First Clinical Report on the Treatment of Parkinson's Disease with Fetal Midbrain Precursor Cells.

BACKGROUND: Because human fetal ventral mesencephalic tissue grafts provide promising results in ameliorating Parkinson's disease-implicated motor dysfunctions, human fetal midbrain-derived dopamine neuronal precursor cells are considered good candidates for cell-based therapy for Parkinson's disease in that large quantities of cells can be supplied through a good manufacturing practice-compliant system. OBJECTIVE: We conducted a prospective, phase I/IIa, dose-escalation, open-label "first-in-human" clinical trial with fetal neural precursor cells to assess their safety and therapeutic efficacy in patients with idiopathic Parkinson's disease. METHODS: Fifteen patients were assigned to receive three different doses of cells (4 × 106 , 12 × 106 , and 40 × 106 cells) and completed a 12-month follow-up. The primary outcome was safety, by measuring the presence of grade 3 or higher cells according to National Cancer Institute guidelines and any contaminated cells. Secondary outcomes assessed motor and neurocognitive function, as well as the level of dopamine transporters, by positron emission tomography-computed tomography. RESULTS: Although a pronation-supination and hand/arm movement performance was remarkably enhanced in all three groups (all P < 0.05), the medium- and high-dose-treated groups exhibited significant improvement in Unified Parkinson's Disease Rating Scale Part III only up to 26.16% and 40%, respectively, at 12 months after transplantation without any serious clinical complications or graft-induced dyskinesia in all patients. However, the motor improvements did not correlate with increase in the dopamine transporter on positron emission tomography images. CONCLUSIONS: Our results primarily demonstrate the safety and plausible dose-dependent efficacy of human fetal midbrain-derived dopamine neuronal precursor cells for idiopathic Parkinson's disease. © 2023 International Parkinson and Movement Disorder Society.

Black Ginseng Extract Suppresses Airway Inflammation Induced by Cigarette Smoke and Lipopolysaccharides In Vivo.

Cigarette smoke (CS) is a risk factor that can induce airway enlargement, airway obstruction, and airway mucus hypersecretion. Although studies have shown that Korean black ginseng extract (BGE) has potent anti-inflammatory and antioxidant activities, the CS-induced inflammatory responses and molecular mechanisms are yet to be examined. The aim of this study was to examine the effect of BGE on the airway inflammatory response and its molecular mechanisms, using CS/lipopolysaccharides (LPS)-exposed animals and PMA-stimulated human airway epithelial NCI-H292 cells. The results show that BGE inhibited the recruitment of immune cells and the release of inflammatory mediators, such as tumor necrosis factor (TNF)-α and interleukin (IL)-6, monocyte chemoattractant protein (MCP)-1, elastase, and reactive oxygen species (ROS) in the airways of CS/LPS-exposed animals. BGE inhibited mucus secretion and the expression of Mucin 5AC (MUC5AC). Furthermore, BGE exhibited an anti-inflammatory effect by downregulating a signaling pathway mediated by transforming growth factor-ß-activated kinase (TAK) 1, an important protein that accelerates inflammation by cigarette smoke (CS). Overall, the findings show that BGE inhibits lung inflammation and mucus secretion by decreasing the activation of TAK1 both in human epithelial cells and in CS/LPS-exposed animals, and could be a potential adjuvant in the treatment and prevention of airway inflammatory diseases caused by airway irritants such as CS.

Decipher reliable biomarkers of brain aging by integrating literature-based evidence with interactome data.

Aging is an inevitable progressive decline in every physiological function and serves as a primary risk factor for cognitive decline and Alzheimer's disease. Thus, age-dependent impairments in cognitive function must be understood in association with general aging processes with an integrative approach in a systemic manner. An integrative aging gene network was constructed based on mutual molecular interactions using literature-curated interactome data and separated into functionally distinct modules. To investigate key surrogate biomarkers of the aging brain in the context of the general aging process, co-expression networks were built on post-mortem and Alzheimer's brain transcriptome data. In both the normal aging brain and the brain affected by Alzheimer's disease, the immune-related co-expression module was positively correlated with advancing age, whereas the synaptic transmission-related co-expression module was decreased with age. Importantly, the network topology-based analysis indicated that complement system genes were prioritized as a surrogate biomarker in evaluating the process of brain aging. Our public data-centered analysis coupled with experimental validation revealed that the complement system is likely to be a master regulator in initiating and regulating the immune system in the aging brain and could serve as reliable and surrogate biomarkers for the diagnosis of cognitive dysfunction.

