing have all been linked to the development of malignancies, especially gastrointestinal (GI) cancers. Recently, increased studies on TLR recognition and binding, as well as their ligands, have significantly advanced our knowledge of the various TLR signaling pathways and offered therapy options for GI malignancies. Upon activation by pathogen-associated or damage-associated molecular patterns (DAMPs and PAMPs), TLRs trigger key pathways like NF-κB, MAPK, and IRF. NF-κB activation promotes inflammation, cell survival, and proliferation, often contributing to tumor growth, metastasis, and therapy resistance. MAPK pathways similarly drive uncontrolled cell growth and invasion, while IRF pathways modulate interferon production, yielding both anti-tumor and protumor effects. The resulting chronic inflammatory environment within tumors can foster progression, yet TLR activation can also stimulate beneficial anti-tumor immune responses. However, the functions of TLR expression in GI cancers and their diagnostic and prognostic along with therapeutic value have not yet entirely been elucidated. Understanding how TLR activation contributes to anti-cancer immunity against GI malignancies may hasten immunotherapy developments and increase patient survival.
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Affiliation(s)
- Chou-Yi Hsu
- Thunderbird School of Global Management, Arizona State University Tempe Campus, Phoenix, Arizona, USA
| | - Saade Abdalkareem Jasim
- Medical Laboratory Techniques Department, Al-maarif University College, Anbar, Iraq; Biotechnology Department, College of Applied Science, Fallujah University, Fallujah, Iraq
| | - Khetam Habeeb Rasool
- Department of Biology, College of Science, University of Mustansiriyah, Mustansiriyah, Iraq
| | - Malathi H
- Department of Biotechnology and Genetics, School of Sciences, JAIN (Deemed to be University), Bangalore, Karnataka, India
| | - Jaswinder Kaur
- Chandigarh Pharmacy College, Chandigarh Group of Colleges, Mohali, Punjab, India
| | - Majid S Jabir
- Department of Applied Sciences, University of Technology, Anbar, Iraq
| | - Sharif Alhajlah
- Department of Medical Laboratories, College of Applied Medical Sciences, Shaqra University, Shaqra, Saudi Arabia.
| | - Abhinav Kumar
- Department of Nuclear and Renewable Energy, Ural Federal University Named after the First President of Russia Boris Yeltsin, Ekaterinburg, Russia; Centre for Research Impact & Outcome, Chitkara University, Rajpura, Punjab, India; Institute of Engineering and Technology, Chitkara University, Rajpura, Punjab, India
| | - Sabrean F Jawad
- Department of Pharmacy, Al-Mustaqbal University College, Hillah, Babylon, Iraq
| | - Beneen Husseen
- Medical Laboratory Technique College, the Islamic University, Najaf, Iraq; Medical Laboratory Technique College, the Islamic University of Al Diwaniyah, Al Diwaniyah, Iraq; Medical Laboratory Technique College, the Islamic University of Babylon, Babylon, Iraq
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5
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Kawanishi S, Wang G, Ma N, Murata M. Cancer Development and Progression Through a Vicious Cycle of DNA Damage and Inflammation. Int J Mol Sci 2025; 26:3352. [PMID: 40244228 PMCID: PMC11989737 DOI: 10.3390/ijms26073352] [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: 02/27/2025] [Revised: 03/22/2025] [Accepted: 04/01/2025] [Indexed: 04/18/2025] Open
Abstract
Infections and chronic inflammation play a crucial role in the development of cancer. During inflammatory processes, reactive oxygen and nitrogen species are generated by both inflammatory and epithelial cells, leading to the induction of oxidative and nitrative DNA damage, such as the formation of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) and 8-nitroguanine (8-nitroG). These DNA alterations can trigger mutations, which are believed to contribute to cancer formation driven by inflammation. The authors observed the generation of 8-nitroG through iNOS expression in human and animal tissues under inflammatory conditions, where cancer is likely to develop. 8-NitroG serves as a predictive and prognostic indicator for cancers linked to inflammation. Inflammation causes DNA damage, and the subsequent DNA damage response can create an inflammatory environment marked by hypoxia, with HMGB1 being a key factor. The interplay between HIF-1α, NF-ĸB, and HMGB1 sustains DNA damage and the accumulation of mutations, driving cancer progression and worsening prognosis. 8-NitroG is involved not only in the onset and advancement of cancer but also in its progression and conversion. Herein, the authors propose a vicious cycle of DNA damage and inflammation in cancer development (initiation and promotion) and progression, including conversion, via HMGB1.
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Affiliation(s)
- Shosuke Kawanishi
- Department of Pharmaceutical Sciences, Suzuka University of Medical Science, Suzuka 513-8670, Mie, Japan
| | - Guifeng Wang
- Department of Acupuncture and Moxibustion Medical Science, Suzuka University of Medical Science, Suzuka 510-0293, Mie, Japan;
| | - Ning Ma
- Graduate School of Health Science, Suzuka University of Medical Science, Suzuka 510-0293, Mie, Japan;
- Institute of Traditional Chinese Medicine, Suzuka University of Medical Science, Suzuka 510-0293, Mie, Japan
| | - Mariko Murata
- Graduate School of Health Science, Suzuka University of Medical Science, Suzuka 510-0293, Mie, Japan;
- Department of Environmental and Molecular Medicine, Mie University Graduate School of Medicine, Tsu 514-8507, Mie, Japan
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6
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Nishida A, Andoh A. The Role of Inflammation in Cancer: Mechanisms of Tumor Initiation, Progression, and Metastasis. Cells 2025; 14:488. [PMID: 40214442 PMCID: PMC11987742 DOI: 10.3390/cells14070488] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2025] [Revised: 03/14/2025] [Accepted: 03/20/2025] [Indexed: 04/14/2025] Open
Abstract
Inflammation is an essential component of the immune response that protects the host against pathogens and facilitates tissue repair. Chronic inflammation is a critical factor in cancer development and progression. It affects every stage of tumor development, from initiation and promotion to invasion and metastasis. Tumors often create an inflammatory microenvironment that induces angiogenesis, immune suppression, and malignant growth. Immune cells within the tumor microenvironment interact actively with cancer cells, which drives progression through complex molecular mechanisms. Chronic inflammation is triggered by factors such as infections, obesity, and environmental toxins and is strongly linked to increased cancer risk. However, acute inflammatory responses can sometimes boost antitumor immunity; thus, inflammation presents both challenges and opportunities for therapeutic intervention. This review examines how inflammation contributes to tumor biology, emphasizing its dual role as a critical factor in tumorigenesis and as a potential therapeutic target.
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Affiliation(s)
- Atsushi Nishida
- Department of Medicine, Shiga University of Medical Science, Seta-Tsukinowa, Otsu 520-2192, Shiga, Japan;
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Németh K, Mezei E, Vörös J, Borka K, Pesti A, Kenessey I, Kiss A, Budai A. Subtype-associated complexity and prognostic significance of the NLRP3 inflammasome landscape in pancreatic neoplasms. J Pathol Clin Res 2025; 11:e70019. [PMID: 39969214 PMCID: PMC11837281 DOI: 10.1002/2056-4538.70019] [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: 09/04/2024] [Revised: 01/01/2025] [Accepted: 01/19/2025] [Indexed: 02/20/2025]
Abstract
Intraductal papillary mucinous neoplasm (IPMN) can progress into malignant pancreatic cancer, posing challenges in accurately assessing the risk of malignancy. While the nucleotide-binding oligomerization domain (NOD)-like receptor pyrin domain containing 3 (NLRP3) inflammasome pathway's role in pancreatic ductal adenocarcinoma (PDAC) has been extensively studied, its implications in IPMN remain unexplored. This study aimed to investigate the prognostic significance of NLRP3 inflammasome-related proteins across IPMN subtypes and their associations with tumor characteristics, with a secondary focus on comparing expression patterns in IPMN and PDAC. A cohort of 187 patients (100 IPMN and 87 PDAC) underwent high-dimensional histopathological imaging using the multiplexed immunohistochemical consecutive staining on single slide method and a semi-automated image analysis workflow. Expression levels of NLRP3, apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC), caspase-1, interleukin-1 beta, interleukin-18 (IL-18), interleukin-1 receptor antagonist, and interleukin-18 binding protein (IL-18BP) were evaluated and compared between IPMN and PDAC samples. The relationships between protein expression and tumor characteristics were examined. Principal component analysis distinguished between intestinal and nonintestinal clusters based on NLRP3-associated proteins. Lower IL-18 expression was linked to the intestinal subtype, while higher caspase-1 was linked to the pancreatobiliary subtype. Elevated caspase-1 and ASC expression were associated with invasiveness in IPMN. No significant correlation was found between the examined proteins and later-stage tumor characteristics in invasive cases. The IL-18/IL-18BP ratio was an independent prognostic factor in invasive IPMN. Our findings highlight the prognostic significance of IL-18 and the IL-18/IL-18BP ratio in invasive IPMNs. These results point to a complex regulation of NLRP3 inflammasome proteins, especially effector cytokines, in pancreatic neoplasms, which are strongly linked to subtype and prognosis.
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Affiliation(s)
- Kristóf Németh
- Department of Pathology, Forensics and Insurance MedicineSemmelweis UniversityBudapestHungary
| | - Eszter Mezei
- Department of Pathology, Forensics and Insurance MedicineSemmelweis UniversityBudapestHungary
| | - Justína Vörös
- Department of Pathology, Forensics and Insurance MedicineSemmelweis UniversityBudapestHungary
| | - Katalin Borka
- Department of Pathology, Forensics and Insurance MedicineSemmelweis UniversityBudapestHungary
| | - Adrián Pesti
- Department of Pathology, Forensics and Insurance MedicineSemmelweis UniversityBudapestHungary
| | - István Kenessey
- Department of Pathology, Forensics and Insurance MedicineSemmelweis UniversityBudapestHungary
- National Cancer Registry and Center for BiostatisticsNational Institute of OncologyBudapestHungary
| | - András Kiss
- Department of Pathology, Forensics and Insurance MedicineSemmelweis UniversityBudapestHungary
| | - András Budai
- Department of Pathology, Forensics and Insurance MedicineSemmelweis UniversityBudapestHungary
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Zhao F, Jia Z, Zhang L, Liu G, Li J, Zhao J, Xie Y, Chen L, Jiang H, He W, Wang A, Peng J, Zheng Y. A MnO 2 nanosheets doping double crosslinked hydrogel for cartilage defect repair through alleviating inflammation and guiding chondrogenic differentiation. Biomaterials 2025; 314:122875. [PMID: 39454507 DOI: 10.1016/j.biomaterials.2024.122875] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2024] [Revised: 08/29/2024] [Accepted: 10/03/2024] [Indexed: 10/28/2024]
Abstract
The inflammatory microenvironment and inferior chondrogenesis are major symptoms after cartilage defect. Although various modifications strategies associated with hydrogels exhibit remarkable capacity of pro-cartilage regeneration, the adverse effect by prolonging inflammation is still formidable to hamper potential biomedical applications of different hydrogel implants. Herein, inspired by the repair microenvironment of articular cartilage defects, an injectable, immunomodulatory, and chondrogenic L-MNS-CMDA hydrogel is prepared through grafting vinyl and catechol groups to chitosan macromolecules using amide reaction, then further loading MnO2 nanosheets (MNS). The double crosslinking of photopolymerization and catechol oxidative polymerization endows L-MNS-CMDA hydrogel with preferable mechanical property, affording a suitable mechanical support for cartilage defect repair. Additionally, the robust tissue adhesion capability stemming from catechol groups guarantees the long-term retention of the hydrogel in the defect site. Meanwhile, L-MNS-CMDA hydrogel decomposes exogenous and intracellular H2O2 into O2 and H2O, to effectively alleviate cellular oxidative stress caused by long-term hypoxia. Under the synergies of catechol groups and MNS, L-MNS-CMDA hydrogel not only inhibits macrophages polarizing into M1 phenotype, but encourages them turn into M2 phenotype, thereby, reconstructing an immunization friendly microenvironment to ultimately enhance cartilage regeneration. Predictably, the hydrogel markedly induces rat bone marrow mesenchymal stem cells differentiating into chondrocytes by expressing abundant glycosaminoglycan and type II collagen. A cartilage defect model of rat knee joint indicates that L-MNS-CMDA hydrogel visually regulate the early inflammatory response of post-implantation, and facilitate cartilage regeneration and recovery of joint function after 12 weeks of post-implantation. All in all, this multifunctional L-MNS-CMDA hydrogel exhibits superior immunomodulatory and chondrogenic properties, holding immense clinical potential in the treatment of cartilage defects.
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Affiliation(s)
- Feilong Zhao
- School of Materials Science and Engineering, University of Science and Technology Beijing, Beijing, 100083, China
| | - Zhibo Jia
- Beijing Key Lab of Regenerative Medicine in Orthopaedics, Key Laboratory of Musculoskeletal Trauma &War Injuries, PLA Institute of Orthopedics, Chinese PLA General Hospital, Beijing, 100853, China
| | - Liyang Zhang
- School of Materials Science and Engineering, University of Science and Technology Beijing, Beijing, 100083, China
| | - Guodong Liu
- School of Materials Science and Engineering, University of Science and Technology Beijing, Beijing, 100083, China
| | - Junfei Li
- School of Materials Science and Engineering, University of Science and Technology Beijing, Beijing, 100083, China
| | - Jianming Zhao
- School of Materials Science and Engineering, University of Science and Technology Beijing, Beijing, 100083, China
| | - Yajie Xie
- School of Materials Science and Engineering, University of Science and Technology Beijing, Beijing, 100083, China
| | - Lu Chen
- School of Materials Science and Engineering, University of Science and Technology Beijing, Beijing, 100083, China
| | - Hongyu Jiang
- Beijing Key Lab of Regenerative Medicine in Orthopaedics, Key Laboratory of Musculoskeletal Trauma &War Injuries, PLA Institute of Orthopedics, Chinese PLA General Hospital, Beijing, 100853, China
| | - Wei He
- School of Materials Science and Engineering, University of Science and Technology Beijing, Beijing, 100083, China
| | - Aiyuan Wang
- Beijing Key Lab of Regenerative Medicine in Orthopaedics, Key Laboratory of Musculoskeletal Trauma &War Injuries, PLA Institute of Orthopedics, Chinese PLA General Hospital, Beijing, 100853, China
| | - Jiang Peng
- Beijing Key Lab of Regenerative Medicine in Orthopaedics, Key Laboratory of Musculoskeletal Trauma &War Injuries, PLA Institute of Orthopedics, Chinese PLA General Hospital, Beijing, 100853, China.
| | - Yudong Zheng
- School of Materials Science and Engineering, University of Science and Technology Beijing, Beijing, 100083, China.
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9
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Kim DK, Kim JI, Lee IH, Son DS. A Longitudinal Study Examining the Impact of Chronic Rhinosinusitis on the Risk of Cancer Development: A National Population-Based Cohort Study. Cancers (Basel) 2025; 17:546. [PMID: 39941912 PMCID: PMC11816809 DOI: 10.3390/cancers17030546] [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: 12/27/2024] [Revised: 02/03/2025] [Accepted: 02/04/2025] [Indexed: 02/16/2025] Open
Abstract
BACKGROUND/OBJECTIVES We investigated the association between chronic rhinosinusitis (CRS) and cancer risk in an adult Korean population. METHODS This retrospective cohort study used data from the Korean National Health Insurance Service database. To ensure comparability between the groups, adjustments were made for potential confounding factors, including sex, age, residence, household income, diabetes, hypertension, and chronic kidney disease. The primary endpoint was the presence of newly diagnosed cancer. RESULTS Among 1,337,120 individuals in the nationally representative cohort database, 10,567 patients with CRS were identified and matched with 42,268 control subjects without CRS. Patients with CRS had a significantly higher risk of overall cancer events than controls. The adjusted hazard ratio (HR) for cancer in the CRS group was 1.16 (95% confidence interval [CI]: 1.05-1.28). Notably, female patients with CRS had an elevated risk of incident cancer events. Furthermore, patients with CRS without nasal polyps exhibited a significantly increased risk of cancer, whereas those with CRS with nasal polyps did not show a similar association. CONCLUSIONS These findings underscore the need for physicians to carefully monitor patients with CRS for potential cancer progression and develop appropriate therapeutic strategies to mitigate the impact of this condition.
