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Background: Despite the development of various therapeutic approaches over the past decades, the treatment of glioblastoma multiforme (GBM) remains a major challenge. The extracellular adenosine-generating enzyme, CD73, is involved in the pathogenesis and progression of GBM, and targeting CD73 may represent a novel approach to treat this cancer. In this study, three-dimensional culture systems based on three hydrogel compositions were characterized and an optimal type was selected to simulate the GBM microenvironment. In addition, the effect of a CD73 inhibitor on GBM cell aggregates and spheroids was investigated as a potential therapeutic approach for this disease. Methods: Rheology measurements, Fourier transform infrared spectroscopy (FT-IR), scanning electron microscopy (SEM) and cell proliferation assays were performed to analyze the synthesized hydrogel and select an optimal formulation. The viability of tumor cells in the optimal hydrogel was examined histologically and by confocal microscopy. In addition, the sensitivity of the tumor cells to the CD73 inhibitor was investigated using a cell proliferation assay and real-time PCR. Results: The data showed that the hydrogel containing 5 wt% gelatin and 5 wt% sodium alginate had better rheological properties and higher cell viability. Therefore, it could provide a more suitable environment for GBM cells and better mimic the natural microenvironment. GBM cells treated with CD73 inhibitors significantly decreased the proliferation rate and expression of VEGF and HIF1-α in the optimal hydrogel. Conclusion: Our current research demonstrates the great potential of CD73 inhibitor for clinical translation of cancer studies by analyzing the behavior and function of 3D tumor cells, and thus for more effective treatment protocols for GBM. [ABSTRACT FROM AUTHOR]

Background: Coronavirus disease 2019 (COVID-19) has become one of the most serious diseases worldwide. The contagiousness of the virus and its unexpectedly rapid spread in different communities have raised many concerns. Objectives: This study investigated the association of clinical findings and hospital stay length of COVID-19 patients with diabetes and hypertension history in Garmsar Hospital. Methods: This cross-sectional study assessed COVID-19 patients admitted to Motamedi Hospital, Garmsar, Iran. Data were recorded in Minitab V17 software and analyzed through analysis of variance (ANOVA). Pearson's and Spearman's correlation coefficients were also computed for quantitative and qualitative variables, respectively. Results: The mean age was significantly higher in the group with underlying diseases than in the control group. The proportion of CRP-positive cases was higher in the hypertensive group than in the diabetes + hypertensive group, but it was not statistically significant. The rate of shortness of breath, length of hospital stay, and mortality were lower in the control group than in the group with underlying diseases, but this difference was not statistically significant. Conclusions: Although the incidence of respiratory distress, the length of hospital stay, and the mortality rate were lower in the control group than in the group with diabetes + hypertension, there was no significant association between these conditions and the risk of death and the length of hospital stay due to COVID-19. [ABSTRACT FROM AUTHOR]

Objective: Asthma, a chronic inflammatory disease with diverse pathomechanisms, presents challenges in developing personalized diagnostic and therapeutic approaches. This review aims to provide a comprehensive overview of the role of exosomes, small extracellular vesicles, in asthma pathophysiology and explores their potential as diagnostic biomarkers and therapeutic tools. Methods: A literature search was conducted to identify recent studies investigating the involvement of exosomes in asthma. The retrieved articles were analyzed to extract relevant information on the role of exosomes in maintaining lung microenvironment homeostasis, regulating inflammatory responses, and their diagnostic and therapeutic potential for asthma. Results: Exosomes secreted by various cell types, have emerged as crucial mediators of intercellular communication in healthy and diseased conditions. Evidence suggest that exosomes play a significant role in maintaining lung microenvironment homeostasis and contribute to asthma pathogenesis by regulating inflammatory responses. Differential exosomal content between healthy individuals and asthmatics holds promise for the development of novel asthma biomarkers. Furthermore, exosomes secreted by immune and nonimmune cells, as well as those detected in biofluids, demonstrate potential in promoting or regulating immune responses, making them attractive candidates for designing new treatment strategies for inflammatory conditions such as asthma. Conclusion: Exosomes, with their ability to modulate immune responses and deliver therapeutic cargo, offer potential as targeted therapeutic tools in asthma management. Further research and clinical trials are required to fully understand the mechanisms underlying exosome‐mediated effects and translate these findings into effective diagnostic and therapeutic strategies for asthma patients. [ABSTRACT FROM AUTHOR]

