Pharmacological Inhibition of Caspase-8 Suppresses Inflammation-Induced Angiogenesis in the Cornea

Inflammation-induced angiogenesis is closely related to many diseases and has been regarded as a therapeutic target. Caspase-8 has attracted increasing attention for its immune properties and therapeutic potential in inflammatory disorders. The aim of our study is to investigate the clinical application of pharmacological inhibition of caspase-8 and the underlying molecular mechanisms in inflammation-induced angiogenesis in the cornea. A model of alkali burn (AB)-induced corneal neovascularization (CNV) in C57BL/6 wild-type (WT) mice and toll-like receptor 4 knockout (Tlr4-/-) mice was used. We found that AB increased caspase-8 activity and the pharmacological inhibition of caspase-8 exerted substantial inhibitory effects on CNV, with consistent decreases in caspase-8 activity, inflammatory cell infiltration, macrophage recruitment and activation, VEGF-A, TNF-α, IL-1β, MIP-1, and MCP-1 expression in the cornea. In vitro, caspase-8 mediated TLR4–dependent chemokines and VEGF-A production by macrophages. The TLR4 knockout significantly alleviated CNV, suppressed caspase-8 activity and downregulated expression of inflammatory cytokines and chemokines after AB. Taken together, these findings provide the first demonstration that the pharmacological inhibition of caspase-8 suppresses inflammation-induced angiogenesis and support the use of a pharmacological caspase-8 inhibitor as a novel clinical treatment for CNV and other angiogenic disorders.

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Alantolactone: A Natural Plant Extract as a Potential Therapeutic Agent for Cancer

Frontiers in Pharmacology ◽

10.3389/fphar.2021.781033 ◽

2021 ◽

Vol 12 ◽

Author(s):

Yuan Cai ◽

Kewa Gao ◽

Bi Peng ◽

Zhijie Xu ◽

Jinwu Peng ◽

...

Keyword(s):

Molecular Mechanisms ◽

Cancer Colorectal ◽

Therapeutic Potential ◽

Inhibitory Effects ◽

Cytotoxic Effects ◽

Cancer Breast ◽

Anticancer Effects ◽

Inula Helenium

Alantolactone (ALT) is a natural compound extracted from Chinese traditional medicine Inula helenium L. with therapeutic potential in the treatment of various diseases. Recently, in vitro and in vivo studies have indicated cytotoxic effects of ALT on various cancers, including liver cancer, colorectal cancer, breast cancer, etc. The inhibitory effects of ALT depend on several cancer-associated signaling pathways and abnormal regulatory factors in cancer cells. Moreover, emerging studies have reported several promising strategies to enhance the oral bioavailability of ALT, such as combining ALT with other herbs and using ALT-entrapped nanostructured carriers. In this review, studies on the anti-tumor roles of ALT are mainly summarized, and the underlying molecular mechanisms of ALT exerting anticancer effects on cells investigated in animal-based studies are also discussed.

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TNF-α Triggers RIP1/FADD/Caspase-8-Mediated Apoptosis of Astrocytes and RIP3/MLKL-Mediated Necroptosis of Neurons Induced by Angiostrongylus cantonensis Infection

Cellular and Molecular Neurobiology ◽

10.1007/s10571-021-01063-w ◽

2021 ◽

Author(s):

Hongli Zhou ◽

Minyu Zhou ◽

Yue Hu ◽

Yanin Limpanon ◽

Yubin Ma ◽

...

Keyword(s):