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Affiliation(s)
- Dong-Kyu Kim
- Department of Otorhinolaryngology-Head and Neck Surgery, Chuncheon Sacred Heart Hospital, Hallym University College of Medicine, Chuncheon 24252, Republic of Korea
- Department of Otorhinolaryngology-Head and Neck Surgery, OneSleep Clinic, Gunpo-si 15856, Republic of Korea
| | - Jae-In Kim
- Department of Physiology, Neurology, Hallym University College of Medicine, Chuncheon 24252, Republic of Korea
| | - Il Hwan Lee
- Department of Otorhinolaryngology-Head and Neck Surgery, Chuncheon Sacred Heart Hospital, Hallym University College of Medicine, Chuncheon 24252, Republic of Korea
| | - Dae-Soon Son
- Department of Data Science, Data Science Convergence Research Center, Hallym University, Chuncheon 24252, Republic of Korea
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10
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Long K, Zhu Z, Zheng X, Xu G, Chen C, Ke X. White blood cell traits and lung cancer risk: a two-sample mendelian randomization analysis. Sci Rep 2025; 15:4227. [PMID: 39905222 PMCID: PMC11794654 DOI: 10.1038/s41598-025-88366-w] [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: 11/01/2024] [Accepted: 01/28/2025] [Indexed: 02/06/2025] Open
Abstract
This study aimed to investigate the potential association between white blood cell counts and the risk of lung cancer, including its subtypes, through Mendelian randomization (MR) analysis. We conducted a two-sample MR analysis using genome-wide association study (GWAS) summary statistics for the both exposure traits (eosinophil count, neutrophil count, lymphocyte count, monocyte count, basophil count, and total white blood cell count) and outcome traits (lung cancer and its subtypes). The GWAS dataset for lung cancer included 29,266 cases (11273 lung adenocarcinoma (LUAD), 7426 lung squamous cell carcinoma (LSCC), 2664 small cell lung cancer (SCLC)) and 56,450 controls. In MR analysis, we employed methods such as Inverse variance weighted (IVW), weighted median, MR-Egger regression, MR pleiotropy residual sum and outlier. MR analysis revealed an elevated total white blood cell (WBC) count significantly increased the risk of LUAD (IVW: OR = 1.484, 95% CI = 1.219-1.749, p = 0.003). The results confirmed a causal relationship between monocyte count and LUAD (IVW: OR = 1.687, 95% CI:1.542-1.830, p < 0.001). An increased total WBC count was associated with a higher risk of LUAD. Additionally, analysis of WBC subtypes counts indicated that monocyte count plays an crucial role in the elevated risk of LUAD.
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Affiliation(s)
- Kaijun Long
- Department of Thoracic Surgery, Affiliated Hospital of Zunyi Medical University, 149 Dalian Road, Zunyi, 563000, Guizhou, China
| | - Zhengfeng Zhu
- Department of Thoracic Surgery, Affiliated Hospital of Zunyi Medical University, 149 Dalian Road, Zunyi, 563000, Guizhou, China
| | - Xinzhe Zheng
- Department of Thoracic Surgery, Affiliated Hospital of Zunyi Medical University, 149 Dalian Road, Zunyi, 563000, Guizhou, China
| | - Gang Xu
- Department of Thoracic Surgery, Affiliated Hospital of Zunyi Medical University, 149 Dalian Road, Zunyi, 563000, Guizhou, China.
| | - Cheng Chen
- Department of Thoracic Surgery, Affiliated Hospital of Zunyi Medical University, 149 Dalian Road, Zunyi, 563000, Guizhou, China.
| | - Xixian Ke
- Department of Thoracic Surgery, Affiliated Hospital of Zunyi Medical University, 149 Dalian Road, Zunyi, 563000, Guizhou, China.
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11
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Xi P, Huang G, Huang K, Qin D, Yao Z, Jiang L, Zhu Q, He C. The Prognostic Significance of the CALLY Index in Ampullary Carcinoma: An Inflammation-Nutrition Retrospective Analysis. J Inflamm Res 2025; 18:621-635. [PMID: 39835294 PMCID: PMC11745071 DOI: 10.2147/jir.s495815] [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: 09/11/2024] [Accepted: 01/07/2025] [Indexed: 01/22/2025] Open
Abstract
Background As a novel inflammatory-nutritional biomarker, the C-reactive protein-albumin-lymphocyte (CALLY) index has demonstrated significant prognostic value in various malignancies. However, research on its association with the prognosis of ampullary carcinoma (AC) is rare. This study aims to investigate the relationship between the CALLY index and the prognosis of patients with AC. Methods We retrospectively analyzed data from 201 patients with AC at Sun Yat-sen University Cancer Center. Several clinicopathological factors and biomarkers were included in the study. Univariate and multivariate Cox regression analyses, along with competing risk analysis, were performed to identify prognostic factors for AC after pancreaticoduodenectomy (PD). Only factors with significant results in univariate analysis were included in multivariate analysis. To ensure the robustness of our findings, propensity score matching (PSM) analyses were conducted to assess survival differences according to the CALLY index. Results The univariate and multivariate Cox regression analyses revealed that pathological type, N stage, T stage, postoperative chemotherapy regimen, and the CALLY index were all statistically significant prognostic factors for patients with AC after PD (all P values < 0.05). Taking into account non-cancer-related mortality as competing hazards, these factors remained significant predictors (all P values < 0.05). After PSM, the survival advantage observed between the low and high CALLY groups remained discernible and consistent. Conclusion This study indicated that a reduced CALLY index correlates with a poorer cancer-specific survival in AC patients after PD, highlighting its utility as a prognostic marker for this condition.
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Affiliation(s)
- Pu Xi
- Department of Pancreatobiliary Surgery, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, People’s Republic of China
| | - Guizhong Huang
- Department of Pancreatobiliary Surgery, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, People’s Republic of China
| | - Kewei Huang
- State Key Laboratory of Oncology in South China, Department of Clinical Laboratory, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, People’s Republic of China
| | - Dailei Qin
- Department of Pancreatobiliary Surgery, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, People’s Republic of China
| | - Zehui Yao
- Department of Pancreatobiliary Surgery, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, People’s Republic of China
| | - Lingmin Jiang
- Department of Pancreatobiliary Surgery, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, People’s Republic of China
| | - Qi Zhu
- Department of Pancreatobiliary Surgery, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, People’s Republic of China
| | - Chaobin He
- Department of Pancreatobiliary Surgery, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, People’s Republic of China
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12
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Maria de Oliveira Barboza M, Ferreira da Costa R, Paulo Por Deus Gomes J, Mário Rodríguez Burbano R, Goberlânio de Barros Silva P, Helena Barem Rabenhorst S. Host repair polymorphisms and H. pylori genes in gastric disease outcomes: Who are the guardian and villains? Gene 2025; 933:148977. [PMID: 39389328 DOI: 10.1016/j.gene.2024.148977] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2024] [Revised: 08/30/2024] [Accepted: 09/30/2024] [Indexed: 10/12/2024]
Abstract
Gastric cancer (GC) is the fourth-leading cause of cancer-related mortality. The intestinal subtype of GC comes after the cascade of Correa, presenting H. pylori infection as the major etiological factor. One of the main mechanisms proposed for the progression from a more benign gastric lesion to cancer is DNA damage caused by chronic inflammation. Polymorphisms in DNA repair genes can lead to an imbalance of host DNA damage and repair, contributing to the development of GC. From there, we evaluated the risk of polymorphisms in DNA repair system genes in progressive gastric diseases and their association with the H. pylori genotype. This study included 504 patients from two public hospitals in Brazil's north and northeast regions. The samples were classified into active and inactive gastritis, metaplasia, and GC. Polymorphisms in the DNA repair genes MLH1-93G > A, APE1 2197 T > G, XRCC1 28,152 G > A, MGMT 533 A > G, and XRCC3 18,067C > T were investigated by RFLP-PCR and H. pylori genotype by PCR. Statistical analyses were conducted using EPINFO 7.0., SNPSTAT, and CART software. The XRCC1 (GA) polymorphic allele stood out because it was associated with a lower risk of more severe gastric disease progression. Haplotypes of XRCC1 (GA) associated with some genotypes of MGMT, XRCC3, MLH1, and APE1 also showed protection against the progression of gastric diseases. XRCC3 (CT) showed a decreased risk of gastric disease progression in women, while a risk 1.3x to GC was observed in the MLH1 (A) polymorphic allele. The interaction between H. pylori genes and the host showed that the H. pylori cagE gene was the most important virulence factor associated with a worse clinical outcome, even overlapping with the XRCC1 polymorphism, where the MLH1 polymorphism response varied according to vacA alleles. Our results show the relevance of XRCC1 G > A for genome integrity, sex influence, and interaction between H. pylori virulence factors and XRCC1 and MLH1 genotypes for gastric lesion outcomes in Brazilian populations.
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Affiliation(s)
- Morgana Maria de Oliveira Barboza
- Federal University of Ceará, Department of Pathology and Forensic Medicine, Coronel Nunes de Melo Street, 1315, Rodolfo Teófilo, Fortaleza, Ceará, Brazil.
| | - Reginaldo Ferreira da Costa
- Harold Juaçaba Diagnostic Center (HHJ) of the Hospital Instituto do Câncer do Ceará (ICC), Papi Júnior Street, 1222, Rodolfo Teófilo, Fortaleza, Ceará, Brazil
| | - João Paulo Por Deus Gomes
- Federal University of Ceará, Computer Science Department, Campus do Pici, Block 910, Fortaleza, Ceará, Brazil
| | - Rommel Mário Rodríguez Burbano
- Federal University of Pará, Human Cytogenetics Laboratory, Biological Science Institute, Augusto Correa Street, 01, Guamá, Belém, Pará, Brazil
| | - Paulo Goberlânio de Barros Silva
- Christus University Centre, Division of Oral and Maxillofacial Surgery, School of Dentistry, Padre Antônio Tomás Avenue 3404, Fortaleza, Ceará, Brazil
| | - Silvia Helena Barem Rabenhorst
- Federal University of Ceará, Department of Pathology and Forensic Medicine, Coronel Nunes de Melo Street, 1315, Rodolfo Teófilo, Fortaleza, Ceará, Brazil.
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13
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Fang S, Jiang M, Jiao J, Zhao H, Liu D, Gao D, Wang T, Yang Z, Yuan H. Unraveling the ROS-Inflammation-Immune Balance: A New Perspective on Aging and Disease. Aging Dis 2025:AD.2024.1253. [PMID: 39812539 DOI: 10.14336/ad.2024.1253] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2024] [Accepted: 01/03/2025] [Indexed: 01/16/2025] Open
Abstract
Increased entropy is a common cause of disease and aging. Lifespan entropy is the overall increase in disorder caused by a person over their lifetime. Aging leads to the excessive production of reactive oxygen species (ROS), which damage the antioxidant system and disrupt redox balance. Organ aging causes chronic inflammation, disrupting the balance of proinflammatory and anti-inflammatory factors. Inflammaging, which is a chronic low-grade inflammatory state, is activated by oxidative stress and can lead to immune system senescence. During this process, entropy increases significantly as the body transitions from a state of low order to high disorder. However, the connection among inflammation, aging, and immune system activity is still not fully understood. This review introduces the idea of the ROS-inflammation-immune balance for the first time and suggests that this balance may be connected to aging and the development of age-related diseases. We also explored how the balance of these three factors controls and affects age-related diseases. Moreover, imbalance in the relationship described above disrupts the regular structures of cells and alters their functions, leading to cellular damage and the emergence of a disorganized state marked by increased entropy. Maintaining a low entropy state is crucial for preventing and reversing aging processes. Consequently, we examined the current preclinical evidence for antiaging medications that target this balance. Ultimately, comprehending the intricate relationships between these three factors and the risk of age-related diseases in organisms will aid in the development of clinical interventions that promote long-term health.
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Affiliation(s)
- Sihang Fang
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing, China
| | - Mingjun Jiang
- Respiratory Department, Beijing Children's Hospital, Capital Medical University, China National Clinical Research Center of Respiratory Diseases, National Center for Children's Health, Beijing, China
| | - Juan Jiao
- Department of Clinical Laboratory, the Seventh Medical Center of PLA General Hospital, Beijing, China
| | - Hongye Zhao
- Department of Biochemistry and Molecular Biology, The Key Laboratory of Neural and Vascular Biology, Ministry of Education of China, Hebei Medical University, Shijiazhuang, Hebei, China
| | - Dizhi Liu
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing, China
| | - Danni Gao
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing, China
| | - Tenger Wang
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing, China
| | - Ze Yang
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing, China
| | - Huiping Yuan
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing, China
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Arzhanova EL, Makusheva Y, Pershina EG, Medvedeva SS, Litvinova EA. Changes in the Phenotype and Metabolism of Peritoneal Macrophages in Mucin-2 Knockout Mice and Partial Restoration of Their Functions In Vitro After L-Fucose Treatment. Int J Mol Sci 2024; 26:13. [PMID: 39795876 PMCID: PMC11719744 DOI: 10.3390/ijms26010013] [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: 11/13/2024] [Revised: 12/18/2024] [Accepted: 12/19/2024] [Indexed: 01/13/2025] Open
Abstract
In the development of inflammatory bowel disease (IBD), peritoneal macrophages contribute to the resident intestinal macrophage pool. Previous studies have demonstrated that oral administration of L-fucose exerts an immunomodulatory effect and repolarizes the peritoneal macrophages in vivo in mice. In this study, we analyzed the phenotype and metabolic profile of the peritoneal macrophages from Muc2-/- mice, as well as the effect of L-fucose on the metabolic and morphological characteristics of these macrophages in vitro. The investigation utilized flow cytometry, quantitative PCR (qPCR), measurement of the intracellular ATP and Ca2+ concentrations, an analysis of mitochondrial respiration and membrane potential, and transmission electron microscopy (TEM) for ultrastructural evaluations. The Muc2-/- mice exhibited lower intracellular ATP and Ca2+ levels in their peritoneal macrophages, a higher percentage of stellate macrophages, and an increased oxygen consumption rate (OCR), combined with a higher percentage of mitochondria displaying an abnormal ultrastructure. Additionally, there was a five-fold increase in condensed mitochondria compared to their level in C57BL/6 mice. The number of CD209+ peritoneal macrophages was reduced three-fold, while the number of M1-like cells increased two-fold in the Muc2-/- mice. L-fucose treatment enhanced ATP production and reduced the expression of the Parp1, Mt-Nd2, and Mt-Nd6 genes, which may suggest a reduction in pro-inflammatory factor production and a shift in the differentiation of peritoneal macrophages towards the M2 phenotype.
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Affiliation(s)
- Elena L. Arzhanova
- Faculty of Natural Sciences, Novosibirsk State University, 630090 Novosibirsk, Russia; (E.L.A.); (E.G.P.)
- Scientific Research Institute of Neurosciences and Medicine, 630117 Novosibirsk, Russia
| | - Yulia Makusheva
- Physical Engineering Faculty, Novosibirsk State Technical University, 630073 Novosibirsk, Russia;
| | - Elena G. Pershina
- Faculty of Natural Sciences, Novosibirsk State University, 630090 Novosibirsk, Russia; (E.L.A.); (E.G.P.)
- Federal Research Center Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russia
| | | | - Ekaterina A. Litvinova
- Physical Engineering Faculty, Novosibirsk State Technical University, 630073 Novosibirsk, Russia;
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15
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Frati G, Brusson M, Sartre G, Mlayah B, Felix T, Chalumeau A, Antoniou P, Hardouin G, Concordet JP, Romano O, Turchiano G, Miccio A. Safety and efficacy studies of CRISPR-Cas9 treatment of sickle cell disease highlights disease-specific responses. Mol Ther 2024; 32:4337-4352. [PMID: 39044427 PMCID: PMC11638826 DOI: 10.1016/j.ymthe.2024.07.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2024] [Revised: 05/15/2024] [Accepted: 07/18/2024] [Indexed: 07/25/2024] Open
Abstract
Fetal hemoglobin (HbF) reactivation expression through CRISPR-Cas9 is a promising strategy for the treatment of sickle cell disease (SCD). Here, we describe a genome editing strategy leading to reactivation of HbF expression by targeting the binding sites (BSs) for the lymphoma-related factor (LRF) repressor in the γ-globin promoters. CRISPR-Cas9 treatment in healthy donor (HD) and patient-derived HSPCs resulted in a high frequency of LRF BS disruption and potent HbF synthesis in their erythroid progeny. LRF BS disruption did not impair HSPC engraftment and differentiation but was more efficient in SCD than in HD cells. However, SCD HSPCs showed a reduced engraftment and a myeloid bias compared with HD cells. We detected off-target activity and chromosomal rearrangements, particularly in SCD samples (likely because of the higher overall editing efficiency) but did not impact the target gene expression and HSPC engraftment and differentiation. Transcriptomic analyses showed that the editing procedure results in the up-regulation of genes involved in DNA damage and inflammatory responses, which was more evident in SCD HSPCs. This study provides evidence of efficacy and safety for an editing strategy based on HbF reactivation and highlights the need of performing safety studies in clinically relevant conditions, i.e., in patient-derived HSPCs.
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Affiliation(s)
- Giacomo Frati
- Université Paris Cité, Imagine Institute, Laboratory of Chromatin and Gene Regulation During Development, INSERM UMR 1163, Paris, France
| | - Megane Brusson
- Université Paris Cité, Imagine Institute, Laboratory of Chromatin and Gene Regulation During Development, INSERM UMR 1163, Paris, France
| | - Gilles Sartre
- Université Paris Cité, Imagine Institute, Laboratory of Chromatin and Gene Regulation During Development, INSERM UMR 1163, Paris, France
| | - Bochra Mlayah
- Université Paris Cité, Imagine Institute, Laboratory of Chromatin and Gene Regulation During Development, INSERM UMR 1163, Paris, France
| | - Tristan Felix
- Université Paris Cité, Imagine Institute, Laboratory of Chromatin and Gene Regulation During Development, INSERM UMR 1163, Paris, France
| | - Anne Chalumeau
- Université Paris Cité, Imagine Institute, Laboratory of Chromatin and Gene Regulation During Development, INSERM UMR 1163, Paris, France
| | - Panagiotis Antoniou
- Université Paris Cité, Imagine Institute, Laboratory of Chromatin and Gene Regulation During Development, INSERM UMR 1163, Paris, France
| | - Giulia Hardouin
- Université Paris Cité, Imagine Institute, Laboratory of Chromatin and Gene Regulation During Development, INSERM UMR 1163, Paris, France
| | - Jean-Paul Concordet
- INSERM U1154, CNRS UMR7196, Museum National d'Histoire Naturelle, Paris, France
| | - Oriana Romano
- University of Padova, Department of Molecular Medicine, Padova, Italy
| | | | - Annarita Miccio
- Université Paris Cité, Imagine Institute, Laboratory of Chromatin and Gene Regulation During Development, INSERM UMR 1163, Paris, France.
