Dynamic Transformation of High-Architectural Nanocrystal Superlattices upon Solvent Molecule Exposure.

The cluster-based body-centered-cubic superlattice (cBCC SL) represents one of the most complicated structures among reported nanocrystal assemblies, comprised of 72 truncated tetrahedral quantum dots per unit cell. Our previous report revealed that truncated tetrahedral quantum dots within cBCC SLs possessed highly controlled translational and orientational order owing to an unusual energetic landscape based on the balancing of entropic and enthalpic contributions during the assembly process. However, the cBCC SL's structural transformability and mechanical properties, uniquely originating from such complicated nanostructures, have yet to be investigated. Herein, we report that cBCC SLs can undergo dynamic transformation to face-centered-cubic SLs in response to post-assembly molecular exposure. We monitored the dynamic transformation process using in situ synchrotron-based small-angle X-ray scattering, revealing a dynamic transformation involving multiple steps underpinned by interactions between incoming molecules and TTQDs' surface ligands. Furthermore, our mechanistic study demonstrated that the precise configuration of TTQDs' ligand molecules in cBCC SLs was key to their high structural transformability and unique jelly-like soft mechanical properties. While ligand molecular configurations in nanocrystal SLs are often considered minor features, our findings emphasize their significance in controlling weak van der Waals interactions between nanocrystals within assembled SLs, leading to previously unremarked superstructural transformability and unique mechanical properties. Our findings promote a facile route toward further creation of soft materials, nanorobotics, and out-of-equilibrium assemblies based on nanocrystal building blocks.

Human Allogeneic Bone Marrow-Derived Mesenchymal Stem Cell Therapy for Cerebellar Ataxia: A Case Report.

To date, there is no curable treatment option for non-hereditary degenerative cerebellar ataxia. Here we report the case of a patient with sporadic adult-onset ataxia (SAOA) who underwent allogeneic bone marrow-derived mesenchymal stem cell (MSC) therapy via the intrathecal route. A 60-year-old male patient visited our clinic complaining of progressive gait disturbance that commenced two years ago. Upon neurologic examination, the patient exhibited limb dysmetria and gait ataxia. Brain magnetic resonance imaging (MRI) revealed cerebellar atrophy whereas the autonomic function test was normal. The patient was diagnosed with SAOA. The medications that were initially prescribed had no significant effects on the course of this disease and the symptoms deteriorated progressively. At the age of 64, the patient was treated with allogeneic bone marrow-derived MSC therapy. The subsequent K-SARA (Korean version of the Scale for the Assessment and Rating of Ataxia) scores demonstrated a distinct improvement up until 10 months post-administration. No adverse events were reported. The improved post-treatment K-SARA scores may suggest that the MSC therapy can have a neuroprotective effect and that stem cell therapy may serve as a potential therapeutic option for degenerative cerebellar ataxia.

Biological markers of mesenchymal stromal cells as predictors of response to autologous stem cell transplantation in patients with amyotrophic lateral sclerosis: an investigator-initiated trial and in vivo study.

Bone marrow mesenchymal stromal cells (MSCs) can modify disease progression in amyotrophic lateral sclerosis (ALS) model. However, there are currently no accurate biological markers for predicting the efficacy of autologous MSC transplants in ALS patients. This open-label, single-arm, investigator-initiated clinical study was designed to identify markers of MSCs that could be used as potential predictors of response to autologous MSC therapy in patients with ALS. We enrolled 37 patients with ALS who received autologous MSCs via intrathecal injection in two monthly doses. After a 6-month follow-up period, the patients were categorized as responders and non-responders based on their scores on the revised ALS Functional Rating Scale (ALSFRS-R). Biological markers including ß-fibroblast growth factor-2, stromal cell-derived factor-1α, vascular endothelial growth factor (VEGF), insulin-like growth factor-1, brain-derived neurotrophic factor, angiogenin (ANG), interleukin (IL)-4, IL-10, and transforming growth factor-ß (TGF-ß) were measured in the MSC cultures and their levels were compared between the responders and nonresponders. To confirm the markers' predictive ability, MSCs isolated from one patient in each group were transplanted into the cisterna magna of mutant SOD1(G93A) transgenic mice to measure their lifespans, locomotor activity, and motor neuron numbers. The levels of VEGF, ANG, and TGF-ß were significantly higher in responders than in nonresponders. In the mouse model, the recipients of responder MSCs had a significantly slower onset of symptoms and a significantly longer lifespan than the recipients of nonresponders or controls. Our data suggest that VEGF, ANG, and TGF-ß levels in MSCs could be used as potential biological markers to predict the effectiveness of autologous MSC therapy and to identify those patients who could optimally benefit from MSC treatment.