Cell Death ◽

Enrichment Analysis ◽

Angiostrongylus Cantonensis ◽

Gene Set Enrichment Analysis ◽

Caspase 8 ◽

Cns Injury ◽

Vitro Assay ◽

Tnf Α

AbstractAngiostrongylus cantonensis (AC) can cause severe eosinophilic meningitis or encephalitis in non-permissive hosts accompanied by apoptosis and necroptosis of brain cells. However, the explicit underlying molecular basis of apoptosis and necroptosis upon AC infection has not yet been elucidated. To determine the specific pathways of apoptosis and necroptosis upon AC infection, gene set enrichment analysis (GSEA) and protein–protein interaction (PPI) analysis for gene expression microarray (accession number: GSE159486) of mouse brain infected by AC revealed that TNF-α likely played a central role in the apoptosis and necroptosis in the context of AC infection, which was further confirmed via an in vivo rescue assay after treating with TNF-α inhibitor. The signalling axes involved in apoptosis and necroptosis were investigated via immunoprecipitation and immunoblotting. Immunofluorescence was used to identify the specific cells that underwent apoptosis or necroptosis. The results showed that TNF-α induced apoptosis of astrocytes through the RIP1/FADD/Caspase-8 axis and induced necroptosis of neurons by the RIP3/MLKL signalling pathway. In addition, in vitro assay revealed that TNF-α secretion by microglia increased upon LSA stimulation and caused necroptosis of neurons. The present study provided the first evidence that TNF-α was secreted by microglia stimulated by AC infection, which caused cell death via parallel pathways of astrocyte apoptosis (mediated by the RIP1/FADD/caspase-8 axis) and neuron necroptosis (driven by the RIP3/MLKL complex). Our research comprehensively elucidated the mechanism of cell death after AC infection and provided new insight into targeting TNF-α signalling as a therapeutic strategy for CNS injury.

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In Vitro Evaluation of the Anti-Inflammatory Effect of KMUP-1 and in Vivo Analysis of Its Therapeutic Potential in Osteoarthritis

Biomedicines ◽

10.3390/biomedicines9060615 ◽

2021 ◽

Vol 9 (6) ◽

pp. 615

Author(s):

Shang-En Huang ◽

Erna Sulistyowati ◽

Yu-Ying Chao ◽

Bin-Nan Wu ◽

Zen-Kong Dai ◽

...

Keyword(s):

Articular Cartilage ◽

Inflammatory Responses ◽

Therapeutic Potential ◽

Antioxidant Properties ◽

Serum Levels ◽

Gene Expressions ◽

Tnf Α ◽

Anti Inflammatory

Osteoarthritis is a degenerative arthropathy that is mainly characterized by dysregulation of inflammatory responses. KMUP-1, a derived chemical synthetic of xanthine, has been shown to have anti-inflammatory and antioxidant properties. Here, we aimed to investigate the in vitro anti-inflammatory and in vivo anti-osteoarthritis effects of KMUP-1. Protein and gene expressions of inflammation markers were determined by ELISA, Western blotting and microarray, respectively. RAW264.7 mouse macrophages were cultured and pretreated with KMUP-1 (1, 5, 10 μM). The productions of TNF-α, IL-6, MMP-2 and MMP- 9 were reduced by KMUP-1 pretreatment in LPS-induced inflammation of RAW264.7 cells. The expressions of iNOS, TNF-α, COX-2, MMP-2 and MMP-9 were also inhibited by KMUP-1 pretreatment. The gene expression levels of TNF and COX families were also downregulated. In addition, KMUP-1 suppressed the activations of ERK, JNK and p38 as well as phosphorylation of IκBα/NF-κB signaling pathways. Furthermore, SIRT1 inhibitor attenuated the inhibitory effect of KMUP-1 in LPS-induced NF-κB activation. In vivo study showed that KMUP-1 reduced mechanical hyperalgesia in monoiodoacetic acid (MIA)-induced rats OA. Additionally, KMUP-1 pretreatment reduced the serum levels of TNF-α and IL-6 in MIA-injected rats. Moreover, macroscopic and histological observation showed that KMUP-1 reduced articular cartilage erosion in rats. Our results demonstrated that KMUP-1 inhibited the inflammatory responses and restored SIRT1 in vitro, alleviated joint-related pain and cartilage destruction in vivo. Taken together, KMUP-1 has the potential to improve MIA-induced articular cartilage degradation by inhibiting the levels and expression of inflammatory mediators suggesting that KMUP-1 might be a potential therapeutic agent for OA.

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HO-1/CO Maintains Intestinal Barrier Integrity through NF-κB/MLCK Pathway in Intestinal HO-1-/- Mice

Oxidative Medicine and Cellular Longevity ◽

10.1155/2021/6620873 ◽

2021 ◽

Vol 2021 ◽

pp. 1-19

Author(s):

Zhenling Zhang ◽

Lijing Zhang ◽

Qiuping Zhang ◽

Bojia Liu ◽

Fang Li ◽

...

