Fenofibrate reduces glucose-induced barrier dysfunction in feline enteroids.

Diabetes mellitus (DM) is a common chronic metabolic disease in humans and household cats that is characterized by persistent hyperglycemia. DM is associated with dysfunction of the intestinal barrier. This barrier is comprised of an epithelial monolayer that contains a network of tight junctions that adjoin cells and regulate paracellular movement of water and solutes. The mechanisms driving DM-associated barrier dysfunction are multifaceted, and the direct effects of hyperglycemia on the epithelium are poorly understood. Preliminary data suggest that fenofibrate, An FDA-approved peroxisome proliferator-activated receptor-alpha (PPARα) agonist drug attenuates intestinal barrier dysfunction in dogs with experimentally-induced DM. We investigated the effects of hyperglycemia-like conditions and fenofibrate treatment on epithelial barrier function using feline intestinal organoids. We hypothesized that glucose treatment directly increases barrier permeability and alters tight junction morphology, and that fenofibrate administration can ameliorate these deleterious effects. We show that hyperglycemia-like conditions directly increase intestinal epithelial permeability, which is mitigated by fenofibrate. Moreover, increased permeability is caused by disruption of tight junctions, as evident by increased junctional tortuosity. Finally, we found that increased junctional tortuosity and barrier permeability in hyperglycemic conditions were associated with increased protein kinase C-α (PKCα) activity, and that fenofibrate treatment restored PKCα activity to baseline levels. We conclude that hyperglycemia directly induces barrier dysfunction by disrupting tight junction structure, a process that is mitigated by fenofibrate. We further propose that counteracting modulation of PKCα activation by increased intracellular glucose levels and fenofibrate is a key candidate regulatory pathway of tight junction structure and epithelial permeability.

Inflammatory cytokines directly disrupt the bovine intestinal epithelial barrier.

The small intestinal mucosa constitutes a physical barrier separating the gut lumen from sterile internal tissues. Junctional complexes between cells regulate transport across the barrier, preventing water loss and the entry of noxious molecules or pathogens. Inflammatory diseases in cattle disrupt this barrier; nonetheless, mechanisms of barrier disruption in cattle are poorly understood. We investigated the direct effects of three inflammatory cytokines, TNFα, IFNγ, and IL-18, on the bovine intestinal barrier utilizing intestinal organoids. Flux of fluorescein isothiocyanate (FITC)-labeled dextran was used to investigate barrier permeability. Immunocytochemistry and transmission electron microscopy were used to investigate junctional morphology, specifically tortuosity and length/width, respectively. Immunocytochemistry and flow cytometry was used to investigate cellular turnover via proliferation and apoptosis. Our study shows that 24-h cytokine treatment with TNFα or IFNγ significantly increased dextran permeability and tight junctional tortuosity, and reduced cellular proliferation. TNFα reduced the percentage of G2/M phase cells, and IFNγ treatment increased cell apoptotic rate. IL-18 did not directly induce significant changes to barrier permeability or cellular turnover. Our study concludes that the inflammatory cytokines, TNFα and IFNγ, directly induce intestinal epithelial barrier dysfunction and alter the tight junctional morphology and rate of cellular turnover in bovine intestinal epithelial cells.

Correction: In silico screening and identification of deleterious missense SNPs along with their effects on CD-209 gene: An insight to CD-209 related-diseases.

[This corrects the article DOI: 10.1371/journal.pone.0247249.].

In silico screening and identification of deleterious missense SNPs along with their effects on CD-209 gene: An insight to CD-209 related-diseases.

DC-SIGN receptor articulated by macrophages and dendritic cells is encoded by CD209 gene and plays a role to activate and proliferate the T-lymphocytes in response of virus attack. The dysfunctional activity of DC-SIGN receptor because of missense SNPs can lead to cause dengue haemorrhage fever, HIV-1 infection etc. Out of 11 transcripts of CD209, all missense SNPs of canonical transcript were retrieved from Ensembl database and evaluated by their deleteriousness by using Polyphen-2, PMut, SIFT, MutPred, PROVEAN and PhD-SNP together with stimulation of its complete 3D structure. 10 nsSNPs were chosen depending on both the significance value of nsSNP and their prediction among SNPs evaluating servers which are based on different algorithms. Moreover, the position and native role of 10 nsSNPs in wild 3D model has been described which assist to acknowledge their importance. This study urges the researcher's community to experimentally validate these SNPs and their association in causing the diseases like dengue fever, Tuberculosis etc.