|
1
|
Kim W, Seo MK, Kim YJ, Choi SH, Ku CR, Kim S, Lee EJ, Yoon JS. Role of the suppressor of cytokine signaling-3 in the pathogenesis of Graves' orbitopathy. Front Endocrinol (Lausanne) 2025; 16:1527275. [PMID: 40104138 PMCID: PMC11913680 DOI: 10.3389/fendo.2025.1527275] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2024] [Accepted: 02/12/2025] [Indexed: 03/20/2025] Open
Abstract
Objective Graves' orbitopathy (GO) is characterized by increased production of proinflammatory cytokines and hyaluronic acid by fibroblasts and their differentiation into adipocytes in response to immunologic stimuli. The suppressor of cytokine signaling-3 (SOCS3) is an inducible negative regulator of the JAK/STAT pathway, implicated in various inflammatory diseases. In this study, we investigated the role of SOCS3 in the inflammatory and adipogenic pathogenesis of GO. Methods Transcriptome profiling of orbital tissues obtained from five patients with GO who underwent orbital decompression surgery and four healthy subjects was performed using RNA-sequencing. Among the top-ranked differentially expressed genes, we identified 24 hub genes and found SOCS3 to be the most significantly upregulated gene in GO samples compared with that in healthy tissue based on quantitative real-time polymerase chain reaction. SOCS3 expression was analyzed in IL-1β-, and IGF-1-stimulated orbital fibroblasts using quantitative real-time polymerase chain reaction and western blot analysis. Knockdown of SOCS3 using siRNA transfection was performed to assess the effect of SOCS3 on the production of proinflammatory cytokines and adipogenic phenotype. Results We identified 184 consistently differentially expressed genes-120 upregulated and 64 downregulated- in GO tissues compared to the control. SOCS3 mRNA expression was significantly higher in GO tissues (n = 17) compared with that in control (n = 15). IL-1β and IGF-1 enhanced the expression of SOCS3 at mRNA and protein levels. Silencing of SOCS3 suppressed the levels of IL-1β-induced proinflammatory cytokines, including IL-6, IL-8, and ICAM-1. Phosphorylation of NF-kB and Akt was suppressed and adipogenic differentiation was significantly attenuated by SOCS3 knockdown. Conclusions SOCS3 was remarkably expressed in the adipose tissues of patients with GO and was induced by IL-1β and IGF-1 in orbital fibroblasts. SOCS3 inhibition attenuated the production of proinflammatory cytokines and adipogenesis, suggesting that SOCS3 may be a therapeutic target for controlling the inflammatory and adipogenic mechanisms in GO.
Collapse
Affiliation(s)
- Wonjin Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, CHA Gangnam Medical Center, CHA University School of Medicine, Seoul, Republic of Korea
| | - Mi-Kyoung Seo
- Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States
| | - Yong Joon Kim
- Institute of Vision Research, Department of Ophthalmology, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Soo Hyun Choi
- Institute of Vision Research, Department of Ophthalmology, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Cheol Ryong Ku
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Sangwoo Kim
- Department of Biochemical Systems Informatics, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Eun Jig Lee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Jin Sook Yoon
- Institute of Vision Research, Department of Ophthalmology, Yonsei University College of Medicine, Seoul, Republic of Korea
| |
Collapse
|
|
2
|
Feng X, Yang C, Wang T, Zhang J, Zhou H, Ma B, Xu M, Deng G. IFN-τ Maintains Immune Tolerance by Promoting M2 Macrophage Polarization via Modulation of Bta-miR-30b-5p in Early Uterine Pregnancy in Dairy Cows. Cells 2025; 14:87. [PMID: 39851515 PMCID: PMC11764194 DOI: 10.3390/cells14020087] [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: 12/22/2024] [Accepted: 12/25/2024] [Indexed: 01/26/2025] Open
Abstract
Pregnancy failure in the first trimester of cows significantly impacts the efficiency of the dairy industry. As a type I interferon exclusively to ruminants, IFN-τ plays a key role in maternal recognition and immune tolerance of fetuses. Macrophages are the most common immune cells within the ruminant endometrium. Nevertheless, deeply analyzing the mechanisms of IFN-τ regulating macrophage polarization still needs further study. In this study, a notable decline of bta-miR-30b-5p expression via the increase of SOCS1 was observed in uterine tissues of pregnant cows. We then confirmed that the 3'UTR of SOCS1 was to be directly targeted by bta-miR-30b-5p. After that, we demonstrated that this obviously promoted the bovine macrophages (BoMac) polarized to M2 through enhancing SOCS1 expression with the treatment of IFN-τ. Furthermore, we found that SOCS1 restrained the expression of the key proteins p65 and p-P65 in the NF-κB pathway. Causing, the wide range of cross-species activities of IFN-τ, therefore we established a pregnant mouse model for the future confirmation of the above mechanism. The results verified that IFN-τ significantly improved this mechanism and maintained normal pregnancy status in mice, but miR-30b-5p significantly reduced the M2 polarization by inhibiting SOCS1, which activated the NF-κB signaling pathway, and then leading to the failure of embryo implantation. All these results indicated that IFN-τ can regulate immune tolerance during pregnancy by promoting M2 macrophage polarization through inhibiting bta-miR-30b-5p targeting SOCS1 to deactivate the NF-κB signaling pathway.
Collapse
Affiliation(s)
| | | | | | | | | | | | - Ming Xu
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China; (X.F.); (C.Y.); (T.W.); (J.Z.); (H.Z.); (B.M.)
| | - Ganzhen Deng
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China; (X.F.); (C.Y.); (T.W.); (J.Z.); (H.Z.); (B.M.)
| |
Collapse
|
|
3
|
Manoharan S, Perumal E. A strategic review of STAT3 signaling inhibition by phytochemicals for cancer prevention and treatment: Advances and insights. Fitoterapia 2024; 179:106265. [PMID: 39437855 DOI: 10.1016/j.fitote.2024.106265] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2024] [Revised: 10/15/2024] [Accepted: 10/17/2024] [Indexed: 10/25/2024]
Abstract
Cancer remains a significant global health concern. The dysregulation of signaling networks in tumor cells greatly affects their functions. This review intends to explore phytochemicals possessing potent anticancer properties that specifically target the STAT3 signaling pathway, elucidating strategies and emphasizing their potential as promising candidates for cancer therapy. The review comprehensively examines various STAT3 inhibitors designed to disrupt the signaling cascade, including those targeting upstream activation, SH2 domain phosphorylation, DNA binding domain (DBD), N-terminal domain (NTD), nuclear translocation, and enhancing endogenous STAT3 negative regulators. A literature review was conducted to identify phytochemicals with anticancer activity targeting the STAT3 signaling pathway. Popular research databases such as Google Scholar, PubMed, Science Direct, Scopus, Web of Science, and ResearchGate were searched from the years 1989 - 2023 based on the keywords "Cancer", "STAT3", "Phytochemicals", "Phytochemicals targeting STAT3 signaling", "upstream activation of STAT3", "SH2 domain of STAT3", "DBD of STAT3", "NTD of STAT3, "endogenous negative regulators of STAT3", or "nuclear translocation of STAT3", and their combinations. A total of 264 relevant studies were selected and analyzed based on the mechanisms of action and the efficacy of the phytocompounds. The majority of the discussed phytochemicals primarily focus on inhibiting upstream activation of STAT3. Additionally, flavonoid and terpenoid compounds exhibit multifaceted effects by targeting one or more checkpoints within the STAT3 pathway. Analysis reveals that phytochemicals targeting upstream activation predominantly belong to the classes of flavonoids and terpenoids, which hold significant promise as effective anticancer therapeutics. Future research in this field can be directed towards exploring and developing these scrutinized classes of phytochemicals to achieve desired therapeutic outcomes in cancer treatment.
Collapse
Affiliation(s)
- Suryaa Manoharan
- Molecular Toxicology Laboratory, Department of Biotechnology, Bharathiar University, Coimbatore 641 046, India
| | - Ekambaram Perumal
- Molecular Toxicology Laboratory, Department of Biotechnology, Bharathiar University, Coimbatore 641 046, India.
| |
Collapse
|
|
4
|
Limanaqi F, Zecchini S, Ogno P, Artusa V, Fenizia C, Saulle I, Vanetti C, Garziano M, Strizzi S, Trabattoni D, Clerici M, Biasin M. Alpha-synuclein shapes monocyte and macrophage cell biology and functions by bridging alterations of autophagy and inflammatory pathways. Front Cell Dev Biol 2024; 12:1421360. [PMID: 39035028 PMCID: PMC11257978 DOI: 10.3389/fcell.2024.1421360] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2024] [Accepted: 06/17/2024] [Indexed: 07/23/2024] Open
Abstract
Introduction: Abnormal spreading of alpha-synuclein (αS), a hallmark of Parkinson's disease, is known to promote peripheral inflammation, which occurs in part via functional alterations in monocytes/macrophages. However, underlying intracellular mechanisms remain unclear. Methods: Herein we investigate the subcellular, molecular, and functional effects of excess αS in human THP-1 monocytic cell line, THP-1-derived macrophages, and at least preliminarily, in primary monocyte-derived macrophages (MDMs). In cells cultured w/wo recombinant αS (1 μM) for 4 h and 24 h, by Confocal microscopy, Western Blot, RT-qPCR, Elisa, and Flow Cytometry we assessed: i) αS internalization; ii) cytokine/chemokine expression/secretion, and C-C motif chemokine receptor 2 (CCR2) levels; iii) autophagy (LC3II/I, LAMP1/LysoTracker, p62, pS6/total S6); and iv) lipid droplets (LDs) accumulation, and cholesterol pathway gene expression. Transwell migration assay was employed to measure THP-1 cell migration/chemotaxis, while FITC-IgG-bead assay was used to analyze phagocytic capacity, and the fate of phagocytosed cargo in THP-1-derived macrophages. Results: Extracellular αS was internalized by THP-1 cells, THP-1-derived macrophages, and MDMs. In THP1 cells, αS induced a general pro-inflammatory profile and conditioned media from αS-exposed THP-1 cells potently attracted unstimulated cells. However, CCL2 secretion peaked at 4 h αS, consistent with early internalization of its receptor CCR2, while this was blunted at 24 h αS exposure, when CCR2 recycled back to the plasma membrane. Again, 4 h αS-exposed THP-1 cells showed increased spontaneous migration, while 24 h αS-exposed cells showed reduced chemotaxis. This occurred in the absence of cell toxicity and was associated with upregulation of autophagy/lysosomal markers, suggesting a pro-survival/tolerance mechanism against stress-related inflammation. Instead, in THP-1-derived macrophages, αS time-dependently potentiated the intracellular accumulation, and release of pro-inflammatory mediators. This was accompanied by mild toxicity, reduced autophagy-lysosomal markers, defective LDs formation, as well as impaired phagocytosis, and the appearance of stagnant lysosomes engulfed with phagocytosed cargo, suggesting a status of macrophage exhaustion reminiscent of hypophagia. Discussion: In summary, despite an apparently similar pro-inflammatory phenotype, monocytes and macrophages respond differently to intracellular αS accumulation in terms of cell survival, metabolism, and functions. Our results suggest that in periphery, αS exerts cell- and context-specific biological effects bridging alterations of autophagy, lipid dynamics, and inflammatory pathways.
Collapse
Affiliation(s)
- Fiona Limanaqi
- Department of Biomedical and Clinical Sciences, University of Milan, Milan, Italy
| | - Silvia Zecchini
- Department of Biomedical and Clinical Sciences, University of Milan, Milan, Italy
| | - Pasquale Ogno
- Department of Biomedical and Clinical Sciences, University of Milan, Milan, Italy
| | - Valentina Artusa
- Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy
| | - Claudio Fenizia
- Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy
| | - Irma Saulle
- Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy
| | - Claudia Vanetti
- Department of Biomedical and Clinical Sciences, University of Milan, Milan, Italy
| | - Micaela Garziano
- Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy
| | - Sergio Strizzi
- Department of Biomedical and Clinical Sciences, University of Milan, Milan, Italy
| | - Daria Trabattoni
- Department of Biomedical and Clinical Sciences, University of Milan, Milan, Italy
| | - Mario Clerici
- Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy
- IRCCS Fondazione Don Carlo Gnocchi, Milan, Italy
| | - Mara Biasin
- Department of Biomedical and Clinical Sciences, University of Milan, Milan, Italy
| |
Collapse
|
|
5
|
Baumgarth N, Prieto AC, Luo Z, Kulaga H. B cells modulate lung antiviral inflammatory responses via the neurotransmitter acetylcholine. RESEARCH SQUARE 2024:rs.3.rs-4421566. [PMID: 38978583 PMCID: PMC11230464 DOI: 10.21203/rs.3.rs-4421566/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/10/2024]
Abstract
The rapid onset of innate immune defenses is critical for early control of viral replication in an infected host, yet it can also lead to irreversible tissue damage, especially in the respiratory tract. Intricate regulatory mechanisms must exist that modulate inflammation, while controlling the infection. Here, B cells expressing choline acetyl transferase (ChAT), an enzyme required for production of the metabolite and neurotransmitter acetylcholine (ACh) are identified as such regulators of the immediate early response to influenza A virus. Lung tissue ChAT + B cells are shown to interact with a7 nicotinic Ach receptor-expressing lung interstitial macrophages in mice within 24h of infection to control their production of TNFa, shifting the balance towards reduced inflammation at the cost of enhanced viral replication. Thus, innate-stimulated B cells are key participants of an immediate-early regulatory cascade that controls lung tissue damage after viral infection.
Collapse
|
|
6
|
Vitali E, Valente G, Panzardi A, Laffi A, Zerbi A, Uccella S, Mazziotti G, Lania A. Pancreatic neuroendocrine tumor progression and resistance to everolimus: the crucial role of NF-kB and STAT3 interplay. J Endocrinol Invest 2024; 47:1101-1117. [PMID: 37882947 DOI: 10.1007/s40618-023-02221-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2023] [Accepted: 10/09/2023] [Indexed: 10/27/2023]
Abstract
PURPOSE The finding of mTOR overactivation in patients affected by pancreatic neuroendocrine tumors (Pa-NETs) led to their treatment with the mTOR inhibitor everolimus. Unfortunately, the efficacy of everolimus is restricted by the occurrence of resistance. The mechanisms leading to Pa-NETs' progression and resistance are not well understood. Notably, chronic inflammation is implicated in NET development. NF-kB is involved in inflammation and drug resistance mechanisms through the activation of several mediators, including STAT3. In this respect, NF-κB and STAT3 interaction is implicated in the crosstalk between inflammatory and tumor cells. METHODS We investigated the expression of NF-kB in different Pa-NETs by RT-qPCR and immunohistochemistry. Then, we studied the role of NF-κB and STAT3 interplay in QGP-1 cells. Subsequently, we assessed the impact of NF-κB and STAT3 inhibitors in QGP-1 cell proliferation and spheroids growth. Finally, we evaluated the implication of the NF-kB pathway in everolimus-resistant Pa-NET cells. RESULTS We found that the increased NF-kB expression correlates with a higher grade in Pa-NETs. The activation of the STAT3 pathway induced by TNFα is mediated by NF-kB p65. NF-kB p65 and STAT3 inhibitors decrease QGP-1 viability, spheroids growth, and Pa-NETs cell proliferation. These effects are maintained in everolimus-resistant QGP-1R cells. Interestingly, we found that NF-kB, STAT3, IL-8, and SOCS3 are overexpressed in QGP-1R compared to QGP-1. CONCLUSION Since the NF-kB pathway is implicated in Pa-NETs' progression and resistance to everolimus, these data could explain the potential use of NF-kB as a novel therapeutic target in Pa-NET patients.
