Oral Adelmidrol Administration Up-Regulates Palmitoylethanolamide Production in Mice Colon and Duodenum through a PPAR-γ Independent Action

Adelmidrol is a promising palmitoylethanolamide (PEA) analog which displayed up-and-coming anti-inflammatory properties in several inflammatory conditions. Recent studies demonstrated that Adelmidrol is an in vitro enhancer of PEA endogenous production, through the so called “entourage” effect. The present study investigated the ability of Adelmidrol (1 and 10 mg/Kg per os) to increase the endogenous level of PEA in the duodenum and colon of mice after 21-day oral administration in the presence and absence of PPAR-γ inhibitor (1 mg/kg). The level of PEA was analyzed by HPLC-MS. The expression of PEA-related enzymatic machinery was evaluated by western blot and RT-PCR analysis. Our findings demonstrated that Adelmidrol significantly increased PEA levels in the duodenum and colon in a dose/time-dependent manner. We also revealed that Adelmidrol up regulated the enzymatic machinery responsible for PEA metabolism and catabolism. Interestingly, the use of the selective irreversible PPAR-γ antagonist did not affect either PEA intestinal levels or expres-sion/transcription of PEA metabolic enzymes following Adelmidrol administration. The “entourage effect” with Adelmidrol as an enhancer of PEA was thus PPAR-γ-independent. The findings suggest that Adelmidrol can maximize a PEA therapeutic-based approach in several intestinal morbidities

Next-Generation Probiotics for Inflammatory Bowel Disease

Engineered probiotics represent a cutting-edge therapy in intestinal inflammatory disease (IBD). Genetically modified bacteria have provided a new strategy to release therapeutically operative molecules in the intestine and have grown into promising new therapies for IBD. Current IBD treatments, such as corticosteroids and immunosuppressants, are associated with relevant side effects and a significant proportion of patients are dependent on these therapies, thus exposing them to the risk of relevant long-term side effects. Discovering new and effective therapeutic strategies is a worldwide goal in this research field and engineered probiotics could potentially provide a viable solution. This review aims at describing the proceeding of bacterial engineering and how genetically modified probiotics may represent a promising new biotechnological approach in IBD treatment

Cannabidiol inhibits SARS-Cov-2 spike (S) protein-induced cytotoxicity and inflammation through a PPARγ-dependent TLR4/NLRP3/Caspase-1 signaling suppression in Caco-2 cell line

Given the abundancy of angiotensin converting enzyme 2 (ACE-2) receptors density, beyond the lung, the intestine is considered as an alternative site of infection and replication for severe acute respiratory syndrome by coronavirus type 2 (SARS-CoV-2). Cannabidiol (CBD) has recently been proposed in the management of coronavirus disease 2019 (COVID-19) respiratory symptoms because of its anti-inflammatory and immunomodulatory activity exerted in the lung. In this study, we demonstrated the in vitro PPAR-γ-dependent efficacy of CBD (10−9-10−7 M) in preventing epithelial damage and hyperinflammatory response triggered by SARS-CoV-2 spike protein (SP) in a Caco-2 cells. Immunoblot analysis revealed that CBD was able to reduce all the analyzed proinflammatory markers triggered by SP incubation, such as tool-like receptor 4 (TLR-4), ACE-2, family members of Ras homologues A-GTPase (RhoA-GTPase), inflammasome complex (NLRP3), and Caspase-1. CBD caused a parallel inhibition of interleukin 1 beta (IL-1β), IL-6, tumor necrosis factor alpha (TNF-α), and IL-18 by enzyme-linked immunosorbent assay (ELISA) assay. By immunofluorescence analysis, we observed increased expression of tight-junction proteins and restoration of transepithelial electrical resistance (TEER) following CBD treatment, as well as the rescue of fluorescein isothiocyanate (FITC)–dextran permeability induced by SP. Our data indicate, in conclusion, that CBD is a powerful inhibitor of SP protein enterotoxicity in vitro

Ultramicronized palmitoylethanolamide inhibits NLRP3 inflammasome expression and pro-inflammatory response activated by SARS-CoV-2 spike protein in cultured murine alveolar macrophages

Despite its possible therapeutic potential against COVID-19, the exact mechanism(s) by which palmitoylethanolamide (PEA) exerts its beneficial activity is still unclear. PEA has demonstrated analgesic, anti-allergic, and anti-inflammatory activities. Most of the anti-inflammatory properties of PEA arise from its ability to antagonize nuclear factor-κB (NF-κB) signalling pathway via the selective activation of the PPARα receptors. Acting at this site, PEA can downstream several genes involved in the inflammatory response, including cytokines (TNF-α, Il-1β) and other signal mediators, such as inducible nitric oxide synthase (iNOS) and COX2. To shed light on this, we tested the anti-inflammatory and immunomodulatory activity of ultramicronized(um)-PEA, both alone and in the presence of specific peroxisome proliferator-activated receptor alpha (PPAR-α) antagonist MK886, in primary cultures of murine alveolar macrophages exposed to SARS-CoV-2 spike glycoprotein (SP). SP challenge caused a significant concentration-dependent increase in proinflammatory markers (TLR4, p-p38 MAPK, NF-κB) paralleled to a marked upregulation of inflammasome-dependent inflammatory pathways (NLRP3, Caspase-1) with IL-6, IL-1β, TNF-α over-release, compared to vehicle group. We also observed a significant concentration-dependent increase in ACE-2 following SP challenge. um-PEA concentration-dependently reduced all the analyzed proinflammatory markers fostering a parallel downregulation of ACE-2. Our data show for the first time that um-PEA, via PPAR-α, markedly inhibits the SP induced NLRP3 signalling pathway outlining a novel mechanism of action of this lipid against COVID-19