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Gutierrez AH, Mazariegos MS, Alemany S, Nevzorova YA, Cubero FJ, Sanz-García C. Tumor progression locus 2 (TPL2): A Cot-plicated progression from inflammation to chronic liver disease. Biochim Biophys Acta Mol Basis Dis 2023; 1869:166660. [PMID: 36764206 DOI: 10.1016/j.bbadis.2023.166660] [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: 10/26/2022] [Revised: 01/24/2023] [Accepted: 01/30/2023] [Indexed: 02/10/2023]
Abstract
The cytoplasmic protein tumor progression locus 2 (TPL2), also known as cancer Osaka thyroid (Cot), or MAP3K8, is thought to have a significant role in a variety of cancers and illnesses and it is a key component in the activation pathway for the expression of inflammatory mediators. Despite the tight connection between inflammation and TPL2, its function has not been extensively studied in chronic liver disease (CLD), a major cause of morbidity and mortality worldwide. Here, we analyze more in detail the significance of TPL2 in CLD to shed light on the pathological and molecular transduction pattern of TPL2 during the progression of CLD. This might result in important advancements and enable progress in the diagnosis and treatment of CLD.
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Affiliation(s)
- Alejandro H Gutierrez
- Department of Immunology, Ophthalmology and ENT, Complutense University School of Medicine, 28040 Madrid, Spain
| | - Marina S Mazariegos
- Department of Immunology, Ophthalmology and ENT, Complutense University School of Medicine, 28040 Madrid, Spain
| | - Susana Alemany
- Department of Metabolism and Cell Signaling, Instituto de Investigaciones Biomédicas Alberto Sols, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, 28049 Madrid, Spain; Biomedicine Unit (Unidad Asociada al CSIC), Universidad de Las Palmas de Gran Canaria, 35001 Las Palmas, Spain
| | - Yulia A Nevzorova
- Department of Immunology, Ophthalmology and ENT, Complutense University School of Medicine, 28040 Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), 28029 Madrid, Spain; Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), 28007 Madrid, Spain
| | - Francisco Javier Cubero
- Department of Immunology, Ophthalmology and ENT, Complutense University School of Medicine, 28040 Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), 28029 Madrid, Spain; Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), 28007 Madrid, Spain
| | - Carlos Sanz-García
- Department of Immunology, Ophthalmology and ENT, Complutense University School of Medicine, 28040 Madrid, Spain.
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Bassotti G, Fruganti A, Stracci F, Marconi P, Fettucciari K. Cytotoxic synergism of Clostridioides difficile toxin B with proinflammatory cytokines in subjects with inflammatory bowel diseases. World J Gastroenterol 2023; 29:582-596. [PMID: 36742168 PMCID: PMC9896618 DOI: 10.3748/wjg.v29.i4.582] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Revised: 12/03/2022] [Accepted: 12/27/2022] [Indexed: 01/20/2023] Open
Abstract
Clostridioides difficile (C. difficile) is progressively colonizing humans and animals living with humans. During this process, hypervirulent strains and mutated toxin A and B of C. difficile (TcdA and TcdB) are originating and developing. While in healthy subjects colonization by C. difficile becomes a risk after the use of antibiotics that alter the microbiome, other categories of people are more susceptible to infection and at risk of relapse, such as those with inflammatory bowel disease (IBD). Recent in vitro studies suggest that this increased susceptibility could be due to the strong cytotoxic synergism between TcdB and proinflammatory cytokines the tumor necrosis factor-alpha and interferon-gamma (CKs). Therefore, in subjects with IBD the presence of an inflammatory state in the colon could be the driver that increases the susceptibility to C. difficile infection and its progression and relapses. TcdB is internalized in the cell via three receptors: chondroitin sulphate proteoglycan 4; poliovirus receptor-like 3; and Wnt receptor frizzled family. Chondroitin sulphate proteoglycan 4 and Wnt receptor frizzled family are involved in cell death by apoptosis or necrosis depending on the concentration of TcdB and cell types, while poliovirus receptor-like 3 induces only necrosis. It is possible that cytokines could also induce a greater expression of receptors for TcdB that are more involved in necrosis than in apoptosis. Therefore, in subjects with IBD there are the conditions: (1) For greater susceptibility to C. difficile infection, such as the inflammatory state, and abnormalities of the microbiome and of the immune system; (2) for the enhancement of the cytotoxic activity of TcdB +Cks; and (3) for a greater expression of TcdB receptors stimulated by cytokines that induce cell death by necrosis rather than apoptosis. The only therapeutic approach currently possible in IBD patients is monitoring of C. difficile colonization for interventions aimed at reducing tumor necrosis factor-alpha and interferon-gamma levels when the infection begins. The future perspective is to generate bacteriophages against C. difficile for targeted therapy.