The immunomodulatory effects of human mesenchymal stem cells on peripheral blood mononuclear cells in ALS patients.

In a previous study, we reported that intrathecal injection of mesenchymal stem cells (MSCs) slowed disease progression in G93A mutant superoxide dismutase1 transgenic mice. In this study, we found that intrathecal MSC administration vastly increased the infiltration of peripheral immune cells into the spinal cord of Amyotrophic lateral sclerosis (ALS) mice (G93A mutant superoxide dismutase1 transgenic). Thus, we investigated the immunomodulatory effect of MSCs on peripheral blood mononuclear cells (PBMCs) in ALS patients, focusing on regulatory T lymphocytes (Treg ; CD4(+) /CD25(high) /FoxP3(+) ) and the mRNA expression of several cytokines (IFN-γ, TNF-α, IL-17, IL-4, IL-10, IL-13, and TGF-ß). Peripheral blood samples were obtained from nine healthy controls (HC) and sixteen patients who were diagnosed with definite or probable ALS. Isolated PBMCs from the blood samples of all subjects were co-cultured with MSCs for 24 or 72 h. Based on a fluorescence-activated cell sorting analysis, we found that co-culture with MSCs increased the Treg /total T-lymphocyte ratio in the PBMCs from both groups according to the co-culture duration. Co-culture of PBMCs with MSCs for 24 h led to elevated mRNA levels of IFN-γ and IL-10 in the PBMCs from both groups. However, after co-culturing for 72 h, although the IFN-γ mRNA level had returned to the basal level in co-cultured HC PBMCs, the IFN-γ mRNA level in co-cultured ALS PBMCs remained elevated. Additionally, the levels of IL-4 and TGF-ß were markedly elevated, along with Gata3 mRNA, a Th2 transcription factor mRNA, in both HC and ALS PBMCs co-cultured for 72 h. The elevated expression of these cytokines in the co-culture supernatant was confirmed via ELISA. Furthermore, we found that the increased mRNA level of indoleamine 2,3-dioxygenase (IDO) in the co-cultured MSCs was correlated with the increase in Treg induction. These findings of Treg induction and increased anti-inflammatory cytokine expression in co-cultured ALS PBMCs provide indirect evidence that MSCs may play a role in the immunomodulation of inflammatory responses when MSC therapy is targeted to ALS patients. We propose the following mechanism for the effect of mesenchymal stem cells (MSCs) administered intrathecally in amyotrophic lateral sclerosis (ALS): MSCs increase infiltration of peripheral immune cells into CNS and skew the infiltrated immune cells toward regulatory T lymphocytes (Treg ) and Th2 lymphocytes. Treg and Th2 secret anti-inflammatory cytokines such as IL-4, IL-10, and TGF-ß. A series of immunomodulatory mechanism provides a new strategy for ALS treatment.

Mesenchymal Stem Cell Transplantation Ameliorates Ara-C-Induced Motor Deficits in a Mouse Model of Cerebellar Ataxia.