Collapse
Affiliation(s)
- E Vitali
- Laboratory of Cellular and Molecular Endocrinology, IRCCS Humanitas Research Hospital, Manzoni 56, 20089, Rozzano, Milan, Italy.
| | - G Valente
- Laboratory of Cellular and Molecular Endocrinology, IRCCS Humanitas Research Hospital, Manzoni 56, 20089, Rozzano, Milan, Italy
| | - A Panzardi
- Laboratory of Cellular and Molecular Endocrinology, IRCCS Humanitas Research Hospital, Manzoni 56, 20089, Rozzano, Milan, Italy
| | - A Laffi
- Oncology Unit, IRCCS Humanitas Research Hospital, Manzoni 56, 20089, Rozzano, Milan, Italy
| | - A Zerbi
- Department of Biomedical Sciences, Humanitas University, Rita Levi Montalcini 4, 20072, Pieve Emanuele, Milan, Italy
- Surgery Unit, IRCCS Humanitas Research Hospital, Manzoni 56, 20089, Rozzano, Milan, Italy
| | - S Uccella
- Department of Biomedical Sciences, Humanitas University, Rita Levi Montalcini 4, 20072, Pieve Emanuele, Milan, Italy
- Pathology Unit, IRCCS Humanitas Research Hospital, Manzoni 56, 20089, Rozzano, ilan, Italy
| | - G Mazziotti
- Department of Biomedical Sciences, Humanitas University, Rita Levi Montalcini 4, 20072, Pieve Emanuele, Milan, Italy
- Endocrinology, Diabetology and Andrology Unit, IRCCS Humanitas Research Hospital, Manzoni 54, 20089, Rozzano, Milan, Italy
| | - A Lania
- Department of Biomedical Sciences, Humanitas University, Rita Levi Montalcini 4, 20072, Pieve Emanuele, Milan, Italy
- Endocrinology, Diabetology and Andrology Unit, IRCCS Humanitas Research Hospital, Manzoni 54, 20089, Rozzano, Milan, Italy
| |
Collapse
|
|
7
|
Huang X, Liu W. Role of microRNAs in host defense against porcine reproductive and respiratory syndrome virus infection: a hidden front line. Front Immunol 2024; 15:1376958. [PMID: 38590524 PMCID: PMC10999632 DOI: 10.3389/fimmu.2024.1376958] [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: 01/26/2024] [Accepted: 03/13/2024] [Indexed: 04/10/2024] Open
Abstract
Porcine reproductive and respiratory syndrome virus (PRRSV) is one of the most globally devastating viruses threatening the swine industry worldwide. Substantial advancements have been achieved in recent years towards comprehending the pathogenesis of PRRSV infection and the host response, involving both innate and adaptive immune responses. Not only a multitude of host proteins actively participate in intricate interactions with viral proteins, but microRNAs (miRNAs) also play a pivotal role in the host response to PRRSV infection. If a PRRSV-host interaction at the protein level is conceptualized as the front line of the battle between pathogens and host cells, then their fight at the RNA level resembles the hidden front line. miRNAs are endogenous small non-coding RNAs of approximately 20-25 nucleotides (nt) that primarily regulate the degradation or translation inhibition of target genes by binding to the 3'-untranslated regions (UTRs). Insights into the roles played by viral proteins and miRNAs in the host response can enhance our comprehensive understanding of the pathogenesis of PRRSV infection. The intricate interplay between viral proteins and cellular targets during PRRSV infection has been extensively explored. This review predominantly centers on the contemporary understanding of the host response to PRRSV infection at the RNA level, in particular, focusing on the twenty-six miRNAs that affect viral replication and the innate immune response.
Collapse
Affiliation(s)
- Xuewei Huang
- College of Veterinary Medicine, Qingdao Agricultural University, Qingdao, China
| | | |
Collapse
|
|
8
|
Cianciulli A, Calvello R, Porro C, Lofrumento DD, Panaro MA. Inflammatory Skin Diseases: Focus on the Role of Suppressors of Cytokine Signaling (SOCS) Proteins. Cells 2024; 13:505. [PMID: 38534350 PMCID: PMC10968894 DOI: 10.3390/cells13060505] [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: 01/30/2024] [Revised: 03/05/2024] [Accepted: 03/12/2024] [Indexed: 03/28/2024] Open
Abstract
Inflammatory skin diseases include a series of disorders characterized by a strong activation of the innate and adaptive immune system in which proinflammatory cytokines play a fundamental role in supporting inflammation. Skin inflammation is a complex process influenced by various factors, including genetic and environmental factors, characterized by the dysfunction of both immune and non-immune cells. Psoriasis (PS) and atopic dermatitis (AD) are the most common chronic inflammatory conditions of the skin whose pathogeneses are very complex and multifactorial. Both diseases are characterized by an immunological dysfunction involving a predominance of Th1 and Th17 cells in PS and of Th2 cells in AD. Suppressor of cytokine signaling (SOCS) proteins are intracellular proteins that control inflammatory responses by regulating various signaling pathways activated by proinflammatory cytokines. SOCS signaling is involved in the regulation and progression of inflammatory responses in skin-resident and non-resident immune cells, and recent data suggest that these negative modulators are dysregulated in inflammatory skin diseases such as PS and AD. This review focuses on the current understanding about the role of SOCS proteins in modulating the activity of inflammatory mediators implicated in the pathogenesis of inflammatory skin diseases such as PS and AD.
Collapse
Affiliation(s)
- Antonia Cianciulli
- Department of Biosciences, Biotechnologies and Environment, University of Bari, I-70125 Bari, Italy; (A.C.); (R.C.)
| | - Rosa Calvello
- Department of Biosciences, Biotechnologies and Environment, University of Bari, I-70125 Bari, Italy; (A.C.); (R.C.)
| | - Chiara Porro
- Department of Clinical and Experimental Medicine, University of Foggia, I-71100 Foggia, Italy;
| | - Dario Domenico Lofrumento
- Department of Biological and Environmental Sciences and Technologies, Section of Human Anatomy, University of Salento, I-73100 Lecce, Italy;
| | - Maria Antonietta Panaro
- Department of Biosciences, Biotechnologies and Environment, University of Bari, I-70125 Bari, Italy; (A.C.); (R.C.)
| |
Collapse
|
|
9
|
Manoharan S, Saha S, Murugesan K, Santhakumar A, Perumal E. Natural bioactive compounds and STAT3 against hepatocellular carcinoma: An update. Life Sci 2024; 337:122351. [PMID: 38103726 DOI: 10.1016/j.lfs.2023.122351] [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: 09/17/2023] [Revised: 11/23/2023] [Accepted: 12/11/2023] [Indexed: 12/19/2023]
Abstract
Hepatocellular carcinoma (HCC) is a challenging and very fatal liver cancer. The signal transducer and activator of transcription 3 (STAT3) pathway is a crucial regulator of tumor development and are ubiquitously active in HCC. Therefore, targeting STAT3 has emerged as a promising approach for preventing and treating HCC. Various natural bioactive compounds (NBCs) have been proven to target STAT3 and have the potential to prevent and treat HCC as STAT3 inhibitors. Numerous kinds of STAT3 inhibitors have been identified, including small molecule inhibitors, peptide inhibitors, and oligonucleotide inhibitors. Due to the undesirable side effects of the conventional therapeutic drugs against HCC, the focus is shifted to NBCs derived from plants and other natural sources. NBCs can be broadly classified into the categories of terpenes, alkaloids, carotenoids, and phenols. Most of the compounds belong to the family of terpenes, which prevent tumorigenesis by inhibiting STAT3 nuclear translocation. Further, through STAT3 inhibition, terpenes downregulate matrix metalloprotease 2 (MMP2), matrix metalloprotease 9 (MMP9) and vascular endothelial growth factor (VEGF), modulating metastasis. Terpenes also suppress the anti-apoptotic proteins and cell cycle markers. This review provides comprehensive information related to STAT3 abrogation by NBCs in HCC with in vitro and in vivo evidences.
Collapse
Affiliation(s)
- Suryaa Manoharan
- Molecular Toxicology Laboratory, Department of Biotechnology, Bharathiar University, Coimbatore 641 046, India
| | - Shreejit Saha
- Molecular Toxicology Laboratory, Department of Biotechnology, Bharathiar University, Coimbatore 641 046, India
| | - Krishnasanthiya Murugesan
- Molecular Toxicology Laboratory, Department of Biotechnology, Bharathiar University, Coimbatore 641 046, India
| | - Aksayakeerthana Santhakumar
- Molecular Toxicology Laboratory, Department of Biotechnology, Bharathiar University, Coimbatore 641 046, India
| | - Ekambaram Perumal
- Molecular Toxicology Laboratory, Department of Biotechnology, Bharathiar University, Coimbatore 641 046, India.
| |
Collapse
|
|
10
|
You Y, Kim SH, Kim CH, Kim IH, Shin Y, Kim TR, Sohn M, Park J. Immune-Stimulating Potential of Lacticaseibacillus rhamnosus LM1019 in RAW 264.7 Cells and Immunosuppressed Mice Induced by Cyclophosphamide. Microorganisms 2023; 11:2312. [PMID: 37764156 PMCID: PMC10535240 DOI: 10.3390/microorganisms11092312] [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: 08/14/2023] [Revised: 09/08/2023] [Accepted: 09/08/2023] [Indexed: 09/29/2023] Open
Abstract
Probiotics, including Lacticaseibacillus rhamnosus (L. rhamnosus), have gained recognition for their potential health benefits, such as enhancing immune function, maintaining gut health, and improving nutrient absorption. This study investigated the effectiveness of L. rhamnosus LM1019 (LM1019) in enhancing immune function. In RAW 264.7 cells, LM1019 demonstrated dose-dependent immune stimulation by increasing nitric oxide production, gene expression of proinflammatory cytokines, and the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). These effects were mediated through the activation of mitogen-activated protein kinases (MAPKs) and nuclear factor-kappa B (NF-κB) translocation without inducing cytotoxicity. Furthermore, orally administered LM1019 was evaluated in immunosuppressed mice induced by cyclophosphamide (CTX). High-dose administration of LM1019 significantly increased the subpopulations of lymphocytes, specifically helper T cells (CD4+), as well as two subtypes of natural killer (NK) cells, namely, IFN-γ+ and granzyme B+ NK cells. Additionally, LM1019 at a high dose led to elevated levels of proinflammatory cytokines, including IFN-γ and IL-12, compared to CTX-treated mice. These findings highlight the potential of LM1019 in enhancing the immune system. The study contributes to the growing body of research on the beneficial effects of probiotics on immune function.
Collapse
Affiliation(s)
- Yeji You
- Microbiome R&D Center, Lactomason Co., Ltd., Jinju 52840, Republic of Korea; (Y.Y.); (T.-R.K.); (M.S.)
| | - Sung-Hwan Kim
- Food Research Center, Binggrae Co., Ltd., Namyangju 12253, Republic of Korea; (S.-H.K.); (C.-H.K.); (I.-H.K.); (Y.S.)
| | - Chul-Hong Kim
- Food Research Center, Binggrae Co., Ltd., Namyangju 12253, Republic of Korea; (S.-H.K.); (C.-H.K.); (I.-H.K.); (Y.S.)
| | - In-Hwan Kim
- Food Research Center, Binggrae Co., Ltd., Namyangju 12253, Republic of Korea; (S.-H.K.); (C.-H.K.); (I.-H.K.); (Y.S.)
| | - YoungSup Shin
- Food Research Center, Binggrae Co., Ltd., Namyangju 12253, Republic of Korea; (S.-H.K.); (C.-H.K.); (I.-H.K.); (Y.S.)
| | - Tae-Rahk Kim
- Microbiome R&D Center, Lactomason Co., Ltd., Jinju 52840, Republic of Korea; (Y.Y.); (T.-R.K.); (M.S.)
| | - Minn Sohn
- Microbiome R&D Center, Lactomason Co., Ltd., Jinju 52840, Republic of Korea; (Y.Y.); (T.-R.K.); (M.S.)
| | - Jeseong Park
- Microbiome R&D Center, Lactomason Co., Ltd., Jinju 52840, Republic of Korea; (Y.Y.); (T.-R.K.); (M.S.)
| |
Collapse
|
|
11
|
Li Q, Liu X, Yan C, Zhao B, Zhao Y, Yang L, Shi M, Yu H, Li X, Luo K. Polysaccharide-Based Stimulus-Responsive Nanomedicines for Combination Cancer Immunotherapy. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2023; 19:e2206211. [PMID: 36890780 DOI: 10.1002/smll.202206211] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/09/2022] [Revised: 02/09/2023] [Indexed: 06/08/2023]
Abstract
Cancer immunotherapy is a promising antitumor approach, whereas nontherapeutic side effects, tumor microenvironment (TME) intricacy, and low tumor immunogenicity limit its therapeutic efficacy. In recent years, combination immunotherapy with other therapies has been proven to considerably increase antitumor efficacy. However, achieving codelivery of the drugs to the tumor site remains a major challenge. Stimulus-responsive nanodelivery systems show controlled drug delivery and precise drug release. Polysaccharides, a family of potential biomaterials, are widely used in the development of stimulus-responsive nanomedicines due to their unique physicochemical properties, biocompatibility, and modifiability. Here, the antitumor activity of polysaccharides and several combined immunotherapy strategies (e.g., immunotherapy combined with chemotherapy, photodynamic therapy, or photothermal therapy) are summarized. More importantly, the recent progress of polysaccharide-based stimulus-responsive nanomedicines for combination cancer immunotherapy is discussed, with the focus on construction of nanomedicine, targeted delivery, drug release, and enhanced antitumor effects. Finally, the limitations and application prospects of this new field are discussed.
Collapse
Affiliation(s)
- Qiuxia Li
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611130, China
| | - Xing Liu
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611130, China
| | - Chunmei Yan
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611130, China
| | - Bolin Zhao
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611130, China
| | - Yuxin Zhao
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611130, China
| | - Lu Yang
- Innovative Institute of Chinese Medicine and Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Mingyi Shi
- School of Intelligent Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Hua Yu
- Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Taipa, Macao SAR, 999078, China
| | - Xiaofang Li
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611130, China
| | - Kaipei Luo
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611130, China
| |
Collapse
|
|
12
|
Wilder CL, Lefaudeux D, Mathenge R, Kishimoto K, Zuniga Munoz A, Nguyen MA, Meyer AS, Cheng QJ, Hoffmann A. A stimulus-contingent positive feedback loop enables IFN-β dose-dependent activation of pro-inflammatory genes. Mol Syst Biol 2023; 19:e11294. [PMID: 36929731 PMCID: PMC10167482 DOI: 10.15252/msb.202211294] [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: 08/10/2022] [Revised: 02/28/2023] [Accepted: 03/01/2023] [Indexed: 03/18/2023] Open
Abstract
Type I interferons (IFN) induce powerful antiviral and innate immune responses via the transcription factor, IFN-stimulated gene factor (ISGF3). However, in some pathological contexts, type I IFNs are responsible for exacerbating inflammation. Here, we show that a high dose of IFN-β also activates an inflammatory gene expression program in contrast to IFN-λ3, a type III IFN, which elicits only the common antiviral gene program. We show that the inflammatory gene program depends on a second, potentiated phase in ISGF3 activation. Iterating between mathematical modeling and experimental analysis, we show that the ISGF3 activation network may engage a positive feedback loop with its subunits IRF9 and STAT2. This network motif mediates stimulus-specific ISGF3 dynamics that are dependent on ligand, dose, and duration of exposure, and when engaged activates the inflammatory gene expression program. Our results reveal a previously underappreciated dynamical control of the JAK-STAT/IRF signaling network that may produce distinct biological responses and suggest that studies of type I IFN dysregulation, and in turn therapeutic remedies, may focus on feedback regulators within it.
Collapse
Affiliation(s)
- Catera L Wilder
- Department of Microbiology, Immunology, and Molecular GeneticsUniversity of CaliforniaLos AngelesCAUSA
- Present address:
Department of Bioengineering and Therapeutic SciencesUniversity of California, San FranciscoSan FranciscoCAUSA
| | - Diane Lefaudeux
- Department of Microbiology, Immunology, and Molecular GeneticsUniversity of CaliforniaLos AngelesCAUSA
- Present address:
Novadiscovery S.A.LyonFrance
| | - Raisa Mathenge
- Department of Microbiology, Immunology, and Molecular GeneticsUniversity of CaliforniaLos AngelesCAUSA
- Present address:
Division of RheumatologyUniversity of California, San FranciscoSan FranciscoCAUSA
| | - Kensei Kishimoto
- Department of Microbiology, Immunology, and Molecular GeneticsUniversity of CaliforniaLos AngelesCAUSA
- Present address:
Department of Molecular, Cell, and Cancer BiologyUniversity of Massachusetts Chan Medical SchoolWorcesterMAUSA
| | - Alma Zuniga Munoz
- Department of Microbiology, Immunology, and Molecular GeneticsUniversity of CaliforniaLos AngelesCAUSA
- Present address:
Department of Physiology and BiophysicsUniversity of Southern CaliforniaLos AngelesCAUSA
| | - Minh A Nguyen
- Department of Microbiology, Immunology, and Molecular GeneticsUniversity of CaliforniaLos AngelesCAUSA
- Present address:
Division of Genetics and Genomics, Department of PediatricsBoston Children's HospitalBostonMAUSA
| | - Aaron S Meyer
- Department of BioengineeringUniversity of CaliforniaLos AngelesCAUSA
| | - Quen J Cheng
- Department of Microbiology, Immunology, and Molecular GeneticsUniversity of CaliforniaLos AngelesCAUSA
- Division of Infectious Diseases, Department of MedicineUniversity of CaliforniaLos AngelesCAUSA
| | - Alexander Hoffmann
- Department of Microbiology, Immunology, and Molecular GeneticsUniversity of CaliforniaLos AngelesCAUSA
| |
Collapse
|
|
13
|
Li F, Zhang Y, Wang ZH, Gao S, Fan YC, Wang K. SOCS1 methylation level is associated with prognosis in patients with acute-on-chronic hepatitis B liver failure. Clin Epigenetics 2023; 15:79. [PMID: 37149648 PMCID: PMC10163770 DOI: 10.1186/s13148-023-01495-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Accepted: 04/28/2023] [Indexed: 05/08/2023] Open
Abstract
BACKGROUND Glucocorticoids could greatly improve the prognosis of patients with acute-on-chronic hepatitis B liver failure (ACHBLF). Suppressor of cytokine signaling (SOCS) 1 methylation has been shown to be associated with mortality in ACHBLF. METHODS Eighty patients with ACHBLF were divided into group glucocorticoid (GC) and group conservative medical (CM). Sixty patients with chronic hepatitis B (CHB), and Thirty healthy controls (HCs) served as control group. SOCS1 methylation levels in peripheral mononuclear cells (PBMCs) was detected by MethyLight. RESULTS SOCS1 methylation levels were significantly higher in patients with ACHBLF than those with CHB and HCs (P < 0.01, respectively). Nonsurvivors showed significantly higher SOCS1 methylation levels (P < 0.05) than survivors in both GC and CM groups in ACHBLF patients. Furthermore, the survival rates of the SOCS1 methylation-negative group were significantly higher than that of the methylation-positive group at 1 month (P = 0.014) and 3 months (P = 0.003) follow-up. Meanwhile, GC group and CM group had significantly lower mortality at 3 months, which may be related to application of glucocorticoid. In the SOCS1 methylation-positive group, the 1-month survival rate was significantly improved, which may be related to GC treatment (P = 0.020). However, no significant difference could be observed between the GC group and CM group in the methylation-negative group (P = 0.190). CONCLUSIONS GC treatment could decrease the mortality of ACHBLF and SOCS1 methylation levels might serve as prognostic marker for favorable response to glucocorticoid treatment.
