H89 Treatment Reduces Intestinal Inflammation and Candida albicans Overgrowth in Mice

Dumortier, Corentin; Charlet, Rogatien; Bettaı̈eb, Ali; Jawhara, Samir

doi:10.3390/microorganisms8122039

Cited by 6 publications

(9 citation statements)

References 53 publications

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“…cDNA synthesis was carried out using a High Capacity DNA Reverse Transcription (RT) kit, with Master Mix (Applied Biosystems, CA, USA). To amplify the cDNA, Fast SYBR green (Applied Biosystems) was employed in a one-step system (Applied Biosystems) [ 39 ]. SYBR green dye intensity was assessed using one-step software.…”

Section: Methodsmentioning

confidence: 99%

Two New Compounds Containing Pyridinone or Triazine Heterocycles Have Antifungal Properties against Candida albicans

et al. 2022

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Candidiasis, caused by the opportunistic yeast Candida albicans, is the most common fungal infection today. Resistance of C. albicans to current antifungal drugs has emerged over the past decade leading to the need for novel antifungal agents. Our aim was to select new antifungal compounds by library-screening methods and to assess their antifungal effects against C. albicans. After screening 90 potential antifungal compounds from JUNIA, a chemical library, two compounds, 1-(4-chlorophenyl)-4-((4-chlorophenyl)amino)-3,6-dimethylpyridin-2(1H)-one (PYR) and (Z)-N-(2-(4,6-dimethoxy-1,3,5-triazin-2-yl)vinyl)-4-methoxyaniline (TRI), were identified as having potential antifungal activity. Treatment with PYR and TRI resulted in a significant reduction of C. albicans bioluminescence as well as the number of fungal colonies, indicating rapid fungicidal activity. These two compounds were also effective against clinically isolated fluconazole- or caspofungin-resistant C. albicans strains. PYR and TRI had an inhibitory effect on Candida biofilm formation and reduced the thickness of the mannan cell wall. In a Caenorhabditis elegans infection model, PYR and TRI decreased the mortality of nematodes infected with C. albicans and enhanced the expression of antimicrobial genes that promote C. albicans elimination. Overall, PYR and TRI showed antifungal properties against C. albicans by exerting fungicidal activities and enhancing the antimicrobial gene expression of Caenorhabditis elegans.

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Section: Methodsmentioning

confidence: 99%

Two New Compounds Containing Pyridinone or Triazine Heterocycles Have Antifungal Properties against Candida albicans

et al. 2022

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“…Based on our previous results, which showed that H89 reduces intestinal inflammation in a murine model of DSS-induced colitis ( 27 ), we investigated its prophylactic potential. In a mouse model of AOM/DSS colitis-associated intestinal carcinogenesis, we showed that H89 decreases tumor incidence as attested by a significant reduction in the total number of colorectal polyps ( Figures 1A, B ).…”

Section: Resultsmentioning

confidence: 99%

Protein Kinase Inhibitor-Mediated Immunoprophylactic and Immunotherapeutic Control of Colon Cancer

et al. 2022

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Immunotherapy has allowed major advances in oncology in the past years, in particular with the development of immune checkpoint inhibitors, but the clinical benefits are still limited, particularly in colorectal cancer (CRC). Our scientific approach is based on the search for innovative immunotherapy with a final goal that aims to induce an effective antitumor immune response in CRC. Here, we focused on a multikinase inhibitor, H89. We carried out in vivo experiments based on syngeneic mouse models of colon cancer in BALB/c mice and chemically colon tumorigenesis. Flow cytometry, RNAseq, RT-qPCR, antibody-specific immune cell depletion, and Western blot were used to identify the immune cell type involved in the preventive and antitumor activity of H89. We demonstrated that H89 delays colon oncogenesis and prevents tumor growth. This latter effect seems to involve NK cells. H89 also inhibits colon tumor growth in a T-cell-dependent manner. Analysis of the immune landscape in the tumor microenvironment showed an increase of CD4+ Th1 cells and CD8+ cytotoxic T cells but a decrease of CD4+ Treg cell infiltration. Mechanistically, we showed that H89 could promote naïve CD4+ T-cell differentiation into Th1, a decrease in Treg differentiation, and an increase in CD8+ T-cell activation and cytotoxicity ex vivo. Furthermore, H89 induced overexpression of genes involved in antitumor immune response, such as IL-15RA, which depletion counteracts the antitumor effect of H89. We also found that H89 regulated Akt/PP2A pathway axis, involved in TCR and IL-15 signaling transduction. Our findings identify the H89 as a potential strategy for immune system activation leading to the prevention and treatment of CRC.

