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Background Application of mesenchymal stem cell-derived exosomes (MSC-EXO) has emerged as a novel therapeutic strategy for myocardial infarction (MI). Our previous study showed that pretreatment with hemin, a potent heme oxygenase-1 (HO-1) inducer, enhanced the cardioprotective effects of MSCs in a mouse model of MI. This study aimed to investigate the therapeutic effects of EXO derived from hemin-pretreated MSCs (Hemin-MSC-EXO) in MI and explore the potential mechanisms. Methods MSC-EXO and Hemin-MSC-EXO were collected and characterized. MSC-EXO and Hemin-MSC-EXO were intramuscularly injected into the peri-infarct region in a mouse model of MI. Heart function of mice was assessed by echocardiography. The mitochondrial morphology of neonatal mice cardiomyocytes (NMCMs) under serum deprivation and hypoxic (SD/H) conditions was examined by Mitotracker staining. The cellular senescence of NMCMs was determined by senescence-associated-β-galactosidase assay. A loss-of-function approach was adopted to determine the role of Hemin-MSC-exosomal-miR-183-5p in the regulation of cardiomyocyte senescence Results EXO were successfully isolated from the supernatant of MSCs and Hemin-pretreated MSCs. Compared with MSC-EXO, injection of Hemin-MSC-EXO significantly improved cardiac function and reduced fibrosis. Both MSC-EXO and Hemin-MSC-EXO ameliorated cardiomyocyte senescence and mitochondrial fission in vitro and in vivo, and the latter exhibited better protective effects. MicroRNA sequencing revealed a higher level of miR-183-5p in Hemin-MSC-EXO than in MSC-EXO. MiR-183-5p knockdown partially abrogated the protective effects of Hemin-MSC-EXO in attenuating mitochondrial fission and cellular senescence of cardiomyocytes induced by SD/H. High mobility group box-1 (HMGB1) abundance was lower in Hemin-MSC-EXO-treated than MSC-EXO-treated mouse hearts, and HMGB1 was identified as one of the potential target genes of miR-183-5p. Mechanistically, Hemin-MSC-EXO inhibited SD/H-induced cardiomyocyte senescence partially by delivering miR-183-5p into recipient cardiomyocytes via regulation of the HMGB1/ERK pathway. Furthermore, knockdown of miR-183-5p reduced the Hemin-MSC-EXO-mediated cardioprotective effects in a mouse model of MI. Conclusion Our results reveal that Hemin-MSC-EXO are superior to MSC-EXO in treating MI. Exosomal miR-183-5p mediates, at least partially, the cardioprotective effects of Hemin-MSC-EXO by inhibiting cardiomyocyte senescence via regulation of the HMGB1/ERK pathway. This study highlights that MSC-EXO have high translational value in repairing cardiac dysfunction following infarction. Graphic abstract

Group 2 innate lymphoid cells (ILC2s) are recognized as key controllers and effectors of type 2 inflammation. Mesenchymal stem cells (MSCs) have been shown to alleviate type 2 inflammation by modulating T lymphocyte subsets and decreasing TH2 cytokine levels. However, the effects of MSCs on ILC2s have not been investigated. In this study, we investigated the potential immunomodulatory effects of MSCs on ILC2s in peripheral blood mononuclear cells (PBMCs) from allergic rhinitis patients and healthy subjects. We further investigated the mechanisms involved in the MSC modulation using isolated lineage negative (Lin−) cells. PBMCs and Lin− cells were cocultured with induced pluripotent stem cell‐derived MSCs (iPSC‐MSCs) under the stimulation of epithelial cytokines IL‐25 and IL‐33. And the ILC2 levels and functions were examined and the possible mechanisms were investigated based on regulatory T (Treg) cells and ICOS‐ICOSL pathway. iPSC‐MSCs successfully decreased the high levels of IL‐13, IL‐9, and IL‐5 in PBMCs in response to IL‐25, IL‐33, and the high percentages of IL‐13+ILC2s and IL‐9+ILC2s in response to epithelial cytokines were significantly reversed after the treatment of iPSC‐MSCs. However, iPSC‐MSCs were found directly to enhance ILC2 levels and functions via ICOS‐ICOSL interaction in Lin− cells and pure ILC2s. iPSC‐MSCs exerted their inhibitory effects on ILC2s via activating Treg cells through ICOS‐ICOSL interaction. The MSC‐induced Treg cells then suppressed ILC2s by secreting IL‐10 in the coculture system. This study revealed that human MSCs suppressed ILC2s via Treg cells through ICOS‐ICOSL interaction, which provides further insight to regulate ILC2s in inflammatory disorders., Human mesenchymal stem cells (MSCs) either directly promote group 2 innate lymphoid cell (ILC2) activation through upregulated ICOS‐ICOSL interaction. MSCs exert inhibitory effects on ILC2s via activating regulatory T (Treg) cells through ICOS‐ICOSL interaction. Treg cells prevent the promotion of MSCs on ILC2s via decreased ICOS‐ICOSL interaction between MSCs and ILC2s. IL‐10 is required for the MSC‐induced Treg cells in suppressing ILC2s alongside ICOS‐ICOSL interaction.