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16
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Guo J, Si G, Song X, Si F. Mediating role of circulating inflammatory proteins in the effect of immune cells on esophageal cancer risk: A Mendelian randomization study. Medicine (Baltimore) 2024; 103:e40374. [PMID: 39496002 PMCID: PMC11537666 DOI: 10.1097/md.0000000000040374] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2024] [Accepted: 10/16/2024] [Indexed: 11/06/2024] Open
Abstract
The immune system and inflammatory processes play crucial roles in the development of esophageal cancer (EC). This study aimed to investigate the causal relationships between 731 immune cell phenotypes, 91 circulating inflammatory proteins, and EC, with a particular focus on the mediating role of circulating inflammatory proteins. Utilizing public genetic data, we applied a 2-sample Mendelian Randomization (MR) method to examine the causal relationships between 731 immune cell phenotypes, 91 circulating inflammatory proteins, and EC. Comprehensive sensitivity analyses were conducted to assess the robustness, heterogeneity, and horizontal pleiotropy of the MR results. Additionally, a 2-step MR method was employed to quantify the impact and proportion of immune cell phenotypes mediated by circulating inflammatory proteins on EC. Eleven immune cell phenotypes and 1 inflammatory cytokine were found to have causal relationships with EC, with results stable across all sensitivity analyses. Mediation analyses revealed that only 2 cell phenotypes had causal relationships with EC through interleukin-10: CD3 on human leukocyte antigen-DR (HLA-DR)+ T cells (mediation effect = -0.009; mediation proportion = 12.01%) and monocytic myeloid-derived suppressor cell absolute count (mediation effect = 0.018; mediation proportion = 18.97%). This study enhances the understanding of the causal relationships between immune cells, circulating inflammatory proteins, and EC. The findings highlight the potential mediating role of interleukin-10, providing new insights into the mechanisms by which immune cells may influence esophageal tumorigenesis.
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Affiliation(s)
- Jinzhou Guo
- Henan University of Chinese Medicine, Zhengzhou, Henan, China
- Laboratory of TCM Syndrome and Prescription Signaling, Academy of Zhongjing, Zhengzhou, Henan, China
- Henan Key Laboratory of TCM Syndrome and Prescription Signaling, Henan International Joint, Zhengzhou, Henan, China
| | - Gao Si
- Department of Orthopedic, Peking University Third Hospital, Beijing, China
| | - Xuejie Song
- Henan University of Chinese Medicine, Zhengzhou, Henan, China
- Laboratory of TCM Syndrome and Prescription Signaling, Academy of Zhongjing, Zhengzhou, Henan, China
- Henan Key Laboratory of TCM Syndrome and Prescription Signaling, Henan International Joint, Zhengzhou, Henan, China
| | - Fuchun Si
- Henan University of Chinese Medicine, Zhengzhou, Henan, China
- Laboratory of TCM Syndrome and Prescription Signaling, Academy of Zhongjing, Zhengzhou, Henan, China
- Henan Key Laboratory of TCM Syndrome and Prescription Signaling, Henan International Joint, Zhengzhou, Henan, China
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17
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Chen G, Ren Q, Zhong Z, Li Q, Huang Z, Zhang C, Yuan H, Feng Z, Chen B, Wang N, Feng Y. Exploring the gut microbiome's role in colorectal cancer: diagnostic and prognostic implications. Front Immunol 2024; 15:1431747. [PMID: 39483461 PMCID: PMC11524876 DOI: 10.3389/fimmu.2024.1431747] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2024] [Accepted: 09/30/2024] [Indexed: 11/03/2024] Open
Abstract
The intricate interplay between the gut microbiome and colorectal cancer (CRC) presents novel avenues for early diagnosis and prognosis, crucial for improving patient outcomes. This comprehensive review synthesizes current findings on the gut microbiome's contribution to CRC pathogenesis, highlighting its potential as a biomarker for non-invasive CRC screening strategies. We explore the mechanisms through which the microbiome influences CRC, including its roles in inflammation, metabolism, and immune response modulation. Furthermore, we assess the viability of microbial signatures as predictive tools for CRC prognosis, offering insights into personalized treatment approaches. Our analysis underscores the necessity for advanced metagenomic studies to elucidate the complex microbiome-CRC nexus, aiming to refine diagnostic accuracy and prognostic assessment in clinical settings. This review propels forward the understanding of the microbiome's diagnostic and prognostic capabilities, paving the way for microbiome-based interventions in CRC management.
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Affiliation(s)
- Guoming Chen
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong SAR, China
| | - Qing Ren
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong SAR, China
| | - Zilan Zhong
- The First Clinical College of Guangzhou University of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Qianfan Li
- The First Clinical College of Guangzhou University of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Zhiqiang Huang
- The First Clinical College of Guangzhou University of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Cheng Zhang
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong SAR, China
| | - Hongchao Yuan
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong SAR, China
| | - Zixin Feng
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong SAR, China
| | - Bonan Chen
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Sir Y.K. Pao Cancer Center, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR, China
| | - Ning Wang
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong SAR, China
| | - Yibin Feng
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong SAR, China
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Vijayraghavan S, Blouin T, McCollum J, Porcher L, Virard F, Zavadil J, Feghali-Bostwick C, Saini N. Widespread mutagenesis and chromosomal instability shape somatic genomes in systemic sclerosis. Nat Commun 2024; 15:8889. [PMID: 39406724 PMCID: PMC11480385 DOI: 10.1038/s41467-024-53332-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2024] [Accepted: 10/09/2024] [Indexed: 10/19/2024] Open
Abstract
Systemic sclerosis is a connective tissue disorder characterized by excessive fibrosis that primarily affects women, and can present as a multisystem pathology. Roughly 4-22% of patients with systemic sclerosis develop cancer, which drastically worsens prognosis. However, the mechanisms underlying systemic sclerosis initiation, propagation, and cancer development are poorly understood. We hypothesize that the inflammation and immune response associated with systemic sclerosis can trigger DNA damage, leading to elevated somatic mutagenesis, a hallmark of pre-cancerous tissues. To test our hypothesis, we culture clonal lineages of fibroblasts from the lung tissues of controls and systemic sclerosis patients and compare their mutation burdens and spectra. We find an overall increase in all major mutation types in systemic sclerosis samples compared to control lung samples, from small-scale events such as single base substitutions and insertions/deletions, to chromosome-level changes, including copy-number changes and structural variants. In the genomes of patients with systemic sclerosis, we find evidence of somatic hypermutation or kategis (typically only seen in cancer genomes), we identify mutation signatures closely resembling the error-prone translesion polymerase Polη activity, and observe an activation-induced deaminase-like mutation signature, which overlaps with genomic regions displaying kataegis.
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Affiliation(s)
- Sriram Vijayraghavan
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC, USA
| | - Thomas Blouin
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC, USA
| | - James McCollum
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC, USA
| | - Latarsha Porcher
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC, USA
| | - François Virard
- University Claude Bernard Lyon 1, INSERM U1052-CNRS UMR5286, Cancer Research Center, Centre Léon Bérard, Lyon, France
| | - Jiri Zavadil
- International Agency for Research on Cancer WHO, Epigenomics and Mechanisms Branch, Lyon, France
| | - Carol Feghali-Bostwick
- Department of Medicine, Division of Rheumatology, Medical University of South Carolina, Charleston, SC, USA
| | - Natalie Saini
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC, USA.
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19
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Hu X, Li Y, Cao Y, Shi F, Shang L. The role of nitric oxide synthase/ nitric oxide in infection-related cancers: Beyond antimicrobial activity. Biochim Biophys Acta Rev Cancer 2024; 1879:189156. [PMID: 39032540 DOI: 10.1016/j.bbcan.2024.189156] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2023] [Revised: 07/11/2024] [Accepted: 07/14/2024] [Indexed: 07/23/2024]
Abstract
As a free radical and endogenous effector molecule, mammalian endogenous nitric oxide (NO) is mainly derived from nitric oxide synthase (NOS) via L-arginine. NO participates in normal physiological reactions and provides immune responses to prevent the invasion of foreign bacteria. However, NO also has complex and contradictory biological effects. Abnormal NO signaling is involved in the progression of many diseases, such as cancer. In the past decades, cancer research has been closely linked with NOS/ NO, and many tumors with poor prognosis are associated with high expression of NOS. In this review, we give a overview of the biological effects of NOS/ NO. Then we focus on the oncogenic role of iNOS/ NO in HPV, HBV, EBV and H. pylori related tumors. In fact, there is growing evidence that iNOS could be used as a potential therapeutic target in cancer therapy. We emphasize that the pro-tumor effect of NOS/ NO is greater than the anti-tumor effect.
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Affiliation(s)
- Xudong Hu
- Key Laboratory of Carcinogenesis and Cancer Invasion of Chinese Ministry of Education, XiangYa Hospital, Central South University, Changsha 410078, China; Department of Pathology, National Clinical Research Center for Geriatric Disorders/ XiangYa Hospital, Central South University, Changsha 410078, China; Key Laboratory of Carcinogenesis of National Health Commission, Cancer Research Institute and School of Basic Medical Science, Xiangya School of Medicine, Central South University, Changsha 410078, China
| | - Yueshuo Li
- Key Laboratory of Carcinogenesis and Cancer Invasion of Chinese Ministry of Education, XiangYa Hospital, Central South University, Changsha 410078, China; Key Laboratory of Carcinogenesis of National Health Commission, Cancer Research Institute and School of Basic Medical Science, Xiangya School of Medicine, Central South University, Changsha 410078, China
| | - Ya Cao
- Key Laboratory of Carcinogenesis and Cancer Invasion of Chinese Ministry of Education, XiangYa Hospital, Central South University, Changsha 410078, China; Key Laboratory of Carcinogenesis of National Health Commission, Cancer Research Institute and School of Basic Medical Science, Xiangya School of Medicine, Central South University, Changsha 410078, China
| | - Feng Shi
- Key Laboratory of Carcinogenesis and Cancer Invasion of Chinese Ministry of Education, XiangYa Hospital, Central South University, Changsha 410078, China; Department of Pathology, National Clinical Research Center for Geriatric Disorders/ XiangYa Hospital, Central South University, Changsha 410078, China; Key Laboratory of Carcinogenesis of National Health Commission, Cancer Research Institute and School of Basic Medical Science, Xiangya School of Medicine, Central South University, Changsha 410078, China
| | - Li Shang
- Key Laboratory of Carcinogenesis and Cancer Invasion of Chinese Ministry of Education, XiangYa Hospital, Central South University, Changsha 410078, China; Department of Pathology, National Clinical Research Center for Geriatric Disorders/ XiangYa Hospital, Central South University, Changsha 410078, China.
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Huma Arya P, Vadhwana B, Tarazi M. Microbial dysbiosis in gastric cancer: Association or causation? Best Pract Res Clin Gastroenterol 2024; 72:101961. [PMID: 39645283 DOI: 10.1016/j.bpg.2024.101961] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2024] [Revised: 10/26/2024] [Accepted: 11/21/2024] [Indexed: 12/09/2024]
Affiliation(s)
- Pallavi Huma Arya
- Department of Surgery and Cancer, Imperial College London, Hammersmith Campus, Du Cane Road, White City, W12 0HS, UK.
| | - Bhamini Vadhwana
- Department of Surgery and Cancer, Imperial College London, Hammersmith Campus, Du Cane Road, White City, W12 0HS, UK.
| | - Munir Tarazi
- Department of Surgery and Cancer, Imperial College London, Hammersmith Campus, Du Cane Road, White City, W12 0HS, UK.
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21
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Li C, Chen H, Chen X, Wang P, Shi Y, Xie X, Chen Y, Cai X. Identification of inflammatory response-related molecular mechanisms based on the ATM/ATR/p53 pathway in tumor cells. Comput Biol Med 2024; 180:108776. [PMID: 39089116 DOI: 10.1016/j.compbiomed.2024.108776] [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: 02/16/2024] [Revised: 05/07/2024] [Accepted: 06/15/2024] [Indexed: 08/03/2024]
Abstract
Inflammatory response is a crucial factor that affects prognosis and therapeutic effect in tumor cells. Although some studies have shown that inflammation could make DNA more vulnerable to external attacks, resulting in serious DNA damage, the underlying mechanism remains unknown. Then, using tumor necrosis factor α (TNF-α) and lipopolysaccharide (LPS), this research elevated the level of inflammation in cancer cells, and hydrogen peroxide (H2O2) and ultraviolet (UV) were utilized as common reactive oxygen species (ROS)-induced DNA damage agents. We show that either H2O2 or UV achieved a more substantial antiproliferative effect in the inflammation environment compared with H2O2 or UV treatment alone. The inflammation environment enhanced H2O2- or UV-induced cell apoptosis and ROS production. Although the phenomenon that inflammation itself could trigger ROS-dependent DNA damage was well known, the underlying mechanism for the sensitization of inflammation to trigger intense DNA damage via ROS in cancer cells remains unclear. In this study, the inflammation-related genes and the corresponding expression information were obtained from the TCGA and fetched genes associated with inflammatory factors. Screening of thirteen inflammatory-related, including ATM, and prognostic genes. In addition, KEGG analysis of prognostic genes shows that biological processes such as DNA replication. ATM and ATR, which belong to the PI3/PI4-kinase family, can activate p53. Inflammation promotes the vulnerability of DNA by activating the ATM/ATR/p53 pathway, while not affecting the DNA damage repair pathway. In brief, this research suggested that inflammation made DNA vulnerable due to the amplifying H2O2- or UV-induced ROS production and the motoring ATM/ATR/p53 pathway. In addition, our findings revealed that inflammation's motoring of the ATM/ATR/p53 pathway plays a crucial role in DNA damage. Therefore, exploring the mechanism between inflammation and ROS-dependent DNA damage would be extremely valuable and innovative. This study would somewhat establish a better understanding of inflammation, DNA damage, and cancer.
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Affiliation(s)
- Chengye Li
- Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, People's Republic of China
| | - Hanbin Chen
- Department of Medical Oncology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, People's Republic of China
| | - Xiaojian Chen
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, People's Republic of China
| | - Peizhen Wang
- Department of Pathology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China
| | - Yunjiao Shi
- Department of Medical Oncology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, People's Republic of China
| | - Xiaona Xie
- Department of Medical Oncology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, People's Republic of China
| | - Yanfan Chen
- Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, People's Republic of China
| | - Xueding Cai
- Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, People's Republic of China.
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22
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Wang G, Hiramoto K, Ma N, Ohnishi S, Morita A, Xu Y, Yoshikawa N, Chinzei Y, Murata M, Kawanishi S. Immunohistochemical analyses reveal FoxP3 expressions in spleen and colorectal cancer in mice treated with AOM/DSS, and their suppression by glycyrrhizin. PLoS One 2024; 19:e0307038. [PMID: 39150932 PMCID: PMC11329161 DOI: 10.1371/journal.pone.0307038] [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: 06/27/2024] [Indexed: 08/18/2024] Open
Abstract
We previously demonstrated that glycyrrhizin (GL) suppressed inflammation and carcinogenesis in an azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced murine model of colorectal cancer (CC). In this study, we found an accumulation of regulatory T cells (Tregs) in the spleen and suppression by GL in model mice. ICR mice were divided into four groups: Control, GL, CC, and GL-treated CC (CC+GL), and were sacrificed 20 weeks after AOM/DSS treatment. We measured spleen weight, areas of white and red pulp, and CD8+ T cells (cytotoxic T lymphocytes, CTL), and CD11c-positive cells (dendritic cells) in splenic tissues and forkhead box protein 3 (FoxP3)-positive cells (Tregs) in colorectal and splenic tissues. In all cases, the CC group showed a significant increase compared with those in Control group, and GL administration significantly attenuated this increase. These results indicate that Tregs accumulated in the spleen may participate in inflammation-related carcinogenesis by suppressing CTL. We also suggest that GL which binds to high-mobility group box 1 (HMGB1), suppresses carcinogenesis with decreasing Tregs in the spleen. Furthermore, there was an expression of FoxP3 in cancer cells, indicating that it may be involved in the malignant transformation of cancer cells.
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Affiliation(s)
- Guifeng Wang
- Department of Acupuncture and Moxibustion Medical Science, Suzuka University of Medical Science, Suzuka, Mie, Japan
| | - Keiichi Hiramoto
- Faculty of Pharmaceutical Sciences, Suzuka University of Medical Science, Suzuka, Mie, Japan
| | - Ning Ma
- Graduate School of Health Science, Suzuka University of Medical Science, Suzuka, Mie, Japan
- Institute of Traditional Chinese Medicine, Suzuka University of Medical Science, Suzuka, Mie, Japan
| | - Shiho Ohnishi
- Faculty of Pharmaceutical Sciences, Suzuka University of Medical Science, Suzuka, Mie, Japan
| | - Akihiro Morita
- Faculty of Pharmaceutical Sciences, Suzuka University of Medical Science, Suzuka, Mie, Japan
| | - Yifei Xu
- Department of Environmental and Molecular Medicine, Mie University Graduate School of Medicine, Tsu, Mie, Japan
| | | | - Yasuo Chinzei
- Graduate School of Health Science, Suzuka University of Medical Science, Suzuka, Mie, Japan
| | - Mariko Murata
- Department of Environmental and Molecular Medicine, Mie University Graduate School of Medicine, Tsu, Mie, Japan
| | - Shosuke Kawanishi
- Faculty of Pharmaceutical Sciences, Suzuka University of Medical Science, Suzuka, Mie, Japan
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23
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Hwang YK, Lee DH, Lee EC, Oh JS. Importance of Autophagy Regulation in Glioblastoma with Temozolomide Resistance. Cells 2024; 13:1332. [PMID: 39195222 PMCID: PMC11353125 DOI: 10.3390/cells13161332] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2024] [Revised: 08/01/2024] [Accepted: 08/08/2024] [Indexed: 08/29/2024] Open
Abstract
Glioblastoma (GBM) is the most aggressive and common malignant and CNS tumor, accounting for 47.7% of total cases. Glioblastoma has an incidence rate of 3.21 cases per 100,000 people. The regulation of autophagy, a conserved cellular process involved in the degradation and recycling of cellular components, has been found to play an important role in GBM pathogenesis and response to therapy. Autophagy plays a dual role in promoting tumor survival and apoptosis, and here we discuss the complex interplay between autophagy and GBM. We summarize the mechanisms underlying autophagy dysregulation in GBM, including PI3K/AKT/mTOR signaling, which is most active in brain tumors, and EGFR and mutant EGFRvIII. We also review potential therapeutic strategies that target autophagy for the treatment of GBM, such as autophagy inhibitors used in combination with the standard of care, TMZ. We discuss our current understanding of how autophagy is involved in TMZ resistance and its role in glioblastoma development and survival.
