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Background: Data on pandemic H1N1 influenza (pH1N1) virus infection in hospitalised children are limited. Aims and Objectives: To examine the epidemiological and clinical characteristics of children hospitalised with pH1N1 at a large tertiary-care centre in Athens and compare them with those of children hospitalised with seasonal influenza A in previous years. Methods: All children (n = 146) admitted with confirmed pH1N1 between October 2009 to February 2010 and January 2011 to May 2011 were included. Data on children ≧6 months of age (n = 109) were compared with those of 138 children admitted with seasonal influenza A who were examined during two previous influenza seasons (2002–2003 and 2004–2005). Results: The age distribution was similar between seasonal and pandemic H1N1. Bronchial asthma was significantly more common in the seasonal influenza group but the clinical presentation was similar in the two groups, except that fever was more common in patients with pH1N1. Children admitted with seasonal influenza were more likely to develop acute otitis media. There were no significant differences between the two groups for severe outcomes (admission to the ICU, mechanical ventilation or death). Only one child with seasonal influenza (0·6%) and three with pH1N1 influenza (2%) required admission to the ICU. Mean length of hospitalisation was longer in the seasonal influenza group. Conclusion: Clinical manifestations were similar between pH1N1 and seasonal influenza, and the pandemic virus did not appear to cause more severe disease in hospitalised children. [ABSTRACT FROM AUTHOR]

Aims: COVID-19, caused by the SARS-CoV-2 virus, can lead to serious lung conditions, notably interstitial pulmonary fibrosis., Main Methods: Our study tracked the progression of fibrosis markers in serial bronchoalveolar lavage (BAL) measurements collected from 16 COVID-19 patients at 1, 3, and 6 months post-infection. Additionally, BAL samples from 10 healthy control subjects were included. Using RT-PCR, ELISA, and immunofluorescence, we monitored molecular markers of fibrosis and investigated the interplay between galectins-1 and -3 and key pro-fibrotic mediators., Key Findings: We found increased α-smooth muscle actin (αSMA)-positive macrophages and heightened levels of αSMA, TGFβ, and CTGF mRNA and proteins at six months compared to controls. Furthermore, galectin-1 and galectin-3 concentrations showed a time-dependent increase and correlated significantly with pro-fibrotic markers., Significance: These findings suggest that galectins contribute to fibrotic progression following COVID-19 and highlight their potential as therapeutic targets., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Cerebral pericytes are mural cells covering brain microvessels, organized as ensheathing, mesh and thin-strand pericytes. These latter two, together called capillary pericytes, have low levels of alpha smooth muscle actin (α-SMA), regulating basal vascular tone and applying a slow influence on cerebral blood flow. Pericytes are subject to alterations in ageing which may be even more pronounced in age-related pathologies, including microinfarcts, which usually affect a large number of vessels in the ageing brain. We modelled this condition by injecting 10 µm-size microspheres into the circulation of mice resulting in the occlusion of capillaries covered by ensheathing and mesh pericytes. We observed that α-SMA and Acta2, the gene encoding it, as well as TGF-β1/Tgfb1, the major regulator of α-SMA, decreased during ageing in cerebral microvessels. In the vicinity of the microspheres stalled in the capillaries, expression of α-SMA increased significantly in both ensheathing and especially in mesh pericytes, both in young (2 to 3 months of age) and old (24 months of age) mice. On the other hand, γ-actin was detected in endothelial cells, but not in pericytes, and decreased in microvessels of microsphere-containing hemispheres. Altogether, our data show that obstruction of cerebral microvessels increases α-SMA expression in pericytes in both age groups, but this does not compensate for the lower expression of the contractile protein in old animals. Increased α-SMA expression may lead to constriction of the obstructed vessels probably aggravating flow heterogeneity in the aged brain., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