This study investigated the therapeutic effects of transplanting human mesenchymal stem cells (hMSCs) into wild-type mice that were intraperitoneally administered cytosine arabinoside (Ara-C) to develop cerebellar ataxia (CA) during the first three postnatal days. hMSCs were intrathecally injected into 10-week-old mice once or thrice at 4-week intervals. Compared to the nontreated mice, the hMSC-treated mice showed improved motor and balance coordination, as measured using the rotarod, open-field, and ataxic scoring assessments, and increased protein levels in Purkinje and cerebellar granule cells, as measured using calbindin and NeuN protein markers. Multiple hMSC injections preserved Ara-C-induced cerebellar neuronal loss and improved cerebellar weight. Furthermore, the hMSC implantation significantly elevated the levels of neurotrophic factors, including brain-derived and glial cell line-derived neurotrophic factors, and suppressed TNF-α-, IL-1ß-, and iNOS-mediated proinflammatory responses. Collectively, our results demonstrate that hMSCs exhibit therapeutic potential for Ara-C-induced CA by protecting neurons through the stimulation of neurotrophic factors and inhibition of cerebellar inflammatory responses, which can improve motor behavior and alleviate ataxia-related neuropathology. In summary, this study suggests that hMSC administration, particularly multiple treatments, can effectively treat ataxia-related symptoms with cerebellar toxicity.

Strain-controlled switching of hierarchically wrinkled surfaces between superhydrophobicity and superhydrophilicity.

Recent years have witnessed intense interest in multifunctional surfaces that can be designed to switch between different functional states with various external stimuli including electric field, light, pH value, and mechanical strain. The present paper is aimed to explore whether and how a surface can be designed to switch between superhydrophobicity and superhydrophilicity by an applied strain. Based on well-established theories of structure buckling and solid-liquid contact, we show that this objective may be achieved through a hierarchically wrinkled surface. We derive general recursive relations for the apparent contact angle at different levels of the hierarchical surface and investigate the thermodynamic stability of different contact states. Our study may provide useful guidelines for the development of multifunctional surfaces for many technological applications.

Dual Atomic Coherence in the Self-Assembly of Patchy Heterostructural Nanocrystals.

Advances in the synthesis and self-assembly of nanocrystals have enabled researchers to create a plethora of different nanoparticle superlattices. But while many superlattices with complex types of translational order have been realized, rotational order of nanoparticle building blocks within the lattice is more difficult to achieve. Self-assembled superstructures with atomically coherent nanocrystal lattices, which are desirable due to their exceptional electronic and optical properties, have been fabricated only for a few selected systems. Here, we combine experiments with molecular dynamics (MD) simulations to study the self-assembly of heterostructural nanocrystals (HNCs), consisting of a near-spherical quantum dot (QD) host decorated with a small number of epitaxially grown gold nanocrystal (Au NC) "patches". Self-assembly of these HNCs results in face-centered-cubic (fcc) superlattices with well-defined orientational relationships between the atomic lattices of both QD hosts and Au patches. MD simulations indicate that the observed dual atomic coherence is linked to the number, size, and relative positions of gold patches. This study provides a strategy for the design and fabrication of NC superlattices with large structural complexity and delicate orientational order.

Efficacy and safety of Lenzumestrocel (Neuronata-R® inj.) in patients with amyotrophic lateral sclerosis (ALSUMMIT study): study protocol for a multicentre, randomized, double-blind, parallel-group, sham procedure-controlled, phase III trial.

BACKGROUND: A single cycle (two repeated treatments) with intrathecal autologous bone marrow-derived mesenchymal stem cells (BM-MSCs, 26-day interval) showed safety and provided therapeutic benefit lasting 6 months in patients with ALS but did not demonstrate long-term efficacy. This phase III clinical trial (ALSUMMIT) protocol was developed to evaluate the long-term efficacy and safety of the combined protocol of single-cycle intrathecal therapy and three additional booster injections of BM-MSC (Lenzumestrocel) treatment in patients with ALS. METHODS: ALSUMMIT is a multicentre, randomized, double-blind, parallel-group, sham procedure-controlled, phase III trial for ALS. The 115 subjects will be randomized (1:2:2) into three groups: (1) study Group 1 (single-cycle, two repeated injections with 26-day interval), (2) study Group 2 (single-cycle + three additional booster injections at 4, 7, and 10 months), and (3) the control group. Participants who have an intermediate rate of disease progression will be included in this trial to reduce clinical heterogeneity. The primary endpoint will be evaluated by combined assessment of function and survival (CAFS), also known as joint rank scores (JRS), at 6 months (study Group 1 vs. control) and 12 months (study Group 2 vs. control) after the first Lenzumestrocel or placebo administration. Safety assessment will be performed throughout the study period. Additionally, after the 56-week main study, a long-term follow-up observational study will be conducted to evaluate the long-term efficacy and safety up to 36 months. DISCUSSION: Lenzumestrocel is the orphan cell therapy product for ALS conditionally approved by the South Korea Ministry of Food and Drug Safety (MFDS). This ALSUMMIT protocol was developed for the adoption of enrichment enrolment, add-on design, and consideration of ethical issues for the placebo group. TRIAL REGISTRATION: ClinicalTrials.gov NCT04745299 . Registered on Feb 9, 2021. Clinical Research Information Service (CRIS) KCT0005954 . Registered on Mar 4, 2021.

