Induced Stem Cells as a Novel Multiple Sclerosis Therapy.

Stem cell replacement is providing hope for many degenerative diseases that lack effective therapeutic methods including multiple sclerosis (MS), an inflammatory demyelinating disease of the central nervous system. Transplantation of neural stem cells or mesenchymal stem cells is a potential therapy for MS thanks to their capacity for cell repopulation as well as for their immunomodulatory and neurotrophic properties. Induced pluripotent stem cell (iPSC), an emerging cell source in regenerative medicine, is also being tested for the treatment of MS. Remarkable improvement in mobility and robust remyelination have been observed after transplantation of iPSC-derived neural cells into demyelinated models. Direct reprogramming of somatic cells into induced neural cells, such as induced neural stem cells (iNSCs) and induced oligodendrocyte progenitor cells (iOPCs), without passing through the pluripotency stage, is an alternative for transplantation that has been proved effective in the congenital hypomyelination model. iPSC technology is rapidly progressing as efforts are being made to increase the efficiency of iPSC therapy and reduce its potential side effects. In this review, we discuss the recent advances in application of stem cells, with particular focus on induced stem/progenitor cells (iPSCs, iNSC, iOPCs), which are promising in the treatment of MS

Pinocembrin protects against β-amyloid-induced toxicity in neurons through inhibiting receptor for advanced glycation end products (RAGE)-independent signaling pathways and regulating mitochondrion-mediated apoptosis

BACKGROUND: It is known that amyloid-β peptide (Aβ) plays a pivotal role in the pathogenesis of Alzheimer's disease (AD). Interaction between Aβ and the receptor for advanced glycation end products (RAGE) has been implicated in neuronal degeneration associated with this disease. Pinocembrin, a flavonoid abundant in propolis, has been reported to possess numerous biological activities beneficial to health. Our previous studies have demonstrated that pinocembrin has neuroprotective effects on ischemic and vascular dementia in animal models. It has been approved by the State Food and Drug Administration of China for clinical use in stroke patients. Against this background, we investigated the effects of pinocembrin on cognitive function and neuronal protection against Aβ-induced toxicity and explored its potential mechanism. METHODS: Mice received an intracerebroventricular fusion of Aβ(25-35). Pinocembrin was administrated orally at 20 mg/kg/day and 40 mg/kg/day for 8 days. Behavioral performance, cerebral cortex neuropil ultrastructure, neuronal degeneration and RAGE expression were assessed. Further, a RAGE-overexpressing cell model and an AD cell model were used for investigating the mechanisms of pinocembrin. The mechanisms underlying the efficacy of pinocembrin were conducted on target action, mitochondrial function and potential signal transduction using fluorescence-based multiparametric technologies on a high-content analysis platform. RESULTS: Our results showed that oral administration of pinocembrin improved cognitive function, preserved the ultrastructural neuropil and decreased neurodegeneration of the cerebral cortex in Aβ(25-35)-treated mice. Pinocembrin did not have a significant effect on inhibiting Aβ(1-42 )production and scavenging intracellular reactive oxygen species (ROS). However, pinocembrin significantly inhibited the upregulation of RAGE transcripts and protein expression both in vivo and in vitro, and also markedly depressed the activation of p38 mitogen-activated protein kinase (MAPK)-MAPKAP kinase-2 (MK2)-heat shock protein 27 (HSP27) and stress-activated protein kinase (SAPK)/c-Jun N-terminal kinase (JNK)-c-Jun pathways and the downstream nuclear factor κB (NFκB) inflammatory response subsequent to Aβ-RAGE interaction. In addition, pinocembrin significantly alleviated mitochondrial dysfunction through improving mitochondrial membrane potential and inhibiting mitochondrial oxidative stress, and regulated mitochondrion-mediated apoptosis by restoration of B cell lymphoma 2 (Bcl-2) and cytochrome c and inactivation of caspase 3 and caspase 9. CONCLUSIONS: Pinocembrin was shown to infer cognitive improvement and neuronal protection in AD models. The mechanisms of action of the compound were illustrated on RAGE-dependent transduction inhibition and mitochondrion protection. It appears to be a promising candidate for the prevention and therapy of AD

Discontinuation of Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia With Losing Major Molecular Response as a Definition for Molecular Relapse: A Systematic Review and Meta-Analysis