Keyword(s):

Molecular Mechanisms ◽

Intestinal Barrier ◽

Heme Oxygenase 1 ◽

Zinc Protoporphyrin ◽

Barrier Integrity ◽

Tnf Α ◽

Intestinal Barrier Integrity ◽

Deficient Mice

Background. Intestinal barrier injury is an important contributor to many diseases. We previously found that heme oxygenase-1 (HO-1) and carbon monoxide (CO) protect the intestinal barrier. This study is aimed at elucidating the molecular mechanisms of HO-1/CO in barrier loss. Materials and Methods. We induced gut leakiness by injecting carbon tetrachloride (CCl4) to wildtype or intestinal HO-1-deficient mice. In addition, we administrated tumor necrosis factor-α (TNF-α) to cells with gain- or loss-of-HO-1 function. The effects of HO-1/CO maintaining intestinal barrier integrity were investigated in vivo and in vitro. Results. Cobalt protoporphyrin and CO-releasing molecule-2 alleviated colonic mucosal injury and TNF-α levels; upregulated tight junction (TJ) expression; and inhibited epithelial IκB-α degradation and phosphorylation, NF-κB p65 phosphorylation, long MLCK expression, and MLC-2 phosphorylation after administration of CCl4. Zinc protoporphyrin completely reversed these effects. These findings were further confirmed in vitro, using Caco-2 cells with gain- or loss-of-HO-1-function after TNF-α. Pretreated with JSH-23 (NF-κB inhibitor) or ML-7 (long MLCK inhibitor), HO-1 overexpression prevented TNF-α-induced TJ disruption, while HO-1 shRNA promoted TJ damage even in the presence of JSH-23 or ML-7, thus suggesting that HO-1 dependently protected intestinal barrier via the NF-κB p65/MLCK/p-MLC-2 pathway. Intestinal HO-1-deficient mice further demonstrated the effects of HO-1 in maintaining intestinal barrier integrity and its relative mechanisms. Alleviated hepatic fibrogenesis and serum ALT levels finally confirmed the clinical significance of HO-1/CO repairing barrier loss in liver injury. Conclusion. HO-1/CO maintains intestinal barrier integrity through the NF-κB/MLCK pathway. Therefore, the intestinal HO-1/CO-NF-κB/MLCK system is a potential therapeutic target for diseases with a leaky gut.

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TheBDKRB2 +9/-9 Polymorphisms Influence Pro-Inflammatory Cytokine Levels in Knee Osteoarthritis by Altering TLR-2 Expression: Clinical and in Vitro Studies

Cellular Physiology and Biochemistry ◽

10.1159/000443072 ◽

2016 ◽

Vol 38 (3) ◽

pp. 1245-1256 ◽

Cited By ~ 2

Author(s):

Shuo Chen ◽

Lei Zhang ◽

Ruonan Xu ◽

Yunfan Ti ◽

Yunlong Zhao ◽

...

Keyword(s):

Knee Osteoarthritis ◽

Inflammatory Cytokine ◽

Molecular Mechanisms ◽

Enzyme Linked Immunosorbent Assay ◽

Mrna Levels ◽

Knee Oa ◽

Tnf Α ◽

Cytokine Levels ◽

Underlying Mechanisms

Background/Aims: The bradykinin B2 receptor (BDKRB2) +9/-9 gene polymorphisms have been shown to be associated with the susceptibility and severity of osteoarthritis (OA); however, the underlying mechanisms are unclear. In this study, we investigated the correlation between the BDKRB2 +9/-9 polymorphisms and pro-inflammatory cytokine levels in OA and the molecular mechanisms involved. Methods: A total of 156 patients with primary knee OA and 121 healthy controls were enrolled. The BDKRB2 +9/-9 polymorphisms were genotyped. The tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and IL-8 levels were determined using Enzyme-linked immunosorbent assay (ELISA). The toll-like receptor (TLR)-2 and TLR-4 mRNA levels were determined by quantitative real-time PCR. The basal and bradykinin-stimulated pro-inflammatory cytokine secretion in human OA synoviocytes and the involvement of TLR-2 and mitogen-activated protein kinases (MAPKs) were investigated. Results: The presence of -9 bp genotype is associated with higher TNF-α, IL-6, and IL-8 levels and higher TLR-2 expression in OA patients. The basal and bradykinin-induced TLR-2 expressions in human OA synoviocytes were significantly reduced by specific inhibitors of p38, JNK1/2, and ERK1/2. Both the B2 receptor antagonist MEN16132 and TLR-2 silencing inhibited IL-6 and IL-8 secretion in human OA synoviocytes. Conclusion: The data suggested that the BDKRB2 +9/-9 polymorphisms influence pro-inflammatory cytokine levels in knee osteoarthritis by altering TLR-2 expression.

