Preclinical Development of FA5, a Novel AMP-Activated Protein Kinase (AMPK) Activator as an Innovative Drug for the Management of Bowel Inflammation

Antonioli, Luca; Pellegrini, Carolina; Fornai, Matteo; Benvenuti, Laura; D’Antongiovanni, Vanessa; Colucci, Rocchina; Bertani, Lorenzo; Salvo, Clelia Di; Semeghini, Giorgia; Motta, Concettina La; Giusti, Laura; Zallocco, Lorenzo; Ronci, Maurizio; Quattrini, Luca; Angelucci, Francesco; Coviello, Vito; Oh, Won Keun; Ha, Quy Thi Kim; Németh, Zoltán; Haskó, György; Blandizzi, Corrado

doi:10.3390/ijms22126325

Cited by 7 publications

(6 citation statements)

References 59 publications

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“…The role of AMPK in intestinal health has received increasing attention in recent years [ 10 , 27 ]. Studies using mouse models of colitis have showed a correlation between the decrease in intestinal AMPKα Thr172 phosphorylation (the active form of AMPK) and colitis development [ 15 , 17 , 28 ]. Interestingly, reduction in AMPKα Thr172 phosphorylation was also observed in the intestine of IBD patients and appeared to occur in both epithelial and lamina propria compartments [ 17 ], further highlighting the underlying connection between AMPK and intestinal barrier function.…”

Section: Discussionmentioning

confidence: 99%

Intestinal Epithelial AMPK Deficiency Causes Delayed Colonic Epithelial Repair in DSS-Induced Colitis

Olivier

Ilchmann-Diounou

Pochard

et al. 2022

Cells

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Dysfunctions in the intestinal barrier, associated with an altered paracellular pathway, are commonly observed in inflammatory bowel disease (IBD). The AMP-activated protein kinase (AMPK), principally known as a cellular energy sensor, has also been shown to play a key role in the stabilization and assembly of tight junctions. Here, we aimed to investigate the contribution of intestinal epithelial AMPK to the initiation, progression and resolution of acute colitis. We also tested the hypothesis that protection mediated by metformin administration on intestinal epithelium damage required AMPK activation. A dextran sodium sulfate (DSS)-induced colitis model was used to assess disease progression in WT and intestinal epithelial cell (IEC)-specific AMPK KO mice. Barrier integrity was analyzed by measuring paracellular permeability following dextran-4kDa gavage and pro-inflammatory cytokines and tight junction protein expression. The deletion of intestinal epithelial AMPK delayed intestinal injury repair after DSS exposure and was associated with a slower re-epithelization of the intestinal mucosa coupled with severe ulceration and inflammation, and altered barrier function. Following intestinal injury, IEC AMPK KO mice displayed a lower goblet cell counts with concomitant decreased Muc2 gene expression, unveiling an impaired restitution of goblet cells and contribution to wound healing process. Metformin administration during the recovery phase attenuated the severity of DSS-induced colitis through improvement in intestinal repair capacity in both WT and IEC AMPK KO mice. Taken together, these findings demonstrate a critical role for IEC-expressed AMPK in regulating mucosal repair and epithelial regenerative capacity following acute colonic injury. Our studies further underscore the therapeutic potential of metformin to support repair of the injured intestinal epithelium, but this effect is conferred independently of intestinal epithelial AMPK.

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Section: Discussionmentioning

confidence: 99%

Intestinal Epithelial AMPK Deficiency Causes Delayed Colonic Epithelial Repair in DSS-Induced Colitis

Olivier

Ilchmann-Diounou

Pochard

et al. 2022

Cells

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“…The colon was collected from mice and flushed of fecal content with ice-cold phosphate-buffered saline (PBS), as described previously (Antonioli et al, 2021). Tissues were minced and homogenized using a Potter-Elvehjem Grinder homogenizer on ice in 20% (w/v) TNE lysis buffer (50 mM Tris-HCl pH 7.4, 100 mM NaCl, 0.1 mM EDTA, 1% NP-40, 1% SDS, 0.1% DOC) with proteases and phosphatases inhibitors.…”

Section: Western Blot Analysismentioning

confidence: 99%

Palmitoylethanolamide Counteracts Enteric Inflammation and Bowel Motor Dysfunctions in a Mouse Model of Alzheimer’s Disease

