New pyrazole/3-cyanopyridin-2-one conjugates 4a-f and 5a-h were designed and synthesized; their anti-inflammatory activities were evaluated in vitro and in vivo. In the LPS-induced RAW 264.7 cell line, nitric oxide (NO) inhibitory activity revealed that 4b, 4e, and 5c were the most powerful NO inhibitors, with
Introduction:Recently, methods for in vitro organogenesis have been widely developed due to their strong potential for medical applications. Cardiac organoids with functional ion channel activity are necessary for non-clinical applications. Methods:In the present study, we optimized the culturing method of human heart organoids (hHOs) from human embryonic stem cells (hESCs) in the presence of the highly concentrated laminin-entactin and fibroblast growth factor 4 by the supplementation of BMP4, BMP10 and ROCK inhibitor (Y27632). Results:The resulting hHOs showed distinctive cardiac morphology with atrium- and ventricle-like chambers composed of cardiac cells, smooth muscle and endothelial cells as well as expressed the integral proteins of gap junctions like Connexin 40 (Cx40), Cx43 and Cx45, and ion channel proteins including Kir2.1(KCNJ2), hERG (KCNH2), Nav1.5 (SCN5A), and Cav1.2 (CACNA1C). In addition to the contractile ability in hHOs, isolated cardiomyocytes from these hHOs exhibited Na and Ca currents by patch clamp analysis. Conclusions:These results indicate that hHOs generated in this study retain physiological cardiac functions, as they recapitulate in vivo cardiac ion currents and cardiac muscle contraction, although their abilities remain limited. The present method for hHOs will contribute to understanding the fundamental mechanism of cardiogenesis and provide an alternative tool for cardiac safety assessment of newly developed drugs as an in vitro human ESC-derived test system.
BACKGROUND:Fibrosis may coexist with emphysema in COPD, but computed tomography (CT) quantification is challenging. Persistent homology (PH), a topological data analysis technique, provides interpretable structural features in greyscale images. By using PH, this CT study aimed to quantify fibrotic lesions in nonemphysematous and emphysematous lungs and to investigate clinical implications of PH-based fibrosis quantification in patients with COPD. METHODS:The study included subjects from the Lung Cancer Screening (LCS) cohort (n=346) and two prospective COPD cohorts (Kyoto University n=234; Kyoto-Himeji n=166). Based on CT value patterns and spatial topology, PH assigned each voxel as fibrotic or nonfibrotic and calculated the percentage of fibrotic lung volume (PH-fibrosis%) in association with visually identified interstitial lung abnormality and COPD outcomes. RESULTS:Higher PH-fibrosis% was associated with interstitial lung abnormalities in the LCS and Kyoto University cohorts. The two COPD cohorts consistently showed significant associations between higher baseline PH-fibrosis% and future exacerbation risk independent of emphysema and airway wall thickness (hazard ratio (HR) 1.39 and 3.35 for Kyoto University and Kyoto-Himeji, respectively). In the Kyoto University cohort, higher PH-fibrosis% was significantly associated with increased mortality (HR 1.94), with a similar trend in the Kyoto-Himeji cohort (HR 1.86). Longitudinal increases in PH-fibrosis% over median 4.98 years were associated with higher exacerbation frequency and patients experiencing greater increase in PH-fibrosis% subsequently exhibited higher mortality in the Kyoto University cohort. CONCLUSIONS:PH can be used to quantify fibrotic lesions on CT and PH-fibrosis% could be a prognostic imaging marker in patients with COPD.