This study investigated the efficacy of a new chrysin-loaded calixarene-cyclodextrin ternary drug delivery system (DDS) in reversing liver fibrosis in a mouse model of chronic diabetes. The system was designed to enhance the solubility and bioavailability of chrysin (CHR) and calixarene 0118 (OTX008). Adult male CD1 mice received streptozotocin (STZ) injections to induce diabetes. After 20 weeks, they underwent intraperitoneal treatments twice weekly for a two-week period. Histological analyses revealed that long-term hyperglycaemia increased liver fibrosis and altered hepatic ultrastructure, characterized by lipid accumulation, hepatic stellate cell activation, and collagen deposition. The treatment with the chrysin-loaded DDS restored liver structure closely to normal levels, as opposed to the minimal impact observed with sulfobutylated β-cyclodextrin (SBECD) alone. The treatment significantly decreased serum activities of alanine /aspartate transaminases and reduced the gene expression of collagen type I (Col-I). It also modulated the transforming growth factor beta 1 (TGF-β1)/Smad signalling pathway, inhibiting the activation and proliferation of hepatic stellate cells. The treatment led to a downregulation of the TGF-β1 gene and its receptors TGFβR1 and TGFβR2, together with a decrease in Smad 2 and 3 mRNA levels. Conversely, Smad 7 mRNA expression was increased by the DDS. Furthermore, it downregulated galectin-1 (Gal-1) gene and protein levels, which correlated with fibrotic markers. In conclusion, the chrysin-loaded calixarene-cyclodextrin ternary DDS presents a promising therapeutic approach for diabetic liver fibrosis, effectively targeting fibrotic pathways and restoring hepatic function and structure., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Silicon-based quantum dots (SiQDs) represent a special class of nanoparticles due to their low toxicity and easily modifiable surface properties. For this reason, they are used in applications such as bioimaging, fluorescent labeling, drug delivery, protein detection techniques, and tissue engineering despite a serious lack of information on possible in vivo effects. The present study aimed to characterize and evaluate the in vivo toxicity of SiQDs obtained by laser ablation in the lung and spleen of mice. The particles were administered in three different doses (1, 10, and 100 mg QDs/kg of body weight) by intravenous injection into the caudal vein of Swiss mice. After 1, 6, 24, and 72 h, the animals were euthanized, and the lung and spleen tissues were harvested for the evaluation of antioxidant enzyme activity, lipid peroxidation, protein expression, and epigenetic and morphological changes. The obtained results highlighted a low toxicity in pulmonary and splenic tissues for concentrations up to 10 mg SiQDs/kg body, demonstrated by biochemical and histopathological analysis. Therefore, our study brings new experimental evidence on the biocompatibility of this type of QD, suggesting the possibility of expanding research on the biomedical applications of SiQDs.

The aim of this study was the investigation of biochemical and histological changes induced in different tissues, as a result of the subcutaneous administration of Gd nanohydrogels (GdDOTA⸦CS-TPP/HA) in a CD-1 mouse strain. The nanohydrogels were obtained by encapsulating contrast agents (GdDOTA) in a biocompatible polymer matrix composed of chitosan (CS) and hyaluronic acid (HA) through the ionic gelation process. The effects of Gd nanohydrogels on the redox status were evaluated by measuring specific activities of the antioxidant enzymes catalase (CAT), glutathione peroxidase (GPx), and superoxide dismutase (SOD), as well as oxidative stress markers, such as reduced glutathione (GSH), malondialdehyde (MDA), advanced oxidation protein products (AOPP), and protein-reactive carbonyl groups (PRCG), in the liver, kidney, and heart tissues. The nitrosylated proteins expression were analyzed with Western Blot and the serum biochemical markers were measured with spectrophotometric methods. Also, a histological analysis of CD-1 mouse tissues was investigated. These results indicated that Gd nanohydrogels could potentially be an alternative to current MRI contrast agents thanks to their low toxicity in vivo.

Introduction: The pathogenesis of post-COVID interstitial lung disease, marked by lung tissue scarring and functional decline, remains largely unknown., Objectives: We aimed to elucidate the temporal cytokine/chemokine changes in bronchoalveolar lavage (BAL) from patients with post-COVID interstitial lung disease to uncover potential immune drivers of pulmonary complications., Design: We evaluated 16 females diagnosed with post-COVID interstitial lung disease, originating from moderate to severe cases during the second epidemic wave in the Autumn of 2020, treated at the Pneumology Department of the Arad County Clinical Hospital, Romania. Their inflammatory response over time was compared to a control group., Methods: A total of 48 BAL samples were collected over three intervals (1, 3, and 6 months) and underwent cytology, gene, and protein expression analyses for pro/anti-inflammatory lung cytokines and chemokines using reverse transcription polymerase chain reaction and enzyme-linked immunosorbent assay., Results: One month after infection, there were significant increases in the levels of IL-6 and IL-8. These levels decreased gradually over the course of 6 months but were still higher than those seen in control. Interferon-gamma and tumor necrosis factor alpha exhibited similar patterns. Persistent elevations were found in IL-10, IL-13, and pro-fibrotic M2 macrophages' chemokines (CCL13 and CCL18) for 6 months. Furthermore, pronounced neutrophilia was observed at 1 month post-COVID, highlighting persistent inflammation and lung damage. Neutrophil efferocytosis, aiding inflammation resolution and tissue repair, was evident at the 1-month time interval. A notable time-dependent reduction in CD28 was also noticed., Conclusion: Our research provides insight into the immunological processes that may lead to the fibrotic changes noted in the lungs following COVID-19., Competing Interests: The authors declare that there is no conflict of interest., (© The Author(s), 2024.)