et al. 2021

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Palmitoylethanolamide (PEA), an endogenous lipid mediator, is emerging as a promising pharmacological agent in multiple neurodegenerative disorders for its anti-inflammatory and neuroprotective properties. However, its effects on enteric inflammation and colonic dysmotility associated with Alzheimer’s disease (AD) are lacking. This study was designed to investigate the beneficial effect of PEA administration in counteracting the enteric inflammation and relieving the bowel motor dysfunctions in an AD mouse model, SAMP8 mice. In addition, the ability of PEA in modulating the activation of enteric glial cells (EGCs), pivotally involved in the pathophysiology of bowel dysfunctions associated with inflammatory conditions, has also been examined. SAMP8 mice at 4 months of age were treated orally with PEA (5 mg/kg/day) for 2 months. SAMR1 animals were employed as controls. At the end of treatment, parameters dealing with colonic motility, inflammation, barrier integrity and AD protein accumulation were evaluated. The effect of PEA on EGCs was tested in cultured cells treated with lipopolysaccharide (LPS) plus β-amyloid 1–42 (Aβ). SAMP8 treated with PEA displayed: 1) an improvement of in vitro colonic motor activity, citrate synthase activity and intestinal epithelial barrier integrity and 2) a decrease in colonic Aβ and α-synuclein (α-syn) accumulation, S100-β expression as well as enteric IL-1β and circulating LPS levels, as compared with untreated SAMP8 mice. In EGCs, treatment with PEA counteracted the increment of S100-β, TLR-4, NF-κB p65 and IL-1β release induced by LPS and Aβ. These results suggest that PEA, under a condition of cognitive decline, prevents the enteric glial hyperactivation, reduces AD protein accumulation and counteracts the onset and progression of colonic inflammatory condition, as well as relieves intestinal motor dysfunctions and improves the intestinal epithelial barrier integrity. Therefore, PEA represents a viable approach for the management of the enteric inflammation and motor contractile abnormalities associated with AD.

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“…Myeloperoxidase was assumed as a quantitative index to estimate the degree of mucosal infiltration by polymorphonuclear cells and, thereby, the severity of enteropathy elicited by diclofenac. MDA concentration in intestinal tissues was determined to obtain quantitative estimates of membrane lipid peroxidation (Antonioli et al, 2021;Fornai et al, 2020). MPO and MDA levels in the ileum were assessed according to previously adopted methods (Antonioli et al, 2021;Fornai et al, 2020), described in the supporting information.…”

Section: Evaluation Of Tissue Myeloperoxidase (Mpo) and Malondialdehy...mentioning

confidence: 99%

“…MDA concentration in intestinal tissues was determined to obtain quantitative estimates of membrane lipid peroxidation (Antonioli et al, 2021;Fornai et al, 2020). MPO and MDA levels in the ileum were assessed according to previously adopted methods (Antonioli et al, 2021;Fornai et al, 2020), described in the supporting information.…”

Section: Evaluation Of Tissue Myeloperoxidase (Mpo) and Malondialdehy...mentioning

confidence: 99%

Use of Saccharomyces boulardii CNCM I‐745 as therapeutic strategy for prevention of nonsteroidal anti‐inflammatory drug‐induced intestinal injury

D’Antongiovanni

Antonioli

Benvenuti

et al. 2023

British J Pharmacology

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Background and PurposeThe use of nonsteroidal anti‐inflammatory drugs (NSAIDs) can be associated with severe adverse digestive effects. The aim of this study was to examine the protective effects of the probiotic S. boulardii CNCM I‐745 in a rat model of diclofenac‐induced enteropathy.Experimental ApproachEnteropathy was induced in 40‐wk‐old male rats by intragastric diclofenac (4 mg/kg BID for 14 days). S. boulardii CNCM I‐745 (3 g/kg BID by oral gavage) was administered starting 14 days before (preventive protocol) or in concomitance (curative protocol) with diclofenac administration. Ileal damage, inflammation, barrier integrity, gut microbiota composition, and TLRs‐NF‐kB‐pathway were evaluated.Key ResultsDiclofenac elicited intestinal damage, along with increments of myeloperoxidase, malondialdehyde, tumor necrosis factor and interleukin‐1β, overexpression of TLR‐2/‐4, MyD88, and NF‐kB p65, increased faecal calprotectin and butyrate levels as well as a decrease in blood hemoglobin levels, occludin and butyrate transporter MCT1 expression. In addition, diclofenac provoked a shift of bacterial taxa in both faecal and ileal samples. Treatment with S. boulardii CNCM I‐745, in both preventive and curative protocol, counteracted the majority of these deleterious changes. Only preventive administration of the probiotic counteracted NSAID‐induced decreased expression of MCT1 and increase in faecal butyrate levels. No significant changes were observed for the occludin expression after probiotic treatment.Conclusion and ImplicationsTreatment with S. boulardii CNCM I‐745 prevents diclofenac‐induced enteropathy through anti‐inflammatory and antioxidant activities. Such effects are likely to be related to increased tissue butyrate bioavailability, through an improvement of butyrate uptake by the enteric mucosa.

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Preclinical Development of FA5, a Novel AMP-Activated Protein Kinase (AMPK) Activator as an Innovative Drug for the Management of Bowel Inflammation

Cited by 7 publications

References 59 publications

Intestinal Epithelial AMPK Deficiency Causes Delayed Colonic Epithelial Repair in DSS-Induced Colitis

Intestinal Epithelial AMPK Deficiency Causes Delayed Colonic Epithelial Repair in DSS-Induced Colitis

Palmitoylethanolamide Counteracts Enteric Inflammation and Bowel Motor Dysfunctions in a Mouse Model of Alzheimer’s Disease

Use of Saccharomyces boulardii CNCM I‐745 as therapeutic strategy for prevention of nonsteroidal anti‐inflammatory drug‐induced intestinal injury

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