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Strategie antifibrotiche in modelli in vitro e in vivo di malattia infiammatoria intestinale
No full textThis study investigates intestinal fibrosis in inflammatory bowel disease (IBD), particularly Crohn’s Disease (CD), where fibrosis leads to complications like stenosis and fistulae. While current treatments focus on inflammation, effective anti-fibrotic therapies remain limited. The study evaluates commonly used IBD drugs for their ability to counteract fibrosis-related processes, specifically fibroblast activation and epithelial-to-mesenchymal transition (EMT). Among the tested drugs, prednisone, methylprednisolone, budesonide, and adalimumab effectively reduced fibrosis markers, with methylprednisolone, budesonide, and adalimumab also mitigating EMT.
Additionally, the study examines losartan, an angiotensin II receptor blocker, for its anti-fibrotic potential. In vitro, losartan reversed angiotensin II-induced fibroblast activation and downregulated profibrotic genes. In vivo, using the SAMP mouse model of CD-like ileitis, losartan reduced inflammation and fibrosis, prevented fibrosis recurrence after steroid treatment, and downregulated AGTR1 expression. These findings suggest that losartan has direct anti-fibrotic effects independent of its anti-inflammatory properties, offering a potential new strategy for managing fibrosis in IBD
Streptococcus thermophilus CNCM I-5570 lysate counteracts the aging process in human dermal fibroblast cells by neutralizing harmful free radicals and impacting antioxidant and anti-inflammatory pathways, thus restoring their physiological functions
Get PDFPrevious studies have highlighted the in vitro and in vivo anti-aging potential of Streptococcus thermophilus prompting us to investigate the biomolecular mechanisms underlying its effects. We evaluated the reparative ability of S. thermophilus lysate in a hydrogen peroxide (H2O2)-induced senescence model of human dermal fibroblasts (HDFs). Cell proliferation, cell number, and senescence level were evaluated by IncuCyte® Live Cell Imager system, trypan blue dye exclusion test and β-galactosidase activity, respectively. We analyzed p21, prolyl 4-hydroxylase A1, intracellular collagen I, nuclear factor E2-related factor 2 (Nrf2), nuclear factor kappa B (NF-κB) and heme oxygenase-1 expression through western blot. Extracellular levels of collagen I, interleukin-1β, and IL-6 were assessed by ELISA. The oxidative stress markers were assayed using standard methods. The direct antioxidant activity of probiotic was quantified using multiple techniques. The presence of antioxidant genes in probiotic was detected via PCR assay. Probiotic lysate exposure increased the proliferation rate, counteracted the aging by reducing β-galactosidase activity and p21 levels, promoted collagen I synthesis and neutralized oxidative stress by activating Nrf2. The probiotic lysate inhibited the NF-κB pathway with pro-inflammatory marker downregulation. Notably, we revealed that probiotic exhibited strong free radical scavenging ability, iron-chelating properties, and significant ferric reducing power in a concentration-dependent manner. We identified seven genes with antioxidant function in its genome. Our results show that S. thermophilus lysate is efficacious in suppressing the biomolecular events associated with H2O2-induced cellular aging, thus supporting the reparative action of S. thermophilus, helpful in treating skin aging
Multi-Strain Probiotic Lysate Attenuates TGF-β1-Induced Intestinal Fibrosis and EMT Modulating Smad, Akt, and WNT/β-Catenin Pathways
Get PDFIntestinal fibrosis is a common complication of inflammatory bowel diseases (IBD), and, to date, effective and safe antifibrotic drugs are still lacking. Emerging evidence suggests that probiotics may provide novel strategies to counteract fibrotic processes. In this study, we evaluated the anti-fibrotic potential of a multi-strain probiotic formulation, OxxySlabTM, using in vitro models of intestinal fibrosis and epithelial-to-mesenchymal transition (EMT). Human intestinal fibroblasts (CCD-18Co cell line) and epithelial cells (Caco-2 cell line, IECs) were stimulated with transforming growth factor-β1 (TGF-β1) to induce fibrotic and EMT phenotypes, respectively. Treatment with OxxySlab modulated cell proliferation and fibrosis-related markers, which we assessed through CCK-8 assay, Western blotting, and immunofluorescence. The probiotic lysate inhibited both canonical and non-canonical TGF-β1 signaling pathways, and it also reduced TGF-β1 gene expression in activated myofibroblasts, as shown by RT-qPCR. Furthermore, probiotic treatment reversed EMT features by restoring epithelial markers and downregulating mesenchymal markers. These findings highlight the beneficial effects of the multi-strain probiotic formulation as an adjunctive therapeutic agent targeting key pathways involved in intestinal fibrosis
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Cyclooxygenase-2 Upregulated by Temozolomide in Glioblastoma Cells Is Shuttled In Extracellular Vesicles Modifying Recipient Cell Phenotype