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“…The stress responses mediating triazole resistance activate the cyclic AMP (cAMP)-protein kinase A (PKA) signalling pathway [ 91 ]. Dumortier et al showed that N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide (H89), a PKA inhibitor, reduced the viability of C. albicans and decreased the expression of pro-inflammatory cytokines and innate immune receptors in colonic epithelial Caco-2 cells and macrophages [ 97 ]. Additionally, H89 decreased colonic inflammation in mice with DSS-induced colitis and allowed elimination of C. albicans from the gut [ 97 ].…”

Section: Role Of Novel Antifungal Compounds On the Modulation Of Infl...mentioning

confidence: 99%

“…Dumortier et al showed that N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide (H89), a PKA inhibitor, reduced the viability of C. albicans and decreased the expression of pro-inflammatory cytokines and innate immune receptors in colonic epithelial Caco-2 cells and macrophages [ 97 ]. Additionally, H89 decreased colonic inflammation in mice with DSS-induced colitis and allowed elimination of C. albicans from the gut [ 97 ]. In line with these observations, 2,3-dihydroxy-4-methoxybenzaldehyde (DHMB), a key intermediate in the synthesis of some natural compounds, including the antibacterial agents (±)-isoperbergin and perbergin, was efficient against clinically isolated caspofungin- or fluconazole-resistant C. albicans strains [ 98 ].…”

Section: Role Of Novel Antifungal Compounds On the Modulation Of Infl...mentioning

confidence: 99%

How Gut Bacterial Dysbiosis Can Promote Candida albicans Overgrowth during Colonic Inflammation

Jawhara

2022

Microorganisms

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Candida albicans is a commensal opportunistic yeast, which is capable of colonising many segments of the human digestive tract. Excessive C. albicans overgrowth in the gut is associated with multiple risk factors such as immunosuppression, antibiotic treatment associated with changes to the gut microbiota and digestive mucosa that support C. albicans translocation across the digestive intestinal barrier and haematogenous dissemination, leading to invasive fungal infections. The C. albicans cell wall contains mannoproteins, β-glucans, and chitin, which are known to trigger a wide range of host cell activities and to circulate in the blood during fungal infection. This review describes the role of C. albicans in colonic inflammation and how various receptors are involved in the immune defence against C. albicans with a special focus on the role of mannose-binding lectin (MBL) and TLRs in intestinal homeostasis and C. albicans sensing. This review highlights gut microbiota dysbiosis during colonic inflammation in a dextran sulphate sodium (DSS)-induced colitis murine model and the effect of fungal glycan fractions, in particular β-glucans and chitin, on the modification of the gut microbiota, as well as how these glycans modulate the immuno-inflammatory response of the host.

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H89 Treatment Reduces Intestinal Inflammation and Candida albicans Overgrowth in Mice

Cited by 6 publications

References 53 publications

Two New Compounds Containing Pyridinone or Triazine Heterocycles Have Antifungal Properties against Candida albicans

Two New Compounds Containing Pyridinone or Triazine Heterocycles Have Antifungal Properties against Candida albicans

Protein Kinase Inhibitor-Mediated Immunoprophylactic and Immunotherapeutic Control of Colon Cancer

How Gut Bacterial Dysbiosis Can Promote Candida albicans Overgrowth during Colonic Inflammation

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