Exosomes for angiogenesis induction in ischemic disorders.

Ischaemic disorders are leading causes of morbidity and mortality worldwide. While the current therapeutic approaches have improved life expectancy and quality of life, they are unable to "cure" ischemic diseases and instate regeneration of damaged tissues. Exosomes are a class of extracellular vesicles with an average size of 100-150 nm, secreted by many cell types and considered a potent factor of cells for paracrine effects. Since exosomes contain multiple bioactive components such as growth factors, molecular intermediates of different intracellular pathways, microRNAs and nucleic acids, they are considered as cell-free therapeutics. Besides, exosomes do not rise cell therapy concerns such as teratoma formation, alloreactivity and thrombotic events. In addition, exosomes are stored and utilized more convenient. Interestingly, exosomes could be an ideal complementary therapeutic tool for ischemic disorders. In this review, we discussed therapeutic functions of exosomes in ischemic disorders including angiogenesis induction through various mechanisms with specific attention to vascular endothelial growth factor pathway. Furthermore, different delivery routes of exosomes and different modification strategies including cell preconditioning, gene modification and bioconjugation, were highlighted. Finally, pre-clinical and clinical investigations in which exosomes were used were discussed.

Folate-Targeted Curcumin-Loaded Niosomes for Site-Specific Delivery in Breast Cancer Treatment: In Silico and In Vitro Study.

As the most common cancer in women, efforts have been made to develop novel nanomedicine-based therapeutics for breast cancer. In the present study, the in silico curcumin (Cur) properties were investigated, and we found some important drawbacks of Cur. To enhance cancer therapeutics of Cur, three different nonionic surfactants (span 20, 60, and 80) were used to prepare various Cur-loaded niosomes (Nio-Cur). Then, fabricated Nio-Cur were decorated with folic acid (FA) and polyethylene glycol (PEG) for breast cancer suppression. For PEG-FA@Nio-Cur, the gene expression levels of Bax and p53 were higher compared to free drug and Nio-Cur. With PEG-FA-decorated Nio-Cur, levels of Bcl2 were lower than the free drug and Nio-Cur. When MCF7 and 4T1 cell uptake tests of PEG-FA@Nio-Cur and Nio-Cur were investigated, the results showed that the PEG-FA-modified niosomes exhibited the most preponderant endocytosis. In vitro experiments demonstrate that PEG-FA@Nio-Cur is a promising strategy for the delivery of Cur in breast cancer therapy. Breast cancer cells absorbed the prepared nanoformulations and exhibited sustained drug release characteristics.

The Optimized Formulation of Tamoxifen-Loaded Niosomes Efficiently Induced Apoptosis and Cell Cycle Arrest in Breast Cancer Cells.

The aim, as proof of concept, was to optimize niosomal formulations of tamoxifen in terms of size, morphology, encapsulation efficiency, and release kinetics for further treatment of the breast cancer (BC). Different assays were carried out to evaluate the pro-apoptotic and cytotoxicity impact of tamoxifen-loaded niosomes in two BC cells, MDA-MB-231 and SKBR3. In this study, tamoxifen was loaded in niosomes after optimization in the formulation. The formulation of niosomes supported maximized drug entrapment and minimized their size. The novel formulation showed improvement in storage stability, and after 60 days only, small changes in size, polydispersity index, and drug entrapment were observed. Besides, a pH-dependent release pattern of formulated niosomes displayed slow release at physiological pH (7.4) and a considerable increase of release at acidic pH (5.4), making them a promising candidate for drug delivery in the BC treatment. The cytotoxicity study exhibited high biocompatibility with MCF10A healthy cells, while remarkable inhibitory effects were observed after treatment of cancerous lines, MDA-MB-231, and SKBR3 cells. The IC50 values for the tamoxifen-loaded niosomes were significantly less than other groups. Moreover, treatment with drug-loaded niosomes significantly changed the gene expression pattern of BC cells. Statistically significant down-regulation of cyclin D, cyclin E, VEGFR-1, MMP-2, and MMP-9 genes and up-regulation of caspase-3 and caspase-9 were observed. These results were in correlation with cell cycle arrest, lessoned migration capacity, and increased caspase activity and apoptosis induction in cancerous cells. Optimization in the formulation of tamoxifen-loaded niosomes can make them a novel candidate for drug delivery in BC treatment.