There were gender differences in the prevalence and severity of allergic diseases. Group 2 innate lymphoid cells (ILC2s) were recently reported to play a critical role in allergic diseases. We investigated the sex-dependent differences in ILC2-dominant allergic airway inflammation model using T\B cell-deficient mice, and determined the gender differences of ILC2 levels in patients with asthma and allergic rhinitis. Female mice exhibited higher levels of inflammatory infiltration and large production of IL-5 and IL-13, especially for ILC2 levels compared to male mice with the induction of IL-33. However, no significant differences were found for the levels of circulating ILC2s between the genders of patients. The treatment of testosterone significantly decreased the intracellular type 2 cytokines in ILC2s and the proliferation of pure ILC2s in response to epithelial cytokines. Our study suggested the sex differences and the involvement of androgen on ILC2s in allergic diseases.

Mesenchymal stem cells (MSCs) have been extensively investigated for the treatment of various diseases. The therapeutic potential of MSCs is attributed to complex cellular and molecular mechanisms of action including differentiation into multiple cell lineages and regulation of immune responses via immunomodulation. The plasticity of MSCs in immunomodulation allow these cells to exert different immune effects depending on different diseases. Understanding the biology of MSCs and their role in treatment is critical to determine their potential for various therapeutic applications and for the development of MSC-based regenerative medicine. This review summarizes the recent progress of particular mechanisms underlying the tissue regenerative properties and immunomodulatory effects of MSCs. We focused on discussing the functional roles of paracrine activities, direct cell–cell contact, mitochondrial transfer, and extracellular vesicles related to MSC-mediated effects on immune cell responses, cell survival, and regeneration. This will provide an overview of the current research on the rapid development of MSC-based therapies.

BackgroundAllergic rhinitis (AR) is characterized by IgE-mediated mucosa response after exposure to allergens. Extracellular vesicles (EVs) are nano-size vesicles containing biological cargos for intercellular communications. However, the role of plasma EVs in pathogenesis of AR remains largely unknown.MethodsPlasma EVs from patients with AR were isolated, quantified, and characterized. The expression of Der p 1 and antigen-presenting molecules on EVs was determined by Western blot, flow cytometry, or ELISA. PKH26- and CFSE (carboxyfluorescein succinimidyl ester)-stained AR-EVs were used to determine the uptake of EVs by CD4+T cells and their effects on CD4+T cell proliferation, respectively.ResultsPlasma EVs in healthy control (HC) and AR patients were similar in the concentration of particles, expression for specific EV markers, and both had structural lipid bilayer. However, the levels of Der p 1 on plasma EVs from both mild and moderate-severe AR patients were significantly higher than that on HC. The levels of antigen-presenting molecules on plasma EVs were similar from three subjects. Moreover, levels of Der p 1 on EVs in plasma, but not nasal secretion, were significantly associated with the symptom score of AR patients and level of plasma IL-13. Additionally, plasma EVs from patients with AR promoted the development of Th2 cells, while no effect was found on CD4+ T-cell proliferation.ConclusionsPlasma EVs derived from patients with AR exhibited antigen-presenting characteristics and promoted differentiation of Th2 cells, thus providing novel understanding of the pathogenesis of AR.

The diversity of immune responses in allergic diseases is critically mediated by dendritic cells (DCs), including myeloid and plasmacytoid DCs. Allergen inhalation increased the release of IL-33 from patients with allergic rhinitis (AR), which affecting the downstream cells by binding to its receptor (ST2). However, the effects of inhaled allergens on the expression of ST2 by DCs and IL-33 on the function of mDCs are unknown. The levels of ST2+mDCs and ST2+pDCs in the blood from patients with AR and healthy subjects were examined using flow cytometry. Moreover, the patients were challenged using the allergens and the levels of ST2+mDCs and ST2+pDCs were investigated at different time points. We found that there were higher levels of ST2+ mDCs and ST2+ pDCs in patients with AR, and these levels were further increased 0.5 h after allergen inhalation. Additionally, the type 2 immune response was upregulated after challenge. IL-33 treatment increased the expression of ST2 on mDCs. Our study demonstrated that ST2 was upregulated on DCs after allergen inhalation and that mDCs responded directly to IL-33 through ST2, suggesting that the IL-33/ST2 axis might play an important role in the pathogenesis of allergic rhinitis by DCs.