In the last decade, silicon-based quantum dots (SiQDs) have attracted the attention of researchers due to their unique properties for which they are used in medical applications and in vivo imaging. Detection of cytotoxic effects in vivo is essential for understanding the mechanisms of toxicity, a mandatory step before their administration to human subjects. In this context, we aimed to evaluate the in vivo hepatic and renal acute toxicity of SiQDs obtained by laser ablation. The nanoparticles were administrated at different doses (0, 1, 10, and 100 mg of QDs/kg of body weight) by intravenous injection into the caudal vein of Swiss mice. After 1, 6, 24, and 72 h, the animals were euthanatized, and liver and kidney tissues were used in further toxicity tests. The time- and dose-dependent effects of SiQDs on the antioxidant defense system of mice liver and kidney were investigated by quantifying the activity of antioxidant enzymes (catalase, superoxide dismutase, glutathione peroxidase, glutathione reductase, and glutathione S-transferase) in correlation with the morphological changes and inflammatory status in the liver and kidneys. The results showed a decrease in the activities of antioxidant enzymes and histopathological changes, except for superoxide dismutase, in which no significant changes were registered compared with the control. Furthermore, the immunohistochemical expression of TNF-α was significant at doses over 10 mg of QDs/kg of body weight and were still evident at 72 h after administration. Our results showed that doses under 10 mg of SiQDs/kg of b.w. did not induce hepatic and renal toxicity, providing useful information for further clinical trials.

Vitamin D, a steroid hormone synthesized primarily in the skin upon exposure to ultraviolet light, is widely deficient across global populations. This study aimed to fill the data gap in Western Romania by measuring 25-hydroxy-vitamin D levels in a cohort of 7141 from Arad County. It was observed that women, younger adults (18-29 years), and older adults (70-79 years) had notably lower vitamin D levels compared to the average population. Additionally, there was a rise in vitamin D levels over the four-year span of 2018-2022, coinciding with the COVID-19 pandemic. Our research provides fresh data on those most susceptible to vitamin D deficiency and lays the groundwork for educational campaigns on vitamin D supplementation benefits.

Introduction: Cardiac fibrosis is strongly induced by diabetic conditions. Both chrysin (CHR) and calixarene OTX008, a specific inhibitor of galectin 1 (Gal-1), seem able to reduce transforming growth factor beta (TGF-β)/SMAD pro-fibrotic pathways, but their use is limited to their low solubility. Therefore, we formulated a dual-action supramolecular system, combining CHR with sulfobutylated β-cyclodextrin (SBECD) and OTX008 (SBECD + OTX + CHR). Here we aimed to test the anti-fibrotic effects of SBECD + OTX + CHR in hyperglycemic H9c2 cardiomyocytes and in a mouse model of chronic diabetes. Methods: H9c2 cardiomyocytes were exposed to normal (NG, 5.5 mM) or high glucose (HG, 33 mM) for 48 h, then treated with SBECD + OTX + CHR (containing OTX008 0.75-1.25-2.5 µM) or the single compounds for 6 days. TGF-β/SMAD pathways, Mitogen-Activated Protein Kinases (MAPKs) and Gal-1 levels were assayed by Enzyme-Linked Immunosorbent Assays (ELISAs) or Real-Time Quantitative Reverse Transcription Polymerase chain reaction (qRT-PCR). Adult CD1 male mice received a single intraperitoneal (i.p.) administration of streptozotocin (STZ) at a dosage of 102 mg/kg body weight. From the second week of diabetes, mice received 2 times/week the following i.p. treatments: OTX (5 mg/kg)-SBECD; OTX (5 mg/kg)-SBECD-CHR, SBECD-CHR, SBECD. After a 22-week period of diabetes, mice were euthanized and cardiac tissue used for tissue staining, ELISA, qRT-PCR aimed to analyse TGF-β/SMAD, extracellular matrix (ECM) components and Gal-1. Results: In H9c2 cells exposed to HG, SBECD + OTX + CHR significantly ameliorated the damaged morphology and reduced TGF-β1, its receptors (TGFβR1 and TGFβR2), SMAD2/4, MAPKs and Gal-1. Accordingly, these markers were reduced also in cardiac tissue from chronic diabetes, in which an amelioration of cardiac remodeling and ECM was evident. In both settings, SBECD + OTX + CHR was the most effective treatment compared to the other ones. Conclusion: The CHR-based supramolecular SBECD-calixarene drug delivery system, by enhancing the solubility and the bioavailability of both CHR and calixarene OTX008, and by combining their effects, showed a strong anti-fibrotic activity in rat cardiomyocytes and in cardiac tissue from mice with chronic diabetes. Also an improved cardiac tissue remodeling was evident. Therefore, new drug delivery system, which could be considered as a novel putative therapeutic strategy for the treatment of diabetes-induced cardiac fibrosis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2023 Trotta, Herman, Ciceu, Mladin, Rosu, Lepre, Russo, Bácskay, Fenyvesi, Marfella, Hermenean, Balta and D’Amico.)

