MicroRNA (miRNA) as a biomarker for diagnosis, prognosis, and therapeutics molecules in neurodegenerative disease.

Neurodegenerative diseases that include Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), Huntington's disease (HD), and multiple sclerosis (MS) that arise due to numerous causes like protein accumulation and autoimmunity characterized by neurologic depletion which lead to incapacity in normal physiological function such as thinking and movement in these patients. Glial cells perform an important role in protective neuronal function; in the case of neuroinflammation, glial cell dysfunction can promote the development of neurodegenerative diseases. miRNA that participates in gene regulation and plays a vital role in many biological processes in the body; in the central nervous system (CNS), it can play an essential part in neural maturation and differentiation. In neurodegenerative diseases, miRNA dysregulation occurs, enhancing the development of these diseases. In this review, we discuss neurodegenerative disease (Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS)) and how miRNA is preserved as a diagnostic biomarker or therapeutic agent in these disorders. Finally, we highlight miRNA as therapy.

Evaluation of the Safety and Efficacy of Repeated Mesenchymal Stem Cell Transplantations in ALS Patients by Investigating Patients' Specific Immunological and Biochemical Biomarkers.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is an incurable disease. There are vigorous attempts to develop treatments to reduce the effects of this disease, and among these treatments is the transplantation of stem cells. This study aimed to retrospectively evaluate a mesenchymal stem cell (MSC) therapy cohort as a promising novel treatment modality by estimating some additional new parameters, such as immunological and biochemical factors. METHODS: This study was designed as an open-label, one-arm cohort retrospective study to evaluate potential diagnostic biomarkers of repeated infusions of autologous-bone marrow-derived mesenchymal stem cells (BM-MSCs) in 15 confirmed patients with ALS, administered at a dose of 1 × 106 cells/kg BW with a one-month interval, in equal amounts in both an intravenous (IV) and intrathecal (IT) capacity simultaneously, via various biochemical (iron (Fe), ferritin, total-iron-binding capacity (TIBC), transferrin, and creatine kinase (CK)) and immunological parameters (tumor necrosis factor-alpha (TNF-α), neurofilament light chain (NFL), and glial-cell-derived neurotrophic factor (GDNF) levels, evaluated during the three-month follow-up period in serum and cerebrospinal fluid (CSF). RESULTS: Our study indicated that, in the case of immunological biomarkers, TNF-α levels in the CSF showed a significant decrease at month three after transplantation compared with levels at month zero, and the p-value was p < 0.01. No statistically significant changes were observed for other immunological as well as biochemical parameters and a p-value of p > 0.05. CONCLUSIONS: These results can indicate the potential benefit of stem cell transfusion in patients with ALS and suggest some diagnostic biomarkers. Several studies are required to approve these results.

Therapeutic potential of mesenchymal stem cell-derived exosomes for allergic airway inflammation.

Due to their immunomodulatory capacities, mesenchymal stem cells (MSCs) have been extensively used as therapeutic approaches in cell-based therapy for various inflammatory diseases. Several lines of studies have shown that the most beneficial effects of MSCs are associated with MSC-derived exosomes. Exosomes are nanoscale extracellular vesicles that contain important biomolecules such as RNA, microRNAs (miRNAs), DNA, growth factors, enzymes, chemokines, and cytokines that regulate immune cell functions and parenchymal cell survival. Recently, exosomes, especially MSC-derived exosomes, have been shown to have protective effects in allergic airway inflammation. This review focused on the immune-regulatory potential of MSC-derived exosomes as nanoscale delivery systems in the treatment of allergic airway inflammation.

A new generation of mesenchymal stromal/stem cells differentially trained by immunoregulatory probiotics in a lupus microenvironment.