Collapse
Affiliation(s)
- Feng Li
- Department of Hepatology, Qilu Hospital of Shandong University, Wenhuaxi Road 107#, Jinan, 250012, Shandong, China
| | - Ying Zhang
- Department of Hepatology, Qilu Hospital of Shandong University, Wenhuaxi Road 107#, Jinan, 250012, Shandong, China
| | - Zhao-Hui Wang
- Department of Hepatology, Qilu Hospital of Shandong University, Wenhuaxi Road 107#, Jinan, 250012, Shandong, China
| | - Shuai Gao
- Department of Hepatology, Qilu Hospital of Shandong University, Wenhuaxi Road 107#, Jinan, 250012, Shandong, China
- Hepatology Institute of Shandong University, Jinan, 250012, China
| | - Yu-Chen Fan
- Department of Hepatology, Qilu Hospital of Shandong University, Wenhuaxi Road 107#, Jinan, 250012, Shandong, China
- Hepatology Institute of Shandong University, Jinan, 250012, China
| | - Kai Wang
- Department of Hepatology, Qilu Hospital of Shandong University, Wenhuaxi Road 107#, Jinan, 250012, Shandong, China.
- Hepatology Institute of Shandong University, Jinan, 250012, China.
| |
Collapse
|
|
14
|
Li X, Yang Z, Chen B, Gu L, Tian G, Sui X. SOCS3 as a potential driver of lung metastasis in colon cancer patients. Front Immunol 2023; 14:1088542. [PMID: 37025997 PMCID: PMC10070831 DOI: 10.3389/fimmu.2023.1088542] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Accepted: 02/23/2023] [Indexed: 04/08/2023] Open
Abstract
Background The suppressor of cytokine signaling 3 (SOCS3) is the negative feedback regulator of the JAK-STAT signaling pathway. The purpose of our study was to investigate the SOCS3 status in colon primary tumor and lung metastasis and its relationship with macrophages. Methods The SOCS3 expression pattern and its relationship with the immune response in pan-cancer was investigated using multiple methods. Samples and corresponding clinical information of 32 colon cancer patients with lung metastasis were collected, and the CD68, CD163, and SOCS3 status were conducted using immunohistochemistry (IHC). The relationship between SOCS3 status and macrophage markers was analyzed. Besides, we explored the molecular mechanisms of SOCS3 in lung metastasis via the TCGA database. Results High SOCS3 expression was more inclined to poor prognosis and was positively correlated with main immune cell infiltration in almost each cancer type, especially in colon cancer. Compared with the colon primary tumor, lung metastasis harbored higher CD163 and SOCS3 expression, and high SOCS3 expression was more likely to be associated with high CD163 expression in lung metastasis. Besides, the exceptional differentially expressed genes in lung metastasis significantly enriched in immune responses and regulations. Conclusions SOCS3 possessed value as a prognostic marker and target for immunotherapeutic intervention in different tumors and might be a potential target of tumor progression and tumor immunotherapy in colon cancer.
Collapse
Affiliation(s)
- Xuejie Li
- Department of Pathology, The First Affiliated Hospital of Medical School of Zhejiang University, Hangzhou, China
| | - Zuyi Yang
- Department of Hematology and Oncology, the Affiliated Hospital of Hangzhou Normal University, College of Medicine, Hangzhou Normal University, Hangzhou, China
| | - Bi Chen
- School of Pharmacy, Hangzhou Normal University, Hangzhou, China
- Key Laboratory of Elemene Class Anti-cancer Chinese Medicine of Zhejiang Province, Hangzhou Normal University, Hangzhou, China
| | - Lei Gu
- Department of Hematology and Oncology, the Affiliated Hospital of Hangzhou Normal University, College of Medicine, Hangzhou Normal University, Hangzhou, China
| | - Guoyan Tian
- Department of Hematology and Oncology, the Affiliated Hospital of Hangzhou Normal University, College of Medicine, Hangzhou Normal University, Hangzhou, China
| | - Xinbing Sui
- School of Pharmacy, Hangzhou Normal University, Hangzhou, China
- Key Laboratory of Elemene Class Anti-cancer Chinese Medicine of Zhejiang Province, Hangzhou Normal University, Hangzhou, China
| |
Collapse
|
|
15
|
Zhang Y, Li BX, Mao QZ, Zhuo JC, Huang HJ, Lu JB, Zhang CX, Li JM, Chen JP, Lu G. The JAK-STAT pathway promotes persistent viral infection by activating apoptosis in insect vectors. PLoS Pathog 2023; 19:e1011266. [PMID: 36928081 PMCID: PMC10069781 DOI: 10.1371/journal.ppat.1011266] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2023] [Revised: 04/03/2023] [Accepted: 03/04/2023] [Indexed: 03/18/2023] Open
Abstract
The Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway is an evolutionarily conserved signaling pathway that can regulate various biological processes. However, the role of JAK-STAT pathway in the persistent viral infection in insect vectors has rarely been investigated. Here, using a system that comprised two different plant viruses, Rice stripe virus (RSV) and Rice black-streaked dwarf virus (RBSDV), as well as their insect vector small brown planthopper, we elucidated the regulatory mechanism of JAK-STAT pathway in persistent viral infection. Both RSV and RBSDV infection activated the JAK-STAT pathway and promoted the accumulation of suppressor of cytokine signaling 5 (SOCS5), an E3 ubiquitin ligase regulated by the transcription factor STAT5B. Interestingly, the virus-induced SOCS5 directly interacted with the anti-apoptotic B-cell lymphoma-2 (BCL2) to accelerate the BCL2 degradation through the 26S proteasome pathway. As a result, the activation of apoptosis facilitated persistent viral infection in their vector. Furthermore, STAT5B activation promoted virus amplification, whereas STAT5B suppression inhibited apoptosis and reduced virus accumulation. In summary, our results reveal that virus-induced JAK-STAT pathway regulates apoptosis to promote viral infection, and uncover a new regulatory mechanism of the JAK-STAT pathway in the persistent plant virus transmission by arthropod vectors.
Collapse
Affiliation(s)
- Yan Zhang
- College of Plant Protection, Northwest Agriculture and Forestry University, Yangling, Shaanxi, China
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Key Laboratory of Biotechnology in Plant Protection of MARA and Zhejiang Province, Institute of Plant Virology, Ningbo University, Ningbo, China
| | - Bo-Xue Li
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Key Laboratory of Biotechnology in Plant Protection of MARA and Zhejiang Province, Institute of Plant Virology, Ningbo University, Ningbo, China
| | - Qian-Zhuo Mao
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Key Laboratory of Biotechnology in Plant Protection of MARA and Zhejiang Province, Institute of Plant Virology, Ningbo University, Ningbo, China
| | - Ji-Chong Zhuo
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Key Laboratory of Biotechnology in Plant Protection of MARA and Zhejiang Province, Institute of Plant Virology, Ningbo University, Ningbo, China
| | - Hai-Jian Huang
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Key Laboratory of Biotechnology in Plant Protection of MARA and Zhejiang Province, Institute of Plant Virology, Ningbo University, Ningbo, China
| | - Jia-Bao Lu
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Key Laboratory of Biotechnology in Plant Protection of MARA and Zhejiang Province, Institute of Plant Virology, Ningbo University, Ningbo, China
| | - Chuan-Xi Zhang
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Key Laboratory of Biotechnology in Plant Protection of MARA and Zhejiang Province, Institute of Plant Virology, Ningbo University, Ningbo, China
| | - Jun-Min Li
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Key Laboratory of Biotechnology in Plant Protection of MARA and Zhejiang Province, Institute of Plant Virology, Ningbo University, Ningbo, China
| | - Jian-Ping Chen
- College of Plant Protection, Northwest Agriculture and Forestry University, Yangling, Shaanxi, China
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Key Laboratory of Biotechnology in Plant Protection of MARA and Zhejiang Province, Institute of Plant Virology, Ningbo University, Ningbo, China
- * E-mail: (J-PC); (GL)
| | - Gang Lu
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Key Laboratory of Biotechnology in Plant Protection of MARA and Zhejiang Province, Institute of Plant Virology, Ningbo University, Ningbo, China
- * E-mail: (J-PC); (GL)
| |
Collapse
|
|
16
|
Sumiya K, Izumi H, Sakurai K. Enhanced Therapeutic Efficacy of Immunostimulatory CpG-ODN by Silencing SOCS-1 with Polysaccharide/miR-155 Complexes. ACS APPLIED BIO MATERIALS 2023; 6:774-783. [PMID: 36632777 DOI: 10.1021/acsabm.2c00963] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
For the induction of antigen-specific immune responses, adjuvants as well as antigens are essential. CpG-ODN is a potent agonist of toll-like receptor 9 (TLR9) and is known as an adjuvant to induce cellular immune responses. We previously developed a therapeutic oligonucleotide delivery system based on the formation of a complex between schizophyllan (SPG), a kind of β-1,3-glucan, and poly(dA), which actively delivered CpG-ODN to antigen-presenting cells (APCs) in the draining lymph nodes and induced antigen-specific immune responses. However, unfortunately, the signaling pathway of TLR9 is negatively regulated by an intracellular protein called suppressor of cytokine signaling-1 (SOCS-1), which suppresses the adjuvant effect of CpG-ODN. To solve this, we focused on microRNA-155 (miR-155), which regulates innate and autoimmune processes by targeting SOCS-1. In this study, we proposed a strategy of combining miR-155 and CpG-ODN, each complexed with SPG (denoted as SPG/miR-155 and SPG/CpG, respectively), to induce a more potent immune response. As a result, we showed that the efficient delivery of miR-155 to APCs by a complex form could induce much more potent cellular immune responses than SPG/CpG alone. Furthermore, the mice treated with the combination of SPG/miR-155 and SPG/CpG showed a long delay in tumor growth occurrence and improved survival after tumor inoculation. These results indicate the possibility of therapeutic strategies for cancer.
Collapse
Affiliation(s)
- Kazuki Sumiya
- Department of Chemistry and Biochemistry, University of Kitakyushu, 1-1 Hibikino, Wakamatsu-ku, Kitakyushu, Fukuoka808-0135, Japan
| | - Hiroto Izumi
- Department of Occupational Pneumology, Institute of Industrial Ecological Sciences, University of Occupational and Environmental Health, 1-1 Isegaoka, Yahatanishi-ku, Kitakyushu, Fukuoka807-8555, Japan
| | - Kazuo Sakurai
- Department of Chemistry and Biochemistry, University of Kitakyushu, 1-1 Hibikino, Wakamatsu-ku, Kitakyushu, Fukuoka808-0135, Japan
| |
Collapse
|
|
17
|
Hashimoto S, Hashimoto A, Muromoto R, Kitai Y, Oritani K, Matsuda T. Central Roles of STAT3-Mediated Signals in Onset and Development of Cancers: Tumorigenesis and Immunosurveillance. Cells 2022; 11:cells11162618. [PMID: 36010693 PMCID: PMC9406645 DOI: 10.3390/cells11162618] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Revised: 08/12/2022] [Accepted: 08/20/2022] [Indexed: 02/07/2023] Open
Abstract
Since the time of Rudolf Virchow in the 19th century, it has been well-known that cancer-associated inflammation contributes to tumor initiation and progression. However, it remains unclear whether a collapse of the balance between the antitumor immune response via the immunological surveillance system and protumor immunity due to cancer-related inflammation is responsible for cancer malignancy. The majority of inflammatory signals affect tumorigenesis by activating signal transducer and activation of transcription 3 (STAT3) and nuclear factor-κB. Persistent STAT3 activation in malignant cancer cells mediates extremely widespread functions, including cell growth, survival, angiogenesis, and invasion and contributes to an increase in inflammation-associated tumorigenesis. In addition, intracellular STAT3 activation in immune cells causes suppressive effects on antitumor immunity and leads to the differentiation and mobilization of immature myeloid-derived cells and tumor-associated macrophages. In many cancer types, STAT3 does not directly rely on its activation by oncogenic mutations but has important oncogenic and malignant transformation-associated functions in both cancer and stromal cells in the tumor microenvironment (TME). We have reported a series of studies aiming towards understanding the molecular mechanisms underlying the proliferation of various types of tumors involving signal-transducing adaptor protein-2 as an adaptor molecule that modulates STAT3 activity, and we recently found that AT-rich interactive domain-containing protein 5a functions as an mRNA stabilizer that orchestrates an immunosuppressive TME in malignant mesenchymal tumors. In this review, we summarize recent advances in our understanding of the functional role of STAT3 in tumor progression and introduce novel molecular mechanisms of cancer development and malignant transformation involving STAT3 activation that we have identified to date. Finally, we discuss potential therapeutic strategies for cancer that target the signaling pathway to augment STAT3 activity.
Collapse
Affiliation(s)
- Shigeru Hashimoto
- Division of Molecular Psychoimmunology, Institute for Genetic Medicine, Hokkaido University, Sapporo 060-0815, Japan
- Correspondence: (S.H.); (T.M.)
| | - Ari Hashimoto
- Department of Molecular Biology, Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan
| | - Ryuta Muromoto
- Department of Immunology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan
| | - Yuichi Kitai
- Department of Immunology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan
| | - Kenji Oritani
- Department of Hematology, International University of Health and Welfare, Narita 286-8686, Japan
| | - Tadashi Matsuda
- Department of Immunology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan
- Correspondence: (S.H.); (T.M.)
| |
Collapse
|
|
18
|
Macedo AB, Levinger C, Nguyen BN, Richard J, Gupta M, Cruz CRY, Finzi A, Chiappinelli KB, Crandall KA, Bosque A. The HIV Latency Reversal Agent HODHBt Enhances NK Cell Effector and Memory-Like Functions by Increasing Interleukin-15-Mediated STAT Activation. J Virol 2022; 96:e0037222. [PMID: 35867565 PMCID: PMC9364794 DOI: 10.1128/jvi.00372-22] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Accepted: 06/29/2022] [Indexed: 11/20/2022] Open
Abstract
Elimination of human immunodeficiency virus (HIV) reservoirs is a critical endpoint to eradicate HIV. One therapeutic intervention against latent HIV is "shock and kill." This strategy is based on the transcriptional activation of latent HIV with a latency-reversing agent (LRA) with the consequent killing of the reactivated cell by either the cytopathic effect of HIV or the immune system. We have previously found that the small molecule 3-hydroxy-1,2,3-benzotriazin-4(3H)-one (HODHBt) acts as an LRA by increasing signal transducer and activator of transcription (STAT) factor activation mediated by interleukin-15 (IL-15) in cells isolated from aviremic participants. The IL-15 superagonist N-803 is currently under clinical investigation to eliminate latent reservoirs. IL-15 and N-803 share similar mechanisms of action by promoting the activation of STATs and have shown some promise in preclinical models directed toward HIV eradication. In this work, we evaluated the ability of HODHBt to enhance IL-15 signaling in natural killer (NK) cells and the biological consequences associated with increased STAT activation in NK cell effector and memory-like functions. We showed that HODHBt increased IL-15-mediated STAT phosphorylation in NK cells, resulting in increases in the secretion of CXCL-10 and interferon gamma (IFN-γ) and the expression of cytotoxic proteins, including granzyme B, granzyme A, perforin, granulysin, FASL, and TRAIL. This increased cytotoxic profile results in increased cytotoxicity against HIV-infected cells and different tumor cell lines. HODHBt also improved the generation of cytokine-induced memory-like NK cells. Overall, our data demonstrate that enhancing the magnitude of IL-15 signaling with HODHBt favors NK cell cytotoxicity and memory-like generation, and thus, targeting this pathway could be further explored for HIV cure interventions. IMPORTANCE Several clinical trials targeting the HIV latent reservoir with LRAs have been completed. In spite of a lack of clinical benefit, they have been crucial to elucidate hurdles that "shock and kill" strategies have to overcome to promote an effective reduction of the latent reservoir to lead to a cure. These hurdles include low reactivation potential mediated by LRAs, the negative influence of some LRAs on the activity of natural killer and effector CD8 T cells, an increased resistance to apoptosis of latently infected cells, and an exhausted immune system due to chronic inflammation. To that end, finding therapeutic strategies that can overcome some of these challenges could improve the outcome of shock and kill strategies aimed at HIV eradication. Here, we show that the LRA HODHBt also improves IL-15-mediated NK cell effector and memory-like functions. As such, pharmacological enhancement of IL-15-mediated STAT activation can open new therapeutic avenues toward an HIV cure.