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Affiliation(s)
- Gabrio Bassotti
- Department of Medicine and Surgery, Gastroenterology, Hepatology & Digestive Endoscopy Section University of Perugia Medical School, Piazza Lucio Severi, Perugia 06132, Italy, and Santa Maria della Misericordia Hospital, Gastroenterology & Hepatology Unit Perugia 06156, Italy
| | - Alessandro Fruganti
- School of Biosciences and Veterinary Medicine, University of Camerino, Matelica 62024, Italy
| | - Fabrizio Stracci
- Medicine and Surgery, Hygiene and Public Health Section, University of Perugia, Perugia 06123, Italy
| | - Pierfrancesco Marconi
- Medicine and Surgery, Biosciences & Medical Embryology Section, University of Perugia, Perugia 06132, Italy
| | - Katia Fettucciari
- Medicine and Surgery, Biosciences & Medical Embryology Section, University of Perugia, Perugia 06132, Italy
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Huang Z, Chen Y, Yang C, Ma B, Guo S, Zhang J, Chen N, Umar T, Yin B, Deng G. Enhanced expression of miR-26a ameliorates lipopolysaccharide-induced endometritis by targeting MAP3K8 to inactivate MAPK signaling pathway. J Reprod Immunol 2022; 154:103751. [PMID: 36252394 DOI: 10.1016/j.jri.2022.103751] [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: 08/10/2022] [Revised: 09/08/2022] [Accepted: 09/16/2022] [Indexed: 12/14/2022]
Abstract
Endometritis is a severe postpartum inflammatory disease that puts cows' reproductive health at risk and causes the dairy industry to suffer significant financial losses. The present study aimed to investigate the regulatory role of miR‑26a in LPS‑induced bovine endometrial epithelial cells (bEECs) and the implication for endometritis. Here, we found inflammatory cell infiltration and destruction of endometrial structure in cow uterus, and dramatic increase in myeloperoxidase (MPO) activity and upregulation of pro-inflammatory cytokines (IL-1β, TNF-α, and IL-6) in endometritis. Meanwhile, miR-26a was down-regulated, but MAP3K8 was increased in the uterine tissue of endometritis. Similarly, the expression of miR-26a was significantly decreased in LPS-stimulated bEECs, while MAP3K8 was risen. In addition, we further verified that MAP3K8 was a target of miR-26a by dual-luciferase reporter assay. Under LPS stress, over-expressing miR-26a markedly decreased MAP3K8 expression levels, along with the reduced expression of inflammatory factors, such as IL-1β, TNF-α and IL-6, whereas this effect was countered by the inhibition of miR-26a. Furthermore, we demonstrated that miR-26a overexpression prevented the MAPK pathway from being activated by targeting MAP3K8. Then we carried out experiments in LPS-stimulated mice uterus to expound that MAP3K8 was essential in endometritis development, which further confirmed the reliability of the above results. In conclusion, overexpression of miR-26a effectively inhibited the expression of MAP3K8 in LPS-induced bEECs and thereby partially suppressed the activation of MAPK signaling pathway. miR-26a and MAP3K8 may be a promising biomarker and therapeutic target for dairy cow endometritis.
