Artificial Intelligence-rationalized balanced PPARα/γ dual agonism resets the dysregulated macrophage processes in inflammatory bowel disease

A computational platform, the Boolean network explorer (BoNE), has recently been developed to infuse AI-enhanced precision into drug discovery; it enables querying and navigating invariant Boolean Implication Networks of disease maps for prioritizing high-value targets. Here we used BoNE to query an Inflammatory Bowel Disease (IBD)-map and prioritize a therapeutic strategy that involves dual agonism of two nuclear receptors, PPARα/γ. Balanced agonism of PPARα/γ was predicted to modulate macrophage processes, ameliorate colitis in network-prioritized animal models, reset the gene expression network from disease to health, and achieve a favorable therapeutic index that tracked other FDA-approved targets. Predictions were validated using a balanced and potent PPARα/γ-dual agonist (PAR5359) in two pre-clinical murine models, i.e., Citrobacter rodentium-induced infectious colitis and DSS-induced colitis. Using a combination of selective inhibitors and agonists, we show that balanced dual agonism promotes bacterial clearance more efficiently than individual agonists, both in vivo and in vitro. PPARα is required and its agonism is sufficient to induce the pro-inflammatory cytokines and cellular ROS, which are essential for bacterial clearance and immunity, whereas PPARγ-agonism blunts these responses, delays microbial clearance and induces the anti-inflammatory cytokine, IL10; balanced dual agonism achieved controlled inflammation while protecting the gut barrier and reversal of the transcriptomic network. Furthermore, dual agonism reversed the defective bacterial clearance observed in PBMCs derived from IBD patients. These findings not only deliver a macrophage modulator for use as barrier-protective therapy in IBD, but also highlight the potential of BoNE to rationalize combination therapy.

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AI-guided use of balanced PPARα/γ dual agonist finetunes macrophage responses in inflammatory bowel disease

10.21203/rs.3.rs-243294/v1 ◽

2021 ◽

Author(s):

Gajanan Katkar ◽

Ibrahim Sayed ◽

Mahitha Shree Anandachar ◽

Vanessa Castillo ◽

Vidales Eleadah ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

Drug Discovery ◽

Bowel Disease ◽

Therapeutic Index ◽

Bacterial Clearance ◽

Infectious Colitis ◽

Inflammatory Bowel ◽

Dual Agonist

Abstract A computational platform, the Boolean network explorer (BoNE), has recently been developed to infuse AI-enhanced precision into drug discovery; it enables querying and navigating invariant Boolean Implication Networks of disease maps for prioritizing high-value targets. Here we used BoNE to query an Inflammatory Bowel Disease (IBD)-map and prioritize two nuclear receptors, PPARα/γ. Balanced agonism of PPARα/γ was predicted to impact macrophage processes, ameliorate colitis in network-prioritized animal models, ‘reset’ the gene expression network from disease to health, and achieve a favorable therapeutic index that tracked other FDA-approved targets. Predictions were validated using a balanced and potent PPARα/γ-dual agonist (PAR5359) in two pre-clinical murine models, i.e., Citrobacter rodentium-induced infectious colitis and DSS-induced colitis. Mechanistically, we show that such balanced dual agonism promotes bacterial clearance more efficiently than individual agonists both in vivo and in vitro; PPARα/γ is required and its agonism is sufficient to induce the pro-inflammatory cytokines and cellular ROS, which are essential for bacterial clearance and immunity, whereas PPARα/γ-agonism blunts these responses, delays microbial clearance and induces the anti-inflammatory cytokine, IL10. Balanced agonism achieved controlled inflammation while protecting the gut barrier and ‘reversal’ of the transcriptomic network. Furthermore, dual agonism effectively reversed the defective bacterial clearance observed in PBMCs derived from IBD patients. These findings not only deliver a macrophage modulator for use as barrier-protective therapy in IBD, but also highlight the potential of BoNE to accelerate and enhance the precision of drug discovery.

