Airway Smooth Muscle Inflammation Is Regulated by MicroRNA-145 in COPD.

Chronic obstructive pulmonary disease (COPD) is a common, highly debilitating disease of the airways, primarily caused by smoking. Chronic inflammation and structural remodelling are key pathological features of this disease, in part caused by the aberrant function of airway smooth muscle (ASM) cells under the regulation of transforming growth factor (TGF)-β. MicroRNAs are short, non-coding gene transcripts involved in the negative regulation of specific target genes, through their interactions with messenger RNAs. Previous studies have proposed that microRNA-145 (miR-145) may interact with SMAD3, an important downstream signalling molecule of the TGF-β pathway. TGF-β was used to stimulate primary human ASM cells isolated from healthy non-smokers, healthy smokers and COPD patients. This resulted in a TGF-β-dependent increase in CXCL8 and IL-6 release, most notably in the cells from COPD patients. TGF-β stimulation increased SMAD3 expression, only in cells from COPD patients, with a concurrent increased miR-145 expression. Regulation of miR-145 was found to be negatively controlled by pathways involving the MAP kinases, MEK-1/2 and p38 MAPK. Subsequent, overexpression of miR-145 (using synthetic mimics) in ASM cells from patients with COPD suppressed IL-6 and CXCL8 release, to levels comparable to the non-smoker controls. Therefore, this study suggests that miR-145 negatively regulates pro-inflammatory cytokine release from ASM cells in COPD by targeting SMAD3

Mesenchymal stromal cells of human umbilical cord Wharton's jelly accelerate wound healing by paracrine mechanisms

名古屋大学Nagoya University博士(医学)Background aims. Mesenchymal stromal cells (MSC) can be isolated from the perivascular connective tissue of umbilical cords, called Wharton's jelly. These human umbilical cord perivascular cells (HUCPVC) might provide therapeutic benefits when treating skeletal or cutaneous malformations in neonatal patients. Methods. HUCPVC were isolated, and their proliferation rate, marker expression and multilineage differentiation potential determined. HUCPVC or their conditioned medium (HUCPVC-CM) was injected into the excisional wound of a mouse splinted-wound model. The effects of the treatment on wound closure were examined by morphohistochemical and gene expression analyses. Results. HUCPVC expressed typical MSC markers and could differentiate into osteoblastic and adipogenic lineages. HUCPVC transplanted into the mouse wound accelerated wound closure. Immunohistologic analysis showed that the HUCPVC accelerated wound healing by enhancing collagen deposition and angiogenesis via paracrine mechanisms. Furthermore, treatment with HUCPVC-CM alone significantly enhanced wound closure. HUCPVC-CM increased the number of anti-inflammatory M2 macrophages expressing resistin-like molecule (RELM)-α/CD11b and promoted neovessel maturation. Quantitative polymerase chain reaction (PCR) analysis showed that HUCPVC-CM increased the expression of tissue-repairing cytokines interleukin (IL)-10, transforming growth factor (TGF)-β1, vascular endothelial growth factor (VEGF)-1 and angiopoietin-1 at the healing wound. Conclusions. Our results show that HUCPVC promotes wound healing via multifaceted paracrine mechanisms. Together with their ability to differentiate into the osteogenic linage, HUCPVC may provide significant therapeutic benefits for treating wounds in neonatal patients.名古屋大学博士学位論文 学位の種類 : 博士(医学)(課程) 学位授与年月日:平成25年1月31日 匠原龍太郎氏の博士論文として提出されたdoctoral thesi

Interaction between the Circadian Clock and Regulators of Heat Stress Responses in Plants.

The circadian clock is found ubiquitously in nature, and helps organisms coordinate internal biological processes with environmental cues that inform the time of the day or year. Both temperature stress and the clock affect many important biological processes in plants. Specifically, clock-controlled gene regulation and growth are impacted by a compromised clock or heat stress. The interactions linking these two regulatory pathways include several rhythmic transcription factors that are important for coordinating the appropriate response to temperature stress. Here we review the current understanding of clock control of the regulators involved in heat stress responses in plants

The Plant Heat Stress Transcription Factors (HSFs): Structure, Regulation, and Function in Response to Abiotic Stresses

Abiotic stresses such as high temperature, salinity and drought adversely affect the survival, growth and reproduction of plants. Plants respond to such unfavorable changes through developmental, physiological and biochemical ways, and these responses require expression of stress-responsive genes, which are regulated by a network of transcription factors (TFs), including heat stress transcription factors (HSFs). HSFs play a crucial role in plants response to several abiotic stresses by regulating the expression of stress-responsive genes, such as heat shock proteins (Hsps). In this review, we describe the conserved structure of plant HSFs, the identification of HSF gene families from various plant species, their expression profiling under abiotic stress conditions, regulation at different levels and function in abiotic stresses. Despite plant HSFs share highly conserved structure, their remarkable diversification across plants reflects their numerous functions as well as their integration into the complex stress signaling and response networks, which can be employed in crop improvement strategies via biotechnological intervention