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Affiliation(s)
- Zhi Huang
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, People's Republic of China
| | - Yu Chen
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, People's Republic of China
| | - Cheng Yang
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, People's Republic of China
| | - Bin Ma
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, People's Republic of China
| | - Shuai Guo
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, People's Republic of China
| | - Jinxin Zhang
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, People's Republic of China
| | - Nuoer Chen
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, People's Republic of China
| | - Talha Umar
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, People's Republic of China
| | - Baoyi Yin
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, People's Republic of China
| | - Ganzhen Deng
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, People's Republic of China.
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4
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You Y, Wen D, Zeng L, Lu J, Xiao X, Chen Y, Song H, Liu Z. ALKBH5/MAP3K8 axis regulates PD-L1+ macrophage infiltration and promotes hepatocellular carcinoma progression. Int J Biol Sci 2022; 18:5001-5018. [PMID: 35982895 PMCID: PMC9379398 DOI: 10.7150/ijbs.70149] [Citation(s) in RCA: 60] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Accepted: 06/30/2022] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma is one of the most common malignant tumors.M6A is a novel epigenetic modification that have been emerged as vital regulators for the progression of HCC. However, the regulatory role, clinical significance and the details of the modification, such as the impact on the local tumor environment, remain largely unclear. Our study showed that ALKBH5 was highly expressed in HCC and high ALKBH5 expression predicted a worse prognosis of HCC patients. Prediction of ALKBH5 function by tissue samples and single cell sequencing Gene Set Variation Analysis. Primary CD3 + T lymphocytes and bone marrow-derived macrophages were used to evaluate the effect of ALKBH5 on immune microenvironment. The results indicated that ALKBH5 promote HCC cell proliferation, metastasis and PD-L1+macrophage recruitment. Mechanistically the results showed that ALKBH5 regulates MAP3K8 expression in a m6A dependent manner which mediates the proliferation and metastasis of HCC cells. ALKBH5 also promotes the activation of JNK and ERK pathways through upregulating MAP3K8, thus regulating the expression of IL-8 and promoting macrophage recruitment. Taken together, these data show that ALKBH5 promotes HCC growth, metastasis and macrophage recruitment through ALKBH5/MAP3K8 axis and it may serve as a potential diagnostic marker and target for treatment of HCC patients.
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Affiliation(s)
- Yu You
- Hepatobiliary Surgery Department, Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China
| | - Diguang Wen
- Hepatobiliary Surgery Department, Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China
| | - Lu Zeng
- Department of Gastroenterology, the Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China
| | - Jiao Lu
- Hepatobiliary Surgery Department, Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China
| | - Xiao Xiao
- Department of Gastroenterology, Chongqing University Central Hospital (Chongqing Emergency Medical Center), Chongqing 400010, China
| | - Yucheng Chen
- Hepatobiliary Surgery Department, Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China
| | - Hua Song
- Hepatobiliary Surgery Department, Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China
| | - Zuojin Liu
- Hepatobiliary Surgery Department, Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China
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Chandra H, Sharma KK, Tuovinen OH, Sun X, Shukla P. Pathobionts: mechanisms of survival, expansion, and interaction with host with a focus on Clostridioides difficile. Gut Microbes 2022; 13:1979882. [PMID: 34724858 PMCID: PMC8565823 DOI: 10.1080/19490976.2021.1979882] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
Pathobionts are opportunistic microbes that emerge as a result of perturbations in the healthy microbiome due to complex interactions of various genetic, exposomal, microbial, and host factors that lead to their selection and expansion. Their proliferations can aggravate inflammatory manifestations, trigger autoimmune diseases, and lead to severe life-threatening conditions. Current surge in microbiome research is unwinding these complex interplays between disease development and protection against pathobionts. This review summarizes the current knowledge of pathobiont emergence with a focus on Clostridioides difficile and the recent findings on the roles of immune cells such as iTreg cells, Th17 cells, innate lymphoid cells, and cytokines in protection against pathobionts. The review calls for adoption of innovative tools and cutting-edge technologies in clinical diagnostics and therapeutics to provide insights in identification and quantification of pathobionts.
