Pioglitazone Attenuates Experimental Colitis-Associated Hyperalgesia through Improving the Intestinal Barrier Dysfunction

Huang, Yulin; Wang, Chenchen; Tian, Xinyu; Mao, Yanting; Hou, Bailin; Sun, Yue; Gu, Xiaoping; Ma, Zhengliang

doi:10.1007/s10753-019-01138-3

Cited by 25 publications

(19 citation statements)

References 52 publications

(54 reference statements)

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“…It must be noted that PPARγ expression suffered no changes due to DSS treatment or to lack of AnxA1, meaning pioglitazone could bind to its target in colon tissue at similar levels for all experimental conditions. This is in accordance with other authors who also reported PPARγ levels suffer little to no variances in colon tissue throughout the development of DSS colitis ( Huang et al, 2020 ).…”

Section: Discussionsupporting

confidence: 94%

“…Data here obtained corroborated other studies which already evidenced the beneficial actions of pioglitazone in murine models of colitis ( Saubermann et al, 2002 ; Takagi et al, 2002 ; Shah et al, 2007 ; Huang et al, 2020 ) and evidenced the lack of pioglitazone effects on AnxA1 −/− mice demonstrating the pivotal role of AnxA1 for pioglitazone anti-inflammatory actions. However, these data do not rule out the effects of pioglitazone and AnxA1 are independent; inflammation exerted when lacking endogenous AnxA1 could be exceedingly exacerbated, overwhelming any attempts of PPARγ-activation linked mechanisms to halt disease progression.…”

Section: Discussionsupporting

confidence: 91%

“…On macrophages, pioglitazone is reported to induce M2 polarization, attenuate TNFα and IL-1ß expressions, reduce actions of CXCL1 and CCL2 and increase the expression of IL-10 and TGF-ß ( Fernandez-Boyanapalli et al, 2010 ; Ahmadian et al, 2013 ; Pisanu et al, 2014 ). Most importantly, however, is pioglitazone role on attenuating the progression of IBDs, as demonstrated by experimental animal models, where treatment of animals induced to development of IBD causes prevention of weight loss, mucosal healing and epithelium restructuration via increase of ZO-1 and claudin-5; pioglitazone also attenuates overall inflammation by reducing NF-kB activation, secretion of cytokines (such as IL-2, TNFα and IL-17) and myeloperoxidase activity ( Takagi et al, 2002 ; Takaki et al, 2006 ; Da Silva et al, 2018 ; El Awdan and Mostafa, 2018 ; Huang et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

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Pioglitazone-Mediated Attenuation of Experimental Colitis Relies on Cleaving of Annexin A1 Released by Macrophages

et al. 2020

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Ulcerative colitis and Crohn’s disease are chronic inflammatory bowel diseases (IBDs) which burden health systems worldwide; available pharmacological therapies are limited and cost-intensive. Use of peroxisome proliferator activated-receptor γ (PPARγ) ligands for IBD treatment, while promising, lacks solid evidences to ensure its efficacy. Annexin A1 (AnxA1), a glucocorticoid-modulated anti-inflammatory protein, plays a key role on IBD control and is a potential biomarker of IBD progression. We here investigated whether effects of pioglitazone, a PPARγ ligand, rely on AnxA1 actions to modulate IBD inflammation. Experimental colitis was evoked by 2% dextran sodium sulfate (DSS) in AnxA1 knockout (AnxA1−/−) or wild type (WT) C57BL/6 mice. Clinical and histological parameters were more severe for AnxA−/− than WT mice, and 10 mg/kg pioglitazone treatment attenuated disease parameters in WT mice only. AnxA1 expression was increased in tissue sections of diseased WT mice, correlating positively with presence of CD68+ macrophages. Metalloproteinase-9 (MMP-9) and inactive 33 kDa AnxA1 levels were increased in the colon of diseased WT mice, which were reduced by pioglitazone treatment. Cytokine secretion, reactive oxygen species generation and MMP-9 expression caused by lipopolysaccharide (LPS) treatment in AnxA1-expressing RAW 264.7 macrophages were reduced by pioglitazone treatment, effects not detected in AnxA1 knockdown macrophages. LPS-mediated increase of AnxA1 cleaving in RAW 264.7 macrophages was also attenuated by pioglitazone treatment. Finally, pioglitazone treatment increased extracellular signal-regulated kinase (ERK) phosphorylation in AnxA1-expressing RAW 264.7 macrophages, but not in AnxA1-knockdown macrophages. Thus, our data highlight AnxA1 as a crucial factor for the therapeutic actions of pioglitazone on IBDs.

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Section: Discussionsupporting

confidence: 94%

Section: Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

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Pioglitazone-Mediated Attenuation of Experimental Colitis Relies on Cleaving of Annexin A1 Released by Macrophages

et al. 2020

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“…Although claimed to be effective on diverse cell types in the gut (epithelium, T-cells, and macrophages), the most notable target cells of PPARg agonists are macrophages and dendritic cells 16 17 18 19 . Furthermore, Phase I and II clinical trials with PPARg agonists either alone 20,21 or in combination with mesalamine 22 show barrier protective effects in UC patients. Despite these insights, the biopharmaceutical industry has not been able to harness the beneficial impact of this major target within emergent therapeutic strategies largely due to a trail of withdrawals after devastating long-term side effects including heart failure, bone fracture, bladder cancer, fluid retention and weight gain 23,24 .…”

Section: Ppar α/G Dual Agonists Are Predicted To Be Effective Barriermentioning

confidence: 99%

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

Katkar

Sayed

et al. 2021

Preprint

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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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“…It is The copyright holder for this preprint this version posted July 19, 2021. ; https://doi.org/10.1101/2021.07. 18.452807 doi: bioRxiv preprint…”

Section: Introductionmentioning

confidence: 99%

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

Katkar

Sayed

Amandachar

et al. 2021

Preprint

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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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Pioglitazone Attenuates Experimental Colitis-Associated Hyperalgesia through Improving the Intestinal Barrier Dysfunction

Cited by 25 publications

References 52 publications

Pioglitazone-Mediated Attenuation of Experimental Colitis Relies on Cleaving of Annexin A1 Released by Macrophages

Pioglitazone-Mediated Attenuation of Experimental Colitis Relies on Cleaving of Annexin A1 Released by Macrophages

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

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

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