Background: A new goal in treatment of chronic myeloid leukemia (CML) in patients with stable deep molecular response (DMR) is maintaining durable treatment-free remission (TFR) after discontinuing tyrosine kinase inhibitor (TKI) treatment.Methods: We conducted a systematic review and meta-analysis focusing on the efficacy and safety of TKI discontinuation but also exploring the factors contributing to successful TFR.Results: The search yielded 10 trials including 1,601 patients. For patients who discontinued TKIs, the estimated weighted mean incidence of major molecular relapse was 16% (95%CI: 11–21), 34% (95%CI: 29–38), 39% (95%CI: 35–43) and 41% (95%CI: 36–47) at 3, 6, 12, and 24 months, respectively. Of these, 39, 82, and 95% of molecular losses occurred within the first 3, 6, and 12 months. In safety analysis, among patients without TFR, 98% (95% CI: 96–100) were sensitive to TKI retreatment. No new safety issues were identified except TKI withdrawal syndrome, which appeared during the early TFR phase, with a weighted mean incidence of 27% (95%CI: 19–35). Our subgroup analysis suggested better TFR associated with interferon therapy (P = 0.007), depth of molecular response (P = 0.018) and duration of DMR (P < 0.001).Conclusions: TFR as an extension of an approach to optimize management of CML is clinically feasible in approximately 59% of patients with sufficient TKI response. In the remaining 41% of patients with molecular relapse, discontinuing TKIs had no negative impact on clinical outcomes. Given the high heterogeneity among studies, the role of these predictors for successful TFR still requires further investigation

Halophilic Actinomycetes in 1 Saharan Soils of Algeria: Isolation, Taxonomy and Antagonistic Properties

The diversity of a population of 52 halophilic actinomycetes was evaluated by a polyphasic approach, which showed the presence of Actinopolyspora, Nocardiopsis, Saccharomonospora, Streptomonospora and Saccharopolyspora genera. One strain was considered to be a new member of the last genus and several other strains seem to be new species. Furthermore, 50% of strains were active against a broad range of indicators and contained genes encoding polyketide synthetases and nonribosomal peptide synthetases

Influenza-Associated Hospitalization in a Subtropical City

BACKGROUND: The impact of influenza on morbidity and hospitalization in the tropics and subtropics is poorly quantified. Uniquely, the Hong Kong Special Administrative Region has computerized hospital discharge diagnoses on 95% of total bed days, allowing disease burden for a well-defined population to be accurately assessed. METHODS AND FINDINGS: Influenza-associated morbidity and hospitalization was assessed by Poisson regression models for weekly counts of hospitalizations in Hong Kong during 1996 to 2000, using proportions of positive influenza types A (H1N1 and H3N2) and B isolations in specimens sent for laboratory diagnosis as measures of influenza virus circulation. We adjusted for annual trend, seasonality, temperature, and relative humidity, as well as respiratory syncytial virus circulation. We found that influenza was significantly associated with hospitalization for acute respiratory disease (International Classification of Diseases version 9 codes [ICD9] 460–466 and 480–487) and its subcategory pneumonia and influenza (ICD9 480–487) for all age groups. The annual rates of excess hospitalization per 100,000 population for acute respiratory diseases for the age groups 0–14, 15–39, 40–64, 65–74, and 75+ were 163.3 (95% confidence interval [CI], 135–190), 6.0 (95% CI, 2.7–8.9), 14.9 (95% CI, 10.7–18.8), 83.8 (95% CI, 61.2–104.2), and 266 (95% CI, 198.7–330.2), respectively. Influenza was also associated with hospitalization for cerebrovascular disease (ICD9 430–438) for those aged over 75 y (55.4; 95% CI, 23.1–87.8); ischemic heart disease (ICD9 410–414) for the age group 40–64 y (5.3; 95% CI, 0.5–9.5) and over 75 y (56.4; 95% CI, 21.1–93.4); and diabetes mellitus (ICD9 250) for all age groups older than 40 y. CONCLUSIONS: Influenza has a major impact on hospitalization due to cardio-respiratory diseases as well as on cerebrovascular disease, ischemic heart disease, and diabetes mellitus in the tropics and subtropics. Better utilization of influenza vaccine during annual epidemics in the tropics will enhance global vaccine production capacity and allow for better preparedness to meet the surge in demand that is inevitable in confronting a pandemic

Insight on the fundamentals of advanced oxidation processes. Role and review of the determination methods of reactive oxygen species

Advanced oxidation processes (AOPs) have known increased application to treat wastewaters containing recalcitrant compounds that are hardly degraded by conventional technologies. AOPs are characterized by the formation of strong oxidants such as hydroxyl radicals, superoxide anions, hydroperoxyl radicals and singlet oxygen, which react with the contaminant, contributing to its degradation. This paper provides an overview of the determination methods of reactive oxygen species, ROS, in the application of AOPs; the methods developed in the available literature for the detection and quantification of ROS are reviewed as a first step in the assessment and detailed description of the mechanisms involved in the oxidation reactions, focusing on the critical analysis of the main strengths and weaknesses presented by the probe molecules employed in the evaluated studies.This research was supported by the Ministry of Economy and Competitiveness (MINECO/SPAIN) and European Regional Development Fund (ERDF) under the project CTQ2011-25262