Shining the light on mesenchymal stem cell-derived exosomes in breast cancer.

In women, breast cancer (BC) is the second most frequently diagnosed cancer and the leading cause of cancer death. Mesenchymal stem cells (MSCs) are a subgroup of heterogeneous non-hematopoietic fibroblast-like cells that have the ability to differentiate into multiple cell types. Recent studies stated that MSCs can migrate into the tumor sites and exert various effect on tumor growth and development. Multiple researches have demonstrated that MSCs can favor tumor growth, while other groups have indicated that MSCs inhibit tumor development. Emerging evidences showed exosomes (Exo) as a new mechanism of cell communication which are essential for the crosstalk between MSCs and BC cells. MSC-derived Exo (MSCs-Exo) could mimic the numerous effects on the proliferation, metastasis, and drug response through carrying a wide scale of molecules, such as proteins, lipids, messenger RNAs, and microRNAs to BC cells. Consequently, in the present literature, we summarized the biogenesis and cargo of Exo and reviewed the role of MSCs-Exo in development of BC.

Clinical application of mesenchymal stem cell in regenerative medicine: a narrative review.

The multipotency property of mesenchymal stem cells (MSCs) has attained worldwide consideration because of their immense potential for immunomodulation and their therapeutic function in tissue regeneration. MSCs can migrate to tissue injury areas to contribute to immune modulation, secrete anti-inflammatory cytokines and hide themselves from the immune system. Certainly, various investigations have revealed anti-inflammatory, anti-aging, reconstruction, and wound healing potentials of MSCs in many in vitro and in vivo models. Moreover, current progresses in the field of MSCs biology have facilitated the progress of particular guidelines and quality control approaches, which eventually lead to clinical application of MSCs. In this literature, we provided a brief overview of immunoregulatory characteristics and immunosuppressive activities of MSCs. In addition, we discussed the enhancement, utilization, and therapeutic responses of MSCs in neural, liver, kidney, bone, heart diseases, and wound healing.

Mechanisms of cancer stem cells drug resistance and the pivotal role of HMGA2.

Nowadays, the focus of researchers is on perceiving the heterogeneity observed in a tumor. The researchers studied the role of a specific subset of cancer cells with high resistance to traditional treatments, recurrence, and unregulated metastasis. This small population of tumor cells that have stem-cell-like specifications was named Cancer Stem Cells (CSCs). The unique features that distinguish this type of cancer cell are self-renewing, generating clones of the tumor, plasticity, recurrence, and resistance to therapies. There are various mechanisms that contribute to the drug resistance of CSCs, such as CSCs markers, Epithelial mesenchymal transition, hypoxia, other cells, inflammation, and signaling pathways. Recent investigations have revealed the primary role of HMGA2 in the development and invasion of cancer cells. Importantly, HMGA2 also plays a key role in resistance to treatment through their function in the drug resistance mechanisms of CSCs and challenge it. Therefore, a deep understanding of this issue can provide a clearer perspective for researchers in the face of this problem.

Role of Acute Myeloid Leukemia (AML)-Derived exosomes in tumor progression and survival.

Acute myeloid leukemia (AML) is a quickly aggressive hematopoietic disorder that progress due to the accumulation and clonal expansion of immature myeloid cells. Despite the latest developments in AML treatment, repeated relapses and drug resistance remain one of the major challenges in treatment of leukemia. Currently, it is well known that the components of the tumor microenvironment such as cellular and non-cellular elements play a critical function in treatment failures of AML, also they are most common cause of complications including suppression of hematopoiesis. Exosomes are membrane-bound extracellular vesicles (EVs) that transfer signaling molecules and have attracted a large amount of attention due to their important role in inter-cellular communication in health and disease. Exosomes participate in the survival and chemoresistance of many leukemia through transferring their rich cargos of molecules including miRNAs, growth factors, and cytokines. The key producers of exosomes that mainly participate to AML pathogenesis are bone marrow mesenchymal stem cell (BMSCs) and AML cell themselves. These cells release an enormous number of exosomes that affect several target cells such as natural killer (NK) and hematopoietic stem cells to the development of leukemia proliferation and progression. In the present study, a comprehensive review of the literature has been done to briefly discuss the biology of exosomes and highlight the role of exosomes derived from AML in the progress of acute myeloid leukemia.