Aleksandar Perić,1 Cveta Milutin Špadijer Mirković,2 Tijana Vidoje Vukadinović,3 Biserka Vukomanović Đurđević,4 Danilo Vojvodić51Department of Otorhinolaryngology, Faculty of Medicine of the Military Medical Academy, University of Defence, Belgrade, Serbia; 2Department of Otorhinolaryngology, University of Priština Faculty of Medicine, Kosovska Mitrovica, Serbia; 3Department of Otorhinolaryngology, University of Montenegro Faculty of Medicine, Podgorica, Montenegro; 4Institute of Pathology, Faculty of Medicine of the Military Medical Academy, University of Defence, Belgrade, Serbia; 5Institute of Medical Research, Division of Clinical & Experimental Immunology, Faculty of Medicine of the Military Medical Academy, University of Defence, Belgrade, SerbiaCorrespondence: Aleksandar Perić, Department of Otorhinolaryngology, Faculty of Medicine of the Military Medical Academy, University of Defence, Belgrade, 11040, Serbia, Email aleksandarperic1971@gmail.comAbstract: Allergic rhinitis (AR) and chronic rhinosinusitis (CRS) in their non-polypous (CRS without nasal polyps - CRSsNP) and polypous (CRS with nasal polyps - CRSwNP) main phenotypes are chronic inflammatory diseases of the nasal mucosa and/or paranasal sinuses with a whole series of unknowns regarding etiology, pathogenesis, clinical manifestations, and therapeutic modalities. Although intranasal and oral antihistamines and intranasal corticosteroids are the main drugs in AR therapy, emerging evidence on the effects of herbal and biological drugs may add a new dimension to the treatment of these patients. CRS is a far more heterogeneous disease with numerous clinical phenotypes that require completely different approaches. In addition to endoscopic sinus surgery (ESS), which remains the mainstay of treatment, intranasal and systemic corticosteroids, macrolide antibiotics, and tetracyclines, as well as nasal irrigation with saline solutions, are the main modalities, especially in the period after surgical treatment. Recently, there has been increasing evidence for the beneficial effects of herbal medicines and biological therapy. However, to assess how well conservative treatment of AR and CRS keeps chronic inflammation under control, numerical parameters derived from cytological findings, biochemical analysis of nasal secretions by enzyme-linked immunoassay (ELISA), flow cytometry, and pathohistological and immunohistochemical analyses of tissue samples are necessary. This narrative review of the literature was done through a critical approach, which included our long-term experience in researching the effects of various drugs, as well as the results of other authors. The results of numerous studies have shown that the application of these drugs can significantly change the profile of inflammatory mediators (cytokines, chemokines, enzymes, growth factors) and thus direct the course of inflammation to a less intense form. Nevertheless, in spite of everything, the control of AR and CRS is still not at a satisfactory level, which directs us towards finding new modalities of conservative therapy, especially in the field of application of biological drugs and plant extracts.Keywords: cytokines, enzymes, inflammation, nasal polyps, rhinitis, allergic, sinusitis
Blastocystis species (spp.), cosmopolitan anaerobic protists, are recently associated with inflammatory bowel diseases, and colorectal cancer. Serious side effects, variable efficacy in different subtypes, and rising resistance against the sole drug of choice, metronidazole (MTZ), necessitate a search for safer, effective alternatives. Thus, the present work aims to determine the total phenolic content and the reducing power of pomegranate peel extract (PPE) and testing its efficacy either alone or loaded with chitosan nanoparticles (PPE CSNPs) against Blastocystis spp. in vitro and in vivo compared to MTZ. Anti-Blastocystis activity of PPE and PPE CSNPs were assessed in vitro after 24 h of incubation by estimating parasite count, viability, and ultrastructural morphological changes by scanning electron microscopy (SEM), while assessed in vivo by estimating parasite count, histopathological examination and biochemical study to assess the potential toxicity after 10 days of oral administration to Swiss albino mice. PPE and PPE CSNPs showed significant anti-Blastocystis activity (75.7%, 69.1%) in vitro that were statistically insignificant compared to MTZ in addition to the remarkable ultrastructural distortion showed by SEM. However, MTZ achieved superior effect over PPE and PPE CSNPs in vivo (91.6%, 58.5% and 73.6%, respectively) with moderate tissue repair compared to PPE CSNPs. Significant increase of liver enzymes and creatinine displayed by MTZ (unlike PPE and PPE CSNPs) clarified its detrimental effects on liver and kidney. In conclusion, PPE and PPE CSNPs revealed promising anti-Blastocystis activity with safer effects on the liver and kidney compared to MTZ.