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Deficiency in the anti-apoptotic protein DJ-1 promotes intestinal epithelial cell apoptosis and aggravates inflammatory bowel disease via p53

Journal of Biological Chemistry ◽

10.1074/jbc.ra119.010143 ◽

2020 ◽

Vol 295 (13) ◽

pp. 4237-4251 ◽

Cited By ~ 1

Author(s):

Jie Zhang ◽

Min Xu ◽

Weihua Zhou ◽

Dejian Li ◽

Hong Zhang ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

Epithelial Cell ◽

Bowel Disease ◽

Intestinal Epithelial Cell ◽

Intestinal Inflammation ◽

Intestinal Epithelial ◽

P53 Expression ◽

Inflammatory Bowel

Parkinson disease autosomal recessive, early onset 7 (PARK7 or DJ-1) is involved in multiple physiological processes and exerts anti-apoptotic effects on multiple cell types. Increased intestinal epithelial cell (IEC) apoptosis and excessive activation of the p53 signaling pathway is a hallmark of inflammatory bowel disease (IBD), which includes ulcerative colitis (UC) and Crohn's disease (CD). However, whether DJ-1 plays a role in colitis is unclear. To determine whether DJ-1 deficiency is involved in the p53 activation that results in IEC apoptosis in colitis, here we performed immunostaining, real-time PCR, and immunoblotting analyses to assess DJ-1 expression in human UC and CD samples. In the inflamed intestines of individuals with IBD, DJ-1 expression was decreased and negatively correlated with p53 expression. DJ-1 deficiency significantly aggravated colitis, evidenced by increased intestinal inflammation and exacerbated IEC apoptosis. Moreover, DJ-1 directly interacted with p53, and reduced DJ-1 levels increased p53 levels both in vivo and in vitro and were associated with decreased p53 degradation via the lysosomal pathway. We also induced experimental colitis with dextran sulfate sodium in mice and found that compared with DJ-1−/− mice, DJ-1−/−p53−/− mice have reduced apoptosis and inflammation and increased epithelial barrier integrity. Furthermore, pharmacological inhibition of p53 relieved inflammation in the DJ-1−/− mice. In conclusion, reduced DJ-1 expression promotes inflammation and IEC apoptosis via p53 in colitis, suggesting that the modulation of DJ-1 expression may be a potential therapeutic strategy for managing colitis.

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P.1.218: INFLAMMATORY BOWEL DISEASE (IBD) PATIENTS ON ANTI TNF-ALPHA TREATMENT: RESPONSE TO THE INFLUENZA A/H1N1 VACCINE IN VIVO AND IN VITRO

Digestive and Liver Disease ◽

10.1016/s1590-8658(11)60446-5 ◽

2011 ◽

Vol 43 ◽

pp. S220

Author(s):

G. Andrisani ◽

D. Frasca ◽

A. Armuzzi ◽

A. Papa ◽

M. Marzo ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

Treatment Response ◽

Bowel Disease ◽

Influenza A ◽

Tnf Alpha ◽

H1n1 Vaccine ◽

Influenza A H1n1 ◽

Inflammatory Bowel

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Inflammatory Bowel Disease–associated GP2 Autoantibodies Inhibit Mucosal Immune Response to Adherent-invasive Bacteria

Inflammatory Bowel Diseases ◽

10.1093/ibd/izaa069 ◽

2020 ◽

Vol 26 (12) ◽

pp. 1856-1868

Author(s):