The treatment of osteosarcoma, as the most destructive bone cancer, is allied with many challenges. One of the new tissue engineering approaches is the use of a local drug delivery system implanted after surgery. This system can be a scaffold mimicking the natural tissue extracellular matrix, loaded with drugs. Therefore, the purpose of this study was to construct different berberine-loaded nano-hydroxyapatite/gelatin scaffolds, and to investigate their effects on osteosarcoma cancer cells. The scaffolds after fabrication were analyzed for physicochemical properties using XRD, EDS, FTIR, and FE-SEM. The drug loading and release, and the biocompatibility (MTT and LDH) were also evaluated. Moreover, apoptosis, viability, colony formation, and scratch tests were conducted on cancer cells. The scaffolds exhibited a porosity of 66.64% with pore sizes of 10–70 micrometers. The results showed that the released berberine had a cytotoxic effect on cancer cells (cell death of ∼38–80% based on LDH, and cell proliferation <56% and <21% in terms of early and late exposure based on MTT). The apoptosis results revealed a remarkable increase in the percentage of apoptotic MG63 cells after treatment with berberine-loaded scaffolds in a dose-dependent manner. All scaffolds with berberine were able to significantly prevent colony formation and cell migration (only 9.7–15.7% closure). [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor (CAR)-engineered natural killer (NK) cells have recently emerged as a promising and safe alternative to CAR-T cells for targeting solid tumors. In the case of triple-negative breast cancer (TNBC), traditional cancer treatments and common immunotherapies have shown limited effectiveness. However, CAR-NK cells have been successfully employed to target epidermal growth factor receptor (EGFR) on TNBC cells, thereby enhancing the efficacy of immunotherapy. The effectiveness of CAR-NK-based immunotherapy is influenced by various factors, including the vaccination dose, vaccination pattern, and tumor immunosuppressive factors in the microenvironment. To gain insights into the dynamics and effects of CAR-NK-based immunotherapy, we propose a computational model based on experimental data and immunological theories. This model integrates an individual-based model that describes the interplay between the tumor and the immune system, along with an ordinary differential equation model that captures the variation of inflammatory cytokines. Computational results obtained from the proposed model shed light on the conditions necessary for initiating an effective anti-tumor response. Furthermore, global sensitivity analysis highlights the issue of low persistence of CAR-NK cells in vivo, which poses a significant challenge for the successful clinical application of these cells. Leveraging the model, we identify the optimal vaccination time, vaccination dose, and time interval between injections for maximizing therapeutic outcomes. [ABSTRACT FROM AUTHOR]

In this research chemical composition and antimicrobial effects of Elaeagnus angustifolia L. (E. angustifolia L.) whole fruit ethanolic extract was investigated on common pathogenic microorganisms (Staphylococcus aureus, Escherichia coli, Enterococcus faecalis, and Candida albicans). The phytochemical composition of E. angustifolia was screened by Gas Chromatography-Mass Spectrometry (GC/MS). The minimum inhibitory concentration (MIC) and the minimal bactericidal concentration (MBC) of the extract were determined using the broth dilution technique. According to the results, 13 major compounds such as flavonoid, aldehyde, alcoholic and fatty acids were identified by GC/MS. In addition, the extract could inhibit the growth of all examined pathogenic strains. The MIC was 3.75 to 1.87 mg ml-1 while maximum activity was found against Staphylococcus aureus. Besides, the MBC was ranging from 7.5 to 3.75 mg ml-1. Since E. angustifolia whole fruit ethanolic extract contains phytochemical compounds and has antimicrobial potential it can be recommended as a natural active agent for application in the food industry. [ABSTRACT FROM AUTHOR]