Background: Hexavalent chromium known as oxidizing agent is able to form reactive oxygen species. Aronia melanocarpa and Hypericum perforatum are two plants known for their antioxidant effects. Our study aimed to establish if CrVI induces apoptosis and structural changes in thyrocytes and if its effect can be counteracted by the administration of both extracts., Materials and Methods: Wistar rats divided in five groups: C - distilled water (DW), Cr - 75 mg/L CrVI in DW for 3 months, Cr 2 - 75 mg/L CrVI in DW for 3 months followed by 1 month DW, CrA - 3 months 75 mg/L CrVI in DW and 1 month Aronia 2.5% extract, CrH - 3 months 75 mg/L CrVI in DW and 1 month Hypericum 2.5% extract. Histological assessment and qRT-PCR for evaluation of BAX and Bcl2 protein levels performed on thyroid samples., Results: The Cr and Cr2 groups were those with altered cytoarchitecture: increase in the diameter of many thyroid follicles, a decrease in their number, a decrease in the height of the follicular cells. The histological examination of the CrH group revealed almost recovery of structural architecture. The BAX gene levels were higher in the Cr and Cr2 groups indicating the apoptotic activity of chromium. In extract receiving groups the BAX gene expressions were significantly lower, but the lowest level presented the CrH group. Bcl2 gene expression levels indicate antiapoptotic activity being elevated in the Cr group, followed by CrA, Cr2, and CrH groups. The BAX/Bcl2 ratio which significantly increased in the case of the Cr and Cr2 group compared to the groups that were administered the two plant extracts., Conclusion: The results obtained in this study confirm that CrVI has toxic effects on thyroid endocrine cells and H. perforatum has stronger antioxidant properties against the action of hexavalent chromium in thyrocytes than A. melanocarpa., (Copyright © 2023 The Authors. Published by Elsevier GmbH.. All rights reserved.)

In this study, we aimed to explore the hepatoprotective effects of the gemmotherapy bud extract of Corylus avellana in a model of liver fibrosis on diabetic mice. An evaluation of total flavonoids and polyphenols contents and LC/MS analyses were performed. Experimental fibrosis was induced with CCl 4 (2 mL/kg by i.p. injections twice a week for 7 weeks) in streptozotocin-induced diabetic mice. Our results showed a content of 6-7% flavonoids, while hyperoside and chlorogenic acids were highlighted in the bud extract. Toxic administration of CCl 4 increased oxidative stress, mRNA expression of the transforming growth factor-β1 ( TGF-β1 ) and Smad 2/3 , and reduced Smad 7 expression. Furthermore, up-regulation of α-smooth muscle actin ( α-SMA ) revealed an activation of hepatic stellate cells (HSCs), while collagen I ( Col I ) up-regulation and matrix metalloproteinases ( MMPs ) unbalance led to an altered extracellular matrix enriched in collagen, confirmed as well by a trichrome stain and electron microscopy analysis. Treatment with gemmotherapy extract significantly restored the liver architecture and the antioxidant balance, and significantly decreased collagen deposits in the liver and improved the liver function. Our results suggest that Corylus avellana gemmotherapy extract may have anti-fibrotic effects and could be useful in the prevention and treatment of liver fibrosis. The hepatoprotective mechanism is based on HSC inhibition, a reduction in oxidative stress and liver damage, a downregulation of the TGF-β1/Smad signaling pathway and a MMPs/TIMP rebalance.

The production of highly porous and three-dimensional (3D) scaffolds with biomimicking abilities has gained extensive attention in recent years for tissue engineering (TE) applications. Considering the attractive and versatile biomedical functionality of silica (SiO 2 ) nanomaterials, we propose herein the development and validation of SiO 2 -based 3D scaffolds for TE. This is the first report on the development of fibrous silica architectures, using tetraethyl orthosilicate (TEOS) and polyvinyl alcohol (PVA) during the self-assembly electrospinning (ES) processing (a layer of flat fibers must first be created in self-assembly electrospinning before fiber stacks can develop on the fiber mat). The compositional and microstructural characteristics of obtained fibrous materials were evaluated by complementary techniques, in both the pre-ES aging period and post-ES calcination. Then, in vivo evaluation confirmed their possible use as bioactive scaffolds in bone TE.

