Analysis of cell-biomaterial interaction through cellular bridge formation in the interface between hGMSCs and CaP bioceramics

The combination of biomaterials and stem cells for clinical applications constitute a great challenge in bone tissue engineering. Hence, cellular networks derived from cells-biomaterials crosstalk have a profound influence on cell behaviour and communication, preceding proliferation and differentiation. The purpose of this study was to investigate in vitro cellular networks derived from human gingival mesenchymal stem cells (hGMSCs) and calcium phosphate (CaP) bioceramic interaction. Biological performance of CaP bioceramic and hGMSCs interaction was evaluated through cell adhesion and distribution, cellular proliferation, and potential osteogenic differentiation, at three different times: 5 h, 1 week and 4 weeks. Results confirmed that hGMSCs met the required MSCs criteria while displaying osteogenic differentiaton capacities. We found a significant increase of cellular numbers and proliferation levels. Also, protein and mRNA OPN expression were upregulated in cells cultured with CaP bioceramic by day 21, suggesting an osteoinductible effect of the CaP bioceramic on hGMSCs. Remarkably, CaP bioceramic aggregations were obtained through hGMSCs bridges, suggesting the in vitro potential of macrostructures formation. We conclude that hGMSCs and CaP bioceramics with micro and macropores support hGMSC adhesion, proliferation and osteogenic differentiation. Our results suggest that investigations focused on the interface cells-biomaterials are essential for bone tissue regenerative therapies

The metabolic features of tumor-associated macrophages : opportunities for immunotherapy?

Funding: This work was supported by the Ministry of Education, Science, and Technological Development of the Republic of Serbia.Besides transformed cells, the tumors are composed of various cell types that contribute to undesirable tumor progression. Tumor-associated macrophages (TAMs) are the most abundant innate immune cells in the tumor microenvironment (TME). Within the TME, TAMs exhibit high plasticity and undergo specific functional metabolic alterations according to the availability of tumor tissue oxygen and nutrients, thus further contributing to tumorigenesis and cancer progression. Here, we review the main functional TAM metabolic patterns influenced by TME, including glycolysis, amino acid, and fatty acid metabolism. Moreover, this review discusses antitumor immunotherapies that affect TAM functionality by inducing cell repolarizing and metabolic profiles towards an antitumoral phenotype. Also, new macrophage-based cell therapeutic technologies recently developed using chimeric antigen receptor bioengineering are exposed, which may overcome all solid tumor physical barriers impeding the current adoptive cell therapies and contribute to developing novel cancer immunotherapies.Publisher PDFPeer reviewe

Effect of Dietary Supplements with ω-3 Fatty Acids, Ascorbic Acid, and Polyphenolic Antioxidant Flavonoid on Gene Expression, Organ Failure, and Mortality in Endotoxemia-Induced Septic Rats

Sepsis syndrome develops through enhanced secretion of pro-inflammatory cytokines and the generation of reactive oxygen species (ROS). Sepsis syndrome is characterized by vascular hyperpermeability, hypotension, multiple organ dysfunction syndrome (MODS), and increased mortality, among others. Endotoxemia-derived sepsis is an important cause of sepsis syndrome. During endotoxemia, circulating endotoxin interacts with endothelial cells (ECs), inducing detrimental effects on endothelium function. The endotoxin induces the conversion of ECs into fibroblasts, which are characterized by a massive change in the endothelial gene-expression pattern. This downregulates the endothelial markers and upregulates fibrotic proteins, mesenchymal transcription factors, and extracellular matrix proteins, producing endothelial fibrosis. Sepsis progression is modulated by the consumption of specific nutrients, including ω-3 fatty acids, ascorbic acid, and polyphenolic antioxidant flavonoids. However, the underlying mechanism is poorly described. The notion that gene expression is modulated during inflammatory conditions by nutrient consumption has been reported. However, it is not known whether nutrient consumption modulates the fibrotic endothelial gene-expression pattern during sepsis as a mechanism to decrease vascular hyperpermeability, hypotension, MODS, and mortality. Therefore, the aim of this study was to investigate the impact of the consumption of dietary ω-3 fatty acids, ascorbic acid, and polyphenolic antioxidant flavonoid supplements on the modulation of fibrotic endothelial gene-expression patterns during sepsis and to determine the effects on sepsis outcomes. Our results indicate that the consumption of supplements based on ω-3 fatty acids and polyphenolic antioxidant flavonoids was effective for improving endotoxemia outcomes through prophylactic ingestion and therapeutic usage. Thus, our findings indicated that specific nutrient consumption improves sepsis outcomes and should be considered in treatment

Relationships between the structural characteristic of curcumins that affect cell proliferation of hepatocarcinoma cells

Relationships between the structural characteristic of curcumin and dimethoxycurcumin and their antitumoral activity were studied. Treatment of HepG2 cells for 24 h with the curcumin and dimethoxycurcumin resulted in apoptosis induction and dose-dependent inhibition of cell proliferation. The calculated docking and the DFT method, suggest a structure-activity relationship between the activities of dimethoxycurcumin and curcumin structure and the apoptosis in HepG2 cell

SKIP is required for TGF-beta 1-induced epithelial mesenchymal transition and migration in transformed keratinocytes