In this study, hydroxyapatite (HA) scaffolds were synthesized and characterized, following the osteogenic and angiogenic effects of HA scaffolds with or without endometrial mesenchymal stem stromal cells (hEnSCs) derived Exosomes were investigated in rat animal model with calvaria defect. The X-ray diffraction (XRD) analysis of HA powder formation was confirmed with Joint Corporation of Powder Diffraction Standards (JCPDS) files numbers of 34-0010 and 24-0033A and Ball mill, and sintering manufactured Nano-size particles. Obtained results containing FE-SEM images presented that the surface of scaffolds has a rough and porous structure, which makes them ideal and appropriate for tissue engineering. Additionally, the XRD showed that these scaffolds exhibited a crystallized structure without undergoing phase transformation; meanwhile, manufactured scaffolds consistently release exosomes; moreover, in vivo findings containing hematoxylin–eosin staining, immunohistochemistry, Masson's trichrome staining, and histomorphometric analysis confirmed that our implant has an osteogenic and angiogenic characteristic. So prepared scaffolds containing exosomes can be proposed as a promising substitute in tissue engineering. [ABSTRACT FROM AUTHOR]

In this study, the biological activities of whole herb extract of a medicinal plant named Smirnovia Iranica were investigated. The extraction was performed using Supercritical CO2 and phytochemical compounds, total phenolic content (TPC), total flavonoid content (TFC), antioxidant, anti-bacterial, and anti-cancer effect were determined in the extract. Based on the results, high TPC concentration (120.36 mg GAE/100 g FW) and TFC (17.41 mg quercetin/100g FW) were obtained in the extract. Besides, the extract showed significant antioxidant activity (IC50=53.97 µg mL-1). Moreover, the extract showed a notable inhibitory effect against Escherichia coli (MIC=15.63 mg mL-1) and Salmonella enterica (MIC=31.25 mg mL-1). On the other hand, this extract showed the cytotoxic effect on glioblastoma cancer cell lines in the MTT assay. This is the first, yet comprehensive, scientific report about the chemical composition and pharmacological properties of the extract of Smirnovia Iranica whole herb. According to current results, the Smirnovia Iranica extract has excellent antioxidant properties for application as bioactive components for various objects such as as food supplements. The experiment confirmed the efficacy of the extracts as natural antimicrobials and suggested the possibility of employing them in drugs for the treatment of infectious diseases caused by the test organisms. [ABSTRACT FROM AUTHOR]

Background: Three-dimensional (3D) printing is a capable approach for the fabrication of bone tissue scaffolds. Nevertheless, a purely made scaffold such as polylactic acid (PLA) may suffer from shortcomings and be restricted due to its biological behavior. Gelatin, hydroxyapatite and platelet-rich plasma (PRP) have been revealed to be of potential to enhance the osteogenic effect. In this study, it was tried to improve the properties of 3D-printed PLA scaffolds by infilling them with gelatin-nano-hydroxyapatite (PLA/G-nHA) and subsequent coating with PRP. For comparison, bare PLA and PLA/G-nHA scaffolds were also fabricated. The printing accuracy, the scaffold structural characterizations, mechanical properties, degradability behavior, cell adhesion, mineralization, systemic effect of the scaffolds on the liver enzymes, osteocalcin level in blood serum and in vivo bone regeneration capability in rat critical-sized calvaria defect were evaluated. Results: High printing accuracy (printing error of < 11%) was obtained for all measured parameters including strut thickness, pore width, scaffold density and porosity%. The highest mean ultimate compression strength (UCS) was associated with PLA/G-nHA/PRP scaffolds, which was 10.95 MPa. A slow degradation rate was observed for all scaffolds. The PLA/G-nHA/PRP had slightly higher degradation rate, possibly due to PRP release, with burst release occurred at week 4. The MTT results showed that PLA/G-nHA/PRP provided the highest cell proliferation at all time points, and the serum biochemistry (ALT and AST level) results indicated no abnormal/toxic influence caused by scaffold biomaterials. Superior cell adhesion and mineralization were obtained for PLA/G-nHA/PRP. Furthermore, all the developed scaffolds showed bone repair capability. The PLA/G-nHA/PRP scaffolds could better support bone regeneration than bare PLA and PLA/G-nHA scaffolds. Conclusion: The PLA/G-nHA/PRP scaffolds can be considered as potential for hard tissue repair. [ABSTRACT FROM AUTHOR]