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Affiliation(s)
- Harish Chandra
- Department of Environmental Microbiology, School of Earth and Environmental Sciences, Babasaheb Bhimrao Ambedkar University, Lucknow, Uttar Pradesh, India,Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Krishna Kant Sharma
- Laboratory of Enzymology and Recombinant DNA Technology, Department of Microbiology, Maharshi Dayanand University, Rohtak, Haryana, India
| | - Olli H. Tuovinen
- Department of Microbiology, Ohio State University, Columbus, OH, USA
| | - Xingmin Sun
- Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL, USA,Xingmin Sun Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA
| | - Pratyoosh Shukla
- School of Biotechnology, Institute of Science, Banaras Hindu University, Varanasi, India,Enzyme Technology and Protein Bioinformatics Laboratory, Department of Microbiology, Maharshi Dayanand University, Rohtak, Haryana, India,CONTACT Pratyoosh Shukla School of Biotechnology, Institute of Science, Banaras Hindu University, Varanasi 221005, India
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6
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Fettucciari K, Marconi P, Marchegiani A, Fruganti A, Spaterna A, Bassotti G. Invisible steps for a global endemy: molecular strategies adopted by Clostridioides difficile. Therap Adv Gastroenterol 2021; 14:17562848211032797. [PMID: 34413901 PMCID: PMC8369858 DOI: 10.1177/17562848211032797] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2021] [Accepted: 06/26/2021] [Indexed: 02/06/2023] Open
Abstract
Clostridioides difficile infection (CDI) is on the rise worldwide and is associated with an increase in deaths and socio-health burden. C. difficile has become ubiquitous in anthropized environments because of the extreme resistance of its spores. Based on the epidemiological data and knowledge of molecular pathogenesis of C. difficile, it is possible to predict its progressive colonization of the human population for the following reasons: first, its global spread is unstoppable; second, the toxins (Tcds) produced by C. difficile, TcdA and TcdB, mainly cause cell death by apoptosis, but the surviving cells acquire a senescence state that favours persistence of C. difficile in the intestine; third, proinflammatory cytokines, tumour necrosis factor-α and interferon-γ, induced during CDI, enhance the cytotoxicity of Tcds and can increase the survival of senescent cells; fourth, Tcds block mobility and induce apoptosis in immune cells recruited at the infection site; and finally, after remission from primary infection or relapse, C. difficile causes functional abnormalities in the enteric glial cell (EGC) network that can result in irritable bowel syndrome, characterized by a latent inflammatory response that contributes to C. difficile survival and enhances the cytotoxic activity of low doses of TcdB, thus favouring further relapses. Since a 'global endemy' of C. difficile seems inevitable, it is necessary to develop an effective vaccine against Tcds for at-risk individuals, and to perform a prophylaxis/selective therapy with bacteriophages highly specific for C. difficile. We must be aware that CDI will become a global health problem in the forthcoming years, and we must be prepared to face this menace.