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Affiliation(s)
- Young Keun Hwang
- Department of Medical Life Sciences, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea; (Y.K.H.); (E.C.L.)
| | - Dong-Hun Lee
- Industry-Academic Cooperation Foundation, The Catholic University of Korea, 222, Banpo-daro, Seocho-gu, Seoul 06591, Republic of Korea;
| | - Eun Chae Lee
- Department of Medical Life Sciences, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea; (Y.K.H.); (E.C.L.)
| | - Jae Sang Oh
- Department of Neurosurgery, Uijeongbu St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
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24
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Jiménez-Cortegana C, Gutiérrez-García C, Sánchez-Jiménez F, Vilariño-García T, Flores-Campos R, Pérez-Pérez A, Garnacho C, Sánchez-León ML, García-Domínguez DJ, Hontecillas-Prieto L, Palazón-Carrión N, De La Cruz-Merino L, Sánchez-Margalet V. Impact of obesity‑associated myeloid‑derived suppressor cells on cancer risk and progression (Review). Int J Oncol 2024; 65:79. [PMID: 38940351 PMCID: PMC11251741 DOI: 10.3892/ijo.2024.5667] [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: 04/09/2024] [Accepted: 06/12/2024] [Indexed: 06/29/2024] Open
Abstract
Obesity is a chronic disease caused by the accumulation of excessive adipose tissue. This disorder is characterized by chronic low‑grade inflammation, which promotes the release of proinflammatory mediators, including cytokines, chemokines and leptin. Simultaneously, chronic inflammation can predispose to cancer development, progression and metastasis. Proinflammatory molecules are involved in the recruitment of specific cell populations in the tumor microenvironment. These cell populations include myeloid‑derived suppressor cells (MDSCs), a heterogeneous, immature myeloid population with immunosuppressive abilities. Obesity‑associated MDSCs have been linked with tumor dissemination, progression and poor clinical outcomes. A comprehensive literature review was conducted to assess the impact of obesity‑associated MDSCs on cancer in both preclinical models and oncological patients with obesity. A secondary objective was to examine the key role that leptin, the most important proinflammatory mediator released by adipocytes, plays in MDSC‑driven immunosuppression Finally, an overview is provided of the different therapeutic approaches available to target MDSCs in the context of obesity‑related cancer.
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Affiliation(s)
- Carlos Jiménez-Cortegana
- Department of Medical Biochemistry and Molecular Biology, School of Medicine, Virgen Macarena University Hospital, University of Seville, 41009 Seville, Spain
| | - Cristian Gutiérrez-García
- Department of Medical Biochemistry and Molecular Biology, School of Medicine, Virgen Macarena University Hospital, University of Seville, 41009 Seville, Spain
| | - Flora Sánchez-Jiménez
- Department of Medical Biochemistry and Molecular Biology, School of Medicine, Virgen Macarena University Hospital, University of Seville, 41009 Seville, Spain
| | - Teresa Vilariño-García
- Department of Medical Biochemistry and Molecular Biology, School of Medicine, Virgen Macarena University Hospital, University of Seville, 41009 Seville, Spain
| | - Rocio Flores-Campos
- Department of Medical Biochemistry and Molecular Biology, School of Medicine, Virgen Macarena University Hospital, University of Seville, 41009 Seville, Spain
| | - Antonio Pérez-Pérez
- Department of Medical Biochemistry and Molecular Biology, School of Medicine, Virgen Macarena University Hospital, University of Seville, 41009 Seville, Spain
| | - Carmen Garnacho
- Department of Normal and Pathological Histology and Cytology, School of Medicine, University of Seville, 41009 Seville, Spain
| | - Maria L. Sánchez-León
- Oncology Service, Virgen Macarena University Hospital, School of Medicine, University of Seville, 41009 Seville, Spain
| | - Daniel J. García-Domínguez
- Department of Medical Biochemistry and Molecular Biology, School of Medicine, Virgen Macarena University Hospital, University of Seville, 41009 Seville, Spain
| | - Lourdes Hontecillas-Prieto
- Department of Medical Biochemistry and Molecular Biology, School of Medicine, Virgen Macarena University Hospital, University of Seville, 41009 Seville, Spain
| | - Natalia Palazón-Carrión
- Oncology Service, Virgen Macarena University Hospital, School of Medicine, University of Seville, 41009 Seville, Spain
| | - Luis De La Cruz-Merino
- Oncology Service, Virgen Macarena University Hospital, School of Medicine, University of Seville, 41009 Seville, Spain
- Institute of Biomedicine of Seville, Virgen Macarena University Hospital, CSIC, University of Seville, Seville 41013, Spain
| | - Víctor Sánchez-Margalet
- Department of Medical Biochemistry and Molecular Biology, School of Medicine, Virgen Macarena University Hospital, University of Seville, 41009 Seville, Spain
- Institute of Biomedicine of Seville, Virgen Macarena University Hospital, CSIC, University of Seville, Seville 41013, Spain
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25
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Dong W, Liu J, Zhang Y, Huang M, Lin M, Peng X. DNA damages in hepatocytes are amended by an inflammation-driven rescue repair mechanism in chronic hepatitis B. Pathol Res Pract 2024; 260:155391. [PMID: 38850878 DOI: 10.1016/j.prp.2024.155391] [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: 09/11/2023] [Revised: 04/23/2024] [Accepted: 06/05/2024] [Indexed: 06/10/2024]
Abstract
BACKGROUND Our previous study has shown that intrahepatic necroinflammation favors the eliminations of HBV integration and clonal hepatocytes. Here, the effect of inflammation on host DNA damage eliminations in liver biopsy tissues from patients with chronic hepatitis B (CHB) was further investigated. METHODS DNA damage markers, histone γ-H2AX and phosphorylated heterochromatin protein 1γ (p-HP1γ), and senescent marker p21 were detected using immunohistochemical and immunofluorescent assays in liver biopsy samples from 69 CHB patients and 12 liver cirrhosis (LC) patients. Twenty paired hepatocellular carcinoma (HCC) surgical samples were used as controls. RESULTS Both γ-H2AX and p-HP1γ were sensitively detected in nuclear and cytoplasmic/nuclear patterns. Nuclear γ-H2AX was superior as a DNA damage marker in hepatocytes. The level of nuclear γ-H2AX in CHB, comparable to those in LC and HCC, was correlated with liver fibrosis and coexisted with the senescent marker p21. However, hepatocytes carried an alleviated level of DNA damages, which was associated with the level of cytoplasmic γ-H2AX. Cytoplasmic γ-H2AX chiefly occurred in hepatocytes near necroinflammatory foci, was correlated with liver inflammation and usually indicated the decrease or disappearance of nuclear γ-H2AX. The lack of cytoplasmic γ-H2AX together with the high level of nuclear γ-H2AX was associated with the progression from large cell changes/dysplasia to small cell changes/dysplasia. CONCLUSIONS Hepatocytes in CHB already carry massive DNA damages and undergo cellular senescence. The DNA damages in those senescent hepatocytes are histopathologically demonstrated to be amended by a novel cytoplasmic γ-H2AX-indicated and inflammation-driven rescue repair mechanism, which may be involved in hepatocarcinogenesis if it works improperly.
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Affiliation(s)
- Wenxiao Dong
- Department of Infectious Diseases, Jiangmen Central Hospital, Jiangmen, Guangdong 529000, China
| | - Jian Liu
- Department of Infectious Diseases, The Fifth Affiliated Hospital, Sun Yat-Sen University, Zhuhai, Guangdong 519000, China
| | - Yansong Zhang
- Department of Infectious Diseases, The Fifth Affiliated Hospital, Sun Yat-Sen University, Zhuhai, Guangdong 519000, China
| | - Mingxing Huang
- Department of Infectious Diseases, The Third People's Hospital of Zhuhai, Zhuhai, Guangdong 519000, China
| | - Minyi Lin
- Department of Infectious Diseases, The Fifth Affiliated Hospital, Sun Yat-Sen University, Zhuhai, Guangdong 519000, China.
| | - Xiaomou Peng
- Department of Infectious Diseases, The Fifth Affiliated Hospital, Sun Yat-Sen University, Zhuhai, Guangdong 519000, China.
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26
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Luo QH, Chen HJ, Zhong QY, He HE, Huang YQ, Liu YC, Lan B, Wen YQ, Deng SL, Du XH, Lin BQ, Zhan YX. Prevention of supercritical carbon dioxide fluid extract from Chrysanthemum indicum Linnén on cutaneous squamous cell carcinomas progression following UV irradiation in mice. Exp Ther Med 2024; 28:330. [PMID: 38979021 PMCID: PMC11229401 DOI: 10.3892/etm.2024.12619] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2023] [Accepted: 04/26/2024] [Indexed: 07/10/2024] Open
Abstract
Chrysanthemum indicum Linnén (C. indicum), a medicinal and food herb with various bioactive components, may be of beneficial use in cosmetics and the treatment of skin-related diseases. However, to date, few studies have been reported on its potential preventive and therapeutic effects on skin cancer. Therefore, the present study aimed to investigate the effect and potential mechanism of action of supercritical carbon dioxide extract from C. indicum (CISCFE) on UV-induced skin cancer in a mouse model. Kunming mice were allocated randomly to five treatment groups: Sham, model, low concentration CISCFE, high concentration CISCFE and positive control nicotinamide groups. The dorsal skin of mice was irradiated with UV light for 31 weeks. Histopathological changes, ELISA assays, immunohistochemical analysis and western blotting were performed to investigate the potential therapeutic effects of CISCFE. The results showed that CISCFE alleviated skin oxidative and inflammatory damage in a UV-induced mouse model of skin cancer. Moreover, CISCFE suppressed abnormal activation of proto-oncogene c-Myc and the overexpression of Ki-67 and VEGF, and increased expression of the anti-oncogene PTEN, thereby reducing abnormal proliferation of the epidermis and blood vessels. Additionally, CISCFE increased the protein expression levels of NAD-dependent protein deacetylase sirtuin-1 (SIRT1), Kelch-like ECH associated protein 1 (Keap1) and inhibited the expression of nuclear factor 2 erythroid 2-related factor 2 (Nrf2), phosphorylated (p)-p62 (Ser 349), p-p65 and acetyl-p65 proteins in a UV-induced skin cancer mouse model. In summary, CISCFE exhibited potent anti-skin cancer activity, which may be attributed its potential effects on the p62/Keap1-Nrf2 and SIRT1/NF-κB pathways.
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Affiliation(s)
- Qi-Hong Luo
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, P.R. China
| | - Hong-Juan Chen
- Department of Pharmacy, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Qing-Yuan Zhong
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, P.R. China
| | - Hao-En He
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, P.R. China
| | - Ying-Qi Huang
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, P.R. China
| | - You-Chen Liu
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, P.R. China
| | - Bin Lan
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, P.R. China
| | - Yao-Qi Wen
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, P.R. China
| | - Si-Liang Deng
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, P.R. China
| | - Xian-Hua Du
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, P.R. China
| | - Bao-Qin Lin
- Experimental Center, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510405, P.R. China
| | - Ya-Xian Zhan
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, P.R. China
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27
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Rompou AV, Bletsa G, Tsakogiannis D, Theocharis S, Vassiliu P, Danias N. An Updated Review of Resistin and Colorectal Cancer. Cureus 2024; 16:e65403. [PMID: 39184804 PMCID: PMC11344879 DOI: 10.7759/cureus.65403] [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] [Accepted: 07/25/2024] [Indexed: 08/27/2024] Open
Abstract
Resistin is one of the most important adipokines, and its role lies mainly in controlling insulin sensitivity and inflammation. However, over the last years, the study of resistin gained increased popularity since it was proved that there is a considerable relationship between high levels of resistin and obesity as well as obesity-induced diseases, including diabetes, cardiovascular disorders, and cancer. Regarding cancer risk, circulating resistin levels have been correlated with several types of cancer, including colorectal, breast, lung, endometrial, gastroesophageal, prostate, renal, and pancreatic cancer. Colorectal cancer is regarded as a multi-pathway disease. Several pathophysiological features seem to promote colorectal cancer (CRC) such as chronic inflammation, insulin resistance, and obesity. Even though the molecular mechanisms involved in CRC development remain rather vague, it is widely accepted that several biochemical factors promote CRC by releasing augmented pro-inflammatory cytokines, like IGF-I, insulin, sex-steroid hormones, and adipokines. A wide range of research studies has focused on evaluating the impact of circulating resistin levels on CRC risk and determining the efficacy of chemotherapy in CRC patients by measuring resistin levels. Moreover, significant outcomes have emerged regarding the association of specific single nucleotide polymorphisms (SNPs) in the resistin gene and CRC risk. The present study reviewed the role of circulating resistin levels in CRC development and shed light on specific resistin gene SNPs implicated in the disease's development. Finally, we analyzed the impact of resistin levels on the effectiveness of chemotherapy and further discussed whether resistin can be regarded as a valuable biomarker for CRC prognosis and treatment. Resistin is one of the most important adipokines, and its role lies mainly in controlling insulin sensitivity and inflammation. However, over the last years, the study of resistin gained increased popularity since it was proved that there is a considerable relationship between high levels of resistin and obesity as well as obesity-induced diseases, including diabetes, cardiovascular disorders, and cancer. This review discusses the aberrant expression of resistin and its receptors, its diverse downstream signaling, and its impact on tumor growth, metastasis, angiogenesis, and therapy resistance to support its clinical exploitation in biomarker and therapeutic development.
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Affiliation(s)
- Aliki Vaia Rompou
- Department of Colorectal Surgery, Guy's and St Thomas' NHS Foundation Trust, London, GBR
| | - Garyfalia Bletsa
- Department of Medicine, Research Center, Hellenic Anticancer Institute, Athens, GRC
| | | | - Stamatios Theocharis
- Department of Pathology, National and Kapodistrian University of Athens, Athens, GRC
| | - Panteleimon Vassiliu
- Fourth Department of Surgery, Attikon University Hospital, National and Kapodistrian University of Athens, Athens, GRC
| | - Nick Danias
- Fourth Department of Surgery, Attikon University Hospital, National and Kapodistrian University of Athens, Athens, GRC
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28
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Jafarzadeh A, Jafarzadeh Z, Nemati M, Yoshimura A. The Interplay Between Helicobacter pylori and Suppressors of Cytokine Signaling (SOCS) Molecules in the Development of Gastric Cancer and Induction of Immune Response. Helicobacter 2024; 29:e13105. [PMID: 38924222 DOI: 10.1111/hel.13105] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2024] [Revised: 06/04/2024] [Accepted: 06/06/2024] [Indexed: 06/28/2024]
Abstract
Helicobacter pylori (H. pylori) colonizes the stomach and leads to the secretion of a vast range of cytokines by infiltrated leukocytes directing immune/inflammatory response against the bacterium. To regulate immune/inflammatory responses, suppressors of cytokine signaling (SOCS) proteins bind to multiple signaling components located downstream of cytokine receptors, such as Janus kinase (JAK), signal transducers and activators of transcription (STAT). Dysfunctional SOCS proteins in immune cells may facilitate the immune evasion of H. pylori, allowing the bacteria to induce chronic inflammation. Dysregulation of SOCS expression and function can contribute to the sustained H. pylori-mediated gastric inflammation which can lead to gastric cancer (GC) development. Among SOCS molecules, dysregulated expression of SOCS1, SOCS2, SOCS3, and SOCS6 were indicated in H. pylori-infected individuals as well as in GC tissues and cells. H. pylori-induced SOCS1, SOCS2, SOCS3, and SOCS6 dysregulation can contribute to the GC development. The expression of SOCS molecules can be influenced by various factors, such as epigenetic DNA methylation, noncoding RNAs, and gene polymorphisms. Modulation of the expression of SOCS molecules in gastric epithelial cells and immune cells can be considered to control gastric carcinogenesis as well as regulate antitumor immune responses, respectively. This review aimed to explain the interplay between H. pylori and SOCS molecules in GC development and immune response induction as well as to provide insights regarding potential therapeutic strategies modulating SOCS molecules.