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P0528RENOPROTECTIVE EFFECT OF IL-34 INHIBITION ON CISPLATIN-INDUCED NEPHROTOXICITY IN MICE

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfaa142.p0528 ◽

2020 ◽

Vol 35 (Supplement_3) ◽

Author(s):

Yukihiro Wada ◽

Masayuki Iyoda ◽

Kei Matsumoto ◽

Taihei Suzuki ◽

Ken Iseri ◽

...

Keyword(s):

Caspase 3 ◽

Kidney Injury ◽

Neutralizing Antibody ◽

Inhibitory Effects ◽

Tubulointerstitial Injury ◽

Cisplatin Nephrotoxicity ◽

Physiological Properties ◽

Tnf Α ◽

Vehicle Treatment

Abstract Background and Aims Interleukin (IL)-34, a macrophage (Mø) mediator, is expressed by tubular epithelial cells (TECs). However, the influence of IL-34 on TECs injury has not been fully elucidated. We investigated the physiological properties of IL-34 on TECs damage caused by cisplatin-nephrotoxicity (CP-N). Method 7-week-old male C57BL/6 (B6) mice (n=16) were fasted for 8 hours and then induced CP-N by intraperitoneal injection (IP) of CP (25 mg/kg) on day 0. Groups of animals were given either anti-mouse IL-34 antibody (CP+anti-IL-34 Ab, 400 ng/kg, n=8) or vehicle (CP+V, equal volume of saline, n=8) daily by IP from day -1 to day 2. Three age-matched male B6 mice were used as normal control (NC). All mice were sacrificed on day 3. In addition, mouse renal proximal TECs (MRTEpiC) were cultured to analyze the inhibitory effects of IL-34 on CP-induced TEC apoptosis. Cells were stimulated with CP (2 μg/mL), then treated with or without anti-IL-34 Ab (1000 pg/mL). Results Compared to the NC, CP+V mice exhibited marked acute kidney injury (AKI) and upregulated expression of IL-34 and its two receptors, cFMS and PTP-ζ. Compared to the vehicle treatment, anti-IL-34 Ab treatment significantly suppressed the intrarenal expression levels of IL-34 and its two receptors in CP-N mice; it also significantly suppressed serum IL-34 levels (72.1 ± 5.6 vs. 40.4 ± 7.5 pg/mL, p=0.013). Additionally, treatment with anti-IL-34 Ab significantly improved serum Cr levels (1.3 ± 0.2 vs. 0.7 ± 0.1 mg/mL, p=0.033), ameliorated tubulointerstitial injury (numbers of casts/HPF: 11.9 ± 2.6 vs. 6.5 ± 1.8, p=0.048), and suppressed the number of F4/80+ Mø (17.5 ± 2.7 vs. 11.1 ± 1.1/HPF, p=0.041) and TUNEL+ apoptotic cells (29.2 ± 4.9 vs. 16.7 ± 2.7/HPF, p=0.036) in CP-N mice. The renal cortical transcript levels of Kim-1, MIP-1/CCL3, TNF-α, and Bax were significantly lower in the CP+anti-IL-34 Ab mice than in the CP+V mice. Furthermore, the CP+anti-IL-34 Ab mice showed significantly less renal infiltration of CD11b+F4/80+TNF-α+ cells. In vitro, stimulation with CP induced the expression of IL-34 and its two receptors in MRTEpiC. Treatment with anti-IL-34 Ab significantly suppressed CP-induced caspase-3 and Bax expression with degradation of ERK1/2 phosphorylation in the damaged MRTEpiC. Conclusion IL-34 secreted from damaged TECs was involved in the progression of CP-N. Inhibition of IL-34 with neutralizing antibody directly prevented CP-induced TEC apoptosis by inhibiting the phosphorylation of ERK1/2. Blocking of IL-34 might suppressed proliferation of cytotoxic Mø, which indirectly led to the attenuation of CP-N. Thus, IL-34 represents a potential as therapeutic target for AKI with TECs injury.