In this paper, the in-vivo healing of critical-sized bony defects by cell-free and stem cell-seeded 3D-printed PLA scaffolds was studied in rat calvaria bone. The scaffolds were implanted in the provided defect sites and histological analysis was conducted after 8 and 12 weeks. The results showed that both cell-free and stem cell-seeded scaffolds exhibited superb healing compared with the empty defect controls, and new bone and connective tissues were formed in the healing site after 8 and 12 weeks, postoperatively. The higher filled area, bone formation and bone maturation were observed after 12 weeks, particularly for PLA + Cell scaffolds. [ABSTRACT FROM AUTHOR]

Introduction: Alumina-titanium (Al2O3-Ti) composites with enhanced mechanical and corrosion properties have been recently developed for potential applications in orthopaedics and hard tissue replacements. However, before any clinical use, their interactions with biological environment must be examined. Methods: The aim of this study, therefore, was to assess the biocompatibility of three Al2O3-Ti composites having 25, 50, and 75 volume percentages of titanium. These materials were made by spark plasma sintering (SPS), and MC3T3-E1 cells were cultured onto the sample discs to evaluate the cell viability, proliferation, differentiation, mineralization, and adhesion. Furthermore, the apatite formation ability and wettability of the composites were analysed. Pure Ti (100Ti) and monolithic Al2O3 (0Ti) were also fabricated by SPS and biological characteristics of the composites were compared with them. Results: The results showed that cell viability to 75Ti (95.0%), 50Ti (87.3%), and 25Ti (63.9%) was superior when compared with 100Ti (42.7%). Pure Al2O3 also caused very high cell viability (89.9%). Furthermore, high cell proliferation was seen at early stage for 50Ti, while the cells exposed to 75Ti proliferated more at late stages. Cell differentiation was approximately equal between different groups, and increased by time. Matrix mineralization was higher on the composite surfaces rather than on 0Ti and 100Ti. Moreover, the cells adhered differently to the surfaces of different biomaterials where more spindle-shaped configuration was found on 100Ti, slightly enlarged cells with dendritic shape and early pseudopodia were observed on 75Ti, and more enlarged cells with long dendritic extensions were found on 0Ti, 25Ti, and 50Ti. The results of EDS analysis showed that both Ca and P deposited on the surfaces of all materials, after 20 days of immersion in SBF. Conclusion: Our in-vitro findings demonstrated that the 75Ti, 50Ti, and 25Ti composites have high potential to be used as load-bearing orthopedic materials. [ABSTRACT FROM AUTHOR]