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Affiliation(s)
- Katia Fettucciari
- Biosciences & Medical Embryology Section, Department of Medicine and Surgery, University of Perugia, Medical School -Piazza Lucio Severi 1, Edificio B - IV piano; Sant’Andrea delle Fratte, Perugia, 06132, Italy
| | - Pierfrancesco Marconi
- Biosciences & Medical Embryology Section, Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Andrea Marchegiani
- School of Biosciences and Veterinary Medicine, University of Camerino, Macerata, Italy
| | - Alessandro Fruganti
- School of Biosciences and Veterinary Medicine, University of Camerino, Macerata, Italy
| | - Andrea Spaterna
- School of Biosciences and Veterinary Medicine, University of Camerino, Macerata, Italy
| | - Gabrio Bassotti
- Gastroenterology, Hepatology & Digestive Endoscopy Section, Department of Medicine and Surgery, University of Perugia, Perugia, Italy
- Gastroenterology & Hepatology Unit, Santa Maria della Misericordia Hospital, Perugia, Italy
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Li Y, Xu S, Xu Q, Chen Y. Clostridium difficile toxin B induces colonic inflammation through the TRIM46/DUSP1/MAPKs and NF-κB signalling pathway. ARTIFICIAL CELLS NANOMEDICINE AND BIOTECHNOLOGY 2020; 48:452-462. [PMID: 31918570 DOI: 10.1080/21691401.2019.1709856] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Clostridium difficile (C. difficile) infection results in toxin-induced epithelial injury and marked colonic inflammation. Mitogen-activated protein kinase (MAPK) and NF-κB which regulated by MAP kinase phosphatase (MKP, also known as dual specificity phosphatases, DUSP) are fundamental signalling pathways that mediate multiple cellular processes. However, the regulation of DUSP/MAPKs and NF-κB pathway in C. difficile-induced colonic inflammation remains unclear. Here, we report that TcdB significantly inhibits cell viability and induces production of IL-1β and TNF-α and activation of MAPKs and NF-κB. An E3-ubiquitin ligase, TRIM46, ubiquitinates DUSP1, and its knockdown significantly inhibit TcdB-induced activation of MAPKs and NF-κB and production of IL-1β and TNF-α. Moreover, TRIM46 overexpression induced production of IL-1β and TNF-α also reversed by DUSP1 overexpression. We further found that promoter of TRIM46 also demonstrated binding to NF-κBp65, leading to regulate TRIM46 expression. In addition, the increased colonic inflammation induced by C. difficile administration was inhibited by TRIM46 knockdown in vivo. Taken together, the present study shows that TRIM46, as a new regulator of DUSP1/MAPKs and NF-κB signalling pathway, plays an important role in TcdB-induced colonic inflammation.
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Affiliation(s)
- Ying Li
- Institute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, China.,Key Laboratory of Clinical Pharmacology of Antibiotics, National Health Commission, Shanghai, China
| | - Su Xu
- Institute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, China.,Key Laboratory of Clinical Pharmacology of Antibiotics, National Health Commission, Shanghai, China
| | - Qingqing Xu
- Institute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, China.,Key Laboratory of Clinical Pharmacology of Antibiotics, National Health Commission, Shanghai, China
| | - Yijian Chen
- Institute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, China.,Key Laboratory of Clinical Pharmacology of Antibiotics, National Health Commission, Shanghai, China
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Njunge LW, Estania AP, Guo Y, Liu W, Yang L. Tumor progression locus 2 (TPL2) in tumor-promoting Inflammation, Tumorigenesis and Tumor Immunity. Am J Cancer Res 2020; 10:8343-8364. [PMID: 32724474 PMCID: PMC7381748 DOI: 10.7150/thno.45848] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2020] [Accepted: 06/03/2020] [Indexed: 12/15/2022] Open
Abstract
Over the years, tumor progression locus 2 (TPL2) has been identified as an essential modulator of immune responses that conveys inflammatory signals to downstream effectors, subsequently modulating the generation and function of inflammatory cells. TPL2 is also differentially expressed and activated in several cancers, where it is associated with increased inflammation, malignant transformation, angiogenesis, metastasis, poor prognosis and therapy resistance. However, the relationship between TPL2-driven inflammation, tumorigenesis and tumor immunity has not been addressed. Here, we reconcile the function of TPL2-driven inflammation to oncogenic functions such as inflammation, proliferation, apoptosis resistance, angiogenesis, metastasis, immunosuppression and immune evasion. We also address the controversies reported on TPL2 function in tumor-promoting inflammation and tumorigenesis, and highlight the potential role of the TPL2 adaptor function in regulating the mechanisms leading to pro-tumorigenic inflammation and tumor progression. We discuss the therapeutic implications and limitations of targeting TPL2 for cancer treatment. The ideas presented here provide some new insight into cancer pathophysiology that might contribute to the development of more integrative and specific anti-inflammatory and anti-cancer therapeutics.