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Protective Effects of Pelargonidin on Lipopolysaccharide-induced Hepatic Failure

Natural Product Communications ◽

10.1177/1934578x1801300114 ◽

2018 ◽

Vol 13 (1) ◽

pp. 1934578X1801300 ◽

Cited By ~ 1

Author(s):

Wonhwa Lee ◽

Yuri Lee ◽

Jaehong Kim ◽

Jong-Sup Bae

Keyword(s):

Liver Failure ◽

Molecular Mechanisms ◽

Biological Activities ◽

Serum Levels ◽

Primary Response ◽

Protective Effects ◽

Toll Like Receptor 4 ◽

Extracellular Signal ◽

Tnf Α ◽

Lps Treatment

Pelargonidin (PEL) is a well-known red pigment found in plants and has important biological activities that are potentially beneficial for human health. The aim of this study was to investigate the effect of PEL on lipopolysaccharide (LPS)-induced liver failure in mice, and to elucidate its underlying molecular mechanisms. Liver failure was induced by LPS (15 mg/kg, i.p) in mice, and 12 h later, they were treated intravenously with PEL. Administration of LPS significantly increased mortality, serum levels of alanine transaminase (ALT), aspartate transaminase (AST), and inflammatory cytokines, and expression of toll-like receptor 4 (TLR4) protein; PEL treatment effectively countered these effects of LPS. Further, LPS treatment markedly increased the expression of myeloid differentiation primary response gene 88 (MyD88), phosphorylation of p38, extracellular signal-regulated kinase (ERK), and c-Jun N-terminal kinase (JNK), and expressions of nuclear proteins, such as nuclear factor (NF)-κB and phosphorylated c-Jun. Additionally, LPS increased the serum levels of tumor necrosis factor (TNF)-α and interleukin (IL)-6. All these effects of LPS were attenuated by PEL. In addition, the LPS-mediated increase in the level of serum interferon (IFN)-β expression of the TLR-associated activator of IFN (TRIF) protein, and phosphorylation of IFN regulator factor 3 (IRF3) were reduced by PEL. Our results suggest that PEL attenuates LPS-induced liver damage by inhibition of the TLR-mediated inflammatory pathway and could be used to treat liver diseases.

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MyD88/ERK/NFkB pathways and pro-inflammatory cytokines release in periodontal ligament stem cells stimulated by Porphyromonas gingivalis

European Journal of Histochemistry ◽

10.4081/ejh.2017.2791 ◽

2017 ◽

Vol 61 (2) ◽

Cited By ~ 24

Author(s):

Francesca Diomede ◽

Maria Zingariello ◽

Marcos F.X.B. Cavalcanti ◽

Ilaria Merciaro ◽

Natalia De Isla ◽

...

Keyword(s):

Stem Cells ◽

Periodontal Ligament ◽

Nuclear Translocation ◽

Type I ◽

Toll Like Receptor 4 ◽

Periodontal Ligament Stem Cells ◽

Innate Immune Signaling ◽

Tnf Α ◽

Microbial Infections

The present study was aimed at investigating whether human Periodontal Ligament Stem Cells (hPDLSCs) were capable of sensing and reacting to lipopolysaccharide from Porphyromonas gingivalis (LPS-G) which is widely recognized as a major pathogen in the development and progression of periodontitis. At this purpose hPDLCs were stimulated with 5 μg/mL LPS-G various times and the expression of toll-like receptor 4 (TLR4) was evaluated. Toll-like receptors (TLRs) play an essential role in innate immune signaling in response to microbial infections, and in particular TLR4, type-I transmembrane proteins, has been shown recognizing LPS-G. Our results put in evidence, in treated samples, an overexpression of TLR4 indicating that, hPDLSCs express a functional TLR4 receptor. In addition, LPS-G challenge induces a significant cell growth decrease starting from 24 h until 72 h of treatment. LPS-G leads the activation of the TLR4/MyD88 complex, triggering the secretion of proinflammatory cytokines cascade as: IL-1α, IL-8, TNF-α and β and EOTAXIN. Moreover, the upregulation of pERK/ERK signaling pathways and NFkB nuclear translocation was evident. On the basis of these observations, we conclude that hPDLSCs could represent an appropriate stem cells niche modeling leading to understand and evaluate the biological mechanisms of periodontal stem cells in response to LPS-G, mimicking in vitro an inflammatory process occurring in vivo in periodontal disease.