Collapse
Affiliation(s)
- Amanda B. Macedo
- Department of Microbiology, Immunology, & Tropical Medicine, The George Washington University, Washington, DC, USA
| | - Callie Levinger
- Department of Microbiology, Immunology, & Tropical Medicine, The George Washington University, Washington, DC, USA
| | - Bryan N. Nguyen
- Computational Biology Institute, Milken Institute School of Public Health, The George Washington University, Washington, DC, USA
- Department of Biostatistics & Bioinformatics, Milken Institute School of Public Health, The George Washington University, Washington, DC, USA
| | - Jonathan Richard
- Centre de Recherche du CHUM, Montreal, Quebec, Canada
- Département de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montreal, Quebec, Canada
| | - Mamta Gupta
- Department of Biochemistry & Molecular Medicine, School of Medicine & Health Sciences, The George Washington University, Washington, DC, USA
- GW Cancer Center, Washington, DC, USA
| | - Conrad Russell Y. Cruz
- GW Cancer Center, Washington, DC, USA
- Children’s National Medical Center, Washington, DC, USA
| | - Andrés Finzi
- Centre de Recherche du CHUM, Montreal, Quebec, Canada
- Département de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montreal, Quebec, Canada
| | - Katherine B. Chiappinelli
- Department of Microbiology, Immunology, & Tropical Medicine, The George Washington University, Washington, DC, USA
- GW Cancer Center, Washington, DC, USA
| | - Keith A. Crandall
- Computational Biology Institute, Milken Institute School of Public Health, The George Washington University, Washington, DC, USA
- Department of Biostatistics & Bioinformatics, Milken Institute School of Public Health, The George Washington University, Washington, DC, USA
| | - Alberto Bosque
- Department of Microbiology, Immunology, & Tropical Medicine, The George Washington University, Washington, DC, USA
| |
Collapse
|
|
19
|
Han H, Zhu W, Lin T, Liu C, Zhai H. N4BP3 promotes angiogenesis in Hepatocellular Carcinoma by binding with KAT2B. Cancer Sci 2022; 113:3390-3404. [PMID: 35848906 PMCID: PMC9530875 DOI: 10.1111/cas.15498] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Revised: 07/08/2022] [Accepted: 07/13/2022] [Indexed: 11/28/2022] Open
Abstract
Although angiogenesis is a critical event in hepatocellular carcinoma (HCC), and this process provides the tumor with sufficient oxygen and nutrients, the precise molecular mechanism by which it occurs is not fully understood. NEDD4 binding protein 3 (N4BP3) was identified in this study as a novel pro‐angiogenic factor in HCC cell lines and tissues. We discovered that N4BP3 was significantly expressed in HCC and that its level of expression was positively correlated with the density of tumor microvessels in HCC tissues. Cell biology experiments have shown that N4BP3 knockdown in HCC cells significantly inhibits the formation of complete tubular structures by HUVECs in vitro and HCC angiogenesis in vivo. In HCC cells, overexpression of N4BP3 has the opposite effects. Further cell and molecular biology experiments have revealed that N4BP3 interacts with KAT2B (lysine acetyltransferase 2B), increasing signal transducer and activator of transcription 3 (STAT3) expression by regulating the distribution of acetyl‐histone H3 (Lys27) (H3K27ac) in its promoter region. This, in addition, regulates the activity of the STAT3 signaling pathway, which promotes the proliferation of microvessels in HCC and accelerates the malignant process of the tumor. In vivo experiments in nude mice have confirmed our findings, and also suggested that N4BP3 could be a potential target for the treatment of HCC in combination with sorafenib.
Collapse
Affiliation(s)
- Hexu Han
- Department of Gastroenterology, Taizhou People's Hospital, Taizhou, Jiangsu, People's Republic of China
| | - Wei Zhu
- Department of Pathology, Xishan People's Hospital Of Wuxi City, Wuxi, Jiangsu, People's Republic of China
| | - Ting Lin
- Department of Basic Medicine, Jiangsu College of Nursing, Huai'an, Jiangsu, People's Republic of China
| | - Cuixia Liu
- Department of Gastroenterology, Taizhou People's Hospital, Taizhou, Jiangsu, People's Republic of China
| | - Hengyong Zhai
- Department of Gastroenterology, Taizhou People's Hospital, Taizhou, Jiangsu, People's Republic of China
| |
Collapse
|
|
20
|
Ni Y, Low JT, Silke J, O’Reilly LA. Digesting the Role of JAK-STAT and Cytokine Signaling in Oral and Gastric Cancers. Front Immunol 2022; 13:835997. [PMID: 35844493 PMCID: PMC9277720 DOI: 10.3389/fimmu.2022.835997] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Accepted: 05/16/2022] [Indexed: 12/12/2022] Open
Abstract
When small proteins such as cytokines bind to their associated receptors on the plasma membrane, they can activate multiple internal signaling cascades allowing information from one cell to affect another. Frequently the signaling cascade leads to a change in gene expression that can affect cell functions such as proliferation, differentiation and homeostasis. The Janus kinase-signal transducer and activator of transcription (JAK-STAT) and the tumor necrosis factor receptor (TNFR) are the pivotal mechanisms employed for such communication. When deregulated, the JAK-STAT and the TNF receptor signaling pathways can induce chronic inflammatory phenotypes by promoting more cytokine production. Furthermore, these signaling pathways can promote replication, survival and metastasis of cancer cells. This review will summarize the essentials of the JAK/STAT and TNF signaling pathways and their regulation and the molecular mechanisms that lead to the dysregulation of the JAK-STAT pathway. The consequences of dysregulation, as ascertained from founding work in haematopoietic malignancies to more recent research in solid oral-gastrointestinal cancers, will also be discussed. Finally, this review will highlight the development and future of therapeutic applications which modulate the JAK-STAT or the TNF signaling pathways in cancers.
Collapse
Affiliation(s)
- Yanhong Ni
- Central Laboratory, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, China
| | - Jun T. Low
- Inflammation Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia
- Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia
| | - John Silke
- Inflammation Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia
- Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia
| | - Lorraine A. O’Reilly
- Inflammation Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia
- Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia
| |
Collapse
|
|
21
|
Cheng J, Zhang Y, Yang J, Wang Y, Xu J, Fan Y. MiR-155-5p modulates inflammatory phenotype of activated oral lichen-planus-associated-fibroblasts by targeting SOCS1. Mol Biol Rep 2022; 49:7783-7792. [PMID: 35733067 DOI: 10.1007/s11033-022-07603-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2022] [Revised: 05/12/2022] [Accepted: 05/13/2022] [Indexed: 10/17/2022]
Abstract
BACKGROUND Oral lichen planus (OLP) is a chronic inflammatory oral mucosal disease. Cytokines are closely associated with OLP development. In addition to immune cells, fibroblasts have been reported to induce regional inflammation. MicroRNA(miR)-155-5p is reportedly increased significantly in OLP and is known to regulate inflammation. This study aimed to investigate the role of miR-155-5p in fibroblasts of OLP lesions. METHODS AND RESULTS Normal mucosal fibroblasts (NFs) and OLP associated-fibroblasts (OLP AFs) were isolated from the oral mucosa of 15 healthy controls and 30 OLP patients. We detected the expression of miR-155-5p and fibroblast activation protein alpha (FAP-α) using quantitative RT-PCR and analyzed their correlation. Interleukin (IL)-6 and IL-8 levels were determined using ELISA. Expression of suppressor of cytokine signaling (SOCS) 1 was analyzed by western blotting. A dual-luciferase reporter assay was performed to investigate the interaction between miR-155-5p and SOCS1. MiR-155-5p and FAP-α were significantly increased and positively correlated in OLP AFs. Overexpression of miR-155-5p in OLP AFs augmented IL-6 and IL-8 release and decreased SOCS1 expression, whereas knockdown of miR-155-5p in OLP AFs decreased IL-6 and IL-8 release. The expression of SOCS1 was downregulated in OLP AFs, and SOCS1 silencing augmented IL-6 and IL-8 production in OLP AFs. Furthermore, miR-155-5p inhibited SOCS1 expression by directly targeting its 3'-UTR in OLP AFs. CONCLUSIONS MiR-155-5p regulates the secretion of IL-6 and IL-8 by downregulating the expression of SOCS1 in activated OLP AFs. Our results provide novel insights into the pathogenesis of OLP and identify a potential new target for OLP therapy.
Collapse
Affiliation(s)
- Juehua Cheng
- Department of Oral Mucosal Diseases, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China.,Jiangsu Province Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, China.,Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing, China
| | - Yuyao Zhang
- Department of Oral Mucosal Diseases, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China.,Jiangsu Province Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, China.,Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing, China
| | - Jingjing Yang
- Department of Oral Mucosal Diseases, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China.,Jiangsu Province Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, China.,Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing, China
| | - Yanting Wang
- Department of Oral Mucosal Diseases, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China.,Jiangsu Province Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, China.,Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing, China
| | - Juanyong Xu
- Department of Oral Mucosal Diseases, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China.,Jiangsu Province Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, China.,Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing, China
| | - Yuan Fan
- Department of Oral Mucosal Diseases, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China. .,Jiangsu Province Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, China. .,Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing, China.
| |
Collapse
|
|
22
|
Sun Q, Geng H, Zhao M, Li Y, Chen X, Sha Q, Lai P, Tang D, Yang D, Liang J, Guo M. FTO-mediated m 6 A modification of SOCS1 mRNA promotes the progression of diabetic kidney disease. Clin Transl Med 2022; 12:e942. [PMID: 35731980 PMCID: PMC9217105 DOI: 10.1002/ctm2.942] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Revised: 05/31/2022] [Accepted: 06/06/2022] [Indexed: 02/05/2023] Open
Affiliation(s)
- Qiang Sun
- Jiangsu Key Laboratory of New Drug Research and Clinical PharmacyXuzhou Medical UniversityXuzhouJiangsuChina
| | - Houfa Geng
- Department of EndocrinologyXuzhou Central Hospital, Xuzhou Clinical School of Nanjing Medical UniversityXuzhouJiangsuChina
| | - Meng Zhao
- Jiangsu Key Laboratory of New Drug Research and Clinical PharmacyXuzhou Medical UniversityXuzhouJiangsuChina
| | - Yang Li
- Institute of Thoracic Oncology and Department of Thoracic SurgeryWest China Hospital, Sichuan UniversityChengduSichuanChina
| | - Xi Chen
- Jiangsu Key Laboratory of New Drug Research and Clinical PharmacyXuzhou Medical UniversityXuzhouJiangsuChina
| | - Qian Sha
- Jiangsu Key Laboratory of New Drug Research and Clinical PharmacyXuzhou Medical UniversityXuzhouJiangsuChina
| | - Peng Lai
- Department of EndocrinologyXuzhou Central Hospital, Xuzhou Clinical School of Nanjing Medical UniversityXuzhouJiangsuChina
| | - Daoquan Tang
- Jiangsu Key Laboratory of New Drug Research and Clinical PharmacyXuzhou Medical UniversityXuzhouJiangsuChina
| | - Dongzhi Yang
- Jiangsu Key Laboratory of New Drug Research and Clinical PharmacyXuzhou Medical UniversityXuzhouJiangsuChina
| | - Jun Liang
- Jiangsu Key Laboratory of New Drug Research and Clinical PharmacyXuzhou Medical UniversityXuzhouJiangsuChina
- Department of EndocrinologyXuzhou Central Hospital, Xuzhou Clinical School of Nanjing Medical UniversityXuzhouJiangsuChina
| | - Mengzhe Guo
- Jiangsu Key Laboratory of New Drug Research and Clinical PharmacyXuzhou Medical UniversityXuzhouJiangsuChina
| |
Collapse
|
|
23
|
Läsche M, Gallwas J, Gründker C. Like Brothers in Arms: How Hormonal Stimuli and Changes in the Metabolism Signaling Cooperate, Leading HPV Infection to Drive the Onset of Cervical Cancer. Int J Mol Sci 2022; 23:5050. [PMID: 35563441 PMCID: PMC9103757 DOI: 10.3390/ijms23095050] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Revised: 04/27/2022] [Accepted: 04/28/2022] [Indexed: 02/06/2023] Open
Abstract
Despite all precautionary actions and the possibility of using vaccinations to counteract infections caused by human papillomaviruses (HPVs), HPV-related cancers still account for approximately 5% of all carcinomas. Worldwide, many women are still excluded from adequate health care due to their social position and origin. Therefore, immense efforts in research and therapy are still required to counteract the challenges that this disease entails. The special thing about an HPV infection is that it is not only able to trick the immune system in a sophisticated way, but also, through genetic integration into the host genome, to use all the resources available to the host cells to complete the replication cycle of the virus without activating the alarm mechanisms of immune recognition and elimination. The mechanisms utilized by the virus are the metabolic, immune, and hormonal signaling pathways that it manipulates. Since the virus is dependent on replication enzymes of the host cells, it also intervenes in the cell cycle of the differentiating keratinocytes and shifts their terminal differentiation to the uppermost layers of the squamocolumnar transformation zone (TZ) of the cervix. The individual signaling pathways are closely related and equally important not only for the successful replication of the virus but also for the onset of cervical cancer. We will therefore analyze the effects of HPV infection on metabolic signaling, as well as changes in hormonal and immune signaling in the tumor and its microenvironment to understand how each level of signaling interacts to promote tumorigenesis of cervical cancer.
Collapse
Affiliation(s)
| | | | - Carsten Gründker
- Department of Gynecology and Obstetrics, University Medicine Göttingen, 37075 Göttingen, Germany; (M.L.); (J.G.)
| |
Collapse
|
|
24
|
Zhang S, Fan Y, Zheng B, Wang Y, Miao C, Su Y, Li K, E. Y, Wang X, He X, Wu X, Xu C, Tang Y, Liu WT, Kong X, Hu L. Bilirubin Improves Gap Junction to Alleviate Doxorubicin-Induced Cardiotoxicity by Regulating AMPK-Axl-SOCS3-Cx43 Axis. Front Pharmacol 2022; 13:828890. [PMID: 35548345 PMCID: PMC9082937 DOI: 10.3389/fphar.2022.828890] [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: 01/10/2022] [Accepted: 03/29/2022] [Indexed: 11/29/2022] Open
Abstract
Doxorubicin induces severe cardiotoxicity, accompanied by the high level of bilirubin in the blood. The conventional wisdom is that bilirubin is considered as a marker of liver damage. By contrast, here we aim to explore the potential protective effect of bilirubin on doxorubicin-induced cardiotoxicity, and investigate the mechanism for drug development. Doxorubicin was used to establish cardiotoxicity model in vitro and in vivo. The electrocardiogram (ECG), echocardiography and molecular biological methods were used to detect the effects of bilirubin on doxorubicin-induced cardiotoxicity. Consecutive intraperitoneal injection of bilirubin for 7 days significantly attenuated doxorubicin-induced arrhythmia, prolonged survival time and reduced the levels of aspartate aminotransferase (AST), lactate dehydrogenase (LDH), creatine kinase MB (CK-MB) and α-hydroxybutyrate dehydrogenase (α-HBDH) in mice. Bilirubin also markedly inhibited doxorubicin-induced phosphorylation of c-Jun N-terminal kinase (JNK) and connexin 43 (Cx43), and improved gap junction function in vitro and in vivo. In addition, bilirubin activated adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) and induced suppressor of cytokine signaling 3 (SOCS3) expression, which was abolished by Axl inhibition. Moreover, pretreatment with AMPK agonist or AMPK inhibitor could mimic or abolish the cardioprotective effect of bilirubin on H9C2 cells in vitro, respectively. Altogether, bilirubin upregulates gap junctions' function to protect against doxorubicin-induced cardiotoxicity by activating AMPK-Axl-SOCS3 signaling axis. We enrich the physiological function of bilirubin, and provide theoretical support for drug development.
Collapse
Affiliation(s)
- Siqi Zhang
- Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yixin Fan
- Department of Pharmacy, Sir Run Run Hospital, Nanjing Medical University, Nanjing, China
- Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, Nanjing, China
| | - Binbin Zheng
- Department of Pharmacy, Xinghua People’s Hospital, Taizhou, China
| | - Yu Wang
- Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, Nanjing, China
| | - Chen Miao
- Department of Pathology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yue Su
- Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, Nanjing, China
| | - Kun Li
- Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, Nanjing, China
| | - Yan E.
- Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, Nanjing, China
| | - Xueli Wang
- Center for Clinical Research and Translational Medicine, The Affiliated Lianyungang Oriental Hospital of Kangda College of Nanjing Medical University, Lianyungang, China
| | - Xueming He
- Center for Clinical Research and Translational Medicine, The Affiliated Lianyungang Oriental Hospital of Kangda College of Nanjing Medical University, Lianyungang, China
| | - Xuefeng Wu
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China
| | - Chenjie Xu
- Department of Anesthesiology and Pain, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Yulin Tang
- Department of Pharmacy, Sir Run Run Hospital, Nanjing Medical University, Nanjing, China
| | - Wen-Tao Liu
- Department of Pharmacy, Sir Run Run Hospital, Nanjing Medical University, Nanjing, China
- Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, Nanjing, China
| | - Xiangqing Kong
- Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Liang Hu
- Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, Nanjing, China
| |
Collapse
|
|
25
|
IL-6 Signaling Link between Inflammatory Tumor Microenvironment and Prostatic Tumorigenesis. Anal Cell Pathol (Amst) 2022; 2022:5980387. [PMID: 35464825 PMCID: PMC9019459 DOI: 10.1155/2022/5980387] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Revised: 02/28/2022] [Accepted: 03/09/2022] [Indexed: 12/02/2022] Open
Abstract
Benign prostatic hyperplasia and prostate cancer are tumoral pathologies characterized by the overexpression of inflammatory processes. The exploration of tumor microenvironment and understanding the sequential events that take place in the stromal area of the prostate could help for an early management of these pathologies. This way, it is feasible the hypothesis that normalizing the stromal environment would help to suppress or even to reverse tumor fenotype. A number of immunological and genetic factors, endocrine dysfunctions, metabolic disorders, infectious foci, nutritional deficiencies, and chemical irritants could be involved in prostate tumor development by maintaining inflammation, affecting local microcirculation, and promoting oxidative stress. Inflammatory processes activate hyperproliferative programs that ensure fibromuscular growth of the prostate and a number of extracellular changes. Acute and chronic inflammations cause accumulation of immunocompetent cells in affected prostate tissue (T cells, macrophages, mastocytes, dendritic cells, neutrophils, eosinophils, monocytes). Prostate epithelial and stromal cells, peri-prostatic fat cells, prostatic microvascular endothelial cells, and inflammatory cells produce cytokines, generating a local inflammatory environment. Interleukin-6 (IL-6) proved to be involved in the prostate tumor pathogenesis. IL-6 ability to induce pro- and anti-inflammatory responses by three mechanisms of signal transduction (classical signaling, transsignaling, cluster signaling), to interact with a diversity of target cells, to induce endocrine effects in an autocrine/paracrine manner, and the identification of an IL-6 endogenous antagonist that blocks the transmission of IL-6 mediated intracellular signals could justify current theories on the protective effects of this cytokine or by alleviating inflammatory reactions or by exacerbating tissue damage. This analysis presents recent data about the role of the inflammatory process as a determining factor in the development of benign and malign prostate tumors. The presented findings could bring improvements in the field of physiopathology, diagnosis, and treatment in patients with prostate tumors. Modulation of the expression and activity of interleukin-6 could be a mean of preventing or improving these pathologies.
Collapse
|
|
26
|
Manore SG, Doheny DL, Wong GL, Lo HW. IL-6/JAK/STAT3 Signaling in Breast Cancer Metastasis: Biology and Treatment. Front Oncol 2022; 12:866014. [PMID: 35371975 PMCID: PMC8964978 DOI: 10.3389/fonc.2022.866014] [Citation(s) in RCA: 126] [Impact Index Per Article: 42.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2022] [Accepted: 02/16/2022] [Indexed: 12/12/2022] Open
Abstract
Breast cancer is the most commonly diagnosed cancer in women. Metastasis is the primary cause of mortality for breast cancer patients. Multiple mechanisms underlie breast cancer metastatic dissemination, including the interleukin-6 (IL-6)-mediated signaling pathway. IL-6 is a pleiotropic cytokine that plays an important role in multiple physiological processes including cell proliferation, immune surveillance, acute inflammation, metabolism, and bone remodeling. IL-6 binds to the IL-6 receptor (IL-6Rα) which subsequently binds to the glycoprotein 130 (gp130) receptor creating a signal transducing hexameric receptor complex. Janus kinases (JAKs) are recruited and activated; activated JAKs, in turn, phosphorylate signal transducer and activator of transcription 3 (STAT3) for activation, leading to gene regulation. Constitutively active IL-6/JAK/STAT3 signaling drives cancer cell proliferation and invasiveness while suppressing apoptosis, and STAT3 enhances IL-6 signaling to promote a vicious inflammatory loop. Aberrant expression of IL-6 occurs in multiple cancer types and is associated with poor clinical prognosis and metastasis. In breast cancer, the IL-6 pathway is frequently activated, which can promote breast cancer metastasis while simultaneously suppressing the anti-tumor immune response. Given these important roles in human cancers, multiple components of the IL-6 pathway are promising targets for cancer therapeutics and are currently being evaluated preclinically and clinically for breast cancer. This review covers the current biological understanding of the IL-6 signaling pathway and its impact on breast cancer metastasis, as well as, therapeutic interventions that target components of the IL-6 pathway including: IL-6, IL-6Rα, gp130 receptor, JAKs, and STAT3.
Collapse
Affiliation(s)
- Sara G Manore
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, United States
| | - Daniel L Doheny
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, United States
| | - Grace L Wong
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, United States
| | - Hui-Wen Lo
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, United States.,Wake Forest Baptist Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, NC, United States
| |
Collapse
|
|
27
|
The Mammary Gland: Basic Structure and Molecular Signaling during Development. Int J Mol Sci 2022; 23:ijms23073883. [PMID: 35409243 PMCID: PMC8998991 DOI: 10.3390/ijms23073883] [Citation(s) in RCA: 48] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Revised: 03/22/2022] [Accepted: 03/30/2022] [Indexed: 01/27/2023] Open
Abstract
The mammary gland is a compound, branched tubuloalveolar structure and a major characteristic of mammals. The mammary gland has evolved from epidermal apocrine glands, the skin glands as an accessory reproductive organ to support postnatal survival of offspring by producing milk as a source of nutrition. The mammary gland development begins during embryogenesis as a rudimentary structure that grows into an elementary branched ductal tree and is embedded in one end of a larger mammary fat pad at birth. At the onset of ovarian function at puberty, the rudimentary ductal system undergoes dramatic morphogenetic change with ductal elongation and branching. During pregnancy, the alveolar differentiation and tertiary branching are completed, and during lactation, the mature milk-producing glands eventually develop. The early stages of mammary development are hormonal independent, whereas during puberty and pregnancy, mammary gland development is hormonal dependent. We highlight the current understanding of molecular regulators involved during different stages of mammary gland development.
Collapse
|
|
28
|
Ayyildiz T, Dolar E, Oral B, Erturk B, Haktanir AE, Adim SB, Yerci O. SOCS-1 1478 CA/del gene polymorphism affects survival in colorectal carcinoma. Niger J Clin Pract 2022; 25:239-247. [PMID: 35295043 DOI: 10.4103/njcp.njcp_1309_21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
Aims and Background Suppressor of cytokine signaling 1 (SOCS1) is a prototype molecule of the SOCS family. Alterations in the SOCS1 expression have been reported in human cancers and some studies suggest that SOCS1 might act as a tumor suppressor in carcinogenesis. In the present study, we aimed to evaluate the association of SOCS1 promoter -1478CA/del gene polymorphism detected in DNA isolated from the tissues of patients with colorectal cancer (CRC) for histopathological characteristics and survival. Patients and Methods For the study, we retrospectively enrolled 53 patients with resected colon due to CRC and 23 control subjects with no systemic illness. SOCS1- 1478CA/del gene polymorphism was determined using the polymerase chain reaction-restriction fragment length polymorphism methodology. These results were evaluated in relation to histopathological features and survival results and analyzed statistically. A P value equal to or less than 0.05 was considered significant. Results Neither control subjects nor the CRC group showed a significant association with SOCS1 -1478CA/del gene polymorphism (p = 0.248). SOCS1 -1478CA/del gene polymorphism was not significantly associated with histopathological features either. However, in the overall survival (OS) analysis, those patients with the del/del allele were found to have a 3.9-fold greater risk of mortality compared to those with CA/CA allele (p = 0.05). Progression-free survival (PFS) was also significantly different in such patients (p = 0.05). Conclusion The present study examining the association of SOCS1 -1478CA/del gene polymorphism with CRC showed that CRC patients with del/del allele had both significantly shorter PFS and OS versus those with CA/CA or CA/del allele.
Collapse
Affiliation(s)
- T Ayyildiz
- Department of Gastroenterology, School of Medicine, Ondokuz Mayis University, Samsun, Turkey
| | - E Dolar
- Department of Gastroenterology, are the part of School of Medicine of Ululudag University, Bursa, Turkey
| | - B Oral
- Department of Immunology, are the part of School of Medicine of Ululudag University, Bursa, Turkey
| | - B Erturk
- Department of Internal Medicine, School of Medicine, Erciyes University, Kayseri, Turkey
| | - A Eroglu Haktanir
- Department of Internal Medicine, are the part of School of Medicine of Ululudag University, Bursa, Turkey
| | - S B Adim
- Department of Pathology, are the part of School of Medicine of Ululudag University, Bursa, Turkey
| | - O Yerci
- Department of Pathology, are the part of School of Medicine of Ululudag University, Bursa, Turkey
| |
Collapse
|
|
29
|
Wang D, Bai X, Wang B, Yi Q, Yu W, Zhang X, Tian R, Zhang X, Li C, Chen Y, Liu Y, Cheng Y, He S. CTLA4Ig/VISTAIg combination therapy selectively induces CD4 + T cell-mediated immune tolerance by targeting the SOCS1 signaling pathway in porcine islet xenotransplantation. Immunology 2022; 166:169-184. [PMID: 35263451 DOI: 10.1111/imm.13463] [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: 08/20/2021] [Revised: 01/19/2022] [Accepted: 02/09/2022] [Indexed: 11/29/2022] Open
Abstract
T cell inhibitory receptors can regulate the proliferation or function of T cells by binding to their ligands and present a unique opportunity to manage destructive immune responses during porcine islet xenotransplantation. We applied ex vivo porcine islet xenotransplantation and in vitro mixed lymphocyte-islet reaction models to assess immune checkpoint receptor expression profiles in recipient T cells, investigate whether CTLA4 or VISTA immunoglobulin (Ig) combination therapy alone could suppress porcine islet xenograft rejection and further analyze its potential immune tolerance mechanism. Recipient T cells expressed moderate to high levels of CTLA4, PD-1, TIGIT, and VISTA, and the frequency of CTLA4+ CD4+ , TIGIT+ CD4+ , VISTA+ CD4+ and VISTA+ CD8+ T cells was positively correlated with porcine islet xenograft survival time in xenotransplant recipients. Combined treatment with CTLA4Ig and VISTAIg selectively inhibited recipient CD4+ T cell hyperresponsiveness and proinflammatory cytokine production and significantly delayed xenograft rejection. SOCS1 deficiency in CD4+ T cells stimulated by xenogeneic islets facilitated hyperresponsiveness and abolished the suppressive effect of combination therapy on recipient T cell-mediated porcine islet damage in vivo and in vitro. Further mechanistic studies revealed that combined treatment significantly induced SOCS1 expression and inhibited the Jak-STAT signaling pathway in wild-type recipient CD4+ T cells stimulated by xenogeneic islets, whereas SOCS1 deficiency resulted in Jak-STAT signaling pathway activation in recipient CD4+ T cells. We demonstrated a major role for CTLA4 and VISTA as key targets in CD4+ T cell hyperresponsiveness and porcine islet xenograft rejection. The selective inhibition of CD4+ T cell immunity by CTLA4Ig/VISTAIg is based on SOCS1-dependent signaling.
Collapse
Affiliation(s)
- Dan Wang
- Department of Immunology, College of Basic Medicine, Chongqing Medical University, Chongqing, 400016, P.R. China.,Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, PR China
| | - Xue Bai
- Department of Immunology, College of Basic Medicine, Chongqing Medical University, Chongqing, 400016, P.R. China.,Chongqing Key Laboratory of Basic and Translational Research of Tumor Immunology, College of Basic Medicine, Chongqing Medical University, Chongqing, 400016, P.R. China
| | - Bin Wang
- Institute of Life Science, Chongqing Medical University, Chongqing, 400016, P.R. China
| | - Qiying Yi
- Laboratory Animal Center, Chongqing Medical University, Chongqing, 400016, China
| | - Weihua Yu
- Institutes of Neuroscience, Chongqing Medical University, Chongqing, 400016, China
| | - Xinying Zhang
- Department of Immunology, College of Basic Medicine, Chongqing Medical University, Chongqing, 400016, P.R. China.,Chongqing Key Laboratory of Basic and Translational Research of Tumor Immunology, College of Basic Medicine, Chongqing Medical University, Chongqing, 400016, P.R. China
| | - Ruoyuan Tian
- Department of Immunology, College of Basic Medicine, Chongqing Medical University, Chongqing, 400016, P.R. China.,Chongqing Key Laboratory of Basic and Translational Research of Tumor Immunology, College of Basic Medicine, Chongqing Medical University, Chongqing, 400016, P.R. China
| | - Xiao Zhang
- Department of Immunology, College of Basic Medicine, Chongqing Medical University, Chongqing, 400016, P.R. China.,Chongqing Key Laboratory of Basic and Translational Research of Tumor Immunology, College of Basic Medicine, Chongqing Medical University, Chongqing, 400016, P.R. China
| | - Caihua Li
- Department of Immunology, College of Basic Medicine, Chongqing Medical University, Chongqing, 400016, P.R. China.,Chongqing Key Laboratory of Basic and Translational Research of Tumor Immunology, College of Basic Medicine, Chongqing Medical University, Chongqing, 400016, P.R. China
| | - Yi Chen
- Department of Immunology, College of Basic Medicine, Chongqing Medical University, Chongqing, 400016, P.R. China.,Chongqing Key Laboratory of Basic and Translational Research of Tumor Immunology, College of Basic Medicine, Chongqing Medical University, Chongqing, 400016, P.R. China
| | - Yang Liu
- Department of Immunology, College of Basic Medicine, Chongqing Medical University, Chongqing, 400016, P.R. China.,Chongqing Key Laboratory of Basic and Translational Research of Tumor Immunology, College of Basic Medicine, Chongqing Medical University, Chongqing, 400016, P.R. China
| | - Yao Cheng
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, P.R. China
| | - Sirong He
- Department of Immunology, College of Basic Medicine, Chongqing Medical University, Chongqing, 400016, P.R. China.,Chongqing Key Laboratory of Basic and Translational Research of Tumor Immunology, College of Basic Medicine, Chongqing Medical University, Chongqing, 400016, P.R. China
| |
Collapse
|
|
30
|
Jha NK, Arfin S, Jha SK, Kar R, Dey A, Gundamaraju R, Ashraf GM, Gupta PK, Dhanasekaran S, Abomughaid MM, Das SS, Singh SK, Dua K, Roychoudhury S, Kumar D, Ruokolainen J, Ojha S, Kesari KK. Re-establishing the comprehension of phytomedicine and nanomedicine in inflammation-mediated cancer signaling. Semin Cancer Biol 2022; 86:1086-1104. [PMID: 35218902 DOI: 10.1016/j.semcancer.2022.02.022] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Revised: 01/20/2022] [Accepted: 02/20/2022] [Indexed: 12/12/2022]
Abstract
Recent mounting evidence has revealed extensive genetic heterogeneity within tumors that drive phenotypic variation affecting key cancer pathways, making cancer treatment extremely challenging. Diverse cancer types display resistance to treatment and show patterns of relapse following therapy. Therefore, efforts are required to address tumor heterogeneity by developing a broad-spectrum therapeutic approach that combines targeted therapies. Inflammation has been progressively documented as a vital factor in tumor advancement and has consequences in epigenetic variations that support tumor instigation, encouraging all the tumorigenesis phases. Increased DNA damage, disrupted DNA repair mechanisms, cellular proliferation, apoptosis, angiogenesis, and its incursion are a few pro-cancerous outcomes of chronic inflammation. A clear understanding of the cellular and molecular signaling mechanisms of tumor-endorsing inflammation is necessary for further expansion of anti-cancer therapeutics targeting the crosstalk between tumor development and inflammatory processes. Multiple inflammatory signaling pathways, such as the NF-κB signaling pathway, JAK-STAT signaling pathway, MAPK signaling, PI3K/AKT/mTOR signaling, Wnt signaling cascade, and TGF-β/Smad signaling, have been found to regulate inflammation, which can be modulated using various factors such as small molecule inhibitors, phytochemicals, recombinant cytokines, and nanoparticles in conjugation to phytochemicals to treat cancer. Researchers have identified multiple targets to specifically alter inflammation in cancer therapy to restrict malignant progression and improve the efficacy of cancer therapy. siRNA-and shRNA-loaded nanoparticles have been observed to downregulate STAT3 signaling pathways and have been employed in studies to target tumor malignancies. This review highlights the pathways involved in the interaction between tumor advancement and inflammatory progression, along with the novel approaches of nanotechnology-based drug delivery systems currently used to target inflammatory signaling pathways to combat cancer.