Background: A new tube voltage-switching dual-energy (DE) CT system using a novel deep-learning based reconstruction process has been introduced. Characterizing the performance of this DE approach can help demonstrate its benefits and potential drawbacks., Purpose: To evaluate the technical performance of a novel DECT system and compare it to that of standard single-kV CT and a rotate/rotate DECT, for abdominal imaging., Methods: DE and single-kV images of four different phantoms were acquired on a kV-switching DECT system, and on a rotate/rotate DECT. The dose for the acquisitions of each phantom was set to that selected for the kV-switching DE mode by the automatic tube current modulation (ATCM) at manufacturer-recommended settings. The dose that the ATCM would have selected in single-kV mode was also recorded. Virtual monochromatic images (VMIs) from 40 to 130 keV, as well as iodine maps, were reconstructed from the DE data. Single-kV images, acquired at 120 kV, were reconstructed using body hybrid iterative reconstruction. All reconstructions were made at 0.5 mm section thickness. Task transfer functions (TTFs) were determined for a Teflon and LDPE rod. Noise magnitude (SD), and noise power spectrum (NPS) were calculated using 240 and 320 mm diameter water phantoms. Iodine quantification accuracy and contrast-to-noise ratios (CNRs) relative to water for 2, 5, 10, and 15 mg I/ml were determined using a multi-energy CT (MECT) phantom. Low-contrast visibility was determined and the presence of beam-hardening artifacts and inhomogeneities were evaluated., Results: The TTFs of the kV-switching DE VMIs were higher than that of the single-kV images for Teflon (20% TTF: 6.8 lp/cm at 40 keV, 6.2 lp/cm for single-kV), while for LDPE the DE TTFs at 70 keV and above were equivalent or higher than the single-kV TTF. All TTFs of the kV-switching DECT were higher than for the rotate/rotate DECT. The SD was lowest in the 70 keV VMI (12.0 HU), which was lower than that of single-kV (18.3 HU). The average NPS frequency varied between 2.3 lp/cm and 4.2 lp/cm for the kV-switching VMIs and was 2.2 lp/cm for single-kV. The error in iodine quantification was at maximum 1 mg I/ml (at 5 mg I/ml). The highest CNR for all iodine concentrations was at 60 keV, 2.5 times higher than the CNR for single-kV. At 70-90 keV, the number of visible low contrast objects was comparable to that in single-kV, while other VMIs showed fewer objects. At manufacturer-recommended ATCM settings, the CTDI vol for the DE acquisitions of the water and MECT phantoms were 12.6 and 15.4 mGy, respectively, and higher than that for single-kV. The 70 keV VMI had less severe beam hardening artifacts than single-kV images. Hyper- and hypo-dense blotches may appear in VMIs when object attenuation exceeds manufacturer recommended limits., Conclusions: At manufacturer-recommended ATCM settings for abdominal imaging, this DE implementation results in higher CTDI vol compared to single-kV acquisitions. However, it can create sharper, lower noise VMIs with up to 2.5 times higher iodine CNR compared to single-kV images acquired at the same dose., (© 2022 The Authors. Medical Physics published by Wiley Periodicals LLC on behalf of American Association of Physicists in Medicine.)

Background: Vitamin D deficiency has been associated with dry eye development during Sjögren's syndrome (SS). Here, we investigated whether repeated oral vitamin D3 supplementation could prevent the corneal epithelium damage in an SS mouse model., Methods: 30 female mouse knock-out for the thrombospondin 1 gene were randomized (six per group) in untreated mice euthanized at 6 weeks as negative control (C-) or at 12 weeks as the positive control for dry eye (C+). Other mice were sacrificed after 6 weeks of oral vitamin D3 supplementation in the drinking water (1000, 8000, and 20,000 IU/kg/week, respectively)., Results: The C+ mice showed alterations in their corneal epithelial morphologies and thicknesses ( p < 0.01 vs. C-), while the mice receiving 8000 (M) and 20,000 (H) IU/kg/week of vitamin D3 showed preservation of the corneal epithelium morphology and thickness ( p < 0.01 vs. C+). Moreover, while the C+ mice exhibited high levels and activity of corneal tumor necrosis factor alpha converting enzyme (TACE), neovascularization and fibrosis markers; these were all reduced in the M and H mice., Conclusions: Oral vitamin D3 supplementation appeared to counteract the negative effect of TACE on corneal epithelium in a mouse model of SS-associated dry eye.