BACKGROUND: Increasing evidence suggests that multipotent mesenchymal stem/stromal cells (MSCs) are a promising intervention strategy in treating autoimmune inflammatory diseases. It should be stated that systemic immunoregulation is increasingly recognized among the beneficial effects of MSCs and probiotics in treating morbid autoimmune disorders such as lupus. This study aimed to determine if immunoregulatory probiotics L. rhamnosus or L. delbrueckii can change the immunomodulatory effects of MSCs in lupus-like disease. METHODS: Pristane-induced lupus (PIL) mice model was created via intraperitoneal injection of Pristane and then confirmed. Naïve MSCs (N-MSCs) were coincubated with two Lactobacillus strains, rhamnosus (R-MSCs) or delbrueckii (D-MSCs), and/or a combination of both (DR-MSCs) for 48 h, then administrated intravenously in separate groups. Negative (PBS-treated normal mice) and positive control groups (PBS-treated lupus mice) were also investigated. At the end of the study, flow cytometry and enzyme-linked immunosorbent assay (ELISA) analysis were used to determine the percentage of Th cell subpopulations in splenocytes and the level of their master cytokines in sera, respectively. Moreover, lupus nephritis was investigated and compared. Analysis of variance (ANOVA) was used for multiple comparisons. RESULTS: Abnormalities in serum levels of anti-dsDNA antibodies, creatinine, and urine proteinuria were significantly suppressed by MSCs transplantation, whereas engrafted MSCs coincubation with both L. strains did a lesser effect on anti-dsDNA antibodies. L. rhamnosus significantly escalated the ability of MSCs to scale down the inflammatory cytokines (IFN-É£, IL-17), while L. delbrueckii significantly elevated the capacity of MSCs to scale down the percentage of Th cell subpopulations. However, incubation with both strains induced MSCs with augmented capacity in introducing inflammatory cytokines (IFN-É£, IL-17). Strikingly, R-MSCs directly restored the serum level of TGF-ß more effectively and showed more significant improvement in disease parameters than N-MSCs. These results suggest that R-MSCs significantly attenuate lupus disease by further skew the immune phenotype of MSCs toward increased immunoregulation. CONCLUSIONS: Results demonstrated that Lactobacillus strains showed different capabilities in training/inducing new abilities in MSCs, in such a way that pretreated MSCs with L. rhamnosus might benefit the treatment of lupus-like symptoms, given their desirable properties.

The potential role of miRNA in regulating macrophage polarization.

Macrophage polarization is a dynamic process determining the outcome of various physiological and pathological situations through inducing pro-inflammatory responses or resolving inflammation via exerting anti-inflammatory effects. The miRNAs are epigenetic regulators of different biologic pathways that target transcription factors and signaling molecules to promote macrophage phenotype transition and regulate immune responses. Modulating the macrophage activation, differentiation, and polarization by miRNAs is crucial for immune responses in response to microenvironmental signals and under various physiological and pathological conditions. In term of clinical significance, regulating macrophage polarization via miRNAs could be utilized for inflammation control. Also, understanding the role of miRNAs in macrophage polarization can provide insights into diagnostic strategies associated with dysregulated miRNAs and for developing macrophage-centered therapeutic methods. In this case, targeting miRNAs to further regulate of macrophage polarization may become an efficient strategy for treating immune-associated disorders. The current review investigated and categorized various miRNAs directly or indirectly involved in macrophage polarization by targeting different transcription factors and signaling pathways. In addition, prospects for regulating macrophage polarization via miRNA as a therapeutic choice that could be implicated in various pathological conditions, including cancer or inflammation-mediated injuries, were discussed.

Interactions of mesenchymal stromal/stem cells and immune cells following MSC-based therapeutic approaches in rheumatoid arthritis.

Rheumatoid arthritis (RA) is considered to be a degenerative and progressive autoimmune disorder. Although several medicinal regimens are used to treat RA, potential adverse events such as metabolic disorders and increased risk of infection, as well as drug resistance in some patients, make it essential to find an effective and safe therapeutic approach. Mesenchymal stromal/stem cells (MSCs) are a group of non-hematopoietic stromal cells with immunomodulatory and inhibitory potential. These cells exert their regulatory properties through direct cell-to-cell interactions and paracrine effects on various immune and non-immune cells. As conventional therapeutic approaches for RA are limited due to their side effects, and some patients became refractory to the treatment, MSCs are considered as a promising alternative treatment for RA. In this review, we introduced various experimental and clinical studies conducted to evaluate the therapeutic effects of MSCs on animal models of arthritis and RA patients. Then, possible modulatory and suppressive effects of MSCs on different innate and adaptive immune cells, including dendritic cells, neutrophils, macrophages, natural killer cells, B lymphocytes, and various subtypes of T cells, were categorized and summarized. Finally, limitations and future considerations for the efficient application of MSCs as a therapeutic approach in RA patients were presented.

