Role of NLRP3 inflammasome in central nervous system diseases.

The central nervous system (CNS) is the most delicate system in human body, with the most complex structure and function. It is vulnerable to trauma, infection, neurodegeneration and autoimmune diseases, and activates the immune system. An appropriate inflammatory response contributes to defence against invading microbes, whereas an excessive inflammatory response can aggravate tissue damage. The NLRP3 inflammasome was the first one studied in the brain. Once primed and activated, it completes the assembly of inflammasome (sensor NLRP3, adaptor ASC, and effector caspase-1), leading to caspase-1 activation and increased release of downstream inflammatory cytokines, as well as to pyroptosis. Cumulative studies have confirmed that NLRP3 plays an important role in regulating innate immunity and autoimmune diseases, and its inhibitors have shown good efficacy in animal models of various inflammatory diseases. In this review, we will briefly discuss the biological characteristics of NLRP3 inflammasome, summarize the recent advances and clinical impact of the NLRP3 inflammasome in infectious, inflammatory, immune, degenerative, genetic, and vascular diseases of CNS, and discuss the potential and challenges of NLRP3 as a therapeutic target for CNS diseases.

Therapeutic potential of MSCs and MSC-derived extracellular vesicles in immune thrombocytopenia.

Immune thrombocytopenia (ITP) is an acquired autoimmune disease involving a variety of immune cells and factors. Despite being a benign disease, it is still considered incurable due to its complex pathogenesis. Mesenchymal stem cells (MSCs), with low immunogenicity, pluripotent differentiation, and immunomodulatory ability, are widely used in a variety of autoimmune diseases. In recent years, impaired bone marrow mesenchymal stem cells (BMMSCs) were found to play an important role in the pathogenesis of ITP; and the therapeutic role of MSCs in ITP has also been supported by increasing evidence with encouraging efficacy. MSCs hold promise as a new approach to treat or even cure refractory ITP. Extracellular vesicles (EVs), as novel carriers in the "paracrine" mechanism of MSCs, are the focus of MSCs. Encouragingly, several studies suggested that EVs may perform similar functions as MSCs to treat ITP. This review summarized the role of MSCs in the pathophysiology and treatment of ITP.

Oral Realgar-Indigo Naturalis Formula Treatment for Acute Promyelocytic Leukemia in Children: A Randomized, Control Clinical Trial.

Objective: To analyze the efficacy, safety, and economy of RIF compared with intravenous arsenic trioxide (ATO) for the induction and consolidation therapy of pediatric APL. Materials and Methods: In this randomized control clinical trial (NCT02200978), children with newly diagnosed APL from June 2013 to December 2017 were randomly divided into RIF and ATO groups. The groups were treated with RIF or ATO in combination with all-trans retinoic acid (ARTA) and conventional chemotherapeutic drugs during induction and consolidation therapy. Results: Ninteen patients were enrolled, including eight in the RIF group and 11 in the ATO group. After induction therapy, the bone marrow morphologic complete remission (CR) rate, the median time to CR, and molecular remission (promyelocytic leukemia protein (PML)/retinoic acid receptor α (RARα) conversion) rates showed no significant differences between patients in the RIF versus ATO groups (100% vs. 100%, p=1.000; 22 vs. 24 days, p=0.395; 28.5% vs. 54.5%, p=0.367, resp.). After consolidation therapy, the molecular remission rate was 100% in both groups. At the end of more than two years of follow-up, the disease-free survival (DFS) rate was 100% in both groups. Conclusion: Oral RIF can achieve similar efficacy to intravenous ATO for APL in children with good safety, less toxicity, fewer side effects, and fewer inpatient days. Therefore, oral RIF can be used as an alternative to intravenous ATO for the treatment of APL in children.

MSC-EVs transferring mitochondria and related components: A new hope for the treatment of kidney disease.

Kidney disease is a serious hazard to human health. Acute or chronic renal disease will have a significant negative impact on the body's metabolism. The involvement of mitochondria in renal illness has received a lot of interest as research on kidney disease has advanced. Extracellular vesicles are gaining popularity as a means of intercellular communication in recent years. They have a close connection to both the nephropathy process and the intercellular transfer of mitochondria. The goal of this review is to present the extracellular vesicle transport mitochondria and its related biologically active molecules as new therapeutic options for the treatment of clinical kidney disease. This review focuses on the extracellular vesicles through the transfer of mitochondria and its related bioactive molecules, which affect mitochondrial energy metabolism, take part in immune regulation, and secrete outside the body.