Rationale: Retinal ganglion cell (RGC) degeneration is extremely hard to repair or regenerate and is often coupled with mitochondrial dysfunction. Mesenchymal stem cells (MSCs)-based treatment has been demonstrated beneficial for RGC against degeneration. However, underlying mechanisms of MSC-provided RGC protection are largely unknown other than neuroprotective paracrine actions. In this study, we sought to investigate whether mitochondrial donation from induced pluripotent stem cell-derived MSC (iPSC-MSCs) could preserve RGC survival and restore retinal function. Methods: iPSC-MSCs were injected into the vitreous cavity of one eye in NADH dehydrogenase (ubiquinone) Fe-S protein 4 (Ndufs4) knockout (KO) and wild type mice. Phosphate buffer saline (PBS) or rotenone treated iPSC-MSCs were injected as control groups. Retinal function was detected by flash electroretinogram (ERG). Whole-mount immunofluorescence (IF), morphometric analysis, confocal microscopy imaging, polymerase chain reaction (PCR) of the retinas were conducted to investigate mitochondrial transfer from human iPSC-MSCs to mouse retina. Quantitative mouse cytokine arrays were carried out to measure retinal inflammatory response under difference treatments. Results: RGC survival in the iPSC-MSC injected retina of Ndufs4 KO mice was significantly increased with improved retinal function. GFP labelled human mitochondria from iPSC-MSC were detected in the RGCs in the retina of Ndufs4 KO mice starting from 96 hours post injection. PCR result showed only human mitochondrial DNA without human nuclear DNA could be detected in the mouse retinas after iPSC-MSC treatment in Ndufs4 KO mice eye. Quantitative cytokine array analysis showed pro-inflammatory cytokines was also downregulated by this iPSC-MSC treatment. Conclusion: Intravitreal transplanted iPSC-MSCs can effectively donate functional mitochondria to RGCs and protect against mitochondrial damage-induced RGC loss.

Cadmium (Cd) pollution in agricultural soils has exerted a serious threat due to continuous application of pesticides, fertilizers, and wastewater irrigation. The present study aimed to test the efficiency of KOH-modified and non-modified rice straw-derived biochar (KBC and BC, respectively) for reducing Cd solubility and bioavailability in Cd-contaminated soil. Cadmium-contaminated soil was incubated for 60 d with 15 and 30 g kg−1 BC and KBC. At the end of incubation, Cd mobility was estimated by the European Community Bureau of Reference sequential extraction and toxicity characteristic leaching procedure (TCLP), while bioavailability was determined using 1 mol L−1 NH4NO3 extraction. The bioavailability risk index and bioaccessibility, assessed by a simple bioaccessibility extraction test, of Cd were used to examine the potential effects of Cd on living organisms. The results indicated that application of both KBC and BC significantly increased soil pH, cation exchange capacity, nutrients, and organic carbon. The soluble fraction of Cd was significantly decreased by 30.3% and 27.4%, respectively, with the addition of KBC and BC at 30 g kg−1 compared to the control (without biochar addition). Similarly, the bioaccessible Cd was significantly decreased by 32.4% and 25.2%, respectively, with the addition of KBC and BC at 30 g kg−1 compared to the control. In addition, both KBC and BC significantly reduced Cd leaching in the TCLP and NH4NO3-extractable Cd in the amended soil compared to the control. The reduction in Cd solubility and bioaccessibility by KBC and BC may be due to significant increases in soil pH and surface complexation. Overall, KBC at an application rate of 30 g kg−1 demonstrated positive results as soil amendment for Cd immobilization, and reduced bioaccessible Cd in contaminated soil.

Background Machado-Joseph disease is the most common autosomal dominant hereditary ataxia worldwide without effective treatment. Mesenchymal stem cells (MSCs) could slow the disease progression, but side effects limited their clinical application. Besides, MSC-derived exosomes exerted similar efficacy and have many advantages over MSCs. The aim of this study was to examine the efficacy of MSC-derived exosomes in YACMJD84.2 mice. Methods Rotarod performance was evaluated every 2 weeks after a presymptomatic administration of intravenous MSC-derived exosomes twice in YACMJD84.2 mice. Loss of Purkinje cells, relative expression level of Bcl-2/Bax, cerebellar myelin loss, and neuroinflammation were assessed 8 weeks following treatment. Results MSC-derived exosomes were isolated and purified through anion exchange chromatography. Better coordination in rotarod performance was maintained for 6 weeks in YACMJD84.2 mice with exosomal treatment, compared with those without exosomal treatment. Neuropathological changes including loss of Purkinje cells, cerebellar myelin loss, and neuroinflammation were also attenuated 8 weeks after exosomal treatment. The higher relative ratio of Bcl-2/Bax was consistent with the attenuation of loss of Purkinje cells. Conclusions MSC-derived exosomes could promote rotarod performance and attenuate neuropathology, including loss of Purkinje cells, cerebellar myelin loss, and neuroinflammation. Therefore, MSC-derived exosomes have a great potential in the treatment of Machado-Joseph disease.