Immunotherapy of inflammatory bowel disease (IBD) through mesenchymal stem cells.

Many pathophysiologic pathways and immune-pathologic etiologies are addressed as Inflammatory bowel disease (IBD) causes. Moreover, dysfunction of the immune system leads to inflammatory responses against intestinal components that boost disease severity. The use of routine treatments has limitations. Besides, patients may experience drug resistance. Therefore, the use of novel and effective therapies is essential. Relying on the immune regulatory functions of Mesenchymal Stem Cells (MSCs), researchers have suggested possible benefits of MSCs administration for IBD, both in experimental and clinical studies. Experimental animal models of IBD have shown effects of MSCs, MSC-derived exosomal micro RNAs, and MSC-based drug delivery systems on the regulation of the immune system (Th17 suppression versus T-regular cell biased responses). These studies have suggested MSCs' benefits on intestinal integrity, improved smooth cell function, and tissue repair. On the other hand, various clinical trials have been registered for MSCs application in IBD patients that show reliable safety in humans. Most clinical trials have used MSCs of bone marrow, umbilical cord, and adipose tissue that have been administered by intravenous or intra-tissue injection. Studies have evaluated clinical outcomes, patient symptoms, or healing processes; while immunological studies in the clinical era are missing. As we reviewed, huge shreds of experimental shreds of evidence have led to the inception of multiple clinical trials in phase I/II, showing promising results for IBD treatment. We suggest that further clinical investigation should be more focused on in-vitro/in-vivo assessed outcomes as well as the immunological endpoints to have more reliable results with more support for laboratory evidence.

Targeted therapy of tumour microenvironment by gold nanoparticles as a new therapeutic approach.

Despite advances in cancer diagnosis and treatment, mortality associated with this malignant disease is still a major challenge in the health system. The tumour microenvironment (TME) provides a proper condition for cancer cells and gives rise to growth and metastasis. The TME is composed of fibroblasts, immune cells, extracellular matrix (ECM), endothelial cells, cytokines, and various factors; each of them has a special role in the process of tumour development. Therefore, the targeted treatment approach using gold nanoparticles (AuNPs) due to its unique properties, such as acceptable uptake, drug and ligand loading, low immunogenicity, high permeability, high cytotoxicity for tumour cells, and easy manipulation of particle properties; has had significant results in cancer treatment. In the current review study, we discussed more aspects of TME and associated targeted therapy methods with AuNPs.

Applications of Microfluidic Devices in the Diagnosis and Treatment of Cancer: A Review Study.

Many cancer-related deaths are reported annually due to a lack of appropriate diagnosis and treatment strategies. Microfluidic technology, as new creativity has a great impact on automation and miniaturization via handling a small volume of materials and samples (in microliter to femtoliter range) to set up the system. Microfluidic devices not only detect various cancer-diagnostic factors from biological fluids but also can produce proper nanoparticles for drug delivery. With the contribution of microfluidics; multiple treatments for cancer such as chemotherapy, radiation therapy, and gene delivery can be implemented and studied. Hence, Microfluidics can be worth for the cancer field because of its high Throughput, high sensitivity, less material use, and low expense. In this review study, we intend to look at positive microfluidics prospects, features, benefits, and clinical applications.

Immunotherapy of multisystem inflammatory syndrome in children (MIS-C) following COVID-19 through mesenchymal stem cells.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a new type of coronavirus causing coronavirus 2019 (COVID-19) that was first observed in Wuhan, China, in Dec. 2019. An inflammatory immune response targeting children appeared during the pandemic, which was associated with COVID-19 named multisystem inflammatory syndrome in children (MIS-C). Characteristics of MIS-C include the classic inflammation findings, multi-organ dysfunction, and fever as the cardinal feature. Up to now, no specific therapy has been identified for MIS-C. Currently, considerable progress has been obtained in the MIS-C treatment by cell therapy, specially Mesenchymal stem cells (MSCs). Unique properties have been reported for MSCs, such as various resources for purification of cell, high proliferation, self-renewal, non-invasive procedure, tissue regenerator, multidirectional differentiation, and immunosuppression. As indicated by a recent clinical research, MSCs have the ability of reducing disease inflammation and severity in children with MIS-C. In the present review study, the benefits and characteristics of MSCs and exosomes are discussed for treating patients with MIS-C.