Purpose: In digital breast tomosynthesis (DBT), radiologists need to review a stack of 20 to 80 tomosynthesis images, depending upon breast size. This causes a significant increase in reading time. However, it is currently unknown whether there is a perceptual benefit to viewing a mass in the 3D tomosynthesis volume. To answer this question, this study investigated whether adjacent lesion-containing planes provide additional information that aids lesion detection for DBT-like and breast CT-like (bCT) images., Method: Human reader detection performance was determined for low-contrast targets shown in a single tomosynthesis image at the center of the target (2D) or shown in the entire tomosynthesis image stack (3D). Using simulations, targets embedded in simulated breast backgrounds, and images were generated using a DBT-like (50 deg angular range) and a bCT-like (180 deg angular range) imaging geometry. Experiments were conducted with spherical and capsule-shaped targets. Eleven readers reviewed 1600 images in two-alternative forced-choice experiments. The area under the receiver operating characteristic curve (AUC) and reading time were computed for the 2D and 3D reading modes for the DBT and bCT imaging geometries and for both target shapes., Results: Spherical lesion detection was higher in 2D mode than in 3D, for both DBT- and bCT-like images (DBT: AUC 2 D = 0.790 , AUC 3 D = 0.735 , P = 0.03 ; bCT: AUC 2 D = 0.869 , AUC 3 D = 0.716 , P < 0.05 ), but equivalent for capsule-shaped signals (DBT: AUC 2 D = 0.891 , AUC 3 D = 0.915 , P = 0.19 ; bCT: AUC 2 D = 0.854 , AUC 3 D = 0.847 , P = 0.88 ). Average reading time was up to 134% higher for 3D viewing ( P < 0.05 )., Conclusions: For the detection of low-contrast lesions, there is no inherent visual perception benefit to reviewing the entire DBT or bCT stack. The findings of this study could have implications for the development of 2D synthetic mammograms: a single synthesized 2D image designed to include all lesions present in the volume might allow readers to maintain detection performance at a significantly reduced reading time., (© 2023 The Authors.)

Liver fibrosis can develop on the background of hyperglycemia in diabetes mellitus. However, xenobiotic-related factors may accelerate diabetes-associated liver fibrosis. In this study, we aimed to assess the antfibrotic effect of ADSC and HGF therapy and to establish the cellular and molecular mechanisms through in vitro and in vivo experiments. In vitro, TGF-β1-activated hepatic stellate cells (HSCs) were cocultured with ADSCs or HGF, and the expression of several fibrosis markers was investigated. The antifibrotic effect of the ADSCs, HGF, and ADSCs supplemented with HGF was further assessed in vivo on diabetic mice with liver fibrosis experimentally induced. In vitro results showed the inhibition of HSC proliferation and decrease in fibrogenesis markers. Coadministration of ADSCs and HGF on diabetic mice with liver fibrosis enhanced antifibrotic effects confirmed by the downregulation of Col I, α-SMA, TGF-β1, and Smad2, while Smad7 was upregulated. Moreover, stem cell therapy supplemented with HGF considerably attenuated inflammation and microvesicular steatosis, decreased collagen deposits, and alleviated liver fibrosis. In conclusion, the HGF-based ADSC therapy might be of interest for the treatment of liver fibrosis in diabetic patients, consecutive aggression exerts by different environmental factors.

Background: Diabetic retinopathy (DR) is a neurovascular disease, characterized by a deficiency of brain-derived neurotrophic factor (BDNF), a regulator of autophagy. Beta-hydroxybutyrate (BHB), previously reported as a protective agent in DR, has been associated with BDNF promotion. Here, we investigated whether systemic BHB affects the retinal levels of BDNF and local autophagy in diabetic mice with retinopathy; Methods: C57BL/6J mice were administered with intraperitoneal (i.p.) streptozotocin (STZ) (75 mg/kg) injection to develop diabetes. After 2 weeks, they received i.p. injections of BHB (25−50−100 mg/kg) twice a week for 10 weeks. Retinal samples were collected in order to perform immunofluorescence, Western blotting, and ELISA analysis; Results: BHB 50 mg/kg and 100 mg/kg significantly improved retinal BDNF levels (p < 0.01) in diabetic mice. This improvement was negatively associated with autophagosome−lysosome formations (marked by LC3B and ATG14) and to higher levels of connexin 43 (p < 0.01), a marker of cell integrity. Moreover, BHB administration significantly reduced M1 microglial activation and autophagy (p < 0.01); Conclusions: The systemic administration of BHB in mice with DR improves the retinal levels of BDNF, with the consequent reduction of the abnormal microglial autophagy. This leads to retinal cell safety through connexin 43 restoration., Competing Interests: The authors declare no conflict of interest.