Get PDFTemozolomide (TMZ) resistance is frequent in patients with glioblastoma (GBM), a tumor characterized by a marked inflammatory microenvironment. Recently, we reported that cyclooxygenase-2 (COX-2) is upregulated in TMZ-resistant GBM cells treated with high TMZ concentrations. Moreover, COX-2 activity inhibition significantly counteracted TMZ-resistance of GBM cells. Extracellular vesicles (EV) are considered crucial mediators in orchestrating GBM drug resistance by modulating the tumor microenvironment (TME) and affecting the surrounding recipient cell phenotype and behavior. This work aimed to verify whether TMZ, at low and clinically relevant doses (5-20 µM), could induce COX-2 overexpression in GBM cells (T98G and U87MG) and explore if secreted EV shuttled COX-2 to recipient cells. The effect of COX-2 inhibitors (COXIB), Celecoxib (CXB), or NS398, alone or TMZ-combined, was also investigated. Our results indicated that TMZ at clinically relevant doses upregulated COX-2 in GBM cells. COXIB treatment significantly counteracted TMZ-induced COX-2 expression, confirming the crucial role of the COX-2/PGE2 system in TMZ-resistance. The COXIB specificity was verified on U251MG, COX-2 null GBM cells. Western blotting of GBM-EV cells showed the COX-2 presence, with the same intracellular trend, increasing in EV derived from TMZ-treated cells and decreasing in those derived from COXIB+TMZ-treated cells. We then evaluated the effect of EV secreted by TMZ-treated cells on U937 and U251MG, used as recipient cells. In human macrophage cell line U937, the internalization of EV derived by TMZ-T98G cells led to a shift versus a pro-tumor M2-like phenotype. On the other hand, EV from TMZ-T98G induced a significant decrease in TMZ sensitivity in U251MG cells. Overall, our results, in confirming the crucial role played by COX-2 in TMZ-resistance, provide the first evidence of the presence and effective functional transfer of this enzyme through EV derived from GBM cells, with multiple potential consequences at the level of TME
Evaluation of the Antifibrotic Effects of Drugs Commonly Used in Inflammatory Intestinal Diseases on In Vitro Intestinal Cellular Models
Get PDFThe mechanism underlying intestinal fibrosis, the main complication of inflammatory bowel disease (IBD), is not yet fully understood, and there is no therapy to prevent or reverse fibrosis. We evaluated, in in vitro cellular models, the ability of different classes of drugs currently used in IBD to counteract two pivotal processes of intestinal fibrosis, the differentiation of intestinal fibroblasts to activated myofibroblasts using CCD-18Co cells, and the epithelial-to-mesenchymal transition (EMT) of intestinal epithelial cells using Caco-2 cells (IEC), both being processes induced by transforming growth factor-β1 (TGF-β1). The drugs tested included mesalamine, azathioprine, methotrexate, prednisone, methylprednisolone, budesonide, infliximab, and adalimumab. The expression of fibrosis and EMT markers (collagen-I, α-SMA, pSmad2/3, occludin) was assessed by Western blot analysis and by immunofluorescence. Of the drugs used, only prednisone, methylprednisolone, budesonide, and adalimumab were able to antagonize the pro-fibrotic effects induced by TGF-β1 on CCD-18Co cells, reducing the fibrosis marker expression. Methylprednisolone, budesonide, and adalimumab were also able to significantly counteract the TGF-β1-induced EMT process on Caco-2 IEC by increasing occludin and decreasing α-SMA expression. This is the first study that evaluates, using in vitro cellular models, the direct antifibrotic effects of drugs currently used in IBD, highlighting which drugs have potential antifibrotic effects
Variations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Get PDFWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Involvement of Cyclooxygenase-2 in Establishing an Immunosuppressive Microenvironment in Tumorspheres Derived from TMZ-Resistant Glioblastoma Cell Lines and Primary Cultures
Get PDFGlioblastoma (GBM) is characterized by an immunosuppressive tumor microenvironment (TME) strictly associated with therapy resistance. Cyclooxygenase-2 (COX-2) fuels GBM proliferation, stemness, and chemoresistance. We previously reported that COX-2 upregulation induced by temozolomide (TMZ) supported chemoresistance. Also, COX-2 transfer by extracellular vesicles released by T98G promoted M2 polarization in macrophages, whereas COX-2 inhibition counteracted these effects. Here, we investigated the COX-2 role in the stemness potential and modulation of the GBM immunosuppressive microenvironment. The presence of macrophages U937 within tumorspheres derived from GBM cell lines and primary cultures exposed to celecoxib (COX-2 inhibitor) with or without TMZ was studied by confocal microscopy. M2 polarization was analyzed by TGFβ-1 and CD206 levels. Osteopontin (OPN), a crucial player within the TME by driving the macrophages’ infiltration, and CD44 expression was assessed by Western blot. TMZ strongly enhanced tumorsphere size and induced the M2 polarization of infiltrating macrophages. In macrophage-infiltrated tumorspheres, TMZ upregulated OPN and CD44 expression. These TMZ effects were counteracted by the concurrent addition of CXB. Remarkably, exogenous prostaglandin-E2 restored OPN and CD44, highlighting the COX-2 pivotal role in the protumor macrophages’ state promotion. COX-2 inhibition interfered with TMZ’s ability to induce M2-polarization and counteracted the development of an immunosuppressive TME
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