Immunomodulatory performance of GMP-compliant, clinical-grade mesenchymal stromal cells from four different sources.

Inflammatory and autoimmune diseases are among the most challenging disorders for health care professionals that require systemic immune suppression which associates with various side effects. Mesenchymal stromal cells (MSCs) are capable of regulating immune responses, mainly through paracrine effects and cell-cell contact. Since MSCs are advanced therapy medicinal products (ATMPs), they must follow Good Manufacturing Practice (GMP) regulations to ensure their safety and efficacy. In this study, we evaluated the immunomodulatory effects of GMP-compliant clinical grade MSCs obtained from four different sources (bone marrow, adipose tissue, Wharton's Jelly, and decidua tissue) on allogeneic peripheral blood mononuclear cells (PBMCs). Our results revealed that WJ-MSCs were the most successful group in inhibiting PBMC proliferation as confirmed by BrdU analysis. Moreover, WJ-MSCs were the strongest group in enhancing the regulatory T cell population of PBMCs. WJ-MSCs also had the highest secretory profile of prostaglandin E2 (PGE-2), anti-inflammatory cytokine, while interleukin-10 (IL-10) secretion was highest in the DS-MSC group. DS-MSCs also had the lowest secretion of IL-12 and IL-17 inflammatory cytokines. Transcriptome analysis revealed that WJ-MSCs had the lowest expression of IL-6, while DS-MSCs were the most potent group in the expression of immunomodulatory factors such as hepatocyte growth factor (HGF) and transforming growth factor-ß (TGF- ß). Taken together, our results indicated that GMP-compliant Wharton's Jelly and decidua-derived MSCs showed the best immunomodulatory performance considering paracrine factors.

Immune regulation and therapeutic application of T regulatory cells in liver diseases.

CD4+ CD25+ FOXP3+ T regulatory cells (Tregs) are a subset of the immunomodulatory cell population that can inhibit both innate and adaptive immunity by various regulatory mechanisms. In hepatic microenvironment, proliferation, plasticity, migration, and function of Tregs are interrelated to the remaining immune cells and their secreted cytokines and chemokines. In normal conditions, Tregs protect the liver from inflammatory and auto-immune responses, while disruption of this crosstalk between Tregs and other immune cells may result in the progression of chronic liver diseases and the development of hepatic malignancy. In this review, we analyze the deviance of this protective nature of Tregs in response to chronic inflammation and its involvement in inducing liver fibrosis, cirrhosis, and hepatocellular carcinoma. We will also provide a detailed emphasis on the relevance of Tregs as an effective immunotherapeutic option for autoimmune diseases, liver transplantation, and chronic liver diseases including liver cancer.

Amniotic Membrane and Its Derivatives: Novel Therapeutic Modalities in Liver Disorders.

The liver is a vital organ responsible for metabolic and digestive functions, protein synthesis, detoxification, and numerous other necessary functions. Various acute, chronic, and neoplastic disorders affect the liver and hamper its biological functions. Most of the untreated liver diseases lead to inflammation and fibrosis which develop into cirrhosis. The human amniotic membrane (hAM), the innermost layer of the fetal placenta, is composed of multiple layers that include growth-factor rich basement membrane, epithelial and mesenchymal stromal cell layers. hAM possesses distinct beneficial anti-fibrotic, anti-inflammatory and pro-regenerative properties via the secretion of multiple potent trophic factors and/or direct differentiation into hepatic cells which place hAM-based therapies as potential therapeutic strategies for the treatment of chronic liver diseases. Decellularized hAM is also an ideal scaffold for liver tissue engineering as this biocompatible niche provides an excellent milieu for cell proliferation and hepatocytic differentiation. Therefore, the current review discusses the therapeutic potential of hAM and its derivatives in providing therapeutic solutions for liver pathologies including acute liver failure, metabolic disorders, liver fibrosis as well as its application in liver tissue engineering.