Elaeagnus. angustifolia L. (EA) is a natural plant food with therapeutic and medicinal properties for treating various diseases such as rheumatoid arthritis and osteoporosis. Since herbal agents are origins of bioactive compounds, they can be applied in complementary treatment protocols. In this study, EA whole fruit extract's cytotoxic effects were investigated on both animal and human glioblastoma cancer cell lines. The extract of whole fruit of EA was obtained by maceration in ethanol. The phytochemical compounds were identified using high-performance liquid chromatography (HPLC). The MTT and LDH assays were performed to evaluate the cytotoxicity effect of the extract and the determination of cell death. Wound-healing assay and colony formation analysis were employed for migration and proliferation evaluation. Based on HPLC analysis, the main flavonoid components of the extract were included rutin and apigenin. The results demonstrated that EA extract at the dose of 125 to 2000 µg/ml and 61.5 to 2000 µg/ml inhibited C6 and U87 cells' viability and induced significant cell cytotoxicity at both 48 and 72 h incubation times. Besides, EA extract significantly inhibited cell migration and colony formation at 250 to 1000 µg/ml concentration. Overall, the results showed that EA extract could inhibit several stages in glioblastoma carcinogenesis in vitro. Therefore, it can be suggested as an anticancer in the clinical treatment approaches of glioblastoma cancer. [ABSTRACT FROM AUTHOR]

Recent studies suggest that Spirulina may have great therapeutic benefits due to its antioxidant and anti‐inflammatory properties. The primary objective of this study was to evaluate the chemopreventive properties of the Spirulina microalgae (Spi) on the regression and survival of tumor, histopathological features of glioblastoma, and detection of the molecular mechanism of Spi. Tumor viability versus Spi was determined using the MTT assay. In vivo antitumor activity of Spi was studied using the glioblastoma model. After tumor induction, the animals were euthanized, and their brains were removed. Histological evaluation was performed for tumor size and manifestation. The mechanisms of the anticancer effects of Spi were investigated by evaluating the microRNAs and their targets. The results demonstrated that Spi inhibited C6 and U87 cell proliferation and induced cell death. Histopathologic results showed that the administration of Spi could delay the development of tumors and prolonged the survival of tumor‐bearing animals. Furthermore, Spi significantly upregulated miR‐34a and miR‐125b that have a key role in the progression of PI3K/AKT/mTOR pathway. This is the first in vivo report on the chemo‐preventive effect of Spi against glioblastoma, suggesting its potential use in the chemoprevention of this cancer and the antiglioma molecular mechanism of Spi. [ABSTRACT FROM AUTHOR]

The development of new therapies based on tumor biology is one of the main topics in cancer treatment. In this regard, investigating the microenvironment and cellular composition of the tumor is of particular interest. Mesenchymal stem cells (MSCs) are a major group of cells in the tumor tissue and play a critical role in tumor growth and development. Investigating the mechanisms by which MSCs influence tumor growth and progression is very useful in establishing new therapeutic approaches. MSCs have some immunological capacities, including anti-inflammatory, immune-regulatory, and immune-suppressive abilities, which help the tumor growth in the inflammatory condition. They can suppress the proliferation and activation of CD4 + T cells and direct them toward the regulatory phenotype through the release of some factors such as indoleamine 2,3-dioxygenase, prostaglandin E2, and HO-1, PD-1 ligands (PD-L1 and PD-L2) and promote tolerance and apoptosis. Besides, these cells are able to produce adenosine. Adenosine has a key role in controlling the immune system by signaling through receptors located on the surface of immune cells. It plays a very essential role in tumor growth and progression. In the present review, we investigate and introduce adenosine-producing mesenchymal stem cells as a potential target for cancer treatment. [ABSTRACT FROM AUTHOR]

Background: Alumina-titanium (Al2O3-Ti) biocomposites have been recently developed with improved mechanical properties for use in heavily loaded orthopedic sites. Their biological performance, however, has not been investigated yet. Methods: The aim of the present study was to evaluate the in vivo biological interaction of Al2O3-Ti. Spark plasma sintering (SPS) was used to fabricate Al2O3-Ti composites with 25 vol.%, 50 vol.%, and 75 vol.% Ti content. Pure alumina and titanium were also fabricated by the same procedure for comparison. The fabricated composite disks were cut into small bars and implanted into medullary canals of rat femurs. The histological analysis and scanning electron microscopy (SEM) observation were carried out to determine the bone formation ability of these materials and to evaluate the bone-implant interfaces. Results: The histological observation showed the formation of osteoblast, osteocytes with lacuna, bone with lamellar structures, and blood vessels indicating that the healing and remodeling of the bone, and vasculature reconstruction occurred after 4 and 8 weeks of implantation. However, superior bone formation and maturation were obtained after 8 weeks. SEM images also showed stronger interfaces at week 8. There were differences between the composites in percentages of bone area (TB%) and the number of osteocytes. The 50Ti composite showed higher TB% at week 4, while 25Ti and 75Ti represented higher TB% at week 8. All the composites showed a higher number of osteocytes compared to 100Ti, particularly 75Ti. Conclusions: The fabricated composites have the potential to be used in load-bearing orthopedic applications. [ABSTRACT FROM AUTHOR]

Dendritic cells are important in initiating immune responses; therefore, a range of dendritic cell--based approaches have been established to induce immune response against cancer cells. However, the presence of immunosuppressive mediators such as adenosine in the tumor microenvironment reduces the efficacy of dendritic cell--based cancer immunotherapy. In this study, we investigated whether blockade of the A2A adenosine receptor with a selective antagonist and a CD73 inhibitor may increase the efficacy of a dendritic cell--based cancer vaccine. According to the findings, this therapeutic combination reduced tumor growth, prolonged survival of tumor-bearing mice, and enhanced specific antitumor immune responses. Thus, we suggest that targeting cancer-derived adenosine improves the outcomes of dendritic cell--based cancer immunotherapy. [ABSTRACT FROM AUTHOR]

Considerable evidence shows that the tumor microenvironment is an active participant in preventing immunosurveillance and limiting the efficacy of anticancer therapies. Hypoxia is a prominent characteristic of the solid tumor microenvironment. The transcription factor hypoxia-inducible factor-1α (HIF-1α) is an important mediator of hypoxic response of tumor cells that modulates the expression of specific genes involved in tumor immunosuppression. Using a 4T1 breast cancer model, we show that in vivo administration of PX-478, an inhibitor of oxygen-sensitive HIF-1α, led to reduced expression of Foxp3 and VEGF transcript and/or protein, molecules that are directly controlled by HIF-1. When combined with dendritic cell (DC)-based vaccination, HIF-1α inhibition resulted in an augmented cytotoxic T lymphocyte effector function, improved proliferation status of T cells, increased production of inflammatory cytokine IFN-γ, as well as reduced regulatory function of T cells in association with slower tumor growth. Taken together, our findings indicate that the use of HIF-1α inhibition provides an immune adjuvant activity, thereby improves the efficacy of tumor antigen-based DC vaccine. [ABSTRACT FROM AUTHOR]

The innate immune system utilizes pattern recognition receptors (PRRs) to recognize microbes. Pathogens contain various molecules with diverse effects on immune response. In this study, we evaluated the effect of DNA and protein components derived from two intracellular microorganisms including Listeria monocytogenes (L. monocytogenes) and Toxoplasma gondii (T. gondii) on dendritic cells (DCs) activation and ensuing adaptive immune responses. DNA and protein components of L. monocytogenes and T. gondii were prepared using relevant kits. DNA and protein components of these two pathogens were added to immature DCs (iDCs). Subsequently, co-stimulatory expression and cytokine production by DCs were measured. Finally, we evaluated the stimulatory capacity of mature DCs (mDCs) in DC-T cells co-culture. The results showed that protein matured-DCs produced higher level of IL (Interleukin)-12p70. There was also a significant increase in Interferon-Gamma (IFN-γ) production and proliferative capacity in T cells co-cultured with protein matured-DCs. On the other hand, DNA matured-DCs produced significantly higher amounts of Transforming growth factor-beta (TGF-β). Collectively, these results imply a regulatory nature for DNA and potent stimulatory character for protein components of these two intracellular microorganisms. [ABSTRACT FROM AUTHOR]