Pulmonary fibrosis is a consequence of the pathological accumulation of extracellular matrix (ECM), which finally leads to lung scarring. Although the pulmonary fibrogenesis is almost known, the last two years of the COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its post effects added new particularities which need to be explored. Many questions remain about how pulmonary fibrotic changes occur within the lungs of COVID-19 patients, and whether the changes will persist long term or are capable of resolving. This review brings together existing knowledge on both COVID-19 and pulmonary fibrosis, starting with the main key players in promoting pulmonary fibrosis, such as alveolar and endothelial cells, fibroblasts, lipofibroblasts, and macrophages. Further, we provide an overview of the main molecular mechanisms driving the fibrotic process in connection with Galactin-1, -3, -8, and -9, together with the currently approved and newly proposed clinical therapeutic solutions given for the treatment of fibrosis, based on their inhibition. The work underlines the particular pathways and processes that may be implicated in pulmonary fibrosis pathogenesis post-SARS-CoV-2 viral infection. The recent data suggest that galectin-1, -3, -8, and -9 could become valuable biomarkers for the diagnosis and prognosis of lung fibrosis post-COVID-19 and promising molecular targets for the development of new and original therapeutic tools to treat the disease.

The beneficial effect of antioxidant supplementation in maturation culture media of sow oocytes was evaluated by the expression quantification of apoptotic genes and the genes that ensure stability of germ cells during fertilization. The oocytes were cultivated for 44 h in conventional medium (C) or in medium supplemented with 105 µM rosmarinic acid (R) and 0.5 mM ascorbic acid (A) and classified into three quality classes by morphological observation from which the total RNA was isolated. The gene expression of Ptx3 and the apoptotic regulator p53, Bax and BCL-2 were evaluated by quantitative PCR technique. The decreased expression of the Bax gene in the A and R groups, compared to the control, indicates a protective role of antioxidants in the cells. Cell homeostasis was maintained, as reflected in the ratio of Bax/Bcl-2 in class I COCs (cumulus-oocyte complex) regardless of the experimental group, indicating minimum cellular stress. The expression of p53 genes was higher in all class III COC, but in A1 and R1 the expression was lower than in C1, and a similar Ptx-3 gene decreased significantly in groups A1, A2, A3 and R1 compared with control groups. Antioxidant supplementation showed beneficial effects on all morphological classes of pig COCs.

This study aimed to investigate the interactions between fingolimod, a sphingosine 1-phosphate receptor (S1PR) agonist, and melanocortin receptors 1 and 5 (MCR1, MCR5). In particular, we investigated the effects of fingolimod, a drug approved to treat relapsing-remitting multiple sclerosis, on retinal angiogenesis in a mouse model of diabetic retinopathy (DR). We showed, by a molecular modeling approach, that fingolimod can bind with good-predicted affinity to MC1R and MC5R. Thereafter, we investigated the fingolimod actions on retinal MC1Rs/MC5Rs in C57BL/6J mice. Diabetes was induced in C57BL/6J mice through streptozotocin injection. Diabetic and control C57BL/6J mice received fingolimod, by oral route, for 12 weeks and a monthly intravitreally injection of MC1R antagonist (AGRP), MC5R antagonist (PG20N), and the selective S1PR1 antagonist (Ex 26). Diabetic animals treated with fingolimod showed a decrease of retinal vascular endothelial growth factor A (VEGFA) and vascular endothelial growth factor receptors 1 and 2 (VEGFR1 and VEGFR2), compared to diabetic control group. Fingolimod co-treatment with MC1R and MC5R selective antagonists significantly ( p < 0.05) increased retinal VEGFR1, VEGFR2, and VEGFA levels compared to mice treated with fingolimod alone. Diabetic animals treated with fingolimod plus Ex 26 (S1PR1 selective blocker) had VEGFR1, VEGFR2, and VEGFA levels between diabetic mice group and the group of diabetic mice treated with fingolimod alone. This vascular protective effect of fingolimod, through activation of MC1R and MC5R, was evidenced also by fluorescein angiography in mice. Finally, molecular dynamic simulations showed a strong similarity between fingolimod and the MC1R agonist BMS-470539. In conclusion, the anti-angiogenic activity exerted by fingolimod in DR seems to be mediated not only through S1P1R, but also by melanocortin receptors., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Gesualdo, Balta, Platania, Trotta, Herman, Gharbia, Rosu, Petrillo, Giunta, Della Corte, Grieco, Bellavita, Simonelli, D’Amico, Hermenean, Rossi and Bucolo.)