Allergic airway inflammation is a major public health disease that affects up to 300 million people in the world. However, its management remains largely unsatisfactory. The dysfunction of pulmonary macrophages contributes greatly to the development of allergic airway inflammation. It has been reported that small extracellular vesicles derived from mesenchymal stromal cells (MSC-sEV) were able to display extensive therapeutic effects in some immune diseases. This study aimed to investigate the effects of MSC-sEV on allergic airway inflammation, and the role of macrophages involved in it. We successfully isolated MSC-sEV by using anion exchange chromatography, which were morphologically intact and positive for the specific EV markers. MSC-sEV significantly reduced infiltration of inflammatory cells and number of epithelial goblet cells in lung tissues of mice with allergic airway inflammation. Levels of inflammatory cells and cytokines in bronchoalveolar lavage fluid were also significantly decreased. Importantly, levels of monocytes-derived alveolar macrophages and M2 macrophages were significantly reduced by MSC-sEV. MSC-sEV were excreted through spleen and liver at 24 h post-administration in mice, and were able to be taken in by macrophages both in vivo and in vitro. In addition, proteomics analysis of MSC-sEV revealed that the indicated three types of MSC-sEV contained different quantities of proteins and shared 312 common proteins, which may be involved in the therapeutic effects of MSC-sEV. In total, our study demonstrated that MSC-sEV isolated by anion exchange chromatography were able to ameliorate Th2-dominant allergic airway inflammation through immunoregulation on pulmonary macrophages, suggesting that MSC-sEV were promising alternative therapy for allergic airway inflammation in the future.

Group 2 innate lymphoid cells (ILC2s) are recently reported to play a more critical role in allergic diseases. We previously identified that mesenchymal stromal cells (MSCs) elicited therapeutic effects on allergic airway inflammation. Small extracellular vesicles (sEV) derived from MSCs possess striking advantages including low immunogenicity and high biosafety, and is extremely promising cell-free therapeutic agents. However, the effects of MSC-sEV on ILC2s are still unclear. Additionally, scalable isolation protocols are required for the mass production of homogenous MSC-sEV especially in clinical application. We previously reported that induced pluripotent stem cells-derived MSCs were the ideal cellular source for the large preparation of MSC-sEV. Here we developed a standardized scalable protocol of anion-exchange chromatography for isolation of MSC-sEV, and investigated the effects of MSC-sEV on ILC2 function from patients with allergic rhinitis and in a mouse ILC2-dominant asthma model. The characterization of MSC-sEV was successfully demonstrated in terms of size, morphology and specific markers. Using flow cytometry and human Cytokine Antibody Array, MSC-sEV but not fibroblasts-sEV (Fb-sEV) were found to significantly inhibit the function of human ILC2s. Similarly, systemic administration of MSC-sEV but not Fb-sEV exhibited an inhibition of ILC2 levels, inflammatory cell infiltration and mucus production in the lung, a reduction in levels of T helper 2 cytokines, and alleviation of airway hyperresponsiveness in a mouse model of asthma. Using RNA sequencing, miR-146a-5p was selected as the candidate to mediate the above effects of MSC-sEV. We next revealed the uptake of ILC2s to MSC-sEV, and that transfer of miR-146a-5p in MSC-sEV to ILC2s in part contributed to the effects of MSC-sEV on ILC2s in vitro and in a mouse model. In conclusion, we demonstrated that MSC-sEV were able to prevent ILC2-dominant allergic airway inflammation at least partially through miR-146a-5p, suggesting that MSC-sEV could be a novel cell-free strategy for the treatment of allergic diseases.

Summary We previously identified an immunomodulatory role of human induced pluripotent stem cell (iPSC)-derived mesenchymal stem cells (MSCs) in asthmatic inflammation. Mitochondrial transfer from bone marrow MSCs to epithelial cells can result in the attenuation of acute lung injury in mice. However, the effects of mitochondrial transfer from iPSC-MSCs to epithelial cells in asthma and the mechanisms underlying these effects are unclear. We found that iPSC-MSC transplantation significantly reduced T helper 2 cytokines, attenuated the mitochondrial dysfunction of epithelial cells, and alleviated asthma inflammation in mice. Tunneling nanotubes (TNTs) were formed between iPSC-MSCs and epithelial cells, and mitochondrial transfer from iPSC-MSCs to epithelial cells via TNTs was observed both in vitro and in mice. Overexpression or silencing of connexin 43 (CX43) in iPSC-MSCs demonstrated that CX43 plays a critical role in the regulation of TNT formation by mediating mitochondrial transfer between iPSC-MSCs and epithelial cells. This study provides a therapeutic strategy for targeting asthma inflammation., Graphical Abstract, Highlights • iPSC-MSCs attenuate asthma inflammation and protect epithelial cells • The protection of iPSC-MSCs is attributable to mitochondrial transfer via TNTs • CX43-mediated TNT formation regulates the mitochondrial donation of iPSC-MSCs, In this article, Fu, Lian, and colleagues show that mesenchymal stem cells derived from human induced pluripotent stem cells can transfer their mitochondria to rescue the injured bronchial epithelial cells, which attenuates asthma inflammation. Connexin 43, a component of gap junctions, plays a critical role during the process of mitochondrial transfer by regulating intercellular tunneling nanotube formation.