Transforming growth factor-beta 1 (TGF-beta 1) potently induces the epithelial-mesenchymal transition (EMT) during tumoral progression. Although Sky-interacting protein (SKIP) regulates TGF-beta 1-induced Smad activation, its role in the induction of cell malignance remains uncertain. We found that TGF-beta 1 increases SKIP expression in PDV cells. In cells stably transfected with SKIP antisense, AS-S, Smad3 activation decreased, along with an inhibition of TGF-beta 1-induced EMT, and the cells were sensitized to the TGF-beta 1-dependent inhibition of proliferation. Also, AS-S cells showed a weaker migration and invasion response. Moreover, TGF-beta 1-induced urokinase-type plasminogen activator expression was inhibited, concomitantly with a TGF-beta 1-independent increment of the plasminogen-activator inhibitor-1 expression. Thus, these results suggest that SKIP is required for EMT and invasiveness induced by TGF-beta 1 in transformed cells

Sex Differences and Cytokine Profiles among Patients Hospitalized for COVID-19 and during Their Recovery: The Predominance of Adhesion Molecules in Females and Oxidative Stress in Males

The severity and mortality of coronavirus disease 2019 (COVID-19) are greater in males than in females, though the infection rate is the same in the two sexes. We investigated sex hormone differences associated with the hyperinflammatory immune response to SARS-CoV-2 on the basis of patients’ cytokine profiles and vaccination statuses. Clinical and laboratory data of 117 patients with COVID-19 were collected to examine sex differences associated with oxidative stress markers, neutrophil extracellular traps (NETs), and plasma cytokine levels up to 5 months from hospital admission. The testosterone and free testosterone levels were low in male patients with COVID-19 and returned to normal values after recovery from the disease. The dihydrotestosterone (DHT) levels were transiently reduced, while the sex hormone-binding globulin levels were decreased in post-COVID-19 male patients. The levels of the inflammatory cytokines interleukin-6 (IL-6) and IL-10 appeared generally increased at diagnosis and decreased in post-COVID-19 patients. In females, the concentration of tumor necrosis factor-alpha was increased by four times at diagnosis. The levels of the coagulation markers intercellular adhesion molecule-1 (ICAM-1) and E-selectin were consistently upregulated in post-COVID-19 female patients, in contrast to those of vascular cell adhesion molecule-1 (VCAM-1), P-selectin, and chemokine IL-8. DHT increased the levels of reactive oxygen species in the neutrophils of male patients, while estradiol decreased them in females. Markers for NET, such as circulating DNA and myeloperoxidase, were significantly more abundant in the patients’ plasma. Sex hormones have a potential protective role during SARS-CoV-2 infection, which is weakened by impaired testosterone synthesis in men

Urokinase type plasminogen activator mediates Interleukin-17-induced peripheral blood mesenchymal stem cell motility and transendothelial migration

Mesenchymal stem cells (MSCs) have the potential to migrate toward damaged tissues increasing tissue regeneration. Interleukin-17 (IL-17) is a proinflammatory cytokine with pleiotropic effects associated with many inflammatory diseases. Although IL-17 can modulate MSC functions, its capacity to regulate MSC migration is not well elucidated so far. Here, we studied the role of IL-17 on peripheral blood (PB) derived MSC migration and transmigration across endothelial cells. IL-17 increased PB-MSC migration in a wound healing assay as well as cell mobilization from collagen gel. Concomitantly IL-17 induced the expression of urokinase type plasminogen activator (uPA) without affecting matrix metalloproteinase expression. The incremented uPA expression mediated the capacity of IL-17 to enhance PB-MSC migration in a ERK1,2 MAPK dependent way. Also, IL-17 induced PB-MSC migration alongside with changes in cell polarization and uPA localization in cell protrusions. Moreover, IL-17 increased PB-MSC adhesion to endothelial cells and transendothelial migration, as well as increased the capacity of PB-MSC adhesion to fibronectin, in an uPA-dependent fashion. Therefore, our data suggested that IL-17 may act as chemotropic factor for PB-MSCs by incrementing cell motility and uPA expression during inflammation development

High genetic diversity of measles virus, World Health Organization European region, 2005-2006

During 2005-2006, nine measles virus (MV) genotypes were identified throughout the World Health Organization European Region. All major epidemics were associated with genotypes D4, D6, and B3. Other genotypes (B2, D5, D8, D9, G2, and H1) were only found in limited numbers of cases after importation from other continents. The genetic diversity of endemic D6 strains was low; genotypes C2 and D7, circulating in Europe until recent years, were no longer identified. The transmission chains of several indigenous MV strains may thus have been interrupted by enhanced vaccination. However, multiple importations from Africa and Asia and virus introduction into highly mobile and unvaccinated communities caused a massive spread of D4 and B3 strains throughout much of the region. Thus, despite the reduction of endemic MV circulation, importation of MV from other continents caused prolonged circulation and large outbreaks after their introduction into unvaccinated and highly mobile communities

Endothelial dysfunction in pregnancy metabolic disorders

In recent years, the vascular endothelium has gained attention as a key player in the initiation and development of pregnancy disorders. Endothelium acts as an endocrine organ that preserves the homeostatic balance by responding to changes in metabolic status. However, in metabolic disorders, endothelial cells adopt a dysfunctional function, losing their normal responsiveness. During pregnancy, several metabolic changes occur, in which endothelial function decisively participates. Similarly, when pregnancy metabolic disorders occur, endothelial dysfunction plays a key role in pathogenesis. This review outlines the main findings regarding endothelial dysfunction in three main metabolic pathological conditions observed during pregnancy: gestational diabetes, hypertensive disorders, and obesity and hyperlipidemia. Organ, histological and cellular characteristics were thoroughly described. Also, we focused in discussing the underlying molecular mechanisms involved in the cellular signaling pathways that mediate responses in these pathological conditions

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead