Synergistic effects of mesenchymal stem cell-derived extracellular vesicles and dexamethasone on macrophage polarization under inflammatory conditions.

The undesirable inflammation and the excessive M1 macrophage activity may lead to inflammatory diseases. Corticosteroids and stem cell therapy are used in clinical practice to promote anti-inflammatory responses. However, this protocol has limitations and is associated with numerous side effects. In this study, the synergistic anti-inflammatory effects of dexamethasone (Dex) and mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) were evaluated to enhance the polarization of M1 inflammatory macrophages into the anti-inflammatory (M2) phenotype. Hence, we designed different combinations of Dex and EVs using three methods, including EVs isolated from Dex-preconditioned MSCs (Pre-Dex-EVs), EVs loaded with Dex (L-Dex-EVs), and EVs and Dex co-administration (Dex + EVs). All designed EVs had a significant effect on reducing the expression of M1-related genes (iNOS, Stat1, and IRF5), cytokines (IL6 and TNF-a), and CD markers (CD86) in lipopolysaccharide-stimulated macrophages. On the other hand, these combinations promoted the expression of alternative-activated M2-related genes (Arg-1, Stat6, and IRF4), cytokine (IL10), and CD markers (CD206).The combination of Dex and MSC-EVs enhances the effectiveness of both and synergistically promotes the conversion of inflammatory macrophages into an anti-inflammatory state.

Comparative study of the cytotoxicity, apoptotic, and epigenetic effects of Boswellic acid derivatives on breast cancer.

This study aimed to compare the effect of Boswellic acid derivatives on the viability, apoptosis, and epigenomic profiling of breast cancer. According to the viability assays, 3-O-acetyl-11-keto-ß-Boswellic acid (AKBA) showed more toxicity against MDA-MB-231 cells when compared with the 3-O-acetyl-ß-Boswellic acid (ABA). In contrast, ABA revealed less toxicity against MCF-10A. Cell cycle and apoptosis assays determined the maximum apoptotic effect of AKBA on MCF-7, and MDA-MB-231 cells. Interestingly, ß-Boswellic acid (BA) and ABA did not promote the apoptosis in MCF-10A cells. Transwell migration assay indicated the greatest normalized inhibition (around 160%) in the migration of MDA-MB-231 cells induced by AKBA. The expression of P53, BAX, and BCL2 genes in cancerous cell lines has affirmed that both AKBA and ABA could induce the maximal apoptosis. Western-blot investigation demonstrated that the maximum over-expression of P53 protein (1.96 times) was caused by AKBA in MDA-MB-231 cells, followed by ABA in MCF-7 cells. The BCL2 protein expression was in agreement with the previously reported results. The global DNA methylation in both cancerous cells was reduced by ABA. These results suggest that ABA represented more epigenetic modulatory effect while AKBA shows more cytotoxic and apoptotic effect against breast cancer cell lines.

Microscopic Evaluation of Ovarian Surface Epithelium Following Treatment with Conjugated Estrogens in a Mouse Model.

BACKGROUND: This study was designed to evaluate the effect of different concentrations of conjugated equine estrogens (CEE) on the ovarian epithelium of female CD1 mice. METHODS: Twenty-four female mice at 7 months with irregular estrus cycles were randomly divided into four groups of 6 mice each. Group one was considered as a control group and received a daily dose of 0.5ml of propylene glycol, for three weeks, while those in the treatment groups received a daily dose of 14µg/kg, 28µg/kg and 56µg/kg conjugated equine estrogens, respectively. RESULTS: The results from this study showed a strong correlation between elevated concentrations of CEE and histological changes in ovarian surface epithelium (OSE). They also showed that administration of high-dose estrogen created the conditions for excessive proliferation of OSE which may progress into the development of cysts in the ovaries. CONCLUSION: This study concluded that high concentrations of CEE may increase the chances of developing epithelial ovarian cancer.

Synthesis of gemifloxacin conjugated silver nanoparticles, their amplified bacterial efficacy against human pathogen and their morphological study via TEM analysis.

Drug-loaded nanoparticles (NPs) allow specific accumulation and controlled release of drugs to infected tissues with minimal cytotoxicity. In this study, gemifloxacin conjugated silver nanoparticles (Gemi-AgNPs) were synthesized, and the amplification of their antibacterial potential against the human pathogen as well as their stability was monitored under physiological conditions. Fourier transform infrared spectroscopy (FTIR) analysis demonstrated the interaction between -NH2 and -OH functional moiety and the metal surface. The morphological analyses via transmission electron microscopy revealed that Gemi-AgNPs has a round oval shape and average particle size of 22.23 ± 2 nm. The antibacterial and antibiofilm activities of these NPS showed that Gemi-AgNPs exhibit excellent antimicrobial and biofilm inhibition activity against human pathogens, namely, Proteus mirabilis (P. mirabilis) and methicillin-resistant Staphylococcus aureus (MRSA). A significant increase in the antibiofilm activity of Gemi-AgNPs was confirmed by crystal violet, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) staining, and microscopic analysis. Gemi-AgNPs exhibited the ability to inhibit urease with an IC50 value of 57.4 ± 0.72 µg/mL. The changes in the bacterial cell morphology were analyzed via TEM, which revealed that cell membranes disrupted and completely destroyed the cell morphology by the treatment of Gemi-AgNPs.

An engineered microfluidic blood-brain barrier model to evaluate the anti-metastatic activity of ß-boswellic acid.

BACKGROUND: The development of anti-cancer drugs with the ability to inhibit brain metastasis through the blood-brain barrier (BBB) is substantially limited due to the lack of reliable in vitro models. MAIN METHODS: In this study, the Geltrex-based Transwell and microfluidic BBB models were applied to screen the effect of ß-boswellic acid (ß-BA) on the metastasis of MDA-MB-231 cells through the BBB in static and dynamic conditions, respectively. MAJOR RESULTS: The toxicity assay revealed that ß-BA deteriorates MDA-MB-231 cells, while ß-BA had no detectable toxic effects on human umbilical vein endothelial cells (HUVECs) and astrocytes. Trans-endothelial electrical resistance evaluation showed sustainable barrier integrity upon treatment with ß-BA. Vimentin expression in HUVECs, evaluated using western blot, confirmed superior barrier integrity in the presence of ß-BA. The obtained results were confirmed using an invasion study with a cell tracker and a scanning electron microscope. ß-BA significantly inhibited metastasis by 85%, while cisplatin (Cis), a positive control, inhibited cancer cell migration by 12% under static conditions. Upon applying a dynamic BBB model, it was revealed that ß-BA-mediated metastasis inhibition was significantly higher than that mediated by Cis. CONCLUSIONS AND IMPLICATIONS:  In summary, the current study proved the anti-metastatic potential of ß-BA in both static and dynamic BBB models.