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Affiliation(s)
- Abdollah Jafarzadeh
- Department of Immunology, School of Medicine, Kerman University of Medical Sciences, Kerman, Iran
- Applied Cellular and Molecular Research Center, Kerman University of Medical Sciences, Kerman, Iran
| | - Zahra Jafarzadeh
- Student Research Committee, Faculty of Pharmacy, Kerman University of Medical Sciences, Kerman, Iran
| | - Maryam Nemati
- Department of Hematology and Laboratory Sciences, School of Para-Medicine, Kerman University of Medical Sciences, Kerman, Iran
- Immunology of Infectious Diseases Research Center, Research Institute of Basic Medical Sciences, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Akihiko Yoshimura
- Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo, Japan
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29
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Tong QY, Pang MJ, Hu XH, Huang XZ, Sun JX, Wang XY, Burclaff J, Mills JC, Wang ZN, Miao ZF. Gastric intestinal metaplasia: progress and remaining challenges. J Gastroenterol 2024; 59:285-301. [PMID: 38242996 DOI: 10.1007/s00535-023-02073-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2023] [Accepted: 12/26/2023] [Indexed: 01/21/2024]
Abstract
Most gastric cancers arise in the setting of chronic inflammation which alters gland organization, such that acid-pumping parietal cells are lost, and remaining cells undergo metaplastic change in differentiation patterns. From a basic science perspective, recent progress has been made in understanding how atrophy and initial pyloric metaplasia occur. However, pathologists and cancer biologists have long been focused on the development of intestinal metaplasia patterns in this setting. Arguably, much less progress has been made in understanding the mechanisms that lead to the intestinalization seen in chronic atrophic gastritis and pyloric metaplasia. One plausible explanation for this disparity lies in the notable absence of reliable and reproducible small animal models within the field, which would facilitate the investigation of the mechanisms underlying the development of gastric intestinal metaplasia (GIM). This review offers an in-depth exploration of the current state of research in GIM, shedding light on its pivotal role in tumorigenesis. We delve into the histological subtypes of GIM and explore their respective associations with tumor formation. We present the current repertoire of biomarkers utilized to delineate the origins and progression of GIM and provide a comprehensive survey of the available, albeit limited, mouse lines employed for modeling GIM and engage in a discussion regarding potential cell lineages that serve as the origins of GIM. Finally, we expound upon the myriad signaling pathways recognized for their activity in GIM and posit on their potential overlap and interactions that contribute to the ultimate manifestation of the disease phenotype. Through our exhaustive review of the progression from gastric disease to GIM, we aim to establish the groundwork for future research endeavors dedicated to elucidating the etiology of GIM and developing strategies for its prevention and treatment, considering its potential precancerous nature.
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Affiliation(s)
- Qi-Yue Tong
- Department of Surgical Oncology and General Surgery, The First Affiliated Hospital of China Medical University, 155 N. Nanjing Street, Shenyang, 110001, Liaoning, China
- Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, 155 N. Nanjing Street, Shenyang, 110001, Liaoning, China
| | - Min-Jiao Pang
- Department of Surgical Oncology and General Surgery, The First Affiliated Hospital of China Medical University, 155 N. Nanjing Street, Shenyang, 110001, Liaoning, China
- Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, 155 N. Nanjing Street, Shenyang, 110001, Liaoning, China
| | - Xiao-Hai Hu
- Department of Surgical Oncology and General Surgery, The First Affiliated Hospital of China Medical University, 155 N. Nanjing Street, Shenyang, 110001, Liaoning, China
- Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, 155 N. Nanjing Street, Shenyang, 110001, Liaoning, China
| | - Xuan-Zhang Huang
- Department of Surgical Oncology and General Surgery, The First Affiliated Hospital of China Medical University, 155 N. Nanjing Street, Shenyang, 110001, Liaoning, China
- Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, 155 N. Nanjing Street, Shenyang, 110001, Liaoning, China
| | - Jing-Xu Sun
- Department of Surgical Oncology and General Surgery, The First Affiliated Hospital of China Medical University, 155 N. Nanjing Street, Shenyang, 110001, Liaoning, China
- Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, 155 N. Nanjing Street, Shenyang, 110001, Liaoning, China
| | - Xin-Yu Wang
- Department of Surgical Oncology and General Surgery, The First Affiliated Hospital of China Medical University, 155 N. Nanjing Street, Shenyang, 110001, Liaoning, China
- Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, 155 N. Nanjing Street, Shenyang, 110001, Liaoning, China
| | - Joseph Burclaff
- Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Chapel Hill, North Carolina, USA
- Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill and North Carolina State University, Chapel Hill, North Carolina, USA
| | - Jason C Mills
- Section of Gastroenterology and Hepatology, Department of Medicine, Departments of Pathology and Immunology, Molecular and Cellular Biology, Baylor College of Medicine, Houston, USA
| | - Zhen-Ning Wang
- Department of Surgical Oncology and General Surgery, The First Affiliated Hospital of China Medical University, 155 N. Nanjing Street, Shenyang, 110001, Liaoning, China.
- Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, 155 N. Nanjing Street, Shenyang, 110001, Liaoning, China.
| | - Zhi-Feng Miao
- Department of Surgical Oncology and General Surgery, The First Affiliated Hospital of China Medical University, 155 N. Nanjing Street, Shenyang, 110001, Liaoning, China.
- Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, 155 N. Nanjing Street, Shenyang, 110001, Liaoning, China.
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Wang M, Chen S, He X, Yuan Y, Wei X. Targeting inflammation as cancer therapy. J Hematol Oncol 2024; 17:13. [PMID: 38520006 PMCID: PMC10960486 DOI: 10.1186/s13045-024-01528-7] [Citation(s) in RCA: 29] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2023] [Accepted: 02/07/2024] [Indexed: 03/25/2024] Open
Abstract
Inflammation has accompanied human beings since the emergence of wounds and infections. In the past decades, numerous efforts have been undertaken to explore the potential role of inflammation in cancer, from tumor development, invasion, and metastasis to the resistance of tumors to treatment. Inflammation-targeted agents not only demonstrate the potential to suppress cancer development, but also to improve the efficacy of other therapeutic modalities. In this review, we describe the highly dynamic and complex inflammatory tumor microenvironment, with discussion on key inflammation mediators in cancer including inflammatory cells, inflammatory cytokines, and their downstream intracellular pathways. In addition, we especially address the role of inflammation in cancer development and highlight the action mechanisms of inflammation-targeted therapies in antitumor response. Finally, we summarize the results from both preclinical and clinical studies up to date to illustrate the translation potential of inflammation-targeted therapies.
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Affiliation(s)
- Manni Wang
- Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No.17, Block3, Southern Renmin Road, Chengdu, 610041, Sichuan, People's Republic of China
| | - Siyuan Chen
- Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No.17, Block3, Southern Renmin Road, Chengdu, 610041, Sichuan, People's Republic of China
| | - Xuemei He
- Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No.17, Block3, Southern Renmin Road, Chengdu, 610041, Sichuan, People's Republic of China
| | - Yong Yuan
- Department of Thoracic Surgery, West China Hospital, Sichuan University, Chengdu, People's Republic of China.
| | - Xiawei Wei
- Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No.17, Block3, Southern Renmin Road, Chengdu, 610041, Sichuan, People's Republic of China.
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31
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Crawford B, Steck SE, Sandler DP, Nichols HB, Milne GL, Park YMM. Association between healthy dietary patterns and markers of oxidative stress in the Sister Study. Eur J Nutr 2024; 63:485-499. [PMID: 38070016 DOI: 10.1007/s00394-023-03280-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: 05/15/2023] [Accepted: 11/08/2023] [Indexed: 02/28/2024]
Abstract
PURPOSE We assessed the cross-sectional association between healthy dietary patterns [alternate Mediterranean diet (aMED), Dietary Approaches to Stop Hypertension (DASH), alternative Healthy Eating Index (aHEI), and Healthy Eating Index 2015 (HEI-2015)] and urinary biomarkers of oxidative stress. METHODS Between 2003 and 2009, the Sister Study enrolled 50,884 breast cancer-free US women aged 35 to 74 (non-Hispanic White, 83.7%). Data were analyzed for 844 premenopausal and 454 postmenopausal women who had urine samples analyzed for F2-isoprostanes and non-missing covariate data. Food frequency questionnaire responses were used to calculate dietary pattern scores. Concentrations of 8-iso-prostaglandin F2α (8-iso-PGF2α) and its metabolite (8-iso-PGF2α-M) were measured in urine samples by GC/MS for premenopausal women and LC/MS for postmenopausal women. Multivariable linear regression models were used to estimate associations between aMED, DASH, aHEI, and HEI-2015 and urinary F2-isoprostanes by menopausal status. Effect modification by sociodemographic, lifestyle, and clinical characteristics was also evaluated. RESULTS Among premenopausal women, the four dietary indices were inversely associated with 8-iso-PGF2α (aMED βQ4vsQ1: - 0.17, 95% CI - 0.27, - 0.08; DASH βQ4vsQ1: - 0.18, 95% CI - 0.28, - 0.08; aHEI βQ4vsQ1: - 0.20, 95% CI - 0.30, - 0.10; HEI-2015 βQ4vsQ1: - 0.19, 95% CI - 0.29, - 0.10). In contrast, inverse associations with 8-iso-PGF2α-M were found for the continuous aMED, aHEI, and HEI-2015. Associations between dietary indices and 8-iso-PGF2α were generally stronger among younger women, women with lower income, and women with higher BMI. Similar results were observed among postmenopausal women, though only the continuous DASH and aHEI models were statistically significant. CONCLUSION Healthy dietary patterns were associated with lower levels of oxidative stress.
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Affiliation(s)
- Brittany Crawford
- Department of Epidemiology and Biostatistics, Arnold School of Public Health, University of South Carolina, 915 Greene St. #456, Columbia, SC, 29208, USA
| | - Susan E Steck
- Department of Epidemiology and Biostatistics, Arnold School of Public Health, University of South Carolina, 915 Greene St. #456, Columbia, SC, 29208, USA.
| | - Dale P Sandler
- Epidemiology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA
| | - Hazel B Nichols
- Department of Epidemiology, University of North Carolina, Chapel Hill, NC, USA
| | - Ginger L Milne
- Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Yong-Moon Mark Park
- Epidemiology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA.
- Department of Epidemiology, Fay W. Boozman College of Public Health, University of Arkansas for Medical Sciences, 4301 W. Markham St., #820, Little Rock, AR, 72205, USA.
- Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
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32
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Ma JY, Xia TJ, Li S, Yin S, Luo SM, Li G. Germline cell de novo mutations and potential effects of inflammation on germline cell genome stability. Semin Cell Dev Biol 2024; 154:316-327. [PMID: 36376195 DOI: 10.1016/j.semcdb.2022.11.003] [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: 07/14/2022] [Revised: 11/05/2022] [Accepted: 11/06/2022] [Indexed: 11/13/2022]
Abstract
Uncontrolled pathogenic genome mutations in germline cells might impair adult fertility, lead to birth defects or even affect the adaptability of a species. Understanding the sources of DNA damage, as well as the features of damage response in germline cells are the overarching tasks to reduce the mutations in germline cells. With the accumulation of human genome data and genetic reports, genome variants formed in germline cells are being extensively explored. However, the sources of DNA damage, the damage repair mechanisms, and the effects of DNA damage or mutations on the development of germline cells are still unclear. Besides exogenous triggers of DNA damage such as irradiation and genotoxic chemicals, endogenous exposure to inflammation may also contribute to the genome instability of germline cells. In this review, we summarized the features of de novo mutations and the specific DNA damage responses in germline cells and explored the possible roles of inflammation on the genome stability of germline cells.
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Affiliation(s)
- Jun-Yu Ma
- Fertility Preservation Lab, Guangdong-Hong Kong Metabolism & Reproduction Joint Laboratory, Reproductive Medicine Center, Guangdong Second Provincial General Hospital, Guangzhou, China.
| | - Tian-Jin Xia
- Fertility Preservation Lab, Guangdong-Hong Kong Metabolism & Reproduction Joint Laboratory, Reproductive Medicine Center, Guangdong Second Provincial General Hospital, Guangzhou, China; College of Life Sciences, Qingdao Agricultural University, Qingdao, China
| | - Shuai Li
- Center for Clinical Epidemiology and Methodology, Guangdong Second Provincial General Hospital, Guangzhou, China
| | - Shen Yin
- College of Life Sciences, Qingdao Agricultural University, Qingdao, China.
| | - Shi-Ming Luo
- Fertility Preservation Lab, Guangdong-Hong Kong Metabolism & Reproduction Joint Laboratory, Reproductive Medicine Center, Guangdong Second Provincial General Hospital, Guangzhou, China.
| | - Guowei Li
- Center for Clinical Epidemiology and Methodology, Guangdong Second Provincial General Hospital, Guangzhou, China.
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33
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Jing X, Jia S, Teng M, Day BW, Afolayan AJ, Jarzembowski JA, Lin CW, Hessner MJ, Pritchard KA, Naylor S, Konduri GG, Teng RJ. Cellular Senescence Contributes to the Progression of Hyperoxic Bronchopulmonary Dysplasia. Am J Respir Cell Mol Biol 2024; 70:94-109. [PMID: 37874230 PMCID: PMC12042139 DOI: 10.1165/rcmb.2023-0038oc] [Citation(s) in RCA: 10] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Accepted: 10/23/2023] [Indexed: 10/25/2023] Open
Abstract
Oxidative stress, inflammation, and endoplasmic reticulum (ER) stress sequentially occur in bronchopulmonary dysplasia (BPD), and all result in DNA damage. When DNA damage becomes irreparable, tumor suppressors increase, followed by apoptosis or senescence. Although cellular senescence contributes to wound healing, its persistence inhibits growth. Therefore, we hypothesized that cellular senescence contributes to BPD progression. Human autopsy lungs were obtained. Sprague-Dawley rat pups exposed to 95% oxygen between Postnatal Day 1 (P1) and P10 were used as the BPD phenotype. N-acetyl-lysyltyrosylcysteine-amide (KYC), tauroursodeoxycholic acid (TUDCA), and Foxo4 dri were administered intraperitoneally to mitigate myeloperoxidase oxidant generation, ER stress, and cellular senescence, respectively. Lungs were examined by histology, transcriptomics, and immunoblotting. Cellular senescence increased in rat and human BPD lungs, as evidenced by increased oxidative DNA damage, tumor suppressors, GL-13 stain, and inflammatory cytokines with decreased cell proliferation and lamin B expression. Cellular senescence-related transcripts in BPD rat lungs were enriched at P10 and P21. Single-cell RNA sequencing showed increased cellular senescence in several cell types, including type 2 alveolar cells. In addition, Foxo4-p53 binding increased in BPD rat lungs. Daily TUDCA or KYC, administered intraperitoneally, effectively decreased cellular senescence, improved alveolar complexity, and partially maintained the numbers of type 2 alveolar cells. Foxo4 dri administered at P4, P6, P8, and P10 led to outcomes similar to TUDCA and KYC. Our data suggest that cellular senescence plays an essential role in BPD after initial inducement by hyperoxia. Reducing myeloperoxidase toxic oxidant production, ER stress, and attenuating cellular senescence are potential therapeutic strategies for halting BPD progression.
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Affiliation(s)
- Xigang Jing
- Department of Pediatrics
- Children's Research Institute
| | - Shuang Jia
- Department of Pediatrics
- Children's Research Institute
| | - Maggie Teng
- Department of Anthropology, Washington University in St. Louis, St. Louis, Missouri; and
| | | | | | | | - Chien-Wei Lin
- Division of Biostatistics, Institute for Health and Equity, and
| | | | - Kirkwood A Pritchard
- Children's Research Institute
- Department of Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin
- ReNeuroGen LLC, Milwaukee, Wisconsin
| | | | | | - Ru-Jeng Teng
- Department of Pediatrics
- Children's Research Institute
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Vivarelli F, Morosini C, Rullo L, Losapio LM, Lacorte A, Sangiorgi S, Ghini S, Fagiolino I, Franchi P, Lucarini M, Candeletti S, Canistro D, Romualdi P, Paolini M. Effects of unburned tobacco smoke on inflammatory and oxidative mediators in the rat prefrontal cortex. Front Pharmacol 2024; 15:1328917. [PMID: 38333013 PMCID: PMC10851081 DOI: 10.3389/fphar.2024.1328917] [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: 10/27/2023] [Accepted: 01/04/2024] [Indexed: 02/10/2024] Open
Abstract
Although the Food and Drug Administration has authorized the marketing of "heat-not-burn" (HnB) electronic cigarettes as a modified risk tobacco product (MRTP), toxicological effects of HnB smoke exposure on the brain are still unexplored. Here, paramagnetic resonance of the prefrontal cortex (PFC) of HnB-exposed rats shows a dramatic increase in reactive radical species (RRS) yield coupled with an inflammatory response mediated by NF-κB-target genes including TNF-α, IL-1β, and IL-6 and the downregulation of peroxisome proliferator-activated receptor (PPAR) alpha and gamma expression. The PFC shows higher levels of 8-hydroxyguanosine, a marker of DNA oxidative damage, along with the activation of antioxidant machinery and DNA repair systems, including xeroderma pigmentosum group C (XPC) protein complex and 8-oxoguanine DNA glycosylase 1. HnB also induces the expression of drug-metabolizing enzymes such as CYP1A1, CYP2A6, CYP2B6, and CYP2E, particularly involved in the biotransformation of nicotine and several carcinogenic agents such as aldehydes and polycyclic aromatic hydrocarbons here recorded in the HnB stick smoke. Taken together, these effects, from disruption of redox homeostasis, inflammation, PPAR manipulation along with enhanced bioactivation of neurotoxicants, and upregulation of cMYC protooncogene to impairment of primary cellular defense mechanisms, suggest a possible increased risk of brain cancer. Although the HnB device reduces the emission of tobacco toxicants, our findings indicate that its consumption may carry a risk of potential adverse health effects, especially in non-smokers so far. Further studies are needed to fully understand the long-term effects of these devices.