Hexavalent chromium is a toxin that penetrates the cell, triggering reactive oxygen species (ROS) production. Aronia melanocarpa, due to its proanthocyanidins, anthocyanins, and phenolic acid contents, is a valuable antioxidant. The aim was to observe the influence of hexavalent chromium Cr(VI) on the adrenal gland, and if this impact can be recovered by the administration of A. melanocarpa. Accordingly, 36 rats were divided into six groups: control; Aronia; Cr receiving Cr(VI) in distilled water for 3 months; CrA receiving a mix of Cr(VI) and A. melanocarpa at 2.5% aqueous extract for 3 months; Cr2 receiving, for 3 months, Cr(VI) in distilled water, and next, for 1 month, only distilled water; and respectively, CrA2 receiving, for 3 months, Cr(VI) in distilled water, followed by 1 month of Aronia at 2.5% extract administration. The adrenal gland samples were examined toward histological and molecular assessment, and results were statistically analyzed (ANOVA). Hexavalent chromium induced changes in the adrenal cortex expressed by focal or diffuse hypertrophies, cytoplasmic vacuolization (due to lipidic accumulation), and cells' shape and size alteration, including necrosis. These structural alterations were carried by Bax and Bcl2 gene expression: the Bax gene expression levels, increased significantly (p < 0.001) in all experimental groups, except the Aronia group, compared with control. In the Cr2, CrA, and CrA2 groups, notable reduction of Bax gene expression (p < 0.001) was reported compared with the Cr group. Regarding the Bcl2 gene expression (p < 0.001), a significant increase was observed in the experimental groups, compared with the control. The Bcl2 expression level had a similar pattern to Bax gene, consequently trying to compensate its overexpression. Aronia administered concomitantly, or after Cr(VI), diminished structural changes and expression of the studied genes, thus reducing the Bax/Bcl2 ratio and suggesting that the active ingredients from Aronia are capable of blocking apoptotic cascade induced by the pathway of Bax and Bcl2 proteins.

(1) Background: The pro-resolving lipid mediator Resolvin D1 (RvD1) has already shown protective effects in animal models of diabetic retinopathy. This study aimed to investigate the retinal levels of RvD1 in aged (24 months) and younger (3 months) Balb/c mice, along with the activation of macro- and microglia, apoptosis, and neuroinflammation. (2) Methods: Retinas from male and female mice were used for immunohistochemistry, immunofluorescence, transmission electron microscopy, Western blotting, and enzyme-linked immunosorbent assays. (3) Results: Endogenous retinal levels of RvD1 were reduced in aged mice. While RvD1 levels were similar in younger males and females, they were markedly decreased in aged males but less reduced in aged females. Both aged males and females showed a significant increase in retinal microglia activation compared to younger mice, with a more marked reactivity in aged males than in aged females. The same trend was shown by astrocyte activation, neuroinflammation, apoptosis, and nitrosative stress, in line with the microglia and Müller cell hypertrophy evidenced in aged retinas by electron microscopy. (4) Conclusions: Aged mice had sex-related differences in neuroinflammation and apoptosis and low retinal levels of endogenous RvD1.

Since cadmium is a toxic metal that can cause serious health problems for humans, it is necessary to find bioremediation solutions to reduce its harmful effects. The main goal of our work was to develop a functional food based on elemental selenium nanoparticles (SeNPs) obtained by green synthesis using Lactobacillus casei and to validate their ability to annihilate the hepatic toxic effects induced by cadmium. The characterization of SeNPs was assessed by UV-Vis spectroscopy, FTIR, XRD, DLS and TEM. In order to investigate the dose-dependent protective effects of SeNPs on Cd liver toxicity, mice were assigned to eight experimental groups and fed by gavage, with 5 mg/kg b.w. cadmium, respectively, with co-administration with SeNPs or lacto-SeNPs (LSeNPs) in 3 doses (0.1, 0.2 and 0.4 mg/kg b.w.) for 30 days. The protective effect was demonstrated by the restoration of blood hepatic markers (AST, ALT, GGT and total bilirubin) and antioxidant enzymes, such as catalase (CAT) and glutathione peroxidase (GPx). Moreover, the antioxidant capacity of mice plasma by the FRAP assay, revealed the highest antioxidant capacity for the 0.2 mg/kg LSeNPs group. Histopathological analysis demonstrated the morphological alteration in the group that received only cadmium and was restored after the administration of SeNPs or LSeNPs, while the immunohistochemical analysis of the bcl family revealed anti-apoptotic effects; the Q-PCR analysis showed an upregulation of hepatic inflammatory markers for the group exposed to Cd and a decreased value for the groups receiving oral SeNPs/ LSeNPs in a dose-dependent manner. The best protective effects were obtained for LSeNPs. A functional food that includes both probiotic bacteria and elemental SeNPs could be successfully used to annihilate Cd-induced liver toxicity, and to improve both nutritional values and health benefits.