Chromosomal Instability in Various Generations of Human Mesenchymal Stem Cells Following the Therapeutic Radiation.

Background: Radiotherapy is a crucial treatment for most malignancies. However, it can cause several side effects, including the development of secondary malignancies due to radiation-induced genomic instability (RIGI). The aim of this study was to evaluate genomic instability in human mesenchymal stem cells (hMSCs) at different X-ray radiation doses. Additionally, the study aimed to examine the relative expression of certain genes involved in DNA repair, proto-oncogenes, and tumor suppressor genes. Methods: After extracting, characterizing, and expanding hMSCs, they were exposed to X-ray beams at doses of 0, 0.5, 2, and 6 Gy. Nuclear alterations were evaluated through the cytokinesis-block micronucleus (CBMN) assay at 2, 10, and 15 days postirradiation. The expressions of BRCA1, BRCA2, TP53, Bax, Bcl2, and KRAS genes were analyzed 48 hr after irradiation to evaluate genomic responses to different radiation doses. Results: The mean incidence of micronuclei, nucleoplasmic bridges, and nuclear buds was 4.8 ± 1.6, 47.6 ± 6, and 18 ± 2.6, respectively, in the nonirradiated group 48 hr after the fourth passage, per 1,000 binucleated cells. The incidence of micronuclei in groups exposed to 0.5, 2, and 6 Gy of radiation was 14.3 ± 4.9, 32.3 ± 6.5, and 55 ± 9.1, respectively, 48 hr after irradiation. The expression levels of the BRCA2, Bax, TP53, and KRAS genes significantly increased after exposure to 6 Gy radiation compared to the control groups. However, there was no significant increase in BRCA1 and Bcl2 gene expression in our study. Conclusion: This study demonstrated significant nuclear alterations in the 10 days postirradiation due to the RIGIs that they inherited from their irradiated ancestral cells. While chromosomal instability is a prevalent event in malignant cells, so it seems necessary to optimize radiotherapy treatment protocols for tissues that contain stem cells, especially with IMRT, which delivers a low dose to a larger volume of tissues.

Mesenchymal stem cell therapy in amyotrophic lateral sclerosis (ALS) patients: A comprehensive review of disease information and future perspectives.

Amyotrophic lateral sclerosis (ALS) is a rare deadly progressive neurological disease that primarily affects the upper and lower motor neurons with an annual incidence rate of 0.6 to 3.8 per 100,000 people. Weakening and gradual atrophy of the voluntary muscles are the first signs of the disease onset affecting all aspects of patients' lives, including eating, speaking, moving, and even breathing. Only 5-10% of patients have a familial type of the disease and show an autosomal dominant pattern, but the cause of the disease is unknown in the remaining 90% of patients (Sporadic ALS). However, in both types of disease, the patient's survival is 2 to 5 years from the disease onset. Some clinical and molecular biomarkers, magnetic resonance imaging (MRI), blood or urine test, muscle biopsy, and genetic testing are complementary methods for disease diagnosis. Unfortunately, with the exception of Riluzole, the only medically approved drug for the management of this disease, there is still no definitive cure for it. In this regard, the use of mesenchymal stem cells (MSCs) for the treatment or management of the disease has been common in preclinical and clinical studies for many years. MSCs are multipotent cells having immunoregulatory, anti-inflammatory, and differentiation ability that makes them a good candidate for this purpose. This review article aims to discuss multiple aspects of ALS disease and focus on MSCs' role in disease management based on performed clinical trials.

Investigating the Safety and Efficacy of the Synthetic Drug Herbix on Immune Responses Involved in the Treatment of a Mouse Model of Herpes Simplex Virus.