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Affiliation(s)
- Fabio Vivarelli
- Department of Pharmacy and Biotechnology, Alma Mater Studiorum–University of Bologna, Bologna, Italy
| | - Camilla Morosini
- Department of Pharmacy and Biotechnology, Alma Mater Studiorum–University of Bologna, Bologna, Italy
| | - Laura Rullo
- Department of Pharmacy and Biotechnology, Alma Mater Studiorum–University of Bologna, Bologna, Italy
| | - Loredana Maria Losapio
- Department of Pharmacy and Biotechnology, Alma Mater Studiorum–University of Bologna, Bologna, Italy
| | - Antonio Lacorte
- Department of Pharmacy and Biotechnology, Alma Mater Studiorum–University of Bologna, Bologna, Italy
| | - Stefano Sangiorgi
- Department of Pharmacy and Biotechnology, Alma Mater Studiorum–University of Bologna, Bologna, Italy
| | - Severino Ghini
- Department of Pharmacy and Biotechnology, Alma Mater Studiorum–University of Bologna, Bologna, Italy
| | | | - Paola Franchi
- Department of Chemistry “G. Ciamician”, Alma Mater Studiorum–University of Bologna, Bologna, Italy
| | - Marco Lucarini
- Department of Chemistry “G. Ciamician”, Alma Mater Studiorum–University of Bologna, Bologna, Italy
| | - Sanzio Candeletti
- Department of Pharmacy and Biotechnology, Alma Mater Studiorum–University of Bologna, Bologna, Italy
| | - Donatella Canistro
- Department of Pharmacy and Biotechnology, Alma Mater Studiorum–University of Bologna, Bologna, Italy
| | - Patrizia Romualdi
- Department of Pharmacy and Biotechnology, Alma Mater Studiorum–University of Bologna, Bologna, Italy
| | - Moreno Paolini
- Department of Pharmacy and Biotechnology, Alma Mater Studiorum–University of Bologna, Bologna, Italy
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Jumes J, Jaques H, Dalla Vecchia M, Ferreira M, Orrutéa J, Machado M, Mezoni M, da Silva R, Almeida R, Rech D, Kawassaki A, Panis C. Occupational exposure to pesticides deregulates systemic cortisol levels in women with breast cancer and correlates with poor prognosis features. Braz J Med Biol Res 2024; 57:e13060. [PMID: 38265341 PMCID: PMC10802260 DOI: 10.1590/1414-431x2023e13060] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Accepted: 12/15/2023] [Indexed: 01/25/2024] Open
Abstract
Pesticides have been pointed out as hormone disruptors and may significantly affect the prognosis of hormone-dependent diseases such as breast cancer (BC). Here, we investigated the impact of occupational pesticide exposure on systemic cortisol levels in female rural workers diagnosed with BC. Occupational exposure was assessed by interviews with a standardized questionnaire. Plasma samples (112 from pesticide-exposed women and 77 from unexposed women) were collected in the afternoon, outside the physiological cortisol peak, and analyzed by a chemiluminescent paramagnetic immunoassay for the quantitative determination of cortisol levels in serum and plasma. The results from both groups were categorized according to patients' clinicopathological and exposure data. BC pesticide-exposed women presented higher levels of cortisol than the unexposed. Higher cortisol levels were also detected in the exposed group with more aggressive disease (triple-negative BC), with tumors over 2 cm, with lymph node metastases, and with high risk of disease recurrence and death. These findings demonstrated that there is an association between pesticide exposure and BC that affected cortisol levels and correlated to poor disease prognosis.
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Affiliation(s)
- J.J. Jumes
- Laboratório de Biologia Tumoral, Universidade Estadual do Oeste do Paraná, Francisco Beltrão, PR, Brasil
- Programa de Ciências da Saúde Aplicadas, Universidade Estadual do Oeste do Paraná, Francisco Beltrão, PR, Brasil
| | - H.S. Jaques
- Laboratório de Biologia Tumoral, Universidade Estadual do Oeste do Paraná, Francisco Beltrão, PR, Brasil
| | - M.F. Dalla Vecchia
- Laboratório de Biologia Tumoral, Universidade Estadual do Oeste do Paraná, Francisco Beltrão, PR, Brasil
| | - M.O. Ferreira
- Laboratório de Biologia Tumoral, Universidade Estadual do Oeste do Paraná, Francisco Beltrão, PR, Brasil
- Programa de Ciências da Saúde Aplicadas, Universidade Estadual do Oeste do Paraná, Francisco Beltrão, PR, Brasil
| | - J.F.G. Orrutéa
- Laboratório de Biologia Tumoral, Universidade Estadual do Oeste do Paraná, Francisco Beltrão, PR, Brasil
| | - M.G. Machado
- Laboratório de Biologia Tumoral, Universidade Estadual do Oeste do Paraná, Francisco Beltrão, PR, Brasil
| | - M.F. Mezoni
- Laboratório de Biologia Tumoral, Universidade Estadual do Oeste do Paraná, Francisco Beltrão, PR, Brasil
- Programa de Ciências da Saúde Aplicadas, Universidade Estadual do Oeste do Paraná, Francisco Beltrão, PR, Brasil
| | - R.G.S. da Silva
- Laboratório de Biologia Tumoral, Universidade Estadual do Oeste do Paraná, Francisco Beltrão, PR, Brasil
- Programa de Ciências da Saúde Aplicadas, Universidade Estadual do Oeste do Paraná, Francisco Beltrão, PR, Brasil
| | - R.F. Almeida
- Laboratório de Biologia Tumoral, Universidade Estadual do Oeste do Paraná, Francisco Beltrão, PR, Brasil
| | - D. Rech
- Laboratório de Biologia Tumoral, Universidade Estadual do Oeste do Paraná, Francisco Beltrão, PR, Brasil
- Programa de Ciências da Saúde Aplicadas, Universidade Estadual do Oeste do Paraná, Francisco Beltrão, PR, Brasil
- Hospital de Câncer de Francisco Beltrão, CEONC, Francisco Beltrão, PR, Brasil
| | - A.C.B. Kawassaki
- Laboratório de Biologia Tumoral, Universidade Estadual do Oeste do Paraná, Francisco Beltrão, PR, Brasil
- Programa de Ciências da Saúde Aplicadas, Universidade Estadual do Oeste do Paraná, Francisco Beltrão, PR, Brasil
| | - C. Panis
- Laboratório de Biologia Tumoral, Universidade Estadual do Oeste do Paraná, Francisco Beltrão, PR, Brasil
- Programa de Ciências da Saúde Aplicadas, Universidade Estadual do Oeste do Paraná, Francisco Beltrão, PR, Brasil
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Liu W, Li Z, Li X, Cao H, Jiang H, Niu Q, Hu B. Influence of tumor mycobiome on cancer pathogenesis (Review). Oncol Lett 2023; 26:541. [PMID: 38020300 PMCID: PMC10660446 DOI: 10.3892/ol.2023.14128] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Accepted: 10/18/2023] [Indexed: 12/01/2023] Open
Abstract
Cancer tissues harbor a large microbiome. There is growing evidence that the tumor microbiome is significantly correlated with the prognosis of cancer patients, but the exact underlying mechanisms have remained elusive. Although the tumor mycobiome is less abundant than the biome of bacteria, it is prevalent in most cancers in humans. The present review describes in detail the impact of the tumor mycobiome on cancer pathogenesis. The tumor mycobiome promotes tumor progression and metastasis by affecting the human immune system, maintaining a pro-inflammatory environment, producing aflatoxins, attenuating cell adhesion mechanisms and fungal-bacterial interactions. Furthermore, the tumor mycobiome likewise has great potential for cancer prevention, diagnosis and treatment.
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Affiliation(s)
- Weipeng Liu
- Department of Gastrointestinal Surgery, Binzhou Medical University Hospital, Binzhou, Shandong 256603, P.R. China
| | - Zongrui Li
- Department of Gastrointestinal Surgery, Binzhou Medical University Hospital, Binzhou, Shandong 256603, P.R. China
| | - Xiaopeng Li
- Department of Gastrointestinal Surgery, Binzhou Medical University Hospital, Binzhou, Shandong 256603, P.R. China
| | - Haiyang Cao
- Department of Gastrointestinal Surgery, Binzhou Medical University Hospital, Binzhou, Shandong 256603, P.R. China
| | - He Jiang
- Breast Treatment Center, The Second Affiliated Hospital of Shandong First Medical University, Taian, Shandong 271000, P.R. China
| | - Qingbin Niu
- Department of Gastrointestinal Surgery, Dongying People's Hospital, Dongying, Shandong 257091, P.R. China
| | - Baoguang Hu
- Department of Gastrointestinal Surgery, Binzhou Medical University Hospital, Binzhou, Shandong 256603, P.R. China
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Wu S, Chen Y, Chen Z, Wei F, Zhou Q, Li P, Gu Q. Reactive oxygen species and gastric carcinogenesis: The complex interaction between Helicobacter pylori and host. Helicobacter 2023; 28:e13024. [PMID: 37798959 DOI: 10.1111/hel.13024] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Revised: 09/10/2023] [Accepted: 09/21/2023] [Indexed: 10/07/2023]
Abstract
Helicobacter pylori (H. pylori) is a highly successful human pathogen that colonizes stomach in around 50% of the global population. The colonization of bacterium induces an inflammatory response and a substantial rise in the production of reactive oxygen species (ROS) and reactive nitrogen species (RNS), mostly derived from host neutrophils and gastric epithelial cells, which play a crucial role in combating bacterial infections. However, H. pylori has developed various strategies to quench the deleterious effects of ROS, including the production of antioxidant enzymes, antioxidant proteins as well as blocking the generation of oxidants. The host's inability to eliminate H. pylori infection results in persistent ROS production. Notably, excessive ROS can disrupt the intracellular signal transduction and biological processes of the host, incurring chronic inflammation and cellular damage, such as DNA damage, lipid peroxidation, and protein oxidation. Markedly, the sustained inflammatory response and oxidative stress during H. pylori infection are major risk factor for gastric carcinogenesis. In this context, we summarize the literature on H. pylori infection-induced ROS production, the strategies used by H. pylori to counteract the host response, and subsequent host damage and gastric carcinogenesis.
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Affiliation(s)
- Shiying Wu
- Key Laboratory for Food Microbial Technology of Zhejiang Province, College of Food Science and Biotechnology, Zhejiang Gongshang University, Hangzhou, China
| | - Yongqiang Chen
- Key Laboratory for Food Microbial Technology of Zhejiang Province, College of Food Science and Biotechnology, Zhejiang Gongshang University, Hangzhou, China
| | - Ziqi Chen
- Key Laboratory for Food Microbial Technology of Zhejiang Province, College of Food Science and Biotechnology, Zhejiang Gongshang University, Hangzhou, China
| | - Fangtong Wei
- Key Laboratory for Food Microbial Technology of Zhejiang Province, College of Food Science and Biotechnology, Zhejiang Gongshang University, Hangzhou, China
| | - Qingqing Zhou
- Key Laboratory for Food Microbial Technology of Zhejiang Province, College of Food Science and Biotechnology, Zhejiang Gongshang University, Hangzhou, China
| | - Ping Li
- Key Laboratory for Food Microbial Technology of Zhejiang Province, College of Food Science and Biotechnology, Zhejiang Gongshang University, Hangzhou, China
| | - Qing Gu
- Key Laboratory for Food Microbial Technology of Zhejiang Province, College of Food Science and Biotechnology, Zhejiang Gongshang University, Hangzhou, China
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Li C, Bi R, Wang L, Ma YH, Yao YG, Zheng P. Characterization of long-term ex vivo expansion of tree shrew spermatogonial stem cells. Zool Res 2023; 44:1080-1094. [PMID: 37914523 PMCID: PMC10802108 DOI: 10.24272/j.issn.2095-8137.2023.317] [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: 09/30/2023] [Accepted: 10/30/2023] [Indexed: 11/03/2023] Open
Abstract
Tree shrews ( Tupaia belangeri chinensis) share a close relationship to primates and have been widely used in biomedical research. We previously established a spermatogonial stem cell (SSC)-based gene editing platform to generate transgenic tree shrews. However, the influences of long-term expansion on tree shrew SSC spermatogenesis potential remain unclear. Here, we examined the in vivo spermatogenesis potential of tree shrew SSCs cultured across different passages. We found that SSCs lost spermatogenesis ability after long-term expansion (>50 passages), as indicated by the failure to colonize the seminiferous epithelium and generate donor spermatogonia (SPG)-derived spermatocytes or spermatids marking spermatogenesis. RNA sequencing (RNA-seq) analysis of undifferentiated SPGs across different passages revealed significant gene expression changes after sub-culturing primary SPG lines for more than 40 passages on feeder layers. Specifically, DNA damage response and repair genes (e.g., MRE11, SMC3, BLM, and GEN1) were down-regulated, whereas genes associated with mitochondrial function (e.g., NDUFA9, NDUFA8, NDUFA13, and NDUFB8) were up-regulated after expansion. The DNA damage accumulation and mitochondrial dysfunction were experimentally validated in high-passage cells. Supplementation with nicotinamide adenine dinucleotide (NAD +) precursor nicotinamide riboside (NR) exhibited beneficial effects by reducing DNA damage accumulation and mitochondrial dysfunction in SPG elicited by long-term culture. Our research presents a comprehensive analysis of the genetic and physiological attributes critical for the sustained expansion of undifferentiated SSCs in tree shrews and proposes an effective strategy for extended in vitro maintenance.
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Affiliation(s)
- Cong Li
- State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650201, China
- Key Laboratory of Animal Models and Human Disease Mechanisms of Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650201, China
- Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan 650204, China
| | - Rui Bi
- Key Laboratory of Animal Models and Human Disease Mechanisms of Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650201, China
- Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan 650204, China
| | - Lin Wang
- State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650201, China
- Key Laboratory of Animal Models and Human Disease Mechanisms of Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650201, China
| | - Yu-Hua Ma
- National Resource Center for Non-Human Primates, National Research Facility for Phenotypic & Genetic Analysis of Model Animals (Primate Facility), Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650107, China
| | - Yong-Gang Yao
- Key Laboratory of Animal Models and Human Disease Mechanisms of Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650201, China
- Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan 650204, China
- National Resource Center for Non-Human Primates, National Research Facility for Phenotypic & Genetic Analysis of Model Animals (Primate Facility), Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650107, China
- KIZ/CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650204, China. E-mail:
| | - Ping Zheng
- State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650201, China
- Key Laboratory of Animal Models and Human Disease Mechanisms of Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650201, China
- Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan 650204, China
- National Resource Center for Non-Human Primates, National Research Facility for Phenotypic & Genetic Analysis of Model Animals (Primate Facility), Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650107, China
- KIZ/CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650204, China. E-mail:
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Li Q. Bacterial infection and microbiota in carcinogenesis and tumor development. Front Cell Infect Microbiol 2023; 13:1294082. [PMID: 38035341 PMCID: PMC10684967 DOI: 10.3389/fcimb.2023.1294082] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2023] [Accepted: 10/31/2023] [Indexed: 12/02/2023] Open
Abstract
Microbiota colonize exposed body tissues (e.g., gastrointestinal tract, skin, lungs, female genital tract, and urogenital tracts) and unexposed sites (e.g., breast). Persistent bacterial infection in the host lead to the development of multiple disease. They are implicated in the pathogenesis of various complex diseases, including diabetes, atherosclerosis, autoimmune diseases, Alzheimer's disease, and malignant diseases. Amounting studies have demonstrated the role of bacterial infection in carcinogenesis. The study of microbiota in tumorigenesis is primarily focused on lung cancer, colorectal cancer (CRC), breast cancer, gastric cancer, and gynecologic tumors, and so on. Infection of Helicobacter pylori in gastric cancer carcinogenesis is recognized as class I carcinogen by the World Health Organization (WHO) decades ago. The role of Fusobacterium nucleatum in the development of colorectal cancer is extensively investigated. Variable bacteria have been cultured from the tumor tissues. The identification of microbiota in multiple tumor tissues reveal that bacterial infection and microbiota are associated with tumor development. The microbiota affects multiple aspects of carcinogenesis and tumor development, including favoring epithelial cells proliferation, establishing inflammatory microenvironment, promoting metastasis, and causing resistance to therapy. On the other hand, microbiota can shape a tumor surveillance environment by enhancing cell activity, and sensitize the tumor cells to immune therapy. In the present review, the roles of microbiota in multiple malignancies are summarized, and unraveling the mechanisms of host-microbiota interactions can contribute to a better understanding of the interaction between microbiota and host cells, also the development of potential anti-tumor therapeutic strategies.
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Affiliation(s)
- Qiao Li
- Tongji Hospital, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan, Hubei, China
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Gomes WJ, Marin-Cuartas M, Bakaeen F, Sádaba JR, Dayan V, Almeida R, Parolari A, Myers PO, Borger MA. The ISCHEMIA trial revisited: setting the record straight on the benefits of coronary bypass surgery and the misinterpretation of a landmark trial. Eur J Cardiothorac Surg 2023; 64:ezad361. [PMID: 37889258 DOI: 10.1093/ejcts/ezad361] [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: 08/24/2023] [Revised: 10/12/2023] [Accepted: 10/26/2023] [Indexed: 10/28/2023] Open
Abstract
OBJECTIVES The ISCHEMIA trial is a landmark study that has been the subject of heated debate within the cardiovascular community. In this analysis of the ISCHEMIA trial, we aim to set the record straight on the benefits of coronary artery bypass grafting (CABG) and the misinterpretation of this landmark trial. We sought to clarify and reorient this misinterpretation. METHODS We herein analyse the ISCHEMIA trial in detail and describe how its misinterpretation has led to an erroneous guideline recommendation downgrading for prognosis-altering surgical therapy in these at-risk patients. RESULTS The interim ISCHEMIA trial findings align with previous evidence where CABG reduces the long-term risks of myocardial infarction and mortality in advanced coronary artery disease. The trial outcomes of a significantly lower rate of cardiovascular mortality and a higher rate of non-cardiovascular mortality with the invasive strategy are explained according to landmark evidence. CONCLUSIONS The ISCHEMIA trial findings are aligned with previous evidence and should not be used to downgrade recommendations in recent guidelines for the indisputable benefits of CABG.