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Micrococcus luteus Teichuronic Acids Activate Human and Murine Monocytic Cells in a CD14- and Toll-Like Receptor 4-Dependent Manner

Infection and Immunity ◽

10.1128/iai.69.4.2025-2030.2001 ◽

2001 ◽

Vol 69 (4) ◽

pp. 2025-2030 ◽

Cited By ~ 32

Author(s):

Shuhua Yang ◽

Shunji Sugawara ◽

Toshihiko Monodane ◽

Masahiro Nishijima ◽

Yoshiyuki Adachi ◽

...

Keyword(s):

Lipid A ◽

Micrococcus Luteus ◽

Dependent Manner ◽

Toll Like Receptor ◽

Toll Like Receptor 4 ◽

Necrosis Factor Alpha ◽

Monocytic Cells ◽

Tnf Α

ABSTRACT Teichuronic acid (TUA), a component of the cell walls of the gram-positive organism Micrococcus luteus (formerlyMicrococcus lysodeikticus), induced inflammatory cytokines in C3H/HeN mice but not in lipopolysaccharide (LPS)-resistant C3H/HeJ mice that have a defect in the Toll-like receptor 4 (TLR4) gene, both in vivo and in vitro, similarly to LPS (T. Monodane, Y. Kawabata, S. Yang, S. Hase, and H. Takada, J. Med. Microbiol. 50:4–12, 2001). In this study, we found that purified TUA (p-TUA) induced tumor necrosis factor alpha (TNF-α) in murine monocytic J774.1 cells but not in mutant LR-9 cells expressing membrane CD14 at a lower level than the parent J774.1 cells. The TNF-α-inducing activity of p-TUA in J774.1 cells was completely inhibited by anti-mouse CD14 monoclonal antibody (MAb). p-TUA also induced interleukin-8 (IL-8) in human monocytic THP-1 cells differentiated to macrophage-like cells expressing CD14. Anti-human CD14 MAb, anti-human TLR4 MAb, and synthetic lipid A precursor IVA, an LPS antagonist, almost completely inhibited the IL-8-inducing ability of p-TUA, as well as LPS, in the differentiated THP-1 cells. Reduced p-TUA did not exhibit any activities in J774.1 or THP-1 cells. These findings strongly suggested that M. luteus TUA activates murine and human monocytic cells in a CD14- and TLR4-dependent manner, similar to LPS.

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Intestinal dysbacteriosis activates tumor-associated macrophages to promote epithelial-mesenchymal transition of colorectal cancer

Innate Immunity ◽

10.1177/1753425918801496 ◽

2018 ◽

Vol 24 (8) ◽

pp. 480-489 ◽

Cited By ~ 2

Author(s):

Guangsheng Wan ◽

Manli Xie ◽

Hongjie Yu ◽

Hongyu Chen

Keyword(s):

Colorectal Cancer ◽

Molecular Mechanisms ◽

Epithelial Mesenchymal Transition ◽

Cell Counting ◽

Mice Model ◽

Mesenchymal Transition ◽

Tnf Α ◽

Xenograft Mice Model ◽

Intestinal Dysbacteriosis

In this study we investigated the association between intestinal dysbacteriosis with colorectal cancer progress and the underlying molecular mechanisms. Tumor progression was evaluated using xenograft mice model. The epithelial-mesenchymal transition (EMT) markers were quantified by both real-time PCR and immunoblotting. The serum content of IL-6 and TNF-α were measured with ELISA kits. Cell proliferation was determined by the Cell Counting Kit-8. Intestinal dysbacteriosis was successfully simulated by the administration of a large dose of antibiotics and was demonstrated to promote xenograft tumor growth and induce EMT. Accordingly, the serum concentrations of cytokines IL-6 and TNF-α were significantly increased. Furthermore, the production and secretion of IL-6 and TNF-α were remarkably elevated in macrophages isolated from intestinal dysbiotic mice in comparison with the normal counterparts, and conditioned medium from these was shown to significantly stimulate EMT process in HT29 cells in vitro. Macrophage depletion completely abrogated the pro-tumor effect of intestinal dysbacteriosis. Our results suggest that intestinal dysbacteriosis stimulates macrophage activation and subsequently induces EMT process via secreted pro-inflammatory cytokines IL-6 and TNF-α.

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