Background We calculated the population pharmacokinetics of mizoribine in adult Chinese patients and compared the parameters with those of Japanese patients to determine whether there are any ethnic differences in blood concentration transition between these 2 populations. Methods The blood concentrations of mizoribine in 21 Chinese patients who were administered mizoribine after renal transplantation were measured at 304 time points. The absorption lag time, absorption rate constant, apparent distribution volume, and oral clearance were thereafter calculated and compared with the respective Japanese references. Results The absorption lag time, absorption rate constant, and apparent distribution volume calculated in this study were, respectively, 0.353 hour, 0.856 hour−1, and 0.776 L/kg. The oral clearance was calculated as 2.18 times the creatinine clearance using creatinine clearance as a function. The absorption rate constant, apparent distribution volume, and oral clearance are determinants of the maximum blood concentration, trough, and area under the blood concentration time curve. The relative absorption rate constant, apparent distribution volume, and oral clearance were 0.9-, 0.9-, and 1.2-fold, respectively, in Chinese patients compared with those in Japanese patients. These values are within the confidence limit, suggesting that there is no significant PK difference between the 2 ethnic groups. Conclusions Results of this study showed no ethnic difference in blood mizoribine concentration transition between Chinese and Japanese patients. In addition, the population pharmacokinetic parameters obtained in this study are useful in determining the initial dosage or in the Bayesian analysis of mizoribine concentrations using scarce time points.

The aim of the study was to investigate the effect of immunosuppression therapy early after kidney transplantation, particularly exposure of mycophenolic acid (MPA) and calcineurin inhibitor (CNI), on posttransplantation de novo HLA antibody production. Methods A single-center retrospective cohort study was performed at the First Affiliated Hospital of Sun Yat-sen University, enrolling the kidney transplant or pancreas-kidney transplant recipients who had surgery between January 2010 and February 2016. Results A total of 214 recipients were included in the study with a median follow-up period of 1.06 years. A total of 30 recipients (14.0%) were positive in HLA antibody detection posttransplant with a median follow-up period of 1.46 years. Ten recipients (4.7%) lost their allograft function during follow-up, and 6 of them (60%) developed de novo HLA antibody after graft failure. Multivariate analysis showed that acute rejection significantly increased the risk of de novo HLA antibody (hazard ratio [HR], 2.732). Intensified MPA dosing therapy reduced the risk by 59.8% (HR, 0.402); low-dose CNI therapy increased the risk by 33.3% (HR, 1.333), and the effect of extremely low-dose CNI therapy was even larger (HR, 2.242). Conclusion The risk of de novo HLA antibody can be decreased by reducing the risk of acute rejection. A tendency was seen in low-dose CNI therapy to increase the risk of de novo HLA antibody, but intensified MPA dosing therapy may provide an umbrella protection effect by reducing the risk. Prospective study was required to confirm the effects.

Background Group 2 innate lymphoid cells (ILC2s) were closely associated with asthma. However, there were no perspective studies about the effects of glucocorticoid on ILC2s in asthma patients. Our objective was to perform a perspective study and evaluate the ILC2 activity after glucocorticoid therapy in asthma patients. Methods The asthma and asthma with allergic rhinitis patients were treated with glucocorticoid for 3 months. The circulating ILC2 levels were evaluated. The effects of glucocorticoid on ILC2s and possible signalling pathways were investigated in vitro. Results The patients were well‐controlled, and the high ILC2 levels were significantly decreased at 1 and 3 months after treatment. Peripheral blood monocytes from allergic patients produced dramatic IL‐5, IL‐13 and IL‐9 in response to IL‐25, IL‐33 plus IL‐2, and glucocorticoid significantly decreased their levels. Moreover, ILC2s were identified to be the predominant source of IL‐5, IL‐13 and IL‐9, and glucocorticoid treatment was able to reverse their high levels. STAT3, STAT5, STAT6, JAK3 and MEK signalling pathways were proved to be involved in regulating ILC2 activity under the glucocorticoid treatment. Conclusion The data suggested that glucocorticoid administration could be effective in treating asthma by regulating ILC2s via MEK/JAK‐STAT signalling pathways. This provides a new understanding of glucocorticoid application in regard to allergic diseases.