The Role of B1 Cells in Systemic Lupus Erythematosus.

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by multisystemic and multi-organ involvement, recurrent relapses and remissions, and the presence of large amounts of autoantibodies in the body as the main clinical features. The mechanisms involved in this disease are complex and remain poorly understood; however, they are generally believed to be related to genetic susceptibility factors, external stimulation of the body's immune dysfunction, and impaired immune regulation. The main immune disorders include the imbalance of T lymphocyte subsets, hyperfunction of B cells, production of large amounts of autoantibodies, and further deposition of immune complexes, which result in tissue damage. Among these, B cells play a major role as antibody-producing cells and have been studied extensively. B1 cells are a group of important innate-like immune cells, which participate in various innate and autoimmune processes. Yet the role of B1 cells in SLE remains unclear. In this review, we focus on the mechanism of B1 cells in SLE to provide new directions to explore the pathogenesis and treatment modalities of SLE.

Human umbilical cord mesenchymal stem cells derived extracellular vesicles regulate acquired immune response of lupus mouse in vitro.

Systemic lupus erythematosus (SLE) is an autoimmune disease involving multiple systems. Immunopathology believes that abnormal T cell function and excessive production of autoantibodies by B cells are involved in multi-organ damage. Human umbilical cord mesenchymal stem cells (hUCMSCs) therapies have endowed with promise in SLE, while the function of MSC-derived extracellular vesicles (MSC-EVs) was still unclear. Extracellular vesicles (EVs) are subcellular components secreted by a paracellular mechanism and are essentially a group of nanoparticles. EVs play a vital role in cell-to-cell communication by acting as biological transporters. New evidence has shown beneficial effects of MSC-EVs on autoimmune diseases, such as their immunomodulatory properties. In this study, we investigated whether hUCMSCs derived extracellular vesicles (hUCMSC-EVs) could regulate abnormal immune responses of T cells or B cells in SLE. We isolated splenic mononuclear cells from MRL/lpr mice, a classical animal model of SLE. PBS (Phosphate-buffered saline), 2 × 105 hUCMSCs, 25 µg/ml hUCMSC-EVs, 50 µg/ml hUCMSC-EVs were co-cultured with 2 × 106 activated splenic mononuclear cells for 3 days in vitro, respectively. The proportions of CD4+ T cell subsets, B cells and the concentrations of cytokines were detected. Both hUCMSCs and hUCMSC-EVs inhibited CD4+ T cells, increased the production of T helper (Th)17 cells, promoted the production of interleukin (IL)-17 and transforming growth factor beta1 (TGF-ß1) (P < 0.05), although they had no significant effects on Th1, Th2, T follicular helper (Tfh), regulatory T (Treg) cells and IL-10 (P > 0.05); only hUCMSCs inhibited CD19+ B cells, promoted the production of interferon-gamma (IFN-γ) and IL-4 (P < 0.05). hUCMSCs exert immunoregulatory effects on SLE at least partially through hUCMSC-EVs in vitro, therefore, hUCMSC-EVs play novel and potential regulator roles in SLE.

Natural Killer Cell-Derived Extracellular Vesicles: Novel Players in Cancer Immunotherapy.

Natural killer (NK) cells are critical components of host innate immunity and function as the first line of defense against tumors and viral infection. There is increasing evidence that extracellular vesicles (EVs) are involved in the antitumor activity of NK cells. NK cell-derived EVs (NKEVs) carrying cargo such as cytotoxic proteins, microRNAs, and cytokines employ multiple mechanisms to kill tumor cells, but also exhibit immunomodulatory activity by stimulating other immune cells. Several studies have reported that NKEVs can reverse immune suppression under tolerogenic conditions and contribute to NK-mediated immune surveillance against tumors. Thus, NKEVs are a promising tool for cancer immunotherapy. In this review, we describe the biological effects and potential applications of NKEVs in antitumor immunity.