Herpes simplex virus-1 (HSV-1) infections can cause significant harm to individuals, including blindness, congenital defects, genital herpes, and even cancer, with no definitive cure .so, finding new treatment strategies is crucial. In this study, 25 male BALB/c mice were used to conduct a mouse model of herpes by subcutaneously injecting an HSV-1 suspension (100 µL of 1×  PFU/mL). The mice were divided into 5 groups with groups 1 to 3 designated as intervention groups, and groups 4 and 5 serving as positive and negative control groups, respectively. After 2 days of virus inoculation, the mice were treated with different concentrations of Herbix (100, 200, and 300 mg/mL) via subcutaneous injection. Mice Blood samples (0.5 to 1 mL) were taken from the mice before and after the experiments, and after three-week follow-up period, the mice were sacrificed and the spleens were removed for lymphocyte analysis. we found that administration of Herbix at a dose of 300 mg/mL showed the greatest efficacy, characterized by a delay in skin lesion formation, an increment in survival rate and lymphocyte proliferation, upregulation of the gene expression of interferon alpha (IFN-α) and tumor necrosis factor alpha (TNF-α), and an increase in the polarization of cytotoxic and helper T lymphocytes compared to the control group. These results suggest that Herbix at a dose of 300 mg/mL is effective in treating murine herpes and stimulating immune responses, making it a potential candidate for further investigation as an antiherpetic drug.

Dysregulated balance in Th17/Treg axis of Pristane-induced lupus mouse model, are mesenchymal stem cells therapeutic?

BACKGROUND: Despite advances in general and targeted immunosuppressive therapies, limiting all mainstay treatment options in refractory systemic lupus erythematosus (SLE) cases has necessitated the development of new therapeutic strategies. Mesenchymal stem cells (MSCs) have recently emerged with unique properties, including a solid propensity to reduce inflammation, exert immunomodulatory effects, and repair injured tissues. METHODS: An animal model of acquired SLE mice was induced via intraperitoneal immunization with Pristane and affirmed by measuring specific biomarkers. Bone marrow (BM) MSCs were isolated from healthy BALB/c mice and cultured in vitro, then were identified and confirmed by flow cytometry and cytodifferentiation. Systemic MSCs transplantation was performed and then several parameters were analyzed and compared, including specific cytokines (IL-17, IL-4, IFN-É£, TGF-ß) at the serum level, the percentage of Th cell subsets (Treg/Th17, Th1/Th2) in splenocytes, and also the relief of lupus nephritis, respectively by enzyme-linked immunosorbent assay (ELISA), flow cytometry analysis and by hematoxylin & eosin staining and also immunofluorescence assessment. Experiments were carried out with different initiation treatment time points (early and late stages of disease). Analysis of variance (ANOVA) followed by post hoc Tukey's test was used for multiple comparisons. RESULTS: The rate of proteinuria, anti-double-stranded deoxyribonucleic acid (anti-dsDNA) antibodies, and serum creatinine levels decreased with BM-MSCs transplantation. These results were associated with attenuated lupus renal pathology in terms of reducing IgG and C3 deposition and lymphocyte infiltration. Our findings suggested that TGF-ß (associated with lupus microenvironment) can contribute to MSC-based immunotherapy by modulating the population of TCD4+ cell subsets. Obtained results indicated that MSCs-based cytotherapy could negatively affect the progression of induced SLE by recovering the function of Treg cells, suppressing Th1, Th2, and Th17 lymphocyte function, and downregulating their pro-inflammatory cytokines. CONCLUSION: MSC-based immunotherapy showed a delayed effect on the progression of acquired SLE in a lupus microenvironment-dependent manner. Allogenic MSCs transplantation revealed the ability to re-establish the balance of Th17/Treg, Th1/Th2 and restore the plasma cytokines network in a pattern dependent on disease conditions. The conflicting results of early versus advanced therapy suggest that MSCs may produce different effects depending on when they are administered and their activation status.

Insights into the protective capacity of human dental pulp stem cells and its secretome in cisplatin-induced nephrotoxicity: effects on oxidative stress and histological changes.