Stefanie Derer ◽

Ann-Kathrin Brethack ◽

Carlotta Pietsch ◽

Sebastian T Jendrek ◽

Thomas Nitzsche ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

Bowel Disease ◽

Intestinal Inflammation ◽

Ex Vivo ◽

Expression Patterns ◽

Mucosal Immune Response ◽

Disease Manifestation ◽

Inflammatory Bowel

Abstract Adherent-invasive Escherichia coli have been suggested to play a pivotal role within the pathophysiology of inflammatory bowel disease (IBD). Autoantibodies against distinct splicing variants of glycoprotein 2 (GP2), an intestinal receptor of the bacterial adhesin FimH, frequently occur in IBD patients. Hence, we aimed to functionally characterize GP2-directed autoantibodies as a putative part of IBD’s pathophysiology. Ex vivo, GP2-splicing variant 4 (GP2#4) but not variant 2 was expressed on intestinal M or L cells with elevated expression patterns in IBD patients. The GP2#4 expression was induced in vitro by tumor necrosis factor (TNF)-α. The IBD-associated GP2 autoantibodies inhibited FimH binding to GP2#4 and were decreased in anti-TNFα-treated Crohn’s disease patients with ileocolonic disease manifestation. In vivo, mice immunized against GP2 before infection with adherent-invasive bacteria displayed exacerbated intestinal inflammation. In summary, autoimmunity against intestinal expressed GP2#4 results in enhanced attachment of flagellated bacteria to the intestinal epithelium and thereby may drive IBD’s pathophysiology.

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In vitro and in vivo inhibitory activity of 6-amino-2,4,5-trimethylpyridin-3-ols against inflammatory bowel disease

Bioorganic & Medicinal Chemistry Letters ◽

10.1016/j.bmcl.2016.08.075 ◽

2016 ◽

Vol 26 (19) ◽

pp. 4587-4591 ◽

Cited By ~ 9

Author(s):

Suhrid Banskota ◽

Han-eol Kang ◽

Dong-Guk Kim ◽

Sang Won Park ◽

Hyeonjin Jang ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

Bowel Disease ◽

Inhibitory Activity ◽

Inflammatory Bowel

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Oxidative stress and thromboxane-dependent platelet activation in inflammatory bowel disease: effects of anti-TNF-α treatment

Thrombosis and Haemostasis ◽

10.1160/th16-02-0167 ◽

2016 ◽

Vol 116 (09) ◽

pp. 486-495 ◽

Cited By ~ 7

Author(s):

Marco Guerci ◽

Paola Simeone ◽

Sandro Ardizzone ◽

Alessandro Massari ◽

Paolo Giuffrida ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

Platelet Activation ◽

Bowel Disease ◽

Infliximab Treatment ◽

Soluble Cd40 Ligand ◽

Tnf Α ◽

Inflammatory Bowel ◽

Vitro Effect

SummaryPatients with inflammatory bowel disease (IBD) are at higher risk of venous thromboembolism and coronary artery disease despite having a lower burden of traditional risk factors. Platelets from IBD patients release more soluble CD40 ligand (CD40L), and this has been implicated in IBD platelet hyper-activation. We here measured the urinary F2-isoprostane 8-iso-prostaglandin (PG)2α (8-iso-PGF2α), urinary 11–dehydro–thromboxane (TX) B2 (11-dehydro–TXB2) and plasma CD40L in IBD patients, and explored the in vitro action of anti-tumour necrosis factor (TNF)–α antibody infliximab on IBD differentiating megakaryocytes. Urinary and blood samples were collected from 124 IBD patients and 37 healthy subjects. Thirteen IBD patients were also evaluated before and after 6–week infliximab treatment. The in vitro effect of infliximab on patient-derived megakaryocytes was evaluated by immunoflorescence microscopy and by flow cytometry. IBD patients had significantly (p<0.0001) higher urinary 8–iso–PGF2α and 11–dehydro–TXB2 as well as plasma CD40L levels than controls, with active IBD patients displaying higher urinary and plasma values when compared to inactive patients in remission. A 6-week treatment with infliximab was associated with a significant reduction of the urinary excretion of 8–iso–PGF2α and 11–dehydro–TXB2 (p=0.008) and plasma CD40L (p=0.001). Infliximab induced significantly rescued pro-platelet formation by megakaryocytes derived from IBD patients but not from healthy controls. Our findings provide evidence for enhanced in vivo TX–dependent platelet activation and lipid peroxidation in IBD patients. Anti-TNF–α therapy with infliximab down-regulates in vivo isoprostane generation and TX biosynthesis in responder IBD patients. Further studies are needed to clarify the implication of infliximab induced-proplatelet formation from IBD megakaryocytes.Supplementary Material to this article is available online at www.thrombosis-online.com.

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