Management and Clinical Outcome of Posterior Reversible Encephalopathy Syndrome in Pediatric Oncologic/Hematologic Diseases: A PRES Subgroup Analysis With a Large Sample Size.

This study investigated the management and clinical outcomes along with associated factors of posterior reversible encephalopathy syndrome (PRES) in childhood hematologic/oncologic diseases. We present data from children with hematologic/oncologic diseases who developed PRES after treatment of the primary disease with chemotherapy and hematopoietic stem cell transplantation (HSCT) at 3 medical centers in Changsha, China from 2015 to 2020, and review all previously reported cases with the aim of determining whether this neurologic manifestation affects the disease prognosis. In the clinical cohort of 58 PRES patients, hypertension [pooled odds ratio (OR) = 4.941, 95% confidence interval (CI): 1.390, 17.570; P = 0.001] and blood transfusion (OR = 14.259, 95% CI: 3.273, 62.131; P = 0.001) were significantly associated with PRES. Elevated platelet (OR = 0.988, 95% CI: 0.982, 0.995; P < 0.001), hemoglobin (OR = 0.924, 95% CI: 0.890, 0.995; P < 0.001), and blood sodium (OR = 0.905, 95% CI: 0.860, 0.953; P < 0.001), potassium (OR = 0.599, 95% CI: 0.360, 0.995; P = 0.048), and magnesium (OR = 0.093, 95% CI: 0.016, 0.539; P = 0.008) were protective factors against PRES. Data for 440 pediatric PRES patients with hematologic/oncologic diseases in 21 articles retrieved from PubMed, Web of Science, and Embase databases and the 20 PRES patients from our study were analyzed. The median age at presentation was 7.9 years. The most common primary diagnosis was leukemia (62.3%), followed by solid tumor (7.7%) and lymphoma (7.5%). Most patients (65.0%) received chemotherapy, including non-induction (55.2%) and induction (44.8%) regimens; and 86.5% used corticosteroids before the onset of PRES. Although 21.0% of patients died during follow-up, in most cases (93.2%) this was not attributable to PRES but to severe infection (27.3%), underlying disease (26.1%), graft-vs.-host disease (14.8%), multiple organ dysfunction syndrome (8.0%), and respiratory failure (3.4%). PRES was more common with HSCT compared to chemotherapy and had a nearly 2 times higher mortality rate in patients with oncologic/hematologic diseases than in those with other types of disease. Monitoring neurologic signs and symptoms in the former group is therefore critical for ensuring good clinical outcomes following treatment of the primary malignancy.

Analysis of Risk Factors Associated With Poor Outcome in Posterior Reversible Encephalopathy Syndrome After Treatment in Children: Systematic Review and Meta-Analysis.

Objective: Chemotherapy and hematopoietic stem cell transplantation (HSCT) play important roles in clinical etiology, symptoms, signs, imaging findings, and biochemical parameters for inducing posterior reversible encephalopathy syndrome (PRES) in pediatric oncologic diseases. We aimed to evaluate various risk factors of pediatric oncologic diseases after conducting chemotherapy and HSCT to induce PRES for predicting the clinical prognosis frequency. Methods: The literature was performed on PubMed, Web of Science, and Embase databases to recognize the qualified studies. The odds ratios (ORs) of related risk factors and their corresponding 95% confidence intervals (CIs) were used to compute the pooled assessments of the outcomes. Results: Six studies were included in the meta-analysis, involving 828 records. The risk of female children has a significantly higher incidence than male children in oncologic age groups of PRES. Children over the age of 10 years old in oncologic age groups develop a significantly increased risk of PRES. Acute graft-versus-host disease (GVHD) has a significant promotion effect on the occurrence of PRES. Hypertension can promote the occurrence of PRES in children. The risk of PRES in immunodeficient children increases significantly. Children with sickle cell disease (SCD) have a significantly increased risk of PRES. The risk of PRES in children with T-cell leukemia rises considerably. The central nervous system (CNS) leukemia/involvement has a significant role in promoting the occurrence of PRES in children. The pooled OR for the factors male, ≥ 10 years old of age, acute GVHD, hypertension, immunodeficiency, SCD, T-cell leukemia, CNS leukemia/involvement was 0.66 (95% CI: 0.58, 0.76; P < 0.00001), 2.06 (95% CI: 1.23, 3.43; P < 0.006), 1.32 (95% CI: 1.14, 1.53; P < 0.0003), 8.84 (95% CI: 7.57, 10.32; P < 0.00001), 2.72 (95% CI: 1.81, 4.08; P < 0.00001), 2.87 (95% CI: 2.15, 3.83; P < 0.00001), 2.84 (95% CI: 1.65, 4.88; P < 0.0002), and 3.13 (95% CI: 1.43, 6.84; P < 0.004), respectively. Conclusions: The result of this meta-analysis suggests that female children, age over 10 years old, acute GVHD, hypertension, immunodeficiency, SCD, T-cell leukemia, and CNS leukemia/involvement are likely to have the poor outcome in pediatric oncologic/hematologic diseases in PRES.