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Affiliation(s)
- Walter J Gomes
- Cardiovascular Surgery Discipline, Escola Paulista de Medicina and São Paulo Hospital, Federal University of São Paulo, São Paulo, Brazil
| | - Mateo Marin-Cuartas
- University Department of Cardiac Surgery, Leipzig Heart Center, Leipzig, Germany
| | - Faisal Bakaeen
- Department of Thoracic and Cardiovascular Surgery, Heart, Vascular and Thoracic Institute, Cleveland Clinic, Cleveland, OH, USA
| | - J Rafael Sádaba
- Department of Cardiac Surgery, University Hospital of Navarra, Pamplona, Spain
| | - Victor Dayan
- Centro Cardiovascular Universitario, Montevideo, Uruguay
| | - Rui Almeida
- University Center Assis Gurgacz Foundation, Cascavel, Paraná, Brazil
| | - Alessandro Parolari
- Unit of Cardiac Surgery, IRCCS Policlinico S. Donato, University of Milan, S. Donato Milanese, Italy
| | - Patrick O Myers
- Division of Cardiac Surgery, CHUV-Lausanne University Hospital, Lausanne, Switzerland
| | - Michael A Borger
- University Department of Cardiac Surgery, Leipzig Heart Center, Leipzig, Germany
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Dey DK, Krause D, Rai R, Choudhary S, Dockery LE, Chandra V. The role and participation of immune cells in the endometrial tumor microenvironment. Pharmacol Ther 2023; 251:108526. [PMID: 37690483 DOI: 10.1016/j.pharmthera.2023.108526] [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: 04/24/2023] [Revised: 08/28/2023] [Accepted: 08/30/2023] [Indexed: 09/12/2023]
Abstract
The tumor microenvironment is surrounded by blood vessels and consists of malignant, non-malignant, and immune cells, as well as signalling molecules, which primarily affect the therapeutic response and curative effects of drugs in clinical studies. Tumor-infiltrating immune cells participate in tumor progression, impact anticancer therapy, and eventually lead to the development of immune tolerance. Immunotherapy is evolving as a promising therapeutic intervention to stimulate and activate the immune system to suppress cancer cell growth. Endometrial cancer (EC) is an immunogenic disease, and in recent years, immunotherapy has shown benefit in the treatment of recurrent and advanced EC. This review discusses the key molecular pathways associated with the intra-tumoral immune response and the involvement of circulatory signalling molecules. Specific immunologic signatures in EC which offer targets for immunomodulating agents, are also discussed. We have summarized the available literature in support of using immunotherapy in EC. Lastly, we have also discussed ongoing clinical trials that may offer additional promising immunotherapy options in the future. The manuscript also explored innovative approaches for screening and identifying effective drugs, and to reduce the financial burdens for the development of personalized treatment strategies. Collectively, we aim to provide a comprehensive review of the role of immune cells and the tumor microenvironment in the development, progression, and treatment of EC.
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Affiliation(s)
- Debasish Kumar Dey
- Gynecologic Oncology Section, Obstetrics and Gynecology Department, Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
| | - Danielle Krause
- Gynecologic Oncology Section, Obstetrics and Gynecology Department, Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
| | - Rajani Rai
- Gynecologic Oncology Section, Obstetrics and Gynecology Department, Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
| | - Swati Choudhary
- Gynecologic Oncology Section, Obstetrics and Gynecology Department, Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
| | - Lauren E Dockery
- Gynecologic Oncology Section, Obstetrics and Gynecology Department, Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
| | - Vishal Chandra
- Gynecologic Oncology Section, Obstetrics and Gynecology Department, Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
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de Melo LFM, Barbosa JDS, Cordeiro MLDS, Aquino-Martins VGDQ, da Silva AP, Paiva WDS, Silveira ER, dos Santos DYAC, Rocha HAO, Scortecci KC. The Antioxidant and Immunomodulatory Potential of Coccoloba alnifolia Leaf Extracts. Int J Mol Sci 2023; 24:15885. [PMID: 37958868 PMCID: PMC10650087 DOI: 10.3390/ijms242115885] [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: 10/09/2023] [Revised: 10/23/2023] [Accepted: 10/27/2023] [Indexed: 11/15/2023] Open
Abstract
Oxidative stress has been associated with different diseases, and different medicinal plants have been used to treat or prevent this condition. The leaf ethanolic extract (EE) and aqueous extract (AE) from Coccoloba alnifolia have previously been characterized to have antioxidant potential in vitro and in vivo. In this study, we worked with EE and AE and two partition phases, AF (ethyl acetate) and BF (butanol), from AE extract. These extracts and partition phases did not display cytotoxicity. The EE and AE reduced NO production and ROS in all three concentrations tested. Furthermore, it was observed that EE and AE at 500 μg/mL concentration were able to reduce phagocytic activity by 30 and 50%, respectively. A scratch assay using a fibroblast cell line (NHI/3T3) showed that extracts and fractions induced cell migration with 60% wound recovery within 24 h, especially for BF. It was also observed that AF and BF had antioxidant potential in all the assays evaluated. In addition, copper chelation was observed. This activity was previously not detected in AE. The HPLC-DAD analysis showed the presence of phenolic compounds such as p-cumaric acid and vitexin for extracts, while the GNPS annotated the presence of isoorientin, vitexin, kanakugiol, and tryptamine in the BF partition phase. The data presented here demonstrated that the EE, AE, AF, and BF of C. alnifolia have potential immunomodulatory effects, antioxidant effects, as well as in vitro wound healing characteristics, which are important for dynamic inflammation process control.
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Affiliation(s)
- Luciana Fentanes Moura de Melo
- Laboratory of Plant Transformation and Microscopy Analysis (LPTAM), Cell Biology and Genetics Department, Centro de Biociências, Federal University of Rio Grande do Norte (UFRN), Natal 59078-970, RN, Brazil; (L.F.M.d.M.); (V.G.d.Q.A.-M.); (A.P.d.S.)
- Laboratory of Biotechnology of Natural Polymers (BIOPOL), Biochemistry Department, Centro de Biociências, Federal University of Rio Grande do Norte (UFRN), Natal 59078-970, RN, Brazil; (J.d.S.B.); (W.d.S.P.); (H.A.O.R.)
- Biochemistry and Molecular Biology Graduation School Programa de Pós-Graduação em Bioquímica, Federal University of Rio Grande do Norte (UFRN), Natal 59012-570, RN, Brazil
| | - Jefferson da Silva Barbosa
- Laboratory of Biotechnology of Natural Polymers (BIOPOL), Biochemistry Department, Centro de Biociências, Federal University of Rio Grande do Norte (UFRN), Natal 59078-970, RN, Brazil; (J.d.S.B.); (W.d.S.P.); (H.A.O.R.)
- Federal Institut of Education, Science and Technology of Rio Grande do Norte (IFRN), São Gonçalo do Amarante 59291-727, RN, Brazil
| | - Maria Lúcia da Silva Cordeiro
- Laboratory of Plant Transformation and Microscopy Analysis (LPTAM), Cell Biology and Genetics Department, Centro de Biociências, Federal University of Rio Grande do Norte (UFRN), Natal 59078-970, RN, Brazil; (L.F.M.d.M.); (V.G.d.Q.A.-M.); (A.P.d.S.)
- Laboratory of Biotechnology of Natural Polymers (BIOPOL), Biochemistry Department, Centro de Biociências, Federal University of Rio Grande do Norte (UFRN), Natal 59078-970, RN, Brazil; (J.d.S.B.); (W.d.S.P.); (H.A.O.R.)
- Biochemistry and Molecular Biology Graduation School Programa de Pós-Graduação em Bioquímica, Federal University of Rio Grande do Norte (UFRN), Natal 59012-570, RN, Brazil
| | - Verônica Giuliani de Queiroz Aquino-Martins
- Laboratory of Plant Transformation and Microscopy Analysis (LPTAM), Cell Biology and Genetics Department, Centro de Biociências, Federal University of Rio Grande do Norte (UFRN), Natal 59078-970, RN, Brazil; (L.F.M.d.M.); (V.G.d.Q.A.-M.); (A.P.d.S.)
- Laboratory of Biotechnology of Natural Polymers (BIOPOL), Biochemistry Department, Centro de Biociências, Federal University of Rio Grande do Norte (UFRN), Natal 59078-970, RN, Brazil; (J.d.S.B.); (W.d.S.P.); (H.A.O.R.)
- Biochemistry and Molecular Biology Graduation School Programa de Pós-Graduação em Bioquímica, Federal University of Rio Grande do Norte (UFRN), Natal 59012-570, RN, Brazil
| | - Ariana Pereira da Silva
- Laboratory of Plant Transformation and Microscopy Analysis (LPTAM), Cell Biology and Genetics Department, Centro de Biociências, Federal University of Rio Grande do Norte (UFRN), Natal 59078-970, RN, Brazil; (L.F.M.d.M.); (V.G.d.Q.A.-M.); (A.P.d.S.)
- Laboratory of Biotechnology of Natural Polymers (BIOPOL), Biochemistry Department, Centro de Biociências, Federal University of Rio Grande do Norte (UFRN), Natal 59078-970, RN, Brazil; (J.d.S.B.); (W.d.S.P.); (H.A.O.R.)
| | - Weslley de Souza Paiva
- Laboratory of Biotechnology of Natural Polymers (BIOPOL), Biochemistry Department, Centro de Biociências, Federal University of Rio Grande do Norte (UFRN), Natal 59078-970, RN, Brazil; (J.d.S.B.); (W.d.S.P.); (H.A.O.R.)
- Northeast Biotecnology Network (RENORBIO), Federal University of Rio Grande do Norte (UFRN), Natal 59078-970, RN, Brazil
| | - Elielson Rodrigo Silveira
- Phytochemistry Laboratory, Botany Departament, Bioscience Institut, São Paulo University, São Paulo 05508-070, SP, Brazil; (E.R.S.); (D.Y.A.C.d.S.)
| | - Déborah Yara A. Cursino dos Santos
- Phytochemistry Laboratory, Botany Departament, Bioscience Institut, São Paulo University, São Paulo 05508-070, SP, Brazil; (E.R.S.); (D.Y.A.C.d.S.)
| | - Hugo Alexandre Oliveira Rocha
- Laboratory of Biotechnology of Natural Polymers (BIOPOL), Biochemistry Department, Centro de Biociências, Federal University of Rio Grande do Norte (UFRN), Natal 59078-970, RN, Brazil; (J.d.S.B.); (W.d.S.P.); (H.A.O.R.)
- Biochemistry and Molecular Biology Graduation School Programa de Pós-Graduação em Bioquímica, Federal University of Rio Grande do Norte (UFRN), Natal 59012-570, RN, Brazil
| | - Kátia Castanho Scortecci
- Laboratory of Plant Transformation and Microscopy Analysis (LPTAM), Cell Biology and Genetics Department, Centro de Biociências, Federal University of Rio Grande do Norte (UFRN), Natal 59078-970, RN, Brazil; (L.F.M.d.M.); (V.G.d.Q.A.-M.); (A.P.d.S.)
- Biochemistry and Molecular Biology Graduation School Programa de Pós-Graduação em Bioquímica, Federal University of Rio Grande do Norte (UFRN), Natal 59012-570, RN, Brazil
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Bui I, Baritaki S, Libra M, Zaravinos A, Bonavida B. Cancer Resistance Is Mediated by the Upregulation of Several Anti-Apoptotic Gene Products via the Inducible Nitric Oxide Synthase/Nitric Oxide Pathway: Therapeutic Implications. Antioxid Redox Signal 2023; 39:853-889. [PMID: 37466477 DOI: 10.1089/ars.2023.0250] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/25/2023]
Abstract
Significance: Several therapeutic strategies for cancer treatments have been developed with time, and significant milestones have been achieved recently. However, with these novel therapies, not all cancer types respond and in the responding cancer types only a subset is affected. The failure to respond is principally the result that these cancers develop several mechanisms of resistance. Thus, a focus of current research investigations is to unravel the various mechanisms that regulate resistance and identify suitable targets for new therapeutics. Recent Advances: Hence, many human cancer types have been reported to overexpress the inducible nitric oxide synthase (iNOS) and it has been suggested that iNOS/nitric oxide (NO) plays a pivotal role in the regulation of resistance. We have postulated that iNOS overexpression or NO regulates the overexpression of pivotal anti-apoptotic gene products such as B-cell lymphoma 2 (Bcl-2), B-cell lymphoma extra large (Bcl-xL), myeloid cell leukemia-1 (Mcl-1), and survivin. In this report, we describe the various mechanisms, transcriptional, post-transcriptional, and post-translational, by which iNOS/NO regulates the expression of the above anti-apoptotic gene products. Critical Issues: The iNOS/NO-mediated regulation of the four gene products is not the same with both specific and overlapping pathways. Our findings are, in large part, validated by bioinformatic analyses demonstrating, in several cancers, several direct correlations between the expression of iNOS and each of the four examined anti-apoptotic gene products. Future Directions: We have proposed that targeting iNOS may be highly efficient since it will result in the underexpression of multiple anti-apoptotic proteins and shifting the balance toward the proapoptotic gene products and reversal of resistance. Antioxid. Redox Signal. 39, 853-889.
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Affiliation(s)
- Indy Bui
- Department of Microbiology, Immunology and Molecular Genetics, David Geffen School of Medicine, Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, California, USA
| | - Stavroula Baritaki
- Laboratory of Experimental Oncology, Department of Surgery, School of Medicine, University of Crete, Heraklion, Greece
| | - Massimo Libra
- Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
- Italian League Against Cancer, Catania, Italy
| | - Apostolos Zaravinos
- Department of Life Sciences, School of Sciences, European University Cyprus, Nicosia, Cyprus
- Cancer Genetics, Genomics and Systems Biology Laboratory, Basic and Translational Cancer Research Center (BTCRC), Nicosia, Cyprus
| | - Benjamin Bonavida
- Department of Microbiology, Immunology and Molecular Genetics, David Geffen School of Medicine, Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, California, USA
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Hochmann J, Millán M, Hernández P, Lafon-Hughes L, Aiuto ND, Silva A, Llaguno J, Alonso J, Fernández A, Pereira-Prado V, Sotelo-Silveira J, Bologna-Molina R, Arocena M. Contributions of viral oncogenes of HPV-18 and hypoxia to oxidative stress and genetic damage in human keratinocytes. Sci Rep 2023; 13:17734. [PMID: 37853061 PMCID: PMC10584980 DOI: 10.1038/s41598-023-44880-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2023] [Accepted: 10/12/2023] [Indexed: 10/20/2023] Open
Abstract
Infection with high-risk human papillomaviruses like HPV-16 and HPV-18 is highly associated with the development of cervical and other cancers. Malignant transformation requires viral oncoproteins E5, E6 and E7, which promote cell proliferation and increase DNA damage. Oxidative stress and hypoxia are also key factors in cervical malignant transformation. Increased levels of reactive species of oxygen (ROS) and nitrogen (RNS) are found in the hypoxic tumor microenvironment, promoting genetic instability and invasiveness. In this work, we studied the combined effect of E5, E6 and E7 and hypoxia in increasing oxidative stress and promoting DNA damage and nuclear architecture alterations. HaCaT cells containing HPV-18 viral oncogenes (HaCaT E5/E6/E7-18) showed higher ROS levels in normoxia and higher levels of RNS in hypoxia compared to HaCaT parental cells, as well as higher genetic damage in hypoxia as measured by γH2AX and comet assays. In hypoxia, HaCaT E5/E6/E7-18 increased its nuclear dry mass and both cell types displayed marked heterogeneity in nuclear dry mass distribution and increased nuclear foci. Our results show contributions of both viral oncogenes and hypoxia to oxidative stress, DNA damage and altered nuclear architecture, exemplifying how an altered microenvironment combines with oncogenic transformation to promote tumor progression.
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Affiliation(s)
- Jimena Hochmann
- Departamento de Genómica, Instituto de Investigaciones Biológicas Clemente Estable, Montevideo, Uruguay.