OBJECTIVES: Acute renal injury (AKI) is a major limiting factor for cisplatin administration. Recent evidence suggests the potential contribution of mesenchymal stem cells (MSCs) to rehabilitation from several disorders via both direct and indirect routes. Thus, the present study aimed, for the first time, to explore and compare the reno-protective potential of human dental pulp-derived stem cells (hDPSCs) vs. hDPSC-conditioned medium (hDPSC-CM) in recovery of impaired kidney tissues in a rat animal model of cisplatin-induced AKI. METHODS: AKI was induced via cisplatin injection (n=36). One day after, 24 rats were treated with either hDPSCs or hDPSC-CM (n=12). An extra set of rats (n=12) served as sham group. On days 2 or 7 (n=6), rats were humanly sacrificed for further analysis. Renal injury was explored via measuring serum creatinine and BUN. Renal level of oxidative stress was assessed by determining malondialdehyde, and enzymatic activities of superoxide dismutase and catalase. Renal histopathological changes were scored for comparison among different experimental groups. RESULTS: A single dose of cisplatin resulted in considerable renal dysfunction and oxidative stress. Treatment with hDPSCs or hDPSC-CM resulted in significantly restored renal function, reduced level of oxidative stress, and improved histopathological manifestations. Furthermore, as compared to hDPSC-CM, administration of hDPSCs led to superior results in AKI-induced animals. CONCLUSIONS: The current study described the first comparative evidence of reno-protective potential of hDPSCs and their CM against cisplatin-induced nephrotoxicity in an AKI rat model, proposing them as useful adjunctive therapy in AKI. Yet, future explorations are still needed.

Differentiation of Human Wharton Jelly Mesenchymal Stem Cells into Germ-Like Cells; emphasis on evaluation of Germ-long non-coding RNAs.

BACKGROUND: The proliferation and differentiation of stem cells into Germ-Like Cells (GLCs) is mediated by several growth factors and specific genes, of which some are related to long non-coding RNAs (lncRNAs). We have developed a modified differentiation process and identified a panel of GermlncRNAs related to GLCs. METHODS: Human Wharton Jelly Mesenchymal Stem Cells were treated with 25 ng/ml Bone Morphogenetic Protein (BMP)-4 and 10- 5 M all-trans retinoic acid to differentiate them into germ-like cells. To confirm the differentiation, changes in the expression of Oct-4, C-kit, Stella, and Vasa genes were assessed using quantitative Real-Time PCR (qPCR) and immunocytochemistry. QPCR was also used before and after differentiation to evaluate the changes in a lncRNA panel, using a 96-well array. Statistical analysis of the data was performed by SPSS 21. RESULTS: After 21 days of induction, the HWJ-MSCs derived germ-like cells were formed. Also, qPCR and immunocytochemistry showed that the pluripotent Oct4 marker was expressed in the undifferentiated HWJ-MSCs, but its expression gradually decreased in the differentiated cells. C-kit was expressed on days 7, 14, and 21 of differentiation. Both GLC markers of Stella and Vasa genes/proteins were present only in differentiated cells. Of the 44 lncRNA genes array, 36 of them showed an increase and eight genes showed a decrease. CONCLUSION: Our study showed that BMP4 and RA are effective in inducing HWJ-MSCs differentiation into GLCs. In addition, our study for the first time showed changes in the lncRNAs expression during the differentiation of HWJ-MSCs into GLCs by using BMP4 and RA.

Mesenchymal stromal cell therapy for COVID-19-induced ARDS patients: a successful phase 1, control-placebo group, clinical trial.