Application of newly developed SARS-CoV2 serology test along with real-time PCR for early detection in health care workers and on-time plasma donation.

BACKGROUND: As the daily number of coronavirus infection disease 19 (COVID19) patients increases, the necessity of early diagnosis becomes more obvious. In this respect, we aimed to develop a serological test for specifically detecting anti-SARS-CoV2 antibodies. METHODS: We collected serum and saliva samples from 609 individuals who work at TBZMED affiliated hospitals in Tabriz, Iran, from April to June of 2020. Real-time PCR technique was used to detect SARS-CoV-2 genome using specific primers. An enzyme linked immunosorbent assay (ELISA) test was designed based on virus nucleocapsid (N), spike (S) and its receptor binding domain (RBD) protein, and the collected sera were subjected to IgM and/or IgG analysis. RESULT: Real-time PCR results showed that 66 people were infected with the SARS-CoV-2. Our designed ELISA kit showed 93.75% and 98% of sensitivity and specificity, respectively. In this study, 5.74% of participants had specific IgG against RBD, whereas the percentage for IgM positive individuals was 5.58%. Approximately the same results were observed for S protein. The number of positive participants for NP increased further, and the results of this antigen showed 7.38% for IgG and 7.06% for IgM. CONCLUSION: The ELISA test beside real-time PCR could provide a reliable serologic profile for the status of the disease progress and early detection of individuals. More importantly, it possesses the potential to identify the best candidates for plasma donation according to the antibody titers.

Mesenchymal stem cell alongside exosomes as a novel cell-based therapy for COVID-19: A review study.

In the past year, an emerging disease called Coronavirus disease 2019 (COVID-19), caused by Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been discovered in Wuhan, China, which has become a worrying pandemic and has challenged the world health system and economy. SARS-CoV-2 enters the host cell through a specific receptor (Angiotensin-converting enzyme 2) expressed on epithelial cells of various tissues. The virus, by inducing cell apoptosis and production of pro-inflammatory cytokines, generates as cytokine storm, which is the major cause of mortality in the patients. This type of response, along with responses by other immune cell, such as alveolar macrophages and neutrophils causes extensive damage to infected tissue. Newly, a novel cell-based therapy by Mesenchymal stem cell (MSC) as well as by their exosomes has been developed for treatment of COVID-19 that yielded promising outcomes. In this review study, we discuss the characteristics and benefits of MSCs therapy as well as MSC-secreted exosome therapy in treatment of COVID-19 patients.

Intrauterine administration of autologous hCG- activated peripheral blood mononuclear cells improves pregnancy outcomes in patients with recurrent implantation failure; A double-blind, randomized control trial study.

We aimed to investigate the effect of intrauterine administration of autologous hCG-activated PBMCs in RIF women with low Th-17/Treg cell ratio. 248 women with a history of implantation failure volunteered to receive PBMC-therapy. After immunologic consultation and doing flow cytometry analysis, 100 women with at least three IVF/ET failure who had low Th-17/Treg ratio in comparison with healthy control were enrolled in this study. These 100 patients were randomly divided into two groups as PBMC receiving (n = 50) and controls (n = 50). Then PBMCs were obtained from patients and treated with hCG for 48 h. Afterward, PBMCs were administered into the uterine cavity of the patient in the study group, two days before ET. The concentration of inflammatory cytokines was examined in the supernatant of cultured PBMCs after 2, 24, and 48 h of incubation using the ELISA method. The frequency of Th-17, Treg, and the Th-17/Treg ratio was significantly lower in RIF women than the healthy controls (P < 0.0001). The secretion of inflammatory cytokines was significantly higher after 48 h compared to 2 and 24 h (P < 0.0001). The pregnancy and live birth rate were significantly increased in women undergoing the PBMC-therapy compared to control (PBS-injecting) group (P = 0.032 and P = 0.047, respectively). The miscarriage rate was considerably lower in PBMC-therapy group (P = 0.029). Our findings suggest that intrauterine administration of autologous in vitro hCG-activated PBMCs improves pregnancy outcomes in patients with at least three IVF/ET failures.