Immunomodulatory effect of CD200-positive human placenta-derived stem cells in the early phase of stroke.

Human placenta amniotic membrane-derived mesenchymal stem cells (AMSCs) regulate immune responses, and this property can be exploited to treat stroke patients via cell therapy. We investigated the expression profile of AMSCs cultured under hypoxic conditions and observed interesting expression changes in various genes involved in immune regulation. CD200, an anti-inflammatory factor and positive regulator of TGF-ß, was more highly expressed under hypoxic conditions than normoxic conditions. Furthermore, AMSCs exhibited inhibition of pro-inflammatory cytokine expression in co-cultures with LPS-primed BV2 microglia, and this effect was decreased in CD200-silenced AMSCs. The AMSCs transplanted into the ischemic rat model of stroke dramatically inhibited the expression of pro-inflammatory cytokines and up-regulated CD200, as compared with the levels in the sham-treated group. Moreover, decreased microglia activation in the boundary region and improvements in behavior were confirmed in AMSC-treated ischemic rats. The results suggested that the highly expressed CD200 from the AMSCs in a hypoxic environment modulates levels of inflammatory cytokines and microglial activation, thus increasing the therapeutic recovery potential after hypoxic-ischemic brain injury, and further demonstrated the immunomodulatory function of AMSCs in a stroke model.

Bacterial ß-(1,3)-glucan prevents DSS-induced IBD by restoring the reduced population of regulatory T cells.

Bacterial ß-(1,3)-glucan has more advantages in terms of cost, yield and efficiency than that derived from mushrooms, plants, yeasts and fungi. We have previously developed a novel and high-yield ß-(1,3)-glucan produced by Agrobacterium sp. R259. This study aimed to elucidate the functional mechanism and therapeutic efficacy of bacterial ß-(1,3)-glucan in dextran sulfate sodium (DSS)-induced inflammatory bowel disease (IBD).Mice were orally pretreated with bacterial ß-(1,3)-glucan at daily doses of 2.5 or 5mg/kg for 2 weeks. After 6 days of DSS treatment, clinical assessment of IBD severity and expression of pro-inflammatory cytokines were evaluated. In vivo cell proliferation was examined by immunohistochemistry using Ki-67 and ER-TR7 antibodies. The frequency of regulatory T cells (Tregs) was analyzed by flow cytometry. Natural killer (NK) activity and IgA level were evaluated using NK cytotoxicity assay and ELISA.The deterioration of body weight gain, colonic architecture, disease score and histological score was recovered in DSS-induced IBD mice when pretreated with bacterial ß-(1,3)-glucan. The recruitment of macrophages and the gene expression of proinflammatory cytokines, such as IL-1ß, IL-6 and IL-17A/F, were markedly decreased in the colon of ß-(1,3)-glucan-pretreated mice. ß-(1,3)-Glucan induced the recovery of Tregs in terms of their frequency in DSS-induced IBD mice. Intriguingly, ß-(1,3)-glucan reversed the functional defects of NK cells and excessive IgA production in DSS-induced IBD mice.We conclude that bacterial ß-(1,3)-glucan prevented the progression of DSS-induced IBD by recovering the reduction of Tregs, functional defect of NK cells and excessive IgA production.

Formaldehyde exposure impairs the function and differentiation of NK cells.

We investigated the cytotoxic effects of formaldehyde (FA) on lymphocytes. FA-exposed mice showed a profound reduction not only in the number of natural killer (NK) cells but also in the expression of NK cell-specific receptors, but these mice did not exhibit decreases in the numbers of T or B lymphocytes. FA exposure also induced decreases in NK cytolytic activity and in the expression of NK cell-associated genes, such as IFN-γ, perforin and CD122. To determine the effect of FA on tumorigenicity, C57BL/6 mice were subcutaneously injected with B16F10 melanoma cells after FA exposure. The mass of the B16F10 tumor and the concentration of extravascular polymorphonuclear leukocytes were greater than those in unexposed tumor-bearing control mice. The number and cytolytic activity of NK cells were also reduced in B16F10 tumor-bearing mice exposed to FA. To determine how FA reduces the NK cell number, NK precursor (pNK) cells were treated with FA, and the differentiation status of the NK cells was analyzed. NK cell differentiation was impaired by FA treatment in a concentration-dependent manner. These findings indicate that FA exposure may promote tumor progression by impairing NK cell function and differentiation.