Collapse
Affiliation(s)
- Niraj Kumar Jha
- Department of Biotechnology, School of Engineering & Technology (SET), Sharda University, Greater Noida 201310, India.
| | - Saniya Arfin
- Amity Institute of Molecular Medicine and Stem Cell Research (AIMMSCR), Amity University Uttar Pradesh, Sec 125, Noida 201303, India
| | - Saurabh Kumar Jha
- Department of Biotechnology, School of Engineering & Technology (SET), Sharda University, Greater Noida 201310, India
| | - Rohan Kar
- Indian Institute of Management Ahmedabad (IIMA), Gujarat 380015, India
| | - Abhijit Dey
- Department of Life Sciences, Presidency University, College Street, Kolkata 700073, India
| | - Rohit Gundamaraju
- ER Stress and Mucosal Immunology Laboratory, School of Health Sciences, University of Tasmania, Launceston, TAS 7248, Australia
| | - Ghulam Md Ashraf
- Pre-Clinical Research Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia; Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Piyush Kumar Gupta
- Department of Life Sciences, School of Basic Sciences and Research, Sharda University, Plot 32-34, Knowledge Park III, Greater Noida 201310, India
| | - Sugapriya Dhanasekaran
- Medical Laboratory Sciences Department, College of Applied Medical Sciences, University of Bisha, Bisha 67714, Saudi Arabia
| | - Mosleh Mohammad Abomughaid
- Medical Laboratory Sciences Department, College of Applied Medical Sciences, University of Bisha, Bisha 67714, Saudi Arabia
| | - Sabya Sachi Das
- Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra, 835215 Ranchi, Jharkhand, India
| | - Sachin Kumar Singh
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara 144001, India
| | - Kamal Dua
- Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, Ultimo, Sydney, NSW 2007, Australia; Australian Research Centre in Complementary and Integrative Medicine, Faculty of Health, University of Technology Sydney, Ultimo, Sydney, NSW 2007, Australia
| | | | - Dhruv Kumar
- Amity Institute of Molecular Medicine and Stem Cell Research (AIMMSCR), Amity University Uttar Pradesh, Sec 125, Noida 201303, India
| | - Janne Ruokolainen
- Department of Applied Physics, School of Science, Aalto University, 00076 Espoo, Finland
| | - Shreesh Ojha
- Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, P.O. Box 15551, United Arab Emirates
| | - Kavindra Kumar Kesari
- Department of Applied Physics, School of Science, Aalto University, 00076 Espoo, Finland.
| |
Collapse
|
|
31
|
Zhi Y, Huang S, Lina Z. Suppressor of Cytokine Signaling 6 in cancer development and therapy: deciphering its emerging and suppressive roles. Cytokine Growth Factor Rev 2022; 64:21-32. [DOI: 10.1016/j.cytogfr.2022.02.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Accepted: 02/07/2022] [Indexed: 12/16/2022]
|
|
32
|
Immunomodulatory activity of egg yolk protein hydrolysates prepared by novel two-step hydrolysis: A study of mechanism and stability after in vitro digestion model. Poult Sci 2022; 101:101802. [PMID: 35325833 PMCID: PMC8938909 DOI: 10.1016/j.psj.2022.101802] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Revised: 01/20/2022] [Accepted: 02/13/2022] [Indexed: 11/30/2022] Open
Abstract
The aim of this study was to determine the immunomodulatory activity of 2-step egg yolk protein hydrolysates. A two-step hydrolysate of egg yolk protein was prepared using 2 enzymes sequentially, pancreatin and neutrase (EYPH-PN). Our results illustrated that EYPH-PN increased the expression of inducible nitric oxide synthase (iNOS) mRNA in macrophages, resulting in increased nitric oxide (NO) production. EYPH-PN could also enhance the production of tumor necrosis factor (TNF)-α and interleukin (IL)-6 at both the mRNA and protein levels in macrophages. In addition, treatment with EYPH-PN increased the phagocytic activity of macrophages. According to the evaluation with specific inhibitors, both p38 and JNK cell signaling pathways were involved in the activation of macrophages induced by EYPH-PN. As the TLR-2 receptor of macrophages was blocked, the NO production induced by EYPH-PN was decreased. These results suggest that EYPH-PN activates RAW 264.7 macrophages via the TLR-2/p38/JNK pathway to increase the production of NO, TNF-α, and IL-6, and increases phagocytic activity. Furthermore, the immunomodulatory activity of EYPH-PN was maintained even after applying the in vitro digestion model. Taken together, EYPH-PN could be used as a functional food ingredient with excellent immunomodulatory activity in the food industry. Therefore, this study suggests a new alternative method to effectively utilize egg yolk protein, a by-product of the poultry industry.
Collapse
|
|
33
|
Sana M, Rashid M, Rashid I, Akbar H, Gomez-Marin JE, Dimier-Poisson I. Immune response against toxoplasmosis-some recent updates RH: Toxoplasma gondii immune response. Int J Immunopathol Pharmacol 2022; 36:3946320221078436. [PMID: 35227108 PMCID: PMC8891885 DOI: 10.1177/03946320221078436] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
AIMS Cytokines, soluble mediators of immunity, are key factors of the innate and adaptive immune system. They are secreted from and interact with various types of immune cells to manipulate host body's immune cell physiology for a counter-attack on the foreign body. A study was designed to explore the mechanism of Toxoplasma gondii (T. gondii) resistance from host immune response. METHODS AND RESULTS The published data on aspect of host (murine and human) immune response against T. gondii was taken from Google scholar and PubMed. Most relevant literature was included in this study. The basic mechanism of immune response starts from the interactions of antigens with host immune cells to trigger the production of cytokines (pro-inflammatory and anti-inflammatory) which then act by forming a cytokinome (network of cytokine). Their secretory equilibrium is essential for endowing resistance to the host against infectious diseases, particularly toxoplasmosis. A narrow balance lying between Th1, Th2, and Th17 cytokines (as demonstrated until now) is essential for the development of resistance against T. gondii as well as for the survival of host. Excessive production of pro-inflammatory cytokines leads to tissue damage resulting in the production of anti-inflammatory cytokines which enhances the proliferation of Toxoplasma. Stress and other infectious diseases (human immunodeficiency virus (HIV)) that weaken the host immunity particularly the cellular component, make the host susceptible to toxoplasmosis especially in pregnant women. CONCLUSION The current review findings state that in vitro harvesting of IL12 from DCs, Np and MΦ upon exposure with T. gondii might be a source for therapeutic use in toxoplasmosis. Current review also suggests that therapeutic interventions leading to up-regulation/supplementation of SOCS-3, IL12, and IFNγ to the infected host could be a solution to sterile immunity against T. gondii infection. This would be of interest particularly in patients passing through immunosuppression owing to any reason like the ones receiving anti-cancer therapy, the ones undergoing immunosuppressive therapy for graft/transplantation, the ones suffering from immunodeficiency virus (HIV) or having AIDS. Another imortant suggestion is to launch the efforts for a vaccine based on GRA6Nt or other similar antigens of T. gondii as a probable tool to destroy tissue cysts.
Collapse
Affiliation(s)
- Madiha Sana
- Department of Parasitology, 66920University of Veterinary and Animal Sciences, Lahore, Pakistan
| | - Muhammad Rashid
- Department of Parasitology, Faculty of Veterinary and Animal Sciences, 66920The Islamia University of Bahawalpur, Pakistan
| | - Imran Rashid
- Department of Parasitology, 66920University of Veterinary and Animal Sciences, Lahore, Pakistan
| | - Haroon Akbar
- Department of Parasitology, 66920University of Veterinary and Animal Sciences, Lahore, Pakistan
| | - Jorge E Gomez-Marin
- Grupo Gepamol, Centro de Investigaciones Biomedicas, Universidad del Quindio, Armenia, CO, South America
| | - Isabelle Dimier-Poisson
- Université de Tours, Institut national de recherche pour l'agriculture, l'alimentation et l'environnement (INRAE), Unité mixte de recherche 1282 (UMR1282), Infectiologie et santé publique (ISP), Tours, France
| |
Collapse
|
|
34
|
Neural Stem Cells: Promoting Axonal Regeneration and Spinal Cord Connectivity. Cells 2021; 10:cells10123296. [PMID: 34943804 PMCID: PMC8699545 DOI: 10.3390/cells10123296] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Revised: 11/16/2021] [Accepted: 11/16/2021] [Indexed: 11/17/2022] Open
Abstract
Spinal cord injury (SCI) leads to irreversible functional impairment caused by neuronal loss and the disruption of neuronal connections across the injury site. While several experimental strategies have been used to minimize tissue damage and to enhance axonal growth and regeneration, the corticospinal projection, which is the most important voluntary motor system in humans, remains largely refractory to regenerative therapeutic interventions. To date, one of the most promising pre-clinical therapeutic strategies has been neural stem cell (NSC) therapy for SCI. Over the last decade we have found that host axons regenerate into spinal NSC grafts placed into sites of SCI. These regenerating axons form synapses with the graft, and the graft in turn extends very large numbers of new axons from the injury site over long distances into the distal spinal cord. Here we discuss the pathophysiology of SCI that makes the spinal cord refractory to spontaneous regeneration, the most recent findings of neural stem cell therapy for SCI, how it has impacted motor systems including the corticospinal tract and the implications for sensory feedback.
Collapse
|
|
35
|
Lidocaine Alleviates Sepsis-Induced Acute Lung Injury in Mice by Suppressing Tissue Factor and Matrix Metalloproteinase-2/9. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:3827501. [PMID: 34804364 PMCID: PMC8604580 DOI: 10.1155/2021/3827501] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/12/2021] [Revised: 10/14/2021] [Accepted: 10/22/2021] [Indexed: 02/04/2023]
Abstract
Acute lung injury (ALI) is one of the fatal symptoms of sepsis. However, there were no effective clinical treatments. TF accumulation-induced fibrin deposit formations and coagulation abnormalities in pulmonary vessels contribute to the lethality of ALI. Suppressor of cytokine signaling 3 (SOCS3) acts as an endogenous negative regulator of the TLR4/TF pathway. We hypothesized that inducing SOCS3 expression using lidocaine to suppress the TLR4/TF pathway may alleviate ALI. Hematoxylin and eosin (H&E), B-mode ultrasound, and flow cytometry were used to measure the pathological damage of mice. Gelatin zymography was used to measure matrix metalloproteinase-2/9 (MMP-2/9) activities. Western blot was used to assay the expression of protein levels. Here, we show that lidocaine could increase the survival rate of ALI mice and ameliorate the lung injury of ALI mice including reducing the edema, neutrophil infiltration, and pulmonary thrombosis formation and increasing blood flow velocity. Moreover, in vitro and in vivo, lidocaine could increase the expression of p-AMPK and SOCS3 and subsequently decrease the expression of p-ASK1, p-p38, TF, and the activity of MMP-2/9. Taken together, our study demonstrated that lidocaine could inhibit the TLR4/ASK1/TF pathway to alleviate ALI via activating AMPK-SOCS3 axis.
Collapse
|
|
36
|
Li X, Zhang M, Cai S, Wu Y, You Y, Wang X, Wang L. Concentration-Dependent Decitabine Effects on Primary NK Cells Viability, Phenotype, and Function in the Absence of Obvious NK Cells Proliferation-Original Article. Front Pharmacol 2021; 12:755662. [PMID: 34759824 PMCID: PMC8573336 DOI: 10.3389/fphar.2021.755662] [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: 08/09/2021] [Accepted: 09/22/2021] [Indexed: 11/13/2022] Open
Abstract
Acute myeloid leukemia (AML) cells can evade innate immune killing by modulating natural killer (NK) cells receptors and their cognate ligands in tumor cells, thus it may be possible to restore proper expression of immune receptors or ligands with immune sensitive drugs. Decitabine, as a hypomethylation agent, was approved for the treatment of AML and myelodysplastic syndrome. While clinical responses were contributed by epigenetic effects and the induction of cancer cell apoptosis, decitabine also has immune-mediated anti-tumor effects. After exposure to various concentration of decitabine for 24 h, the primary NK cells (AML-NK cells) cytotoxicity and receptor expression (NKG2D and NKp46) displayed parabola-shaped response, while U-shaped response was seen in cytokine release (IFN-γ and IL-10), and these effects were regulated by ERK and STAT3 phosphorylation level. Furthermore, AML-NK cells function displayed different response when the competitive MEK and STAT3 inhibitors applied respectively. Thus, we could conclude that the different dose of decitabine makes various effects on AML-NK cells function and receptors expression.
Collapse
Affiliation(s)
- Xiang Li
- Institution of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Min Zhang
- Institution of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Sisi Cai
- Institution of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yaohui Wu
- Institution of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yong You
- Institution of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xianghong Wang
- Institution of Hematology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Li Wang
- Institution of Hematology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| |
Collapse
|
|
37
|
Keewan E, Matlawska-Wasowska K. The Emerging Role of Suppressors of Cytokine Signaling (SOCS) in the Development and Progression of Leukemia. Cancers (Basel) 2021; 13:4000. [PMID: 34439155 PMCID: PMC8393695 DOI: 10.3390/cancers13164000] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Revised: 08/04/2021] [Accepted: 08/06/2021] [Indexed: 12/12/2022] Open
Abstract
Cytokines are pleiotropic signaling molecules that execute an essential role in cell-to-cell communication through binding to cell surface receptors. Receptor binding activates intracellular signaling cascades in the target cell that bring about a wide range of cellular responses, including induction of cell proliferation, migration, differentiation, and apoptosis. The Janus kinase and transducers and activators of transcription (JAK/STAT) signaling pathways are activated upon cytokines and growth factors binding with their corresponding receptors. The SOCS family of proteins has emerged as a key regulator of cytokine signaling, and SOCS insufficiency leads to constitutive activation of JAK/STAT signaling and oncogenic transformation. Dysregulation of SOCS expression is linked to various solid tumors with invasive properties. However, the roles of SOCS in hematological malignancies, such as leukemia, are less clear. In this review, we discuss the recent advances pertaining to SOCS dysregulation in leukemia development and progression. We also highlight the roles of specific SOCS in immune cells within the tumor microenvironment and their possible involvement in anti-tumor immunity. Finally, we discuss the epigenetic, genetic, and post-transcriptional modifications of SOCS genes during tumorigenesis, with an emphasis on leukemia.
Collapse
Affiliation(s)
- Esra’a Keewan
- Department of Pediatrics, Division of Hematology and Oncology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA;
- Comprehensive Cancer Center, University of New Mexico, Albuquerque, NM 87131, USA
| | - Ksenia Matlawska-Wasowska
- Department of Pediatrics, Division of Hematology and Oncology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA;
- Comprehensive Cancer Center, University of New Mexico, Albuquerque, NM 87131, USA
| |
Collapse
|
|
38
|
Karki P, Cha B, Zhang CO, Li Y, Ke Y, Promnares K, Kaibuchi K, Yoshimura A, Birukov KG, Birukova AA. Microtubule-dependent mechanism of anti-inflammatory effect of SOCS1 in endothelial dysfunction and lung injury. FASEB J 2021; 35:e21388. [PMID: 33724556 PMCID: PMC10069762 DOI: 10.1096/fj.202001477rr] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Revised: 12/21/2020] [Accepted: 01/07/2021] [Indexed: 12/15/2022]
Abstract
Suppressors of cytokine signaling (SOCS) provide negative regulation of inflammatory reaction. The role and precise cellular mechanisms of SOCS1 in control of endothelial dysfunction and barrier compromise associated with acute lung injury remain unexplored. Our results show that siRNA-mediated SOCS1 knockdown augmented lipopolysaccharide (LPS)-induced pulmonary endothelial cell (EC) permeability and enhanced inflammatory response. Consistent with in vitro data, EC-specific SOCS1 knockout mice developed more severe lung vascular leak and accumulation of inflammatory cells in bronchoalveolar lavage fluid. SOCS1 overexpression exhibited protective effects against LPS-induced endothelial permeability and inflammation, which were dependent on microtubule (MT) integrity. Biochemical and image analysis of unstimulated EC showed SOCS1 association with the MT, while challenge with LPS or MT depolymerizing agent colchicine impaired this association. SOCS1 directly interacted with N2 domains of MT-associated proteins CLIP-170 and CLASP2. Furthermore, N-terminal region of SOCS1 was indispensable for these interactions and SOCS1-ΔN mutant lacking N-terminal 59 amino acids failed to rescue LPS-induced endothelial dysfunction. Depletion of endogenous CLIP-170 or CLASP2 abolished SOCS1 interaction with Toll-like receptor-4 and Janus kinase-2 leading to impairment of SOCS1 inhibitory effects on LPS-induced inflammation. Altogether, these findings suggest that endothelial barrier protective and anti-inflammatory effects of SOCS1 are critically dependent on its targeting to the MT.