BACKGROUND: Acute respiratory distress syndrome (ARDS) is the devastating complication of the new COVID-19 pandemic, directly correlated with releasing large amounts of inflammatory cytokines. Due to their immunoregulatory features, mesenchymal stromal cells (MSCs) provide a promising approach against this disease. In this regard, this study was designed as a single-center, open-label, phase 1 clinical trial with a control group to examine the safety and explore the possible potency of three injections of umbilical cord-derived MSCs (UC-MSCs) in mild-moderate COVID-19-induced ARDS patients. METHODS: Twenty confirmed COVID-19 patients with mild-to-moderate ARDS degree entered the study and were divided into two groups: control group (standard care) and intervention group (standard care + UC-MSCs). The patients received three intravenous infusions of UC-MSCs (1 × [Formula: see text] cells/kg BW per injection) every other day. Respiratory markers, CRP levels and specific serum cytokines were assessed four times (days of 0, 5, 10 and 17) during the 17-day follow-up period. RESULTS: During the study, there were no serious adverse effects after cell transplantations. Besides, significant improvement in SPO2/FIO2 ratio and serum CRP levels was observed. On the other hand, a significant decrease (P < 0.05) in serum cytokine levels of IL-6, IFN-g, TNF-α, IL-17 A and a significant increase in serum cytokine levels of TGF-B, IL-1B and IL-10 were observed. Also, no significant changes were observed in CT scan images of patients during the study period. CONCLUSION: Our obtained results demonstrated that multiple intravenous transplantations of allogenic UC-MSCs in non-severe COVID-19-induced ARDS patients are a safe procedure. In addition, this intervention is a hopeful approach to decline cytokine storm and recover respiratory functions. Indeed, more clinical trials with larger sample sizes are required to confirm these results. Trial registration This clinical trial was registered with the Iranian Registry of Clinical Trials (ID: IRCT20160809029275N1 at 2020.05.30).

Specific Clinical and Immunological Changes Following Mesenchymal Stem Cell Transplantation in COVID-19-induced Acute Respiratory Distress Syndrome Patients: A Phase-I Clinical Trial.

Acute respiratory distress syndrome (ARDS) is a systemic inflammation resulting from immune system overactivity. ARDS is also a fatal complication of COVID-19. Mesenchymal stem cells (MSCs) have immune modulatory properties. This study evaluated the safety and efficacy of three times transplantation of umbilical cord-derived MSCs (UC-MSCs) in terms of specific immunological and clinical changes in mild-to-moderate COVID-19-induced ARDS patients. In this single-center, open-label, phase 1 clinical trial, 20 patients diagnosed with COVID-19 and mild-to-moderate ARDS were included and were divided into two groups: a control group receiving standard care and an intervention group receiving UC-MSC in addition to standard care. Three consecutive intravenous transplants of UC-MSC (1×  cells/kg body weight per each transplant) were performed in the intervention group on days 1, 3, and 5. The biological assay was investigated four times (days 0, 5, 10, and 17). UC-MSCs improved the patients' clinical and paraclinical parameters, including leukocytosis, lymphopenia, thrombocytopenia, and liver enzyme abnormalities compared to the control group. They also decreased pro-inflammatory lymphocytes (TH1 and TH17) and increased anti-inflammatory T lymphocytes. Cell therapy also reduced the mean fluorescence intensity (MFI) in overactivated CD8+ T cells.  These findings show that three UC-MSC injections could regulate a hyperactivated immune system in COVID-19-induced ARDS patients by decreasing the inflammatory T lymphocyte subset and can improve the patient's hematological condition and liver function. However, more studies are needed in this area.

Comparative Analysis of the Effectiveness of Intra-Articular Injection of Platelet-Rich Plasma versus Hyaluronic Acid for Knee Osteoarthritis: Results of an Open-Label Trial.