Background Human induced pluripotent stem cells-derived mesenchymal stem cells (iPSC-MSCs) have been shown to be effective in Type 2 helper T cells (Th2)-dominant eosinophilic allergic airway inflammation. However, the role of iPSC-MSCs in Type 17 helper T cells (Th17)-dominant neutrophilic airway inflammation remains poorly studied. Therefore, this study was to explore the effects of iPSC-MSCs on an experimental mouse model of steroid-resistant neutrophilic airway inflammation and further determine the underlying mechanisms. Methods A mouse model of neutrophilic airway inflammation was established using ovalbumin (OVA) and lipopolysaccharide (LPS). Human iPSC-MSCs were systemically administered, and the lungs or bronchoalveolar lavage fluids (BALF) were collected at 4 h and 48 h post-challenge. The pathology and inflammatory cell infiltration, the T helper cells, T helper cells-associated cytokines, nuclear transcription factors and possible signaling pathways were evaluated. Human CD4+ T cells were polarized to T helper cells and the effects of iPSC-MSCs on the differentiation of T helper cells were determined. Results We successfully induced the mouse model of Th17 dominant neutrophilic airway inflammation. Human iPSC-MSCs but not dexamethasone significantly prevented the neutrophilic airway inflammation and decreased the levels of Th17 cells, IL-17A and p-STAT3. The mRNA levels of Gata3 and RORγt were also decreased with the treatment of iPSC-MSCs. We further confirmed the suppressive effects of iPSC-MSCs on the differentiation of human T helper cells. Conclusions iPSC-MSCs showed therapeutic potentials in neutrophilic airway inflammation through the regulation on Th17 cells, suggesting that the iPSC-MSCs could be applied in the therapy for the asthma patients with steroid-resistant neutrophilic airway inflammation. Electronic supplementary material The online version of this article (10.1186/s13287-018-0897-y) contains supplementary material, which is available to authorized users.

Background In China, clarithromycin is considered an effective treatment option for chronic rhinosinusitis (CRS) due to its unique immunopathologic characteristics. Our study's aim was to determine whether a topical steroid and clarithromycin combination is better than a single topical steroid for Chinese patients with CRS. Methods Patients with CRS with/without nasal polyps were included in this study and randomly assigned to a clarithromycin plus budesonide aqua nasal spray group (CLM + BUD, clarithromycin 0.25 g/d and budesonide 256 μg/d) or a budesonide-alone group (BUD, budesonide 256 μg/d). The treatment period was 3 months. The primary outcome was visual analog scale (VAS) score for 5 major symptoms and a general nasal symptom. Other assessments included the 22-item Sino-Nasal Outcome Test (SNOT-22), computed tomography scan (Lund-Mackay score), and rigid nasal endoscopy (Lund-Kennedy score). Nasal secretion evaluation was the secondary outcome. Results Seventy-four patients were included and randomly assigned to the CLM + BUD group (n = 38) or the BUD group (n = 36). VAS scores for nasal obstruction, rhinorrhea, smell reduction, headache, nasal pain, and general nasal symptom were markedly improved in both treatment arms, but the differences between groups were not significant. Furthermore, SNOT-22, Lund-Mackay, and Lund-Kennedy scores improved significantly after treatment in both groups, and were slightly better in the CLM + BUD group. For the responders in the CLM + BUD group, interleukin (IL)-6 and IL-8 were markedly reduced. Conclusion The combination of CLM + BUD for the treatment of first-time-diagnosed CRS in this Chinese population cohort did not show a better effect compared with a single BUD regimen, but it may have a better effect in some patients with increased IL-6 or IL-8.

Soil aggregates consist of sand, silt, and clay size particles. Many of the clay size particles in soils are clay minerals, which actively influence soil behavior. The properties of clay minerals may change significantly as soil particle size decreases to the nanoscale; however, little information is available about these properties for the Ultisols in China. In the present study, the clay mineral components and structural characteristics of four particle-size fractions (i.e.

Four kidneys from 2 young donors suffering from rhabdomyolysis were rejected for transplantation at the time of procurement because of their severely bruised and black gross appearance. A frozen section revealed a focal tubular injury filled with granular pigmented casts which an immunohistochemistry confirmed to be myoglobin. The 4 kidneys were transplanted successfully and all recipients recovered normal renal function with no delay. These cases indicate that kidneys with patchy black gross appearance caused by myoglobin casts secondary to rhabdomyolysis is not a contraindication for transplantation.