Sirolimus as a new drug to treat RIF patients with elevated Th17/Treg ratio: A double-blind, phase II randomized clinical trial.

BACKGROUND: RIF is clinically defined as the failure of good quality embryos to implant into the uterus following at least three cycles of In Vitro Fertilization/Embryo Transfer (IVF/ET). During human pregnancy, a genetically different fetus is allowed to survive within the uterus despite the maternal recognition of fetal alloantigens. Compared with normal pregnant women, early loss of embryo is associated with systemic lower levels of Treg cells in IVF. Moreover, several lines of evidence have indicated that differentiation of naive T cells into Th17 is deleterious for normal pregnancy and may cause implantation failure. Sirolimus as the most common mTOR (mammalian target of Rapamycin) inhibitor is able to effectively prevent allograft rejection. Here we aimed to evaluate Sirolimus effects on Th17/Treg axis and subsequently on pregnancy outcome. METHODS AND MATERIALS: 121 patients with a history of at least 3 implatation failures were selected and enrolled in this clinical trial. Blood was drawn between days 5 and 10 of the cycle prior to the index IVF/ET cycle to assess baseline value of Th17 cells and regulatory T cells ratios using flowcytometry. A Th17/Treg cell ratio equal or >0.74 was considered to be the elevated Th17/Treg cell ratio. In 76 patients with elevated Th17/Treg ratios, 43 individuals were treated with Sirolimus and 33 remained untreated. RESULTS: Our results demonstrated that Sirolimus treatment led to an increase in Treg cells number and function in treated group and reduced the frequency and function of Th17 cells. Moreover Th17/Treg cell ratio, significantly reduced from 1.18 ±â€¯0.46% to 0.9 ±â€¯0.45% following Sirolimus intervention (P = 0.024). In contrast, no significant difference in Th17 and Treg cell frequencies and Th17/Treg cell ratio was observed in untreated control subjects before and after ET. Finally our data showed a significantly higher clinical pregnancy rate (55.81%) in Sirolimus-treated patients compared with control group (24.24%) (P < 0.0005). We also found a significantly increased live birth rate (48.83%) in RIF women who received Sirolimus compared with control group (21.21%) (P < 0.0001). CONCLUSION: The findings of the current study revealed the fact that Sirolimus exhibit potent immunosuppressive effects by blocking intracellular immune responses downstream of co-stimulatory signals, also is able to improve reproductive outcome in RIF women with imbalanced Th17/Treg ratio by modulate of Th17 /Treg axis, thus representing a new approach for the potential treatment of patients with embryo implantation failure.

Chitosan (CMD)-mediated co-delivery of SN38 and Snail-specific siRNA as a useful anticancer approach against prostate cancer.