BACKGROUND: Platelet-rich plasma (PRP), an autologous source of growth factors, and hyaluronic acid (HA) are among the minimally invasive treatments for knee osteoarthritis (OA). This trial was designed to compare the effectiveness of intra-articular injection of PRP with HA (as one of the standard treatments) on mild to moderate knee OA. METHODS: In this phase I open-label clinical trial, 10 patients underwent intra-articular PRP injection and 10 others received HA injection. At baseline (pre-injection) visit and 1, 3, 6, and 12 months post-injection, clinical assessments were performed using visual analogue scale (VAS) and Knee injury and Osteoarthritis Outcome Score (KOOS) questionnaire. Physical examinations of the knee, including crepitation and range of motion (ROM) were performed at each visit. The follow-up responses were compared with the baseline visit. RESULTS: The PRP treatment was ascertained to be safe and caused no adverse effects. Significant improvements in the majority of KOOS subscales and VAS were found throughout the entire 12-month follow-up, following the PRP injections. HA injection, however, caused only one month significant improvement in the majority of patient-reported outcomes. In the majority of visits, the extent of improvements in the scores of KOOS subscales, as well as the extent of reduction in VAS were significantly greater in PRP recipients, compared to HA recipients. The ROM in both groups slightly increased after interventions. The frequency of coarse crepitation, which was detected in 100% of the patients in both groups at the baseline visit, decreased significantly to fine crepitation at the first follow-up visit in 80% and 40% of the PRP and HA recipients, respectively. CONCLUSION: Intra-articular injection of PRP or HA alleviates symptoms and pain and improves functionality and physical examinations in patients with knee OA. However, PRP therapy produces greater and longer-lasting improvements in most of the outcome parameters compared to HA.

Safety and efficacy of bone marrow derived-mesenchymal stem cells transplantation in patients with amyotrophic lateral sclerosis.

Stem cell-based treatments have emerged as potentially effective approaches to delay the progression of amyotrophic lateral sclerosis (ALS). This study was designed as a single-center, prospective, and open-label study without a placebo control group to assess the safety and efficacy of concurrent intrathecal (IT) and intravenous (IV) administration of autologous bone marrow-derived mesenchymal stem cells (BM-MSCs) in patients with ALS. Autologous BM-MSCs were isolated and expanded under standard conditions. Fifteen patients were neurologically examined before BM-MSCs transplantation (1 × 10 6 cells/kg BW) to evaluate the rate of pre-treatment disease progression. To assess the safety and efficacy, patients were examined at 1, 3, and 6 months following the treatment with BM-MSCs. Adverse reactions were assessed, and the clinical outcome was determined by the evaluation of the ALS functional rating scale-revised (ALSFRS-R) and forced vital capacity (FVC). No serious adverse reaction was observed after combined IT and IV administration of BM-MSCs. The mean ALSFRS-R and FVC values remained stable during the first 3 months of the treatment. However, a significant reduction in ALSFRS-R and FVC levels was observed in these patients 6 months after BM-MSCs administration. Our study revealed that the concurrent IT and IV application of BM-MSCs in patients with ALS is a safe procedure. Furthermore, our data indicate a temporary delay in the progression of ALS after a single combined IT and IV administration of BM-MSCs. Further studies are required to explore if the repeated applications of BM-MSCs could prolong survival and delay the progression of ALS.

Are mesenchymal stem cells able to manage cytokine storm in COVID-19 patients? A review of recent studies.

The Covid-19 disease has recently become one of the biggest challenges globally, and there is still no specific medication. Findings showed the immune system in severe Covid-19 patients loses regulatory control of pro-inflammatory cytokines, especially IL-6 production, called the "Cytokine storm" process. This process can cause injury to vital organs, including lungs, kidneys, liver, and ultimately death if not inhibited. While many treatments have been proposed to reduce cytokine storm, but the safety and effectiveness of each of them are still in doubt. Mesenchymal stem cells (MSCs) are multipotent cells with self-renewal potential capable of suppressing overactive immune responses and leading to tissue restoration and repair. These immuno-modulatory properties of MSCs and their derivatives (like exosomes) can improve the condition of Covid-19 patients with serious infectious symptoms caused by adaptive immune system dysfunction. Many clinical trials have been conducted in this field using various MSCs around the world. Some of these have been published and summarized in the present article, while many have not yet been completed. Based on these available data, MSCs can reduce inflammatory cytokines, increase oxygen saturation, regenerate lung tissue and improve clinical symptoms in Covid-19 patients. The review article aims to collect available clinical data in more detail and investigate the role of MSCs in reducing cytokine storms as well as improving clinical parameters of Covid-19 patients for use in future clinical studies.

The impact of CYP19A1 variants and haplotypes on breast cancer risk, clinicopathological features and prognosis.