Mesenchymal stem cell- (MSC-) based therapy is a novel strategy in regenerative medicine. The functional and regenerative capacities of MSCs decline with senescence. Nonetheless, the potential mechanisms that underlie their senescence are not fully understood. This study was aimed at exploring the potential mechanisms of fibroblast growth factor 21 (FGF21) in the regulation of MSC senescence. The senescence of MSCs was determined by senescence-associated β-galactosidase (SA-β-gal) staining. The morphology and the level of mitochondrial reactive oxygen species (ROS) of MSCs were assessed by MitoTracker and Mito-Sox staining, respectively. The expression of FGF21 and mitochondrial dynamics-related proteins was detected by Western blotting. As MSCs were expanded in vitro, the expression of FGF21 decreased. Depletion of FGF21 enhanced production of mitochondrial reactive oxidative species (ROS) and increased the senescence of early-passage MSCs whereas inhibition of ROS abolished these effects. The senescent MSCs exhibited increased mitochondrial fusion and decreased mitochondrial fission. Treatment of early-passage MSCs with FGF21 siRNA enhanced mitochondrial fusion and reduced mitochondrial fission. Moreover, treatment of mitofusin2- (Mfn2-) siRNA inhibited depletion of FGF21-induced MSC senescence. Furthermore, we demonstrated that depletion of FGF21-induced mitochondrial fusion was regulated by the AMPK signaling pathway. Treatment with an AMPK activator, AICAR, abrogated the depletion of FGF21-induced senescence of MSCs by inhibiting mitochondrial fusion. Compared with MSCs isolated from young donors, those derived from aged donors showed a lower level of FGF21 and a higher level of senescent activity. Furthermore, overexpression of FGF21 in aged MSCs inhibited senescence. Our study shows that FGF21, via the AMPK signaling pathway, regulates the senescence of MSCs by mediating mitochondrial dynamics. Targeting FGF21 might represent a novel strategy to improve the quality and quantity of MSCs.

The regenerative and immunomodulatory characteristics of mesenchymal stem cells (MSCs) make them attractive in the treatment of many diseases. Although they have shown promising preclinical studies of immunomodulation and paracrine effects in inflammatory airway disorders and other lung diseases, there are still challenges that have to be overcome before MSCs can be safely, effectively, and routinely applied in the clinical setting. A good understanding of the roles and mechanisms of the MSC immunomodulatory effects will benefit the application of MSC-based clinical therapy. In this review, we summarize the promises and challenges of the preclinical and clinical trials of MSC therapies, aiming to better understand the role that MSCs play in attempt to treat inflammatory airway disorders.

Background Experience with kidney transplantation from brain-dead donors remains limited in China. Our objective was to evaluate the outcomes of kidney transplantation from brain-dead donors (group 1), compared with those from living ones of the same age (group 2). Methods Clinical data of kidney transplantation from brain-dead donors and living donors in the same age range (18–45 years) performed between May 2007 and December 2011 were analyzed retrospectively. Recipients were analyzed for posttransplantation serum creatinine, creatinine clearance (calculated by the Cockcroft-Gault formula), the number of acute rejection episodes and delayed graft function, and patient/graft survival. Results Mean donor age was comparable between the 2 groups (31.9 ± 6.5 vs 32.8 ± 7.0 years; P = .268). The terminal serum creatinine level of donors was 125.5 ± 63.5 μmol/L in group 1 (n = 30) and 65.1 ± 13.7 μmol/L in group 2 (n = 110; P = .000). Recipient creatinine clearance was comparable between the 2 groups 1 month posttransplantation and thereafter. Acute rejection episodes were seen in 7 cases in recipients of group 1 (15.9%) and in 15 cases in recipients of group 2 (13.6%; P = .716). The incidence of delayed graft function was higher in recipients of group 1 (18.2%) than that of group 2 (3.6%; P = .002). The 1-, 3-, and 5-year patient/graft survival rate was comparable between the 2 groups. Conclusions Our study demonstrated kidney transplantation from brain-dead donors achieved acceptable graft function and patient/graft survival in the 5-year follow-up, encouraging the use of this approach.

Nogo receptor 1 (NgR1) is the most important Nogo-A receptor. By its interaction with myelin-associated inhibitory proteins, NgR1 inhibits the regeneration of axons and is extensively expressed in the central nervous system. However, the expression of NgR1 in regenerable neurons, such as olfactory neurons, and its expression in the regeneration progress of olfactory neurons have not been reported. In this study, we demonstrated that NgR1 was expressed in the cell bodies of certain mature olfactory receptor neurons (ORNs) but was not expressed in immature ORNs in the olfactory epithelium (OE) of normal adult mice. On day 21 after OE injury, NgR1 was expressed not only in the cell bodies of mature ORNs but also in the cell bodies of glial fibrillary acidic protein (GFAP)-positive cells in the top and submucosal layers of the OE. On day 48 after model establishment, NgR1 expression decreased in the cell bodies of the GFAP-positive cells. On day 56 after model establishment, no NgR1 expression was found in the cell bodies of the GFAP-positive cells, and NgR1 was again expressed only in the mature ORNs. Our results demonstrated that NgR1 expression is upregulated in the OE after injury, which suggests that NgR1 might be involved in the regeneration of the OE.