Terminalia chebula extract acts as a potential NF-κB inhibitor in human lymphoblastic T cells.

Terminalia chebula (TC) is native to southern Asia to southwestern China and is used in traditional medicine for the treatment of human ailments including malignant tumors and diabetes. This plant also has antibacterial and immunomodulatory properties. Nuclear factor kappa-light chain-enhancer of activated B cells (NF-κB) is responsible for the expression of numerous genes involved in cell survival, proliferation, angiogenesis, inflammation, invasion and metastasis, among other processes. This study aims to assess the NF-κB inhibitory effect of TC extract in human lymphoblastic T (Jurkat) cells. The effects of TC extract were investigated using the FRET-based Gene Blazer technique in transfected Jurkat-NF-κB-RE-bla cells. The concentration of TC extract required for NF-κB inhibition was determined by a cell proliferation assay. Treatment with TC extract (50 µg/mL) inhibited NF-κB activity and protected against IκBα degradation and strongly suppressed IκBα phosphorylation in Jurkat-NF-κB-RE-bla cells. This treatment might be crucial for inhibiting NF-κB translocation and activation. In addition, the TC extract downregulated certain NF-κB regulated genes, including IL-8 and MCP-1, in Jurkat-NF-κB-RE-bla cells. Moreover, gallic acid was identified from the TC extract demonstrating its ability to inhibit NF-κB activity in Jurkat-NF-κB-RE-bla cells. Further studies to identify the role of gallic acid in NF-κB inhibition may uncover the crucial antiinflammatory and antitumor properties of the TC extract.

Wrinkled, dual-scale structures of diamond-like carbon (DLC) for superhydrophobicity.

We present a simple two-step method to fabricate dual-scale superhydrophobic surfaces by using replica molding of poly(dimethylsiloxane) (PDMS) micropillars, followed by deposition of a thin, hard coating layer of a SiO(x)-incorporated diamond-like carbon (DLC). The resulting surface consists of microscale PDMS pillars covered by nanoscale wrinkles that are induced by residual compressive stress of the DLC coating and a difference in elastic moduli between DLC and PDMS without any external stretching or thermal contraction on the PDMS substrate. We show that the surface exhibits superhydrophobic properties with a static contact angle over 160 degrees for micropillar spacing ratios (interpillar gap divided by diameter) less than 4. A transition of the wetting angle to approximately 130 degrees occurs for larger spacing ratios, changing the wetting from a Cassie-Cassie state (C(m)-C(n)) to a Wenzel-Cassie state (W(m)-C(n)), where m and n denote micro- and nanoscale roughness, respectively. The robust superhydrophobicity of the Cassie-Cassie state is attributed to stability of the Cassie state on the nanoscale wrinkle structures of the hydrophobic DLC coating, which is further explained by a simple mathematical theory on wetting states with decoupling of nano- and microscale roughness in dual scale structures.

Poly(ε-Caprolactone)/Poly(Glycerol Sebacate) Composite Nanofibers Incorporating Hydroxyapatite Nanoparticles and Simvastatin for Bone Tissue Regeneration and Drug Delivery Applications.