BACKGROUND: Different genetic variants in hormone-regulating pathways have been identified to influence the risk of breast cancer. This study aimed to evaluate the association of CYP19A1 rs10046 and rs700519 polymorphisms with the risk, clinicopathological factors and prognosis of breast cancer. METHODS: In a case-control study, rs10046 and rs700519 polymorphisms were genotyped using ARMS-PCR and high-resolution melting (HRM), respectively, in a total of 702 females. Statistical analysis and evaluation of haplotypes and linkage disequilibrium were performed using SPSS v16, PHASE and 2LD. RESULTS: Although no association of rs700519 with breast cancer was observed, rs10046 in different genetic models as well as C-C/C-T and C-C/C-C diplotypes, revealed the association with the risk of breast cancer (p < 0.05). Moreover, the rs700519-C allele was shown to be associated with longer overall survival. In contrast, the T-T haplotype conferred s a shorter overall survival. rs700519-C allele was also significantly associated with menarche age. CONCLUSION: Based on the identified independent association between CYP19A1 diplotypes and rs700519-C allele with the risk and prognosis of the disease, the gene region and its genetic variants may have a diagnostic and prognostic role in breast cancer development. Further confirmation using other variants in this locus can validate these findings.

Expression of Vascular Endothelial Growth Factor A and Its Type 1 Receptor in Supratentorial Neoplasm.

BACKGROUND: Vascular endothelial growth factor (VEGF) is one of the primary angiogenesis regulators in solid cancers. Brain solid tumors are life-threatening diseases in which angiogenesis is an important phase of tumor development and progression. In the present study, VEGF-A and VEGF receptor (VEGF-R1) gene expression was evaluated in CNS brain tumors. METHODS: VEGF-A and VEGF-R1 expression was quantified using real-time PCR on fresh biopsies of 38 supratentorial brain tumors compared to 30 non-tumoral tissues. Then, the correlations were investigated with clinic-pathological and demographic factors of the patients. RESULTS: PCR product sequencing confirmed the validity of qRT-PCR. Although VEGF-A and VEGF-R1 expression showed increasing trends with the progression of cell proliferation in different stages of astrocytoma, VEGF-R1 did not meet the 95% confidence interval in other brain tumors. An increasing trend in VEGF-A expression and a declining trend in VEGF-R1 expression from Stage I to II were observed in meningioma. VEGF-A and VEGF-R1 expression had no significant correlation with age and gender. Although peritumoral brain edema (PTBE) in astrocytoma was significantly associated with tumor stages, VEGF-A and VEGF-R1 were not correlated with PTBE in meningioma and metastasis. CONCLUSION: VEGF-A is a valuable factor for the prognosis of PTBE and malignancy in astrocytoma and is helpful in monitoring treatment approaches.

Intrathecal autologous bone marrow stem cell therapy in children with autism: A randomized controlled trial.

INTRODUCTION: This study aimed to determine the safety and efficacy of treatment with autologous bone marrow mesenchymal stem cell (BMMSCs) compared with the routine treatment in children with autism spectrum disorder (ASD). METHODS: In this ethically approved randomized controlled trial, 32 ASD children aged 5-15 years were randomly assigned to receive either autologous BMMSC plus rehabilitation therapy and risperidone (intervention group) or rehabilitation therapy and risperidone (control group). Autologous BMMSCs were intrathecally injected in the intervention group twice in 4 weeks. Patients were assessed using childhood autism rating scale (CARS), Gilliam autism rating scale-second edition (GARS-II), and clinical global impression (CGI) at the baseline, as well as 6 and 12 months after intervention. RESULTS: Overall, 32 patients in two groups of intervention (n = 14) and control (n = 18) completed the study, of which 27 (84.4%) were male. Mean age was 9.50 ± 2.14 years. The improvements in CARS total score, GARS-II autism index, and CGI global improvement showed no significant differences between the groups over 12 months. However, the main effect for time*group interaction was significant regarding the CGI-severity of illness, showing a significantly more pronounced improvement in the intervention group (F = 6.719; P = .002). DISCUSSION: Intrathecal injection of autologous BMMSCs seems to be safe and feasible, but has limited clinical efficacy in treatment of children with ASD.