Allergic rhinitis (AR) has been a significant healthcare burden on individuals and society. However, the detailed effect of different patterns of allergen exposure on the development of AR remains controversial. A mouse model of AR was established to address the complex relationships between allergen exposure and the development of AR. Allergic symptom, OVA-specific IgE in serum and nasal lavage fluid, allergic inflammation in nasal tissues were evaluated after intranasal sensitization and challenge of ovalbumin (OVA) in mice treated with two different doses of allergen for different sensitized durations. Exposure to different doses and sensitized durations of OVA were capable of inducing allergic nasal response. Repetitive OVA exposure in the sensitization phase induced the recruitment of eosinophils and goblet cell hyperplasia. The level of OVA-specific IgE in serum depended on OVA exposure and was mediated in a duration-related manner. In addition, mice treated with low-dose OVA for prolonged duration manifested the major features of human local allergic rhinitis. There were dose- and duration-related effects of allergen exposure on the development of AR. LAR was associated with repetitive exposure to low-dose allergen. Thus, allergen avoidance should be an important aim of AR management.

SummaryAims The aim of this study was to investigate the efficacy and safety of a transient intensified enteric-coated mycophenolate sodium (EC-MPS) dosing regimen with low exposure of calcineurin inhibitors (CNIs) in Chinese de novo kidney transplantation. Methods In a 6-month prospective study, a total of 97 recipients were enrolled and assigned to either an intensified EC-MPS dosing (IS) regimen or a standard EC-MPS dosing (SD) regimen. The area under the curve (AUC) of MPA was assessed at week 1 post transplant. The incidences of acute rejection, patient and graft survival, renal allograft function and adverse events were analysed. Results The IS regimen displayed a trend of acute rejection risk reduction (IS 2.7% vs. SD 13.3%, p = 0.061) and allograft function improvement (IS 62.8 ± 14.0 ml/min per 1.73 m2 vs. SD 56.6 ± 18.3 ml/min per 1.73 m2, p = 0.084) after 6-month follow-up. MPA-AUC0–12 h was substantially higher in the intensified EC-MPS group than the standard EC-MPS group, though without a significant difference (71.4 ± 41.7 vs. 53.0 ± 27.0 mg·h/l, p = 0.107). The IS regimen did not increase the incidence of adverse effects (IS 54.1% vs. 45.0%, p = 0.39), including diarrhoea or leucopenia. Conclusions The intensified EC-MPS dosing regimen maintaining low-dose CNIs in this study may be beneficial for Chinese adult de novo kidney transplant recipients in terms of acute rejection and allograft function and is safe within 6 months post transplant.

The composition, structure and transformation characteristics of clay minerals in various size particles ( 100 nm) were an important mineral source of nanoparticles, and the 1:1 clay minerals were mainly inherited from the minerals in larger particles and transformed from 2:1 clay minerals into nanoparticles.

Cell specific and cytokine targeted therapeutics have underperformed in systemic lupus erythematosus (SLE). Mesenchymal stem cells (MSCs) have emerged as a novel therapy to address the dysregulation in autoimmune diseases but also have limitations. Human gingiva derived MSCs (GMSCs) are superior in regulating immune responses. Here, we demonstrate that the adoptive transfer of GMSCs homes to and maintains in the kidney and has a robust therapeutic effect in a spontaneous lupus nephritis model. Specifically, GMSCs limits the development of autoantibodies as well as proteinuria, decreases the frequency of plasma cells and lupus nephritis histopathological scores by directly suppressing B cells activation, proliferation and differentiation. The blockage of CD39-CD73 pathway dramatically abrogates the suppressive capacities of GMSCs in vitro and in vivo and highlights the significance of this signaling pathway in SLE. Collectively, manipulation of GMSCs provides a promising strategy for the treatment of patients with SLE and other autoimmune diseases.

Background Group 2 innate lymphoid cells (ILC2s) were reported to serve a critical role in allergic diseases. Myeloid dendritic cells (mDCs) and plasmacytoid DCs (pDCs) play significant roles in allergic immune response. However, effects of DCs on ILC2s in allergic diseases, especially for patients with allergic rhinitis (AR), remain unclear. Objective We sought to address the roles of mDCs and pDCs in regulating ILC2 function in AR. Methods mDCs and pDCs were cocultured with human PBMCs isolated from patients with AR or ILC2s to measure soluble or intracellular TH2 cytokines, transcription factors, signaling pathways in ILC2s, and the following mechanisms were further investigated. The levels of peripheral IL-33+mDCs, pDCs, and ILC2s were studied in patients under an inhaled allergen challenge. Results We confirmed the presence of ILC2s, mDCs, and pDCs in the nasal mucosa of patients with AR. Both allogenic and autologous mDCs were found to activate ILC2s from patients with AR to produce TH2 cytokines, and increase the levels of GATA-3 and signal transducer and activator of transcription signaling pathways, in which IL-33–producing mDCs exerted the major role by binding on ST2 on ILC2s. We further identified high levels of IL-33+mDCs and ILC2s in patients with AR under antigen challenge. Activated pDCs inhibited the cytokine production of ILC2s isolated from patients with AR by secretion of IL-6. Conclusions mDCs promote ILC2 function by the IL-33/ST2 pathway, and activation of pDCs suppresses ILC2 function through IL-6 in patients with AR. Our findings provide new understanding of the interplay between DCs and ILC2s in allergic diseases.