Immunoregulatory Effects of Mitochondria Transferred by Extracellular Vesicles.

Mitochondria participate in immune regulation through various mechanisms, such as changes in the mitochondrial dynamics, as metabolic mediators of the tricarboxylic acid cycle, by the production of reactive oxygen species, and mitochondrial DNA damage, among others. In recent years, studies have shown that extracellular vesicles are widely involved in intercellular communication and exert important effects on immune regulation. Recently, the immunoregulatory effects of mitochondria from extracellular vesicles have gained increasing attention. In this article, we review the mechanisms by which mitochondria participate in immune regulation and exert immunoregulatory effects upon delivery by extracellular vesicles. We also focus on the influence of the immunoregulatory effects of mitochondria from extracellular vesicles to further shed light on the underlying mechanisms.

Immunoregulatory Effects of Stem Cell-Derived Extracellular Vesicles on Immune Cells.

Recent investigations on the regulatory action of extracellular vesicles (EVs) on immune cells in vitro and in vivo have sparked interest on the subject. As commonly known, EVs are subcellular components secreted by a paracellular mechanism and are essentially a group of nanoparticles containing exosomes, microvesicles, and apoptotic bodies. They are double-layer membrane-bound vesicles enriched with proteins, nucleic acids, and other active compounds. EVs are recognized as a novel apparatus for intercellular communication that acts through delivery of signal molecules. EVs are secreted by almost all cell types, including stem/progenitor cells. The EVs derived from stem/progenitor cells are analogous to the parental cells and inhibit or enhance immune response. This review aims to provide its readers a comprehensive overview of the possible mechanisms underlying the immunomodulatory effects exerted by stem/progenitor cell-derived EVs upon natural killer (NK) cells, dendritic cells (DCs), monocytes/macrophages, microglia, T cells, and B cells.

[A study on the transdifferentiation of adipose mesenchymal stem cells into hepatocytes].

OBJECTIVE: To investigate the possibility of transdifferentiation of adipose mesenchymal stem cells (AMSCs) into hepatocytes. METHODS: Human omentum adipose tissue was dispersed with collagenase I. Cells collected were cultured in a DMEM-F12 medium containing 2% FBS supplemented with 20 ng/ml HGF, 10 ng/ml FGF4, 1xITS and 0.1 micromol/L dexasmison. The cells of the control group were also cultured in the same kind of medium but without any cytokines serving as a control. The expression of hepatic transcriptional factors such as GATA4 and HNF1 were checked by RT-PCR. At the end of the induction, hepatocyte markers were analysed by flow cytometry, and cytokeratin expressions were examined using cyto-immunofluorescence methods. RESULTS: AMSCs grew like fibroblasts and were passaged easily. Most of the third passaged AMSCs were positive against anti-CD29, anti-CD44 antibodies, but negative for the anti-CD34 and anti-CD45 ones. The hepatic transcriptional factor was expressed gradually to higher levels during the induction time. AFP and Alb positive cells were 30.0% and 17.8% of the total cultured cells, and the rate of cells positive to the two markers was 6.9%. The inducted cells were positive for CK18 and CK19 antibodies at the end of the induction. The cells in the control group were negative when checked by these methods. CONCLUSIONS: AMSCs could be directed to differentiate into hepatocytes in vitro by a cytokine cocktail with a low concentration FBS culture system.