Herein, we report a drug eluting scaffold composed of a composite nanofibers of poly(ε-caprolactone) (PCL) and poly(glycerol sebacate) (PGS) loaded with Hydroxyapatite nanoparticles (HANPs) and simvastatin (SIM) mimicking the bone extracellular matrix (ECM) to improve bone cell proliferation and regeneration process. Indeed, the addition of PGS results in a slight increase in the average fiber diameter compared to PCL. However, the presence of HANPs in the composite nanofibers induced a greater fiber diameter distribution, without significantly changing the average fiber diameter. The in vitro drug release result revealed that the sustained release of SIM from the composite nanofiber obeying the Korsemeyer-Peppas and Kpocha models revealing a non-Fickian diffusion mechanism and the release mechanism follows diffusion rather than polymer erosion. Biomineralization assessment of the nanofibers was carried out in simulated body fluid (SBF). SEM and EDS analysis confirmed nucleation of the hydroxyapatite layer on the surface of the composite nanofibers mimicking the natural apatite layer. Moreover, in vitro studies revealed that the PCL-PGS-HA displayed better cell proliferation and adhesion compared to the control sample, hence improving the regeneration process. This suggests that the fabricated PCL-PGS-HA could be a promising future scaffold for control drug delivery and bone tissue regeneration application.

Lipopolysaccharide administration for a mouse model of cerebellar ataxia with neuroinflammation.

Most cerebellar ataxias (CAs) are incurable neurological disorders, resulting in a lack of voluntary control by inflamed or damaged cerebellum. Although CA can be either directly or indirectly related to cerebellar inflammation, there is no suitable animal model of CA with neuroinflammation. In this study, we evaluated the utility of an intracerebellar injection of lipopolysaccharide (LPS) to generate an animal model of inflammatory CA. We observed that LPS administration induced the expression of pro-inflammatory molecules following activation of glial cells. In addition, the administration of LPS resulted in apoptotic Purkinje cell death and induced abnormal locomotor activities, such as impaired motor coordination and abnormal hindlimb clasping posture. Our results suggest that intracerebellar LPS administration in experimental animals may be useful for studying the inflammatory component of CA.

Therapeutic Effects of Human Mesenchymal Stem Cells in a Mouse Model of Cerebellar Ataxia with Neuroinflammation.

Cerebellar ataxias (CAs) are neurological diseases characterized by loss of muscle coordination that is a result of damage and inflammation to the cerebellum. Despite considerable efforts in basic and clinical research, most CAs are currently incurable. In this study, we evaluated the therapeutic potential of human mesenchymal stem cells (hMSCs) against CAs associated with neuroinflammation. We observed that hMSC treatment significantly inhibited the symptoms of ataxia in lipopolysaccharide (LPS)-induced inflammatory CA (ICA) mice, which were recently reported as a potential animal model of ICA, through the anti-inflammatory effect of hMSC-derived TNFα-stimulated gene-6 (TSG-6), the protection of Purkinje cells by inhibition of apoptosis, and the modulatory effect for microglial M2 polarization. Thus, our results suggest that hMSC treatment may be an effective therapeutic approach for preventing or improving ataxia symptoms.

Effect of Human Mesenchymal Stem Cells on Xenogeneic T and B Cells Isolated from Lupus-Prone MRL.Fas lpr Mice.

Systemic lupus erythematosus (SLE) is an autoimmune disease, which is characterized by hyperactivation of T and B cells. Human mesenchymal stem cells (hMSCs) ameliorate the progression of SLE in preclinical studies using lupus-prone MRL.Fas lpr mice. However, whether hMSCs inhibit the functions of xenogeneic mouse T and B cells is not clear. To address this issue, we examined the in vitro effects of hMSCs on T and B cells isolated from MRL.Fas lpr mice. Naïve hMSCs inhibited the functions of T cells but not B cells. hMSCs preconditioned with IFN-γ (i) inhibited the proliferation of and IgM production by B cells, (ii) attracted B cells for cell-cell interactions in a CXCL10-dependent manner, and (iii) inhibited B cells by producing indoleamine 2,3-dioxygenase. In summary, our data demonstrate that hMSCs exert therapeutic activity in mice in three steps: first, naïve hMSCs inhibit the functions of T cells, hMSCs are then activated by IFN-γ, and finally, they inhibit B cells.

Phorbol ester activates human mesenchymal stem cells to inhibit B cells and ameliorate lupus symptoms in MRL.Faslpr mice.