Collapse
Affiliation(s)
- Pratap Karki
- Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Boyoung Cha
- Department of Anesthesiology, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Chen-Ou Zhang
- Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Yue Li
- Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Yunbo Ke
- Department of Anesthesiology, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Kamoltip Promnares
- Department of Anesthesiology, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Kozo Kaibuchi
- Department of Cell Pharmacology, Nagoya University, Nagoya, Japan
| | - Akihiko Yoshimura
- Department of Microbiology and Immunology, Keio University, Tokyo, Japan
| | - Konstantin G Birukov
- Department of Anesthesiology, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Anna A Birukova
- Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
| |
Collapse
|
|
39
|
Aganovic-Musinovic I, Burnazovic-Ristic L, Kusturica J, Cesic AK, Ademovic E, Sarac-Hadzihalilovic A, Kapo SM, Loga-Zec S, Rakanovic-Todic M. Effects of topically applied diclofenac and ketoprofen on prostaglandin E2 and Stat3 sera levels and body temperature in two different acute inflammation models in rats. Saudi J Biol Sci 2021; 28:3816-3822. [PMID: 34220236 PMCID: PMC8241605 DOI: 10.1016/j.sjbs.2021.03.049] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Revised: 03/18/2021] [Accepted: 03/21/2021] [Indexed: 12/03/2022] Open
Abstract
Introduction Cytokines exert biological function through signal transducer and activator of transcription factors. Prostaglandins have function as promotors, where play a key role in generation of the inflammatory response and as ones that solve inflammatory process. Non-steroidal anti-inflammatory drugs, inhibit prostaglandin synthesis but the existence of additional mechanisms is present. Thus, we aimed to explore effects of topically applied NSAIDs on the levels of PGE2 and Stat3 in the setting of two in vivo induced acute inflammation models. Methods Male Wistar rats were randomized into five equal groups: 4 treated and a control group. Diclofenac or ketoprofen patches were applied in two different doses, i.e. equivalent to human therapeutic dose, and three times higher dose. Three hours later either model of inflammation (with 20% yeast, or with 1% carrageenan) was induced. Blood samples were taken 3 hours after and concentration levels of PGE 2 and Stat3 were determined using ELISA. Body temperature was measured at 0. 1st, 3rd and 5th hour after inflammation induction and presented in Celsius degrees. Shapiro-Wilk, Leven’s, Welch’s One-Way ANOVA, Kruskal-Wallis test and adjustment by Bonferroni correction were applied. Results In both inflammation models, no differences in the mean values of PGE 2 between control, low and high dose groups treated by either diclofenac or ketoprofen were found. In yeast inflammation, the mean value of Stat3 was significantly higher in both dose ketoprofen groups compared to control group. After ketoprofen application, no significant differences in body temperature between groups at hour 0 and 5 in either model of inflammation induced, while at 1st hour after carrageenan inflammation, significant differences were found with significantly higher values in low dose ketoprofen group compared to control group. In yeast application, significant differences in body temperature were found at hour 3 after inducing inflammation and post hoc pairwise comparison test revealed significant higher values in low dose ketoprofen group compared to control. Conclusion Elevated Stat3 values post ketoprofen application in yeast model of induced inflammation were detected. Further investigation of cytokine microenvironment as well as the mechanisms of ketoprofen influence on inflammation are needed.
Collapse
Affiliation(s)
- Izeta Aganovic-Musinovic
- Immunology Department, Medical Faculty of University in Sarajevo, Cekalusa 90, 71000 Sarajevo, Bosnia and Herzegovina
| | - Lejla Burnazovic-Ristic
- Department of Pharmacology Medical Faculty of University in Sarajevo Cekalusa 90, 71000 Sarajevo, Bosnia and Herzegovina
| | - Jasna Kusturica
- Department of Pharmacology Medical Faculty of University in Sarajevo Cekalusa 90, 71000 Sarajevo, Bosnia and Herzegovina
| | - Aida Kulo Cesic
- Department of Pharmacology Medical Faculty of University in Sarajevo Cekalusa 90, 71000 Sarajevo, Bosnia and Herzegovina
| | - Enisa Ademovic
- Department of Epidemiology and Biostatistics, Medical Faculty of University in Sarajevo, Cekalusa 90, 71000 Sarajevo, Bosnia and Herzegovina
| | - Aida Sarac-Hadzihalilovic
- Department of Anatomy, Medical Faculty of University in Sarajevo, Cekalusa 90, 71000 Sarajevo, Bosnia and Herzegovina
| | - Sanita Maleskic Kapo
- Department of Pharmacology Medical Faculty of University in Sarajevo Cekalusa 90, 71000 Sarajevo, Bosnia and Herzegovina
| | - Svjetlana Loga-Zec
- Department of Pharmacology Medical Faculty of University in Sarajevo Cekalusa 90, 71000 Sarajevo, Bosnia and Herzegovina
| | - Maida Rakanovic-Todic
- Department of Pharmacology Medical Faculty of University in Sarajevo Cekalusa 90, 71000 Sarajevo, Bosnia and Herzegovina
| |
Collapse
|
|
40
|
Läsche M, Urban H, Gallwas J, Gründker C. HPV and Other Microbiota; Who's Good and Who's Bad: Effects of the Microbial Environment on the Development of Cervical Cancer-A Non-Systematic Review. Cells 2021; 10:cells10030714. [PMID: 33807087 PMCID: PMC8005086 DOI: 10.3390/cells10030714] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Revised: 03/15/2021] [Accepted: 03/22/2021] [Indexed: 02/07/2023] Open
Abstract
Cervical cancer is responsible for around 5% of all human cancers worldwide. It develops almost exclusively from an unsolved, persistent infection of the squamocolumnar transformation zone between the endo- and ecto-cervix with various high-risk (HR) human papillomaviruses (HPVs). The decisive turning point on the way to persistent HPV infection and malignant transformation is an immune system weakened by pathobionts and oxidative stress and an injury to the cervical mucosa, often caused by sexual activities. Through these injury and healing processes, HPV viruses, hijacking activated keratinocytes, move into the basal layers of the cervical epithelium and then continue their development towards the distal prickle cell layer (Stratum spinosum). The microbial microenvironment of the cervical tissue determines the tissue homeostasis and the integrity of the protective mucous layer through the maintenance of a healthy immune and metabolic signalling. Pathological microorganisms and the resulting dysbiosis disturb this signalling. Thus, pathological inflammatory reactions occur, which manifest the HPV infection. About 90% of all women contract an HPV infection in the course of their lives. In about 10% of cases, the virus persists and cervical intra-epithelial neoplasia (CIN) develops. Approximately 1% of women with a high-risk HPV infection incur a cervical carcinoma after 10 to 20 years. In this non-systematic review article, we summarise how the sexually and microbial mediated pathogenesis of the cervix proceeds through aberrant immune and metabolism signalling via CIN to cervical carcinoma. We show how both the virus and the cancer benefit from the same changes in the immune and metabolic environment.
Collapse
|
|
41
|
Alaswad HA, Mahbub AA, Le Maitre CL, Jordan-Mahy N. Molecular Action of Polyphenols in Leukaemia and Their Therapeutic Potential. Int J Mol Sci 2021; 22:ijms22063085. [PMID: 33802972 PMCID: PMC8002821 DOI: 10.3390/ijms22063085] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 03/08/2021] [Accepted: 03/10/2021] [Indexed: 02/07/2023] Open
Abstract
Leukaemia is a malignant disease of the blood. Current treatments for leukaemia are associated with serious side-effects. Plant-derived polyphenols have been identified as potent anti-cancer agents and have been shown to work synergistically with standard chemotherapy agents in leukaemia cell lines. Polyphenols have multiple mechanisms of action and have been reported to decrease cell proliferation, arrest cell cycle and induce apoptosis via the activation of caspase (3, 8 and 9); the loss of mitochondrial membrane potential and the release of cytochrome c. Polyphenols have been shown to suppress activation of transcription factors, including NF-kB and STAT3. Furthermore, polyphenols have pro-oxidant properties, with increasing evidence that polyphenols inhibit the antioxidant activity of glutathione, causing oxidative DNA damage. Polyphenols also induce autophagy-driven cancer cell death and regulate multidrug resistance proteins, and thus may be able to reverse resistance to chemotherapy agents. This review examines the molecular mechanism of action of polyphenols and discusses their potential therapeutic targets. Here, we discuss the pharmacological properties of polyphenols, including their anti-inflammatory, antioxidant, anti-proliferative, and anti-tumour activities, and suggest that polyphenols are potent natural agents that can be useful therapeutically; and discuss why data on bioavailability, toxicity and metabolism are essential to evaluate their clinical use.
Collapse
Affiliation(s)
- Hamza A. Alaswad
- Biomolecular Sciences Research Centre, Department of Biosciences and Chemistry, Sheffield Hallam University, The Owen Building, City Campus, Howard Street, Sheffield S1 1WB, UK; (H.A.A.); (C.L.L.M.)
| | - Amani A. Mahbub
- Laboratory Medicine Department, Faculty of Applied Medical Sciences, Umm Al-Qura University, P.O. Box 715, Makkah 21955, Saudi Arabia;
| | - Christine L. Le Maitre
- Biomolecular Sciences Research Centre, Department of Biosciences and Chemistry, Sheffield Hallam University, The Owen Building, City Campus, Howard Street, Sheffield S1 1WB, UK; (H.A.A.); (C.L.L.M.)
| | - Nicola Jordan-Mahy
- Biomolecular Sciences Research Centre, Department of Biosciences and Chemistry, Sheffield Hallam University, The Owen Building, City Campus, Howard Street, Sheffield S1 1WB, UK; (H.A.A.); (C.L.L.M.)
- Correspondence: ; Tel.: +44-0114-225-3120
| |
Collapse
|
|
42
|
Emerging Roles of TRIM8 in Health and Disease. Cells 2021; 10:cells10030561. [PMID: 33807506 PMCID: PMC7998878 DOI: 10.3390/cells10030561] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Revised: 02/24/2021] [Accepted: 03/01/2021] [Indexed: 02/07/2023] Open
Abstract
The superfamily of TRIM (TRIpartite Motif-containing) proteins is one of the largest groups of E3 ubiquitin ligases. Among them, interest in TRIM8 has greatly increased in recent years. In this review, we analyze the regulation of TRIM8 gene expression and how it is involved in many cell reactions in response to different stimuli such as genotoxic stress and attacks by viruses or bacteria, playing a central role in the immune response and orchestrating various fundamental biological processes such as cell survival, carcinogenesis, autophagy, apoptosis, differentiation and inflammation. Moreover, we show how TRIM8 functions are not limited to ubiquitination, and contrasting data highlight its role either as an oncogene or as a tumor suppressor gene, acting as a “double-edged weapon”. This is linked to its involvement in the selective regulation of three pivotal cellular signaling pathways: the p53 tumor suppressor, NF-κB and JAK-STAT pathways. Lastly, we describe how TRIM8 dysfunctions are linked to inflammatory processes, autoimmune disorders, rare developmental and cardiovascular diseases, ischemia, intellectual disability and cancer.
Collapse
|
|
43
|
Gao D, Jin N, Fu Y, Zhu Y, Wang Y, Wang T, Chen Y, Zhang M, Xiao Q, Huang M, Li Y. Rational drug design of benzothiazole-based derivatives as potent signal transducer and activator of transcription 3 (STAT3) signaling pathway inhibitors. Eur J Med Chem 2021; 216:113333. [PMID: 33689932 DOI: 10.1016/j.ejmech.2021.113333] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Revised: 02/19/2021] [Accepted: 02/20/2021] [Indexed: 12/17/2022]
Abstract
The cumulative evidence supports STAT3, a transcriptional mediator of oncogenic signaling, as a therapeutic target in cancer. The development of STAT3 inhibitors remain an active area of research as no inhibitors have yet to be approved for cancer treatment. In a continuing effort to develop more potent STAT3 inhibitors based on our previously identified hit compound 16w, a series of benzothiazole derivatives with unique binding mode in SH2 domain of STAT3 were designed, synthesized and biologically evaluated. Of note, compound B19 demonstrated excellent activity against IL-6/STAT3 signaling pathway with the IC50 value as low as 0.067 μM as determined by a luciferase reporter assay. Moreover, multiple compounds displayed potent antiproliferative activity against MDA-MB-468 and JAK2 mutant HEL cell lines. Further biochemical study using Western blot assay indicated that B19 blocked the phosphorylation of STAT3 at Tyr 705 and Ser 727 and thus suppressed STAT3-mediated gene expression of c-MYC and MCL-1. Simultaneously, it induced cancer cell G2/M phase arrest and apoptosis both in MDA-MB-468 and HEL cell lines. Finally, molecular docking study along with surface plasmon resonance (SPR) and fluorescence polarization (FP) assays disclosed the binding mode of B19 in STAT3 SH2 domain. Taken together, our finding suggests that B19 is a promising therapeutic STAT3 inhibitor for cancer treatment.
Collapse
Affiliation(s)
- Dingding Gao
- School of Pharmacy, Fudan University, Shanghai, 201203, China; Innovation Research Institute of Traditional Chinese Medicine (IRI), Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Nan Jin
- Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Yixian Fu
- Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Yueyue Zhu
- School of Pharmacy, Fudan University, Shanghai, 201203, China
| | - Yujie Wang
- School of Pharmacy, Fudan University, Shanghai, 201203, China
| | - Ting Wang
- Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Yuehong Chen
- Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Mingming Zhang
- School of Pharmacy, Fudan University, Shanghai, 201203, China
| | - Qiang Xiao
- School of Pharmacy, Fudan University, Shanghai, 201203, China
| | - Min Huang
- Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Yingxia Li
- School of Pharmacy, Fudan University, Shanghai, 201203, China.
| |
Collapse
|
|
44
|
Abstract
IL-6 is involved both in immune responses and in inflammation, hematopoiesis, bone metabolism and embryonic development. IL-6 plays roles in chronic inflammation (closely related to chronic inflammatory diseases, autoimmune diseases and cancer) and even in the cytokine storm of corona virus disease 2019 (COVID-19). Acute inflammation during the immune response and wound healing is a well-controlled response, whereas chronic inflammation and the cytokine storm are uncontrolled inflammatory responses. Non-immune and immune cells, cytokines such as IL-1β, IL-6 and tumor necrosis factor alpha (TNFα) and transcription factors nuclear factor-kappa B (NF-κB) and signal transducer and activator of transcription 3 (STAT3) play central roles in inflammation. Synergistic interactions between NF-κB and STAT3 induce the hyper-activation of NF-κB followed by the production of various inflammatory cytokines. Because IL-6 is an NF-κB target, simultaneous activation of NF-κB and STAT3 in non-immune cells triggers a positive feedback loop of NF-κB activation by the IL-6-STAT3 axis. This positive feedback loop is called the IL-6 amplifier (IL-6 Amp) and is a key player in the local initiation model, which states that local initiators, such as senescence, obesity, stressors, infection, injury and smoking, trigger diseases by promoting interactions between non-immune cells and immune cells. This model counters dogma that holds that autoimmunity and oncogenesis are triggered by the breakdown of tissue-specific immune tolerance and oncogenic mutations, respectively. The IL-6 Amp is activated by a variety of local initiators, demonstrating that the IL-6-STAT3 axis is a critical target for treating diseases.
Collapse
Affiliation(s)
- Toshio Hirano
- National Institutes for Quantum and Radiological Science and Technology, Anagawa, Inage-ku, Chiba, Japan
- Division of Molecular Psychoimmunology, Institute for Genetic Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| |
Collapse
|
|
45
|
Jin Q, Liu Z, Chen Q. Controlled release of immunotherapeutics for enhanced cancer immunotherapy after local delivery. J Control Release 2021; 329:882-893. [PMID: 33053396 DOI: 10.1016/j.jconrel.2020.10.019] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Revised: 10/01/2020] [Accepted: 10/09/2020] [Indexed: 12/20/2022]
Abstract
Cancer immunotherapy has been demonstrated as a promising therapeutic strategy in clinic owing to its unique advantages. However, although more and more immunotherapeutic agents have been approved for clinical use to activate the immune system, they also could interfere with the homeostatic role of immune system at non-target sites after systemic administration, which may be associated with fatal side effects such as lifelong autoimmune diseases. Thus, it is desirable to develop local delivery systems that could be applied at the targeted sides and engineered to locally control the pharmacokinetics of various immunotherapeutics, including small molecules, macromolecules or even cells. Advancements in biomaterials, biotechnology, nanomedicine and engineering have facilitated the development of local delivery systems for enhanced cancer immunotherapy. This review will summarize the recent advances in developing different local delivery systems and discuss how these delivery systems could be designed to regulate the release behavior of different immunotherapeutics to sustainably stimulate the systemic immune system, effectively and safely inhibiting the cancer recurrence and metastasis. Furthermore, we will discuss how biomaterials-assisted local delivery systems would contribute to the development of cancer immunotherapy, together with their challenges and potential of clinical translation.
