There are many factors contributing to the development of gastrointestinal diseases, grouped into genetic, environmental, and lifestyle factors. In recent years attention has fallen on pathogens; in particular, Bacteroides fragilis, Fusobacterium nucleatum, Escherichia coli (E. coli) and Helicobacter pylori have been studied. Several points remain to be clarified, and above all, as regards the adherent‐invasive E. coli strains of E. coli, one wonders if they are a cause or a consequence of the disease. In this review, we have tried to clarify some points by examining a series of recent publications regarding the involvement of the bacterium in the pathology, even if other studies are necessary.
Under healthy conditions, foot processes of neighbouring podocytes are interdigitating and connected by an electron‐dense slit diaphragm. Besides slit diaphragm proteins, typical adherens junction proteins are also found to be expressed at this cell‐cell junction. It is therefore considered as a highly specialized type of adherens junction. During podocyte injury, podocyte foot processes lose their characteristic 3D structure and the filtration slits typical meandering structure gets linearized. It is still under debate how this change of structure leads to the phenomenon of proteinuria. Using super‐resolution 3D‐structured illumination microscopy, we observed a spatially restricted up‐regulation of the tight junction protein claudin‐5 (CLDN5) in areas where podocyte processes of patients suffering from minimal change disease (MCD), focal and segmental glomerulosclerosis (FSGS) as well as in murine nephrotoxic serum (NTS) nephritis and uninephrectomy DOCA‐salt hypertension models, were locally injured. CLDN5/nephrin ratios in human glomerulopathies and NTS‐treated mice were significantly higher compared to controls. In patients, the CLDN5/nephrin ratio is significantly correlated with the filtration slit density as a foot process effacement marker, confirming a direct association of local CLDN5 up‐regulation in injured foot processes. Moreover, CLDN5 up‐regulation was observed in some areas of high filtration slit density, suggesting that CLND5 up‐regulation preceded the changes of foot processes. Therefore, CLDN5 could serve as a biomarker predicting early foot process effacement.
Chronic rhinosinusitis with nasal polyps is a multifactorial disease of the nasal and paranasal sinus mucosa and it includes, as comorbidities, anatomic and morphologic alterations, allergic rhinitis, and immunologic diseases. We investigated matrix metalloproteinases (MMP-2, MMP-7, and MMP-9) and their tissue inhibitors (TIMP-1 and TIMP-2) concentration in different etiopathogenetical groups of patients with nasal polyposis (NP) in relation to recurrence after sinonasal surgery. The study group consisted of 45 patients with NP (those with allergic rhinitis, nonallergic rhinitis and asthma or nonallergic rhinitis, and obstruction of osteomeatal complex [OMC]) who underwent endonasal sinus surgery. We also collected 10 patients who underwent septoplasty as control. Immunohistochemistry of nasal mucosa fragments, Western blotting, and polymerase chain reaction analysis showed increased MMPs levels (MMP-9 more than MMP-2 and MMP-7) and decreased tissue inhibitors of MMPs levels (TIMP-1 less than TIMP-2), in patients with chronic rhinosinusitis with nasal polyps compared with control group, in particular in patients with nonallergic rhinitis and asthma compared to those with allergic rhinitis and nonallergic rhinitis and obstruction of OMC. We observed a higher risk of recurrence in patients with nonallergic rhinitis and asthma than in those with allergic rhinitis and nonallergic rhinitis and obstruction of OMC after 36 months from surgery. In this research, we evaluated pathogenesis of NP related to MMPs and their inhibitors concentrations in polypoid tissue.
Increasing the information depth of single kidney biopsies can improve diagnostic precision, personalized medicine and accelerate basic kidney research. Until now, information on mRNA abundance and morphologic analysis has been obtained from different samples, missing out on the spatial context and single‐cell correlation of findings. Herein, we present scoMorphoFISH, a modular toolbox to obtain spatial single‐cell single‐mRNA expression data from routinely generated kidney biopsies. Deep learning was used to virtually dissect tissue sections in tissue compartments and cell types to which single‐cell expression data were assigned. Furthermore, we show correlative and spatial single‐cell expression quantification with super‐resolved podocyte foot process morphometry. In contrast to bulk analysis methods, this approach will help to identify local transcription changes even in less frequent kidney cell types on a spatial single‐cell level with single‐mRNA resolution. Using this method, we demonstrate that ACE2 can be locally upregulated in podocytes upon injury. In a patient suffering from COVID‐19‐associated collapsing FSGS, ACE2 expression levels were correlated with intracellular SARS‐CoV‐2 abundance. As this method performs well with standard formalin‐fixed paraffin‐embedded samples and we provide pretrained deep learning networks embedded in a comprehensive image analysis workflow, this method can be applied immediately in a variety of settings.
Objective:Integrase strand transfer inhibitors (INSTIs) are a class of antiretroviral therapy (ART) medications with a good tolerability profile and a high genetic barrier to HIV drug resistance. However, several studies report significant weight gain among persons receiving INSTI-based ART regimens compared with other regimens.Design:In-vitro model of adipogenesis.Methods:We used 3T3-L1 cells to investigate the effects of the nucleoside reverse transcriptase inhibitors (NRTIs) tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF), alone or in combination with INSTIs: raltegravir (RAL), elvitegravir (ELV), dolutegravir (DTG), and bictegravir (BIC) on adipose differentiation. To monitor adipocyte differentiation, expression levels of PPARɣ and C/EBPα and the intracellular lipid accumulation by Red Oil staining were used. Furthermore, we evaluated the immunohistochemical expression of ER-TR7, a fibroblastic marker, after INSTIs treatment.Results:Compared with control, INSTIs were able to increase adipogenesis, especially RAL and ELV. TAF and TDF inhibited adipogenesis alone and in combination with INSTIs. This ability was more evident when TAF was used in combination with DTG and BIC. Finally, INSTIs increased the expression of ER-TR7 compared with control and cells treated with TAF or TDF.Conclusion:Our data support the evidence that in-vitro challenge of 3T3-L1 cells with INSTIs is able to increase adipocytic differentiation and to drive a number of these cells toward the expression of fibroblastic features, with a different degree according to the various drugs used whereas TAF and TDF have an antagonistic role on this phenomenon.
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