Rationale: Systemic lupus erythematosus (SLE) is a multi-organ autoimmune disease characterized by autoantibody production by hyper-activated B cells. Although mesenchymal stem cells (MSCs) ameliorate lupus symptoms by inhibiting T cells, whether they inhibit B cells has been controversial. Here we address this issue and reveal how to prime MSCs to inhibit B cells and improve the efficacy of MSCs in SLE. Methods: We examined the effect of MSCs on purified B cells in vitro and the therapeutic efficacy of MSCs in lupus-prone MRL.Faslpr mice. We screened chemicals for their ability to activate MSCs to inhibit B cells. Results: Mouse bone marrow-derived MSCs inhibited mouse B cells in a CXCL12-dependent manner, whereas human bone marrow-derived MSCs (hMSCs) did not inhibit human B (hB) cells. We used a chemical approach to overcome this hurdle and found that phorbol myristate acetate (PMA), phorbol 12,13-dibutyrate, and ingenol-3-angelate rendered hMSCs capable of inhibiting IgM production by hB cells. As to the mechanism, PMA-primed hMSCs attracted hB cells in a CXCL10-dependent manner and induced hB cell apoptosis in a PD-L1-dependent manner. Finally, we showed that PMA-primed hMSCs were better than naïve hMSCs at ameliorating SLE progression in MRL.Faslpr mice. Conclusion: Taken together, our data demonstrate that phorbol esters might be good tool compounds to activate MSCs to inhibit B cells and suggest that our chemical approach might allow for improvements in the therapeutic efficacy of hMSCs in SLE.

Characterization of Mesenchymal Stem Cells Derived from Patients with Cerebellar Ataxia: Downregulation of the Anti-Inflammatory Secretome Profile.

Mesenchymal stem cell (MSC) therapy is a promising alternative approach for the treatment of neurodegenerative diseases, according to its neuroprotective and immunomodulatory potential. Despite numerous clinical trials involving autologous MSCs, their outcomes have often been unsuccessful. Several reports have indicated that MSCs from patients have low capacities in terms of the secretion of neurotrophic or anti-inflammatory factors, which might be associated with cell senescence or disease severity. Therefore, a new strategy to improve their capacities is required for optimal efficacy of autologous MSC therapy. In this study, we compared the secretory potential of MSCs among cerebellar ataxia patients (CA-MSCs) and healthy individuals (H-MSCs). Our results, including secretome analysis findings, revealed that CA-MSCs have lower capacities in terms of proliferation, oxidative stress response, motility, and immunomodulatory functions when compared with H-MSCs. The functional differences were validated in a scratch wound healing assay and neuron-glia co-cultures. In addition, the neuroprotective and immunoregulatory protein follistatin-like 1 (FSTL1) was identified as one of the downregulated proteins in the CA-MSC secretome, with suppressive effects on proinflammatory microglial activation. Our study findings suggest that targeting aspects of the downregulated anti-inflammatory secretome, such as FSTL1, might improve the efficacy of autologous MSC therapy for CA.

Critical curvature localization in graphene. II. Non-local flexoelectricity-dielectricity coupling.

As a sequel of part I (Kothari et al. 2018 Proc. R. Soc. A 474, 20180054), we present a general thermodynamic framework of flexoelectric constitutive laws for multi-layered graphene (MLG), and apply these laws to explain the role of crinkles in peculiar molecular adsorption characteristics of highly oriented pyrolytic graphite (HOPG) surfaces. The thermodynamically consistent constitutive laws lead to a non-local interaction model of polarization induced by electromechanical deformation with flexoelectricity-dielectricity coupling. The non-local model predicts curvature and polarization localization along crinkle valleys and ridges very close to those calculated by density functional theory (DFT). Our analysis reveals that the non-local model can be reduced to a simplified uc-local or e-local model (Kothari et al. 2018 Proc. R. Soc. A 474, 20180054) only when the curvature distribution is uniform or highly localized. For the non-local model, we calibrated and formulated the layer-number-dependent dielectric and intrinsic flexoelectric coefficients of MLGs. In addition, we also obtained layer-number dependent flexoelectric coefficients for uc-local and e-local models. Our DFT analysis shows that polarization-induced adsorption of neutral molecules at crinkle ridges depends on the molecular weight of the molecule. Furthermore, our detailed study of polarization localization in graphene crinkles enables us to understand previously unexplained self-organized adsorption of C60 buckyballs in a linear array on an HOPG surface.