Collapse
Affiliation(s)
- Qiutong Jin
- Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Soochow University, Suzhou, Jiangsu 215123, China
| | - Zhuang Liu
- Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Soochow University, Suzhou, Jiangsu 215123, China
| | - Qian Chen
- Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Soochow University, Suzhou, Jiangsu 215123, China.
| |
Collapse
|
|
46
|
Qin T, Wu Y, Liu T, Wu L. Effect of Shenkang on renal fibrosis and activation of renal interstitial fibroblasts through the JAK2/STAT3 pathway. BMC Complement Med Ther 2021; 21:12. [PMID: 33407391 PMCID: PMC7789243 DOI: 10.1186/s12906-020-03180-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2020] [Accepted: 12/07/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Activation of renal fibroblasts is a critical mechanism in the process of renal fibrosis. As a commonly used herbal formula, Shenkang (SK) has been found to attenuate renal fibrosis and renal parenchyma destruction. However, the effect of SK on renal fibroblast activation in unilateral ureteral obstruction (UUO) mice and its molecular mechanism remain undetermined. The present study was performed to elucidate the effect of SK on renal fibroblast activation and renal fibrosis, as well as the potential underlying mechanism, in both NRK-49F cells and UUO mice. METHODS NRK-49F cells were stimulated with 10 ng/ml TGF-β1 for 48 h. After SK treatment, the CCK-8 method was used to evaluate cell viability. Thirty-six C57BL/6 mice were randomly divided into the sham group, UUO group, angiotensin receptor blocker (ARB) group, and SK high-, moderate- and low-dose groups. UUO was induced in mice except those in the sham group. Drugs were administered 1 day later. On the 13th day, the fractional anisotropy (FA) value was determined by MRI to evaluate the degree of renal fibrosis. After 14 days, serum indexes were assessed. Hematoxylin and eosin (HE) and Sirius red staining were used to observe pathological morphology and the degree of fibrosis of the affected kidney. Western blotting and PCR were used to assess the expression of related molecules in both cells and animals at the protein and gene levels. RESULTS Our results showed that SK reduced extracellular matrix (ECM) and α-smooth muscle actin (α-SMA) expression both in vitro and in vivo and attenuated renal fibrosis and the pathological lesion degree after UUO, suppressing JAK2/STAT3 activation. Furthermore, we found that SK regulated the JAK2/STAT3 pathway regulators peroxiredoxin 5 (Prdx5) in vitro and suppressor of cytokine signaling protein 1 (SOCS1) and SOCS3 in vivo. CONCLUSIONS These results indicated that SK inhibited fibroblast activation by regulating the JAK2/STAT3 pathway, which may be a mechanism underlying its protective action in renal fibrosis.
Collapse
Affiliation(s)
- Tianyu Qin
- Beijing University of Chinese Medicine, Beijing, 100029, China
| | - You Wu
- Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Tonghua Liu
- Key Laboratory of Health Cultivation of the Ministry of Education, Beijing University of Chinese Medicine, Beijing, 100029, China.
| | - Lili Wu
- Key Laboratory of Health Cultivation of the Ministry of Education, Beijing University of Chinese Medicine, Beijing, 100029, China
| |
Collapse
|
|
47
|
Ogino H, Okuno T, Murano K, Ueno H. Naturally Oxidized Olive Oil Promotes Active Cutaneous Anaphylaxis and Th2 Cytokine Production. Biol Pharm Bull 2021; 44:838-843. [PMID: 34078816 DOI: 10.1248/bpb.b21-00065] [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] [Indexed: 11/22/2022]
Abstract
The excessive ingestion of oxidized dietary oils may exacerbate some allergic diseases. We previously reported that oxidized olive oil exacerbates active cutaneous anaphylaxis (ACA), one of the immediate allergic reactions. This study was conducted to clarify the effects of oxidized olive oil on the T cell response during ACA. BALB/c female mice were orally administered naturally oxidized olive oil once every 2 d for 2 weeks after ovalbumin (OVA)/aluminum hydroxide gel sensitization, after which ACA was elicited by intracutaneous administration of OVA into the ear auricles. Compared with fresh olive oil, oxidized olive oil administration increased the antigen-specific immunoglobulin E (IgE) antibody titer 2 weeks after OVA-sensitization and vascular hyperpermeability increased due to ACA. In the oxidized olive oil-administered mice, the mRNA expression levels of T-helper 2 (Th2) cytokines, interleukin (IL)-4, -5, -6, and -10, in the lymph nodes increased, as did the proportion of cluster designation (CD)3+CD4+ cells in the spleen and lymph nodes. In CD3+CD4+ cells, the mRNA expression levels of IL-4 and GATA-binding protein 3 (GATA3), the master regulator of Th2, were higher in the oxidized olive oil-group. Antigen-stimulated specific IL-4 production was promoted in CD3+CD4+ cells of oxidized olive oil-administered mice. This suggests that oxidized olive oil exacerbates ACA by promoting Th2 dominance in immediate allergic diseases.
Collapse
Affiliation(s)
- Hirofumi Ogino
- Department of Public Health & Preventive Pharmacology, Faculty of Pharmaceutical Sciences, Setsunan University
| | - Tomofumi Okuno
- Department of Public Health & Preventive Pharmacology, Faculty of Pharmaceutical Sciences, Setsunan University
| | - Koichi Murano
- Division of Hygienic Chemistry, Osaka Institute of Public Health
| | - Hitoshi Ueno
- Department of Public Health & Preventive Pharmacology, Faculty of Pharmaceutical Sciences, Setsunan University
| |
Collapse
|
|
48
|
Eslamloo K, Caballero-Solares A, Inkpen SM, Emam M, Kumar S, Bouniot C, Avendaño-Herrera R, Jakob E, Rise ML. Transcriptomic Profiling of the Adaptive and Innate Immune Responses of Atlantic Salmon to Renibacterium salmoninarum Infection. Front Immunol 2020; 11:567838. [PMID: 33193341 PMCID: PMC7656060 DOI: 10.3389/fimmu.2020.567838] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2020] [Accepted: 09/07/2020] [Indexed: 01/08/2023] Open
Abstract
Bacterial Kidney Disease (BKD), which is caused by a Gram-positive, intracellular bacterial pathogen (Renibacterium salmoninarum), affects salmonids including Atlantic salmon (Salmo salar). However, the transcriptome response of Atlantic salmon to BKD remained unknown before the current study. We used a 44K salmonid microarray platform to characterise the global gene expression response of Atlantic salmon to BKD. Fish (~54 g) were injected with a dose of R. salmoninarum (H-2 strain, 2 × 108 CFU per fish) or sterile medium (control), and then head kidney samples were collected at 13 days post-infection/injection (dpi). Firstly, infection levels of individuals were determined through quantifying the R. salmoninarum level by RNA-based TaqMan qPCR assays. Thereafter, based on the qPCR results for infection level, fish (n = 5) that showed no (control), higher (H-BKD), or lower (L-BKD) infection level at 13 dpi were subjected to microarray analyses. We identified 6,766 and 7,729 differentially expressed probes in the H-BKD and L-BKD groups, respectively. There were 357 probes responsive to the infection level (H-BKD vs. L-BKD). Several adaptive and innate immune processes were dysregulated in R. salmoninarum-infected Atlantic salmon. Adaptive immune pathways associated with lymphocyte differentiation and activation (e.g., lymphocyte chemotaxis, T-cell activation, and immunoglobulin secretion), as well as antigen-presenting cell functions, were shown to be differentially regulated in response to BKD. The infection level-responsive transcripts were related to several mechanisms such as the JAK-STAT signalling pathway, B-cell differentiation and interleukin-1 responses. Sixty-five microarray-identified transcripts were subjected to qPCR validation, and they showed the same fold-change direction as microarray results. The qPCR-validated transcripts studied herein play putative roles in various immune processes including pathogen recognition (e.g., tlr5), antibacterial activity (e.g., hamp and camp), regulation of immune responses (e.g., tnfrsf11b and socs1), T-/B-cell differentiation (e.g., ccl4, irf1 and ccr5), T-cell functions (e.g., rnf144a, il13ra1b and tnfrsf6b), and antigen-presenting cell functions (e.g., fcgr1). The present study revealed diverse immune mechanisms dysregulated by R. salmoninarum in Atlantic salmon, and enhanced the current understanding of Atlantic salmon response to BKD. The identified biomarker genes can be used for future studies on improving the resistance of Atlantic salmon to BKD.
Collapse
Affiliation(s)
- Khalil Eslamloo
- Department of Ocean Sciences, Memorial University of Newfoundland, St. John's, NL, Canada
| | | | - Sabrina M Inkpen
- Department of Ocean Sciences, Memorial University of Newfoundland, St. John's, NL, Canada
| | - Mohamed Emam
- Department of Ocean Sciences, Memorial University of Newfoundland, St. John's, NL, Canada
| | - Surendra Kumar
- Department of Ocean Sciences, Memorial University of Newfoundland, St. John's, NL, Canada
| | | | - Ruben Avendaño-Herrera
- Facultad Ciencias de la Vida, Viña del Mar, and FONDAP Interdisciplinary Center for Aquaculture Research (INCAR), Universidad Andrés Bello, Santiago, Chile
| | - Eva Jakob
- Cargill Innovation Center-Colaco, Calbuco, Chile
| | - Matthew L Rise
- Department of Ocean Sciences, Memorial University of Newfoundland, St. John's, NL, Canada
| |
Collapse
|
|
49
|
Khan MZ, Khan A, Xiao J, Ma Y, Ma J, Gao J, Cao Z. Role of the JAK-STAT Pathway in Bovine Mastitis and Milk Production. Animals (Basel) 2020; 10:ani10112107. [PMID: 33202860 PMCID: PMC7697124 DOI: 10.3390/ani10112107] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2020] [Revised: 10/21/2020] [Accepted: 11/05/2020] [Indexed: 12/23/2022] Open
Abstract
Simple Summary The cytokine-activated Janus kinase (JAK)—signal transducer and activator of transcription (STAT) pathway has an important role in the regulation of immunity and inflammation. In addition, the signaling of this pathway has been reported to be associated with mammary gland development and milk production. Because of such important functions, the JAK-STAT pathway has been widely targeted in both human and animal diseases as a therapeutic agent. Recently, the JAK2, STATs, and inhibitors of the JAK-STAT pathway, especially cytokine signaling suppressors (SOCSs), have been reported to be associated with milk production and mastitis-resistance phenotypic traits in dairy cattle. Thus, in the current review, we attempt to overview the development of the JAK-STAT pathway role in bovine mastitis and milk production. Abstract The cytokine-activated Janus kinase (JAK)—signal transducer and activator of transcription (STAT) pathway is a sequence of communications between proteins in a cell, and it is associated with various processes such as cell division, apoptosis, mammary gland development, lactation, anti-inflammation, and immunity. The pathway is involved in transferring information from receptors on the cell surface to the cell nucleus, resulting in the regulation of genes through transcription. The Janus kinase 2 (JAK2), signal transducer and activator of transcription A and B (STAT5 A & B), STAT1, and cytokine signaling suppressor 3 (SOCS3) are the key members of the JAK-STAT pathway. Interestingly, prolactin (Prl) also uses the JAK-STAT pathway to regulate milk production traits in dairy cattle. The activation of JAK2 and STATs genes has a critical role in milk production and mastitis resistance. The upregulation of SOCS3 in bovine mammary epithelial cells inhibits the activation of JAK2 and STATs genes, which promotes mastitis development and reduces the lactational performance of dairy cattle. In the current review, we highlight the recent development in the knowledge of JAK-STAT, which will enhance our ability to devise therapeutic strategies for bovine mastitis control. Furthermore, the review also explores the role of the JAK-STAT pathway in the regulation of milk production in dairy cattle.
Collapse
Affiliation(s)
- Muhammad Zahoor Khan
- State Key Laboratory of Animal Nutrition, Beijing Engineering Technology Research Center of Raw Milk Quality and Safety Control, College of Animal Science and Technology, China Agricultural University, Beijing 100193, China; (M.Z.K.); (J.X.); (Y.M.); (J.M.)
| | - Adnan Khan
- Key Laboratory of Animal Genetics, Breeding, and Reproduction, Ministry of Agriculture & National Engineering Laboratory for Animal Breeding, College of Animal Science and Technology, China Agricultural University, Beijing 100193, China;
| | - Jianxin Xiao
- State Key Laboratory of Animal Nutrition, Beijing Engineering Technology Research Center of Raw Milk Quality and Safety Control, College of Animal Science and Technology, China Agricultural University, Beijing 100193, China; (M.Z.K.); (J.X.); (Y.M.); (J.M.)
| | - Yulin Ma
- State Key Laboratory of Animal Nutrition, Beijing Engineering Technology Research Center of Raw Milk Quality and Safety Control, College of Animal Science and Technology, China Agricultural University, Beijing 100193, China; (M.Z.K.); (J.X.); (Y.M.); (J.M.)
| | - Jiaying Ma
- State Key Laboratory of Animal Nutrition, Beijing Engineering Technology Research Center of Raw Milk Quality and Safety Control, College of Animal Science and Technology, China Agricultural University, Beijing 100193, China; (M.Z.K.); (J.X.); (Y.M.); (J.M.)
| | - Jian Gao
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China;
| | - Zhijun Cao
- State Key Laboratory of Animal Nutrition, Beijing Engineering Technology Research Center of Raw Milk Quality and Safety Control, College of Animal Science and Technology, China Agricultural University, Beijing 100193, China; (M.Z.K.); (J.X.); (Y.M.); (J.M.)
- Correspondence: ; Tel.: +86-10-62733746
| |
Collapse
|
|
50
|
Yu L, Liu Z, He W, Chen H, Lai Z, Duan Y, Cao X, Tao J, Xu C, Zhang Q, Zhao Z, Zhang J. Hydroxysafflor Yellow A Confers Neuroprotection from Focal Cerebral Ischemia by Modulating the Crosstalk Between JAK2/STAT3 and SOCS3 Signaling Pathways. Cell Mol Neurobiol 2020; 40:1271-1281. [PMID: 32060857 PMCID: PMC11448784 DOI: 10.1007/s10571-020-00812-7] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2019] [Accepted: 01/23/2020] [Indexed: 01/24/2023]
Abstract
Natural bioactive compounds have increasingly proved to be promising in evidence- or target-directed treatment or modification of a spectrum of diseases including cerebral ischemic stroke. Hydroxysafflor yellow A (HSYA), a major active component of the safflower plant, has drawn more interests in recent year for its multiple pharmacological actions in the treatment of cerebrovascular and cardiovascular diseases. Although the Janus kinase signaling, such as JAK2/STAT3 pathway, has been implicated in the modulation of the disease, the inhibition or activation of the pathway that contributed to the neuronal prevention from ischemic damages remains controversial. In this study, a series of experiments were performed to examine the dose- and therapeutic time window-related pharmacological efficacies of HSYA with emphasis on the HSYA-modulated interaction of JAK2/STAT3 and SOCS3 signaling in the MCAO rats. We found that HSYA treatment significantly rescued the neurological and functional deficits in a dose-dependent manner in the MCAO rats within 3 h after ischemia. HSYA treatment with a dosage of 8 mg/kg or higher markedly downregulated the expression of the JAK2-mediated signaling that was activated in response to ischemic insult, while it also promoted the expression of SOCS3 coordinately. In the subsequent experiments with the use of the JAK2 inhibitor WP1066, we found that the treatment of WP1066 alone or combination of WP1066/HSYA all exhibited inhibitory effects on JAK2-mediated signaling, while there was no influence on the SOCS3 activity of corresponding efficacious data in the MCAO rats, suggesting that excessive activation of JAK2/STAT3 might be necessary for HSYA to provoke SOCS3-negative feedback signaling. Taking together, our study demonstrates that HSYA might modulate the crosstalk between JAK2/STAT3 and SOCS3 signaling pathways that eventually contributed to its therapeutic roles against cerebral ischemic stroke.
Collapse
Affiliation(s)
- Lu Yu
- Comprehensive Department of Traditional Chinese Medicine, Putuo Hospital, Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 200062, China
| | - Zhili Liu
- Key Laboratory of Brain Functional Genomics (East China Normal University), Ministry of Education, School of Life Sciences, East China Normal University, Shanghai, 200062, China
| | - Wendi He
- Key Laboratory of Brain Functional Genomics (East China Normal University), Ministry of Education, School of Life Sciences, East China Normal University, Shanghai, 200062, China
| | - Huifen Chen
- Department of Clinical Laboratory, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, 201204, China
| | - Zelin Lai
- Key Laboratory of Brain Functional Genomics (East China Normal University), Ministry of Education, School of Life Sciences, East China Normal University, Shanghai, 200062, China
| | - Yanhong Duan
- Key Laboratory of Brain Functional Genomics (East China Normal University), Ministry of Education, School of Life Sciences, East China Normal University, Shanghai, 200062, China
| | - Xiaohua Cao
- Key Laboratory of Brain Functional Genomics (East China Normal University), Ministry of Education, School of Life Sciences, East China Normal University, Shanghai, 200062, China
| | - Jie Tao
- Comprehensive Department of Traditional Chinese Medicine, Putuo Hospital, Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 200062, China
| | - Chuan Xu
- Department of Neurology, Yueyang Hospital of Integrated Chinese and Western Medicine, Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 200437, China
| | - Qiujuan Zhang
- Department of Neurology, Yueyang Hospital of Integrated Chinese and Western Medicine, Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 200437, China.
| | - Zheng Zhao
- Key Laboratory of Brain Functional Genomics (East China Normal University), Ministry of Education, School of Life Sciences, East China Normal University, Shanghai, 200062, China.
| | - Jun Zhang
- Department of Clinical Laboratory, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, 201204, China.
| |
Collapse
|