BACKGROUND: Prostate cancer is known as the most common malignancy in men. Chitosan has generated great interest as a useful biopolymer for the encapsulation of small interfering RNA (siRNA). Due to cationic nature, chitosan is able to efficiently encapsulate siRNA molecules and form nanoparticles. Furthermore, the biocompatible and biodegradable attributes of chitosan have paved the way for its potential application in the in vivo delivery of therapeutic siRNAs. In this study, we aimed to design chitosan/CMD nanoparticles for the efficient encapsulation of the anti-cancer drugs SN38 and Snail-specific siRNA. METHODS: Physicochemical characteristics, growth inhibitory properties, and anti-migratory capacities of the dual delivery of SN38-Snail siRNA CMD-chitosan nanoparticles were investigated in prostate cancer cells. RESULTS: Our findings provided evidence for the suggestion that, ChNP-CMD-SN38-siRNA treated cells, the mRNA level of snail decreased from 1.00 to 0.30 (±0.14) and 0.09 (±0.04) after 24h and 48h, respectively. Additionally, the fold induction of E-cadherin and Claudin-1 increased from 1.00 to now 3.12 (±0.62), 3.02 (±0.28) after 24h and 5.6 (±0.91), 4.42 (±0.51) after 48h, respectively. Also, co-delivery of SN38 and Snail-specific siRNA by an appropriate nanocerrier (chitosan nanoparticles) could reduce the viability, proliferation, and migration of PC-3 cells. CONCLUSIONS: In conclusion, ChNPs encapsulating SN38 and Snail-specific siRNA may represent huge potential as an effective anti-cancer drug delivery system for the treatment of prostate cancer.

Correction to: Peripheral Th17/Treg imbalance in elderly patients with ischemic stroke.

In the original article the terms RORγt and GF-ß were misspelled throughout the text. They should read RORγt and TGF-ß instead. We apologize for the inconvenience. The original article has been corrected.

Peripheral Th17/Treg imbalance in elderly patients with ischemic stroke.

CD4+CD25+ regulatory T (Treg) cells and Th17 cells play important roles in peripheral immunity. Immune responses are main elements in the pathogenesis of ischemic stroke (IS). The contribution of Th17 cells in IS patients has not been proved, and whether the balance of Treg/Th17 cells is changed in IS patients remains unidentified. In the present study, we studied Th17 and Treg cell frequency, cytokine secretion, expression of transcription factors, and microRNAs related to Th17 and Treg cells differentiation, which is compared between IS patients and control group. Thirty patients with IS and 30 individuals as control group were enrolled in this study. The frequency of Th17 and Treg lymphocytes, the expression of transcription factors and microRNAs related to these cells, and the serum levels of associated cytokines were assessed by flow cytometry, real-time PCR, and ELISA, respectively. A significant reduction in proportion of peripheral Treg cell frequency and the levels of TGF-ß and FOXP3 expression were observed in patients with IS compared with controls, while the proportions of Th17 were increased dramatically, and these effects were along with increases in the levels of IL-17A and RORγt expression in IS patients. The levels of mir-326 and mir-106b-25 expression were increased in patients with IS. These studies suggest that the increase in proportion of Th17 cells and decrease in Treg cells might contribute to the pathogenesis of IS. Manipulating the balance between Tregs and Th17 cells might be helpful for the treatment of IS.

Effects of HMGA2 siRNA and doxorubicin dual delivery by chitosan nanoparticles on cytotoxicity and gene expression of HT-29 colorectal cancer cell line.

OBJECTIVE: Over-expressions of HMGA2, vimentin and MMP-9 and downregulation of E-cadherin occur on colorectal cancer cells followed by a reduction in let-7 as a regulatory factor. In this study, we first used carboxymethyl dextran (CMD)-chitosan nanoparticles (ChNPs) platform to encapsulate HMGA2 siRNA and doxorubicin (DOX), and then, we evaluated the efficacy of the simultaneous delivery of siRNA/drug on viability and gene expression of HT-29 cell lines. METHODS: ChNPs characteristics were determined by a dynamic light scattering and zeta sizer. Morphology of loaded ChNPs was assessed by scanning electron microscopy, and Fourier transform infrared spectroscopy was used to confirm the conjugation of ChNP/siRNA/DOX/CMD. Cell viability and relative mRNA expression were evaluated by MTT assay and real-time PCR, respectively. KEY FINDING: The prepared ChNPs had high efficiency for siRNA and drug encapsulation (78% and 75%) and were stable against serum and heparin. ChNP/siRNA/DOX/CMD was more effective to induce tumour cell death and also could significantly reduce the expressions of HMGA2, vimentin as well as MMP-9 and increase E-cadherin expression. CONCLUSION: In conclusion, our results revealed that dual delivery of a key gene siRNA and appropriate anticancer drug have great impact on the treatment of colorectal cancer.