Mesenchymal Stem Cells Ameliorate Renal Inflammation in Adriamycin-induced Nephropathy.

Mesenchymal stem cells (MSCs) ameliorate the renal injury in Adriamycin (ADR)-induced nephropathy, but the mechanisms underlying their efficacy remain incompletely understood. In this study, we demonstrated that MSCs increased the survival, recovered body weight loss, and decreased proteinuria and serum creatinine levels in ADR-treated mice. MSCs also prevented podocyte damage and renal fibrosis by decreasing the expression of fibronectin, collagen 1α1, and α-smooth muscle actin. From a mechanistic perspective, MSCs inhibited renal inflammation by lowering the expression of CCL4, CCL7, CCL19, IFN-α/ß, TGF-ß, TNF-α, and chitinase 3-like 1. In summary, our data demonstrate that MSCs improve renal functions by inhibiting renal inflammation in ADR-induced nephropathy.

Implantation of human umbilical cord-derived mesenchymal stem cells as a neuroprotective therapy for ischemic stroke in rats.

In the present study, we examined the neuroprotective effects and mechanisms of implanted human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) in ischemic stroke. hUC-MSCs were isolated from the endothelial/subendothelial layers of the human umbilical cord and cultured. Twenty days after the induction of in vitro neuronal differentiation, about 77.4% of the inoculated hUC-MSCs displayed morphological features of neurons and expressed neuronal cell markers like TU-20, Trk A, NeuN, and NF-M. However, functionally active neuronal type channels were not detected by electrophysiological examination. Before, during, or one day after in vitro neuronal differentiation, the hUC-MSCs produced granulocyte-colony stimulating factor, vascular endothelial growth factor, glial cell line-derived neurotrophic factor, and brain-derived neurotrophic factor. In an in vivo study, implantation of the hUC-MSCs into the damaged hemisphere of immunosuppressed ischemic stroke rats improved neurobehavioral function and reduced infarct volume relative to control rats. Three weeks after implantation, most of the implanted hUC-MSCs were present in the damaged hemisphere; some of these cells expressed detectable levels of neuron-specific markers. Nestin expression in the hippocampus was increased in the hUC-MSC-implanted group relative to the control group. Since the hUC-MSCs were both morphologically differentiated into neuronal cells and able to produce neurotrophic factors, but had not become functionally active neuronal cells, the improvement in neurobehavioral function and the reduction of infarct volume might be related to the neuroprotective effects of hUC-MSCs rather than the formation of a new network between host neurons and the implanted hUC-MSCs.

Proteomic analysis of recombinant Saccharomyces cerevisiae upon iron deficiency induced via human H-ferritin production.

In our previous study, the expression of active H-ferritins in Saccharomyces cerevisiae was found to reduce cell growth and reactive oxygen species (ROS) generation upon exposure to oxidative stress; such expression enhanced that of high-affinity iron transport genes (FET3 and FTR1). The results suggested that the recombinant cells expressing H-ferritins induced cytosolic iron depletion. The present study analyzes metabolic changes under these circumstances via proteomic methods. The YGH2 yeast strain expressing H-ferritin, the YGH2-KG (E62K and H65G) mutant strain, and the YGT control strain were used. Comparative proteomic analysis showed that the synthesis of 34 proteins was at least stimulated in YGH2, whereas the other 37 proteins were repressed. Among these, the 31 major protein spots were analyzed via nano-LC/MS/MS. The increased proteins included major heat-shock proteins and proteins related to endoplasmic reticulum-associated degradation (ERAD). On the other hand, the proteins involved with folate metabolism, purine and methionine biosynthesis, and translation were reduced. In addition, we analyzed the insoluble protein fractions and identified the fragments of Idh1p and Pgk1p, as well as several ribosomal assembly-related proteins. This suggests that intracellular iron depletion induces imperfect translation of proteins. Although the proteins identified above result from changes in iron metabolism (i.e., iron deficiency), definitive evidence for iron-related proteins remains insufficient. Nevertheless, this study is the first to present a molecular model for iron deficiency, and the results may provide valuable information on the regulatory network of iron metabolism.