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Oliva A, Aversano L, De Angelis M, Mascellino MT, Miele MC, Morelli S, Battaglia R, Iera J, Bruno G, Corazziari ES, Ciardi MR, Venditti M, Mastroianni CM, Vullo V. Persistent Systemic Microbial Translocation, Inflammation, and Intestinal Damage During Clostridioides difficile Infection. Open Forum Infect Dis 2020; 7:ofz507. [PMID: 31950071 PMCID: PMC6954488 DOI: 10.1093/ofid/ofz507] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2019] [Accepted: 11/30/2019] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND Clostridioides difficile infection (CDI) might be complicated by the development of nosocomial bloodstream infection (n-BSI). Based on the hypothesis that alteration of the normal gut integrity is present during CDI, we evaluated markers of microbial translocation, inflammation, and intestinal damage in patients with CDI. METHODS Patients with documented CDI were enrolled in the study. For each subject, plasma samples were collected at T0 and T1 (before and after CDI therapy, respectively), and the following markers were evaluated: lipopolysaccharide-binding protein (LPB), EndoCab IgM, interleukin-6, intestinal fatty acid binding protein (I-FABP). Samples from nonhospitalized healthy controls were also included. The study population was divided into BSI+/BSI- and fecal microbiota transplantation (FMT) +/FMT- groups, according to the development of n-BSI and the receipt of FMT, respectively. RESULTS Overall, 45 subjects were included; 8 (17.7%) developed primary n-BSI. Markers of microbial translocation and intestinal damage significantly decreased between T0 and T1, however, without reaching values similar to controls (P < .0001). Compared with BSI-, a persistent high level of microbial translocation in the BSI+ group was observed. In the FMT+ group, markers of microbial translocation and inflammation at T1 tended to reach control values. CONCLUSIONS CDI is associated with high levels of microbial translocation, inflammation, and intestinal damage, which are still present at clinical resolution of CDI. The role of residual mucosal perturbation and persistence of intestinal cell damage in the development of n-BSI following CDI, as well as the possible effect of FMT in the restoration of mucosal integrity, should be further investigated.
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Affiliation(s)
- Alessandra Oliva
- Department of Public Health and Infectious Diseases, Sapienza University of Rome, Rome, Italy
- IRCCS INM Neuromed, Pozzilli, Italy
| | - Lucia Aversano
- Department of Public Health and Infectious Diseases, Sapienza University of Rome, Rome, Italy
| | - Massimiliano De Angelis
- Department of Public Health and Infectious Diseases, Sapienza University of Rome, Rome, Italy
| | - Maria Teresa Mascellino
- Department of Public Health and Infectious Diseases, Sapienza University of Rome, Rome, Italy
| | - Maria Claudia Miele
- Department of Public Health and Infectious Diseases, Sapienza University of Rome, Rome, Italy
| | - Sergio Morelli
- Department of Internal Medicine and Medical Specialties, Gastroenterology Unit, Sapienza University of Rome, Rome, Italy
| | - Riccardo Battaglia
- Department of Internal Medicine and Medical Specialties, Gastroenterology Unit, Sapienza University of Rome, Rome, Italy
| | - Jessica Iera
- Department of Internal Medicine and Medical Specialties, Gastroenterology Unit, Sapienza University of Rome, Rome, Italy
| | - Giovanni Bruno
- Department of Internal Medicine and Medical Specialties, Gastroenterology Unit, Sapienza University of Rome, Rome, Italy
| | | | - Maria Rosa Ciardi
- Department of Public Health and Infectious Diseases, Sapienza University of Rome, Rome, Italy
| | - Mario Venditti
- Department of Public Health and Infectious Diseases, Sapienza University of Rome, Rome, Italy
| | | | - Vincenzo Vullo
- Department of Public Health and Infectious Diseases, Sapienza University of Rome, Rome, Italy
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