- Departamento de Diagnóstico en Patología y Medicina Bucal, Facultad de Odontología, Universidad de la República, General Las Heras 1925, Montevideo, Uruguay.
| | - Magdalena Millán
- Departamento de Genómica, Instituto de Investigaciones Biológicas Clemente Estable, Montevideo, Uruguay
| | - Paola Hernández
- Departamento de Genética, Instituto de Investigaciones Biológicas Clemente Estable, Montevideo, Uruguay
| | - Laura Lafon-Hughes
- Departamento de Genética, Instituto de Investigaciones Biológicas Clemente Estable, Montevideo, Uruguay
- Grupo de Biofisicoquímica, Departamento de Ciencias Biológicas, Centro Universitario Regional Litoral Norte -Sede Salto, Universidad de la República (CENUR LN, UdelaR), Montevideo, Uruguay
| | - Natali D' Aiuto
- Departamento de Genómica, Instituto de Investigaciones Biológicas Clemente Estable, Montevideo, Uruguay
- Departamento de Biología Odontológica, Facultad de Odontología, Universidad de la República, General Las Heras 1925, Montevideo, Uruguay
| | - Alejandro Silva
- Instituto de Física, Facultad de Ingeniería, Universidad de la República, Montevideo, Uruguay
| | - Juan Llaguno
- Instituto de Física, Facultad de Ingeniería, Universidad de la República, Montevideo, Uruguay
| | - Julia Alonso
- Instituto de Física, Facultad de Ingeniería, Universidad de la República, Montevideo, Uruguay
| | - Ariel Fernández
- Instituto de Física, Facultad de Ingeniería, Universidad de la República, Montevideo, Uruguay
| | - Vanesa Pereira-Prado
- Departamento de Diagnóstico en Patología y Medicina Bucal, Facultad de Odontología, Universidad de la República, General Las Heras 1925, Montevideo, Uruguay
| | - José Sotelo-Silveira
- Departamento de Genómica, Instituto de Investigaciones Biológicas Clemente Estable, Montevideo, Uruguay
- Sección Biología Celular, Facultad de Ciencias, Universidad de la República, Montevideo, Uruguay
| | - Ronell Bologna-Molina
- Departamento de Diagnóstico en Patología y Medicina Bucal, Facultad de Odontología, Universidad de la República, General Las Heras 1925, Montevideo, Uruguay
| | - Miguel Arocena
- Departamento de Genómica, Instituto de Investigaciones Biológicas Clemente Estable, Montevideo, Uruguay.
- Departamento de Biología Odontológica, Facultad de Odontología, Universidad de la República, General Las Heras 1925, Montevideo, Uruguay.
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Mukherjee A, Ferrao T, Spadigam AE, Dhupar A. Oral Epithelial Dysplasia in Tobacco Non-habitués: A Case Report and Review of Literature. Cureus 2023; 15:e47362. [PMID: 38022123 PMCID: PMC10657477 DOI: 10.7759/cureus.47362] [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] [Accepted: 10/19/2023] [Indexed: 12/01/2023] Open
Abstract
Oral potentially malignant disorders (OPMDs) encompass a diverse group of clinical lesions, which, on histopathological evaluation, may reveal features of hyperplasia, oral epithelial dysplasia (OED), or even early invasive squamous cell carcinoma. OEDs are often perceived to be associated with a deleterious habit such as tobacco chewing. It has emerged that OEDs may occur even in the absence of a tobacco habit and could be attributed to factors such as trauma, chronic inflammation, and inherent genetic aberrations. Authors have reported a preponderance of such lesions in young females, particularly at sites distinct from those noted in habitués. Additionally, the probability of malignant transformation of OED has been reported to be higher in non-habitués as compared to habitués when lesions are left unaddressed. There remains a paucity of data regarding the exact molecular basis, behavior, and response to treatment of OED among tobacco non-habitués. In view of the increasing number of oral lesions demonstrating epithelial dysplasia in the absence of exposure to significant risk factors, we highlight the scenario with a case. A 39-year-old female, non-habitué, presented with a non-scrapable, white lesion on the maxillary buccal gingiva. Incisional biopsy revealed features of moderate epithelial dysplasia that, on further evaluation of the excisional specimen, confirmed features of severe epithelial dysplasia. Genotyping for human papillomavirus (HPV) was carried out to assess the presence of high-risk HPV strains (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68), which are usually associated with OED and/or oral squamous cell carcinomas (OSCCs) in non-habitués. A comprehensive review of various tissue and molecular factors, which play a key role in the pathophysiology of non-habit-associated OED has been illustrated in this report. While the etiological focus of OPMDs is often directed toward deleterious habits and exposure to carcinogens, it is essential to be vigilant for this entity even among non-habitués. A meticulous screening of the oral cavity, for all patients, shall facilitate the prevention and early diagnosis of OED, particularly in individuals not exposed to habit-forming risk factors.
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Affiliation(s)
- Anupama Mukherjee
- Oral and Maxillofacial Pathology, Goa Dental College and Hospital, Bambolim, IND
| | - Twyla Ferrao
- Oral and Maxillofacial Pathology, Goa Dental College and Hospital, Bambolim, IND
| | - Anita E Spadigam
- Oral and Maxillofacial Pathology, Goa Dental College and Hospital, Bambolim, IND
| | - Anita Dhupar
- Oral and Maxillofacial Pathology, Goa Dental College and Hospital, Bambolim, IND
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Ainembabazi D, Zhang Y, Turchi JJ. The mechanistic role of cardiac glycosides in DNA damage response and repair signaling. Cell Mol Life Sci 2023; 80:250. [PMID: 37584722 PMCID: PMC10432338 DOI: 10.1007/s00018-023-04910-9] [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: 04/26/2023] [Revised: 08/01/2023] [Accepted: 08/03/2023] [Indexed: 08/17/2023]
Abstract
Cardiac glycosides (CGs) are a class of bioactive organic compounds well-known for their application in treating heart disease despite a narrow therapeutic window. Considerable evidence has demonstrated the potential to repurpose CGs for cancer treatment. Chemical modification of these CGs has been utilized in attempts to increase their anti-cancer properties; however, this has met limited success as their mechanism of action is still speculative. Recent studies have identified the DNA damage response (DDR) pathway as a target of CGs. DDR serves to coordinate numerous cellular pathways to initiate cell cycle arrest, promote DNA repair, regulate replication fork firing and protection, or induce apoptosis to avoid the survival of cells with DNA damage or cells carrying mutations. Understanding the modus operandi of cardiac glycosides will provide critical information to better address improvements in potency, reduced toxicity, and the potential to overcome drug resistance. This review summarizes recent scientific findings of the molecular mechanisms of cardiac glycosides affecting the DDR signaling pathway in cancer therapeutics from 2010 to 2022. We focus on the structural and functional differences of CGs toward identifying the critical features for DDR targeting of these agents.
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Affiliation(s)
- Diana Ainembabazi
- Department of Medicine, School of Medicine, Joseph E Walther Hall, Indiana University, 980 W. Walnut St, C560, R3-C560, Indianapolis, IN 46202 USA
| | - Youwei Zhang
- Department of Pharmacology, School of Medicine, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106 USA
| | - John J. Turchi
- Department of Medicine, School of Medicine, Joseph E Walther Hall, Indiana University, 980 W. Walnut St, C560, R3-C560, Indianapolis, IN 46202 USA
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Muthupalani S, Annamalai D, Feng Y, Ganesan SM, Ge Z, Whary MT, Nakagawa H, Rustgi AK, Wang TC, Fox JG. IL-1β transgenic mouse model of inflammation driven esophageal and oral squamous cell carcinoma. Sci Rep 2023; 13:12732. [PMID: 37543673 PMCID: PMC10404242 DOI: 10.1038/s41598-023-39907-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2023] [Accepted: 08/02/2023] [Indexed: 08/07/2023] Open
Abstract
Chronic inflammation is integral to the development of esophageal adenocarcinoma (EAC) and esophageal squamous cell carcinoma (ESCC), although the latter has not been associated with reflux esophagitis. The L2-IL-1β transgenic mice, expressing human interleukin (IL)-1β in the oral, esophageal and forestomach squamous epithelia feature chronic inflammation and a stepwise development of Barrett's esophagus-like metaplasia, dysplasia and adenocarcinoma at the squamo-columnar junction. However, the functional consequences of IL-1β-mediated chronic inflammation in the oral and esophageal squamous epithelia remain elusive. We report for the first time that in addition to the previously described Barrett's esophagus-like metaplasia, the L2-IL-1β mice also develop squamous epithelial dysplasia with progression to squamous cell carcinoma (SCC) in the esophagus and the tongue. L2-IL-1β showed age-dependent progression of squamous dysplasia to SCC with approximately 40% (n = 49) and 23.5% (n = 17) incidence rates for esophageal and tongue invasive SCC respectively, by 12-15 months of age. Interestingly, SCC development and progression in L2-IL-1β was similar in both Germ Free (GF) and Specific Pathogen Free (SPF) conditions. Immunohistochemistry revealed a T cell predominant inflammatory profile with enhanced expression of Ki67, Sox2 and the DNA double-strand break marker, γ-H2AX, in the dysplastic squamous epithelia of L2-IL-1β mice. Pro-inflammatory cytokines, immunomodulatory players, chemoattractants for inflammatory cells (T cells, neutrophils, eosinophils, and macrophages) and oxidative damage marker, iNOS, were significantly increased in the esophageal and tongue tissues of L2-IL-1β mice. Our recent findings have expanded the translational utility of the IL-1β mouse model to aid in further characterization of the key pathways of inflammation driven BE and EAC as well as ESCC and Oral SCC.
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Affiliation(s)
- Sureshkumar Muthupalani
- Division of Comparative Medicine, Massachusetts Institute of Technology, 77 Massachusetts Avenue, 16-825C, Cambridge, MA, 02139, USA.
- StageBio, 5930 Main St, Mount Jackson, VA, 22842, USA.
| | - Damodaran Annamalai
- Division of Comparative Medicine, Massachusetts Institute of Technology, 77 Massachusetts Avenue, 16-825C, Cambridge, MA, 02139, USA
| | - Yan Feng
- Division of Comparative Medicine, Massachusetts Institute of Technology, 77 Massachusetts Avenue, 16-825C, Cambridge, MA, 02139, USA
| | - Suresh M Ganesan
- Division of Comparative Medicine, Massachusetts Institute of Technology, 77 Massachusetts Avenue, 16-825C, Cambridge, MA, 02139, USA
| | - Zhongming Ge
- Division of Comparative Medicine, Massachusetts Institute of Technology, 77 Massachusetts Avenue, 16-825C, Cambridge, MA, 02139, USA
| | - Mark T Whary
- Division of Comparative Medicine, Massachusetts Institute of Technology, 77 Massachusetts Avenue, 16-825C, Cambridge, MA, 02139, USA
| | - Hiroshi Nakagawa
- Division of Digestive and Liver Diseases and Herbert Irving Cancer Research Center, Columbia University College of Physicians and Surgeons, New York, NY, 10032, USA
| | - Anil K Rustgi
- Division of Digestive and Liver Diseases and Herbert Irving Cancer Research Center, Columbia University College of Physicians and Surgeons, New York, NY, 10032, USA
| | - Timothy C Wang
- Division of Digestive and Liver Diseases and Herbert Irving Cancer Research Center, Columbia University College of Physicians and Surgeons, New York, NY, 10032, USA
| | - James G Fox
- Division of Comparative Medicine, Massachusetts Institute of Technology, 77 Massachusetts Avenue, 16-825C, Cambridge, MA, 02139, USA.
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.
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Gong Y, Huang X, Wang M, Liang X. Intratumor microbiota: a novel tumor component. J Cancer Res Clin Oncol 2023; 149:6675-6691. [PMID: 36639531 DOI: 10.1007/s00432-023-04576-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Accepted: 01/05/2023] [Indexed: 01/15/2023]
Abstract
Bacteria have been found in tumors for over 100 years, but the irreproducibility of experiments on bacteria, the limitations of science and technology, and the contamination of the host environment have severely hampered most research into the role of bacteria in carcinogenesis and cancer treatment. With the development of molecular tools and techniques (e.g., macrogenomics, metabolomics, lipidomics, and macrotranscriptomics), the complex relationships between hosts and different microorganisms are gradually being deciphered. In the past, attention has been focused on the impact of the gut microbiota, the site where the body's microbes gather most, on tumors. However, little is known about the role of microbes from other sites, particularly the intratumor microbiota, in cancer. In recent years, an increasing number of studies have identified the presence of symbiotic microbiota within a large number of tumors, bringing the intratumor microbiota into the limelight. In this review, we aim to provide a better understanding of the role of the intratumor microbiota in cancer, to provide direction for future experimental and translational research, and to offer new approaches to the treatment of cancer and the improvement of patient prognosis.
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Affiliation(s)
- Yanyu Gong
- Hunan Province Key Laboratory of Tumor Cellular and Molecular Pathology, Cancer Research Institute, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China
| | - Xinqi Huang
- Excellent Class, Clinical Medicine, Grade 20, Hengyang Medical College, University of South China, Hengyang, 421001, Hunan, China
| | - Minhui Wang
- Hunan Province Key Laboratory of Tumor Cellular and Molecular Pathology, Cancer Research Institute, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China
| | - Xiaoqiu Liang
- Hunan Province Key Laboratory of Tumor Cellular and Molecular Pathology, Cancer Research Institute, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China.
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Oh JM, Kim H. The effect of oral bacterial infection on DNA damage response in host cells. Am J Cancer Res 2023; 13:3157-3168. [PMID: 37559975 PMCID: PMC10408462] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Accepted: 06/29/2023] [Indexed: 08/11/2023] Open
Abstract
Maintaining and transferring intact genomes from one generation to another plays a pivotal role in all living organisms. DNA damage caused by numerous endogenous and exogenous factors must be adequately repaired, as unrepaired and accumulated DNA mutations can cause severe deleterious effects, such as cell death and cancer. To prevent adverse consequences, cells have established DNA damage response mechanisms that address different forms of DNA damage, including DNA double-strand breaks, mismatches, nucleotide excision, and base excision. Among several sources of exogenous DNA damage, bacterial infections cause inflammation in the host, generating reactive oxygen species (ROS) and causing oxidative DNA damage. Recent studies have revealed the importance of the oral microbiome in inflammation and several systemic host diseases. Dysbiosis of oral bacteria can induce chronic inflammation, which enhances ROS-induced DNA damage, and improperly repaired damage can lead to carcinogenesis. This review describes the various DNA repair pathways that are affected by chronic inflammation and the discovery of the DNA damage response induced by oral bacteria such as Porphyromonas gingivalis and Fusobacterium nucleatum.
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Affiliation(s)
- Jung-Min Oh
- Department of Oral Biochemistry, Dental and Life Science Institute, School of Dentistry, Pusan National UniversityYangsan 50612, Republic of Korea
- Department of Life Science in Dentistry, School of Dentistry, Pusan National UniversityYangsan 50612, Republic of Korea
| | - Hongtae Kim
- Department of Life Sciences, Ulsan National Institute of Science and Technology (UNIST)Ulsan 44919, Republic of Korea
- Center for Genomic Integrity Institute for Basic Science (IBS), UNISTUlsan 44919, Republic of Korea
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Truong NC, Phan TNM, Huynh NT, Pham KD, Van Pham P. Interferon-Gamma Increases the Immune Modulation of Umbilical Cord-Derived Mesenchymal Stem Cells but Decreases Their Chondrogenic Potential. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2023. [PMID: 37291444 DOI: 10.1007/5584_2023_776] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
INTRODUCTION The pro-inflammatory cytokine interferon-gamma (IFN-γ) is reported to be an agent that boosts the immune modulation of mesenchymal stem cells (MSCs). However, the effects of IFN-γ on the chondrogenic potential of treated MSCs have not been evaluated in depth. This study aimed to evaluate the effects of IFN-γ on the immune modulation and chondrogenic potential of human umbilical cord-derived MSCs (hUC-MSCs). METHODS UC-MSCs were isolated and expanded following published protocols. They were characterized as MSCs before their use in further experiments. The UC-MSCs were treated with IFN-γ at 10 ng/mL for 48 h. Changes in phenotype were investigated based on changes in MSC markers, immunomodulatory genes (TGF-β, IL-4, and IDO) for immune modulation, and cartilage-related genes during the induction of differentiation (Col1a2, Col2a1, Sox9, Runx2, and Acan) for chondrogenic potential. RESULTS IFN-γ-treated UC-MSCs maintained MSC markers and exhibited decreased expression of transcriptional regulatory factors in chondrogenesis (Sox9 and Runx2) and the extracellular matrix-specific genes Col1a2 and Acan but not Col2a1 compared to non-treated cells (p < 0.05). Furthermore, the immunomodulatory capability of IFN-γ-treated UC-MSCs was clearly revealed through their increased expression of IDO and IL-4 and decreased expression of TGF-β compared to non-treated cells (p < 0.05). CONCLUSION This study demonstrated that UC-MSCs treated with IFN-γ at 10 ng/mL had reduced expression of chondrocyte-specific genes; however, they maintained multi-lineage differentiation and exhibited immunomodulatory properties.
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Affiliation(s)
- Nhat Chau Truong
- Stem Cell Institute, University of Science, Ho Chi Minh City, Viet Nam
- Vietnam National University Ho Chi Minh City, Ho Chi Minh City, Viet Nam
| | - Thu Ngoc-Minh Phan
- Stem Cell Institute, University of Science, Ho Chi Minh City, Viet Nam
- Vietnam National University Ho Chi Minh City, Ho Chi Minh City, Viet Nam
| | - Nhi Thao Huynh
- Vietnam National University Ho Chi Minh City, Ho Chi Minh City, Viet Nam
- Laboratory of Stem Cell Research and Application, University of Science, Ho Chi Minh City, Viet Nam
| | - Khuong Duy Pham
- Vietnam National University Ho Chi Minh City, Ho Chi Minh City, Viet Nam
- Laboratory of Stem Cell Research and Application, University of Science, Ho Chi Minh City, Viet Nam
| | - Phuc Van Pham
- Stem Cell Institute, University of Science, Ho Chi Minh City, Viet Nam.
- Vietnam National University Ho Chi Minh City, Ho Chi Minh City, Viet Nam.
- Laboratory of Cancer Research, University of Science, Ho Chi Minh City, Viet Nam.
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