Human Embryonic and Fetal Mesenchymal Stem Cells Differentiate toward Three Different Cardiac Lineages in Contrast to Their Adult Counterparts

Mesenchymal stem cells (MSCs) show unexplained differences in differentiation potential. In this study, differentiation of human (h) MSCs derived from embryonic, fetal and adult sources toward cardiomyocytes, endothelial and smooth muscle cells was investigated. Labeled hMSCs derived from embryonic stem cells (hESC-MSCs), fetal umbilical cord, bone marrow, amniotic membrane and adult bone marrow and adipose tissue were co-cultured with neonatal rat cardiomyocytes (nrCMCs) or cardiac fibroblasts (nrCFBs) for 10 days, and also cultured under angiogenic conditions. Cardiomyogenesis was assessed by human-specific immunocytological analysis, whole-cell current-clamp recordings, human-specific qRT-PCR and optical mapping. After co-culture with nrCMCs, significantly more hESC-MSCs than fetal hMSCs stained positive for α-actinin, whereas adult hMSCs stained negative. Furthermore, functional cardiomyogenic differentiation, based on action potential recordings, was shown to occur, but not in adult hMSCs. Of all sources, hESC-MSCs expressed most cardiac-specific genes. hESC-MSCs and fetal hMSCs contained significantly higher basal levels of connexin43 than adult hMSCs and co-culture with nrCMCs increased expression. After co-culture with nrCFBs, hESC-MSCs and fetal hMSCs did not express α-actinin and connexin43 expression was decreased. Conduction velocity (CV) in co-cultures of nrCMCs and hESC-MSCs was significantly higher than in co-cultures with fetal or adult hMSCs. In angiogenesis bioassays, only hESC-MSCs and fetal hMSCs were able to form capillary-like structures, which stained for smooth muscle and endothelial cell markers.Human embryonic and fetal MSCs differentiate toward three different cardiac lineages, in contrast to adult MSCs. Cardiomyogenesis is determined by stimuli from the cellular microenvironment, where connexin43 may play an important role

Alpha-boswellic acid accelerates acute wound healing via NF-κB signaling pathway.

BackgroundBoswellic acids (BAs) showed promising effects in cancer treatment, immune response regulation, and anti-inflammatory therapy. We aimed to assess the roles of alpha-BA (α-BA) in treating acute wound healing.MethodsIn vivo wound-healing models were established to evaluate the therapeutic effects of α-BA. Cell assays were conducted to assess the impact of α-BA on cellular biological functions. Western blot analysis was employed to validate the potential mechanisms of action of α-BA.ResultsAnimal models indicated that wound healing was notably accelerated in the α-BA group compared to the control group (P Conclusionsα-BA demonstrated the ability to counteract the abnormal proliferation of skin scar tissues, consequently expediting wound healing. These findings suggest its potential for development as a new agent for treating acute wound healing

Tomato plant response to heat stress: a focus on candidate genes for yield-related traits

Climate change and global warming represent the main threats for many agricultural crops. Tomato is one of the most extensively grown and consumed horticultural products and can survive in a wide range of climatic conditions. However, high temperatures negatively affect both vegetative growth and reproductive processes, resulting in losses of yield and fruit quality traits. Researchers have employed different parameters to evaluate the heat stress tolerance, including evaluation of leaf- (stomatal conductance, net photosynthetic rate, Fv/Fm), flower- (inflorescence number, flower number, stigma exertion), pollen-related traits (pollen germination and viability, pollen tube growth) and fruit yield per plant. Moreover, several authors have gone even further, trying to understand the plants molecular response mechanisms to this stress. The present review focused on the tomato molecular response to heat stress during the reproductive stage, since the increase of temperatures above the optimum usually occurs late in the growing tomato season. Reproductive-related traits directly affects the final yield and are regulated by several genes such as transcriptional factors, heat shock proteins, genes related to flower, flowering, pollen and fruit set, and epigenetic mechanisms involving DNA methylation, histone modification, chromatin remodelling and non-coding RNAs. We provided a detailed list of these genes and their function under high temperature conditions in defining the final yield with the aim to summarize the recent findings and pose the attention on candidate genes that could prompt on the selection and constitution of new thermotolerant tomato plant genotypes able to face this abiotic challenge

HTRgene: a computational method to perform the integrated analysis of multiple heterogeneous time-series data: case analysis of cold and heat stress response signaling genes in Arabidopsis

Background Integrated analysis that uses multiple sample gene expression data measured under the same stress can detect stress response genes more accurately than analysis of individual sample data. However, the integrated analysis is challenging since experimental conditions (strength of stress and the number of time points) are heterogeneous across multiple samples. Results HTRgene is a computational method to perform the integrated analysis of multiple heterogeneous time-series data measured under the same stress condition. The goal of HTRgene is to identify response order preserving DEGs that are defined as genes not only which are differentially expressed but also whose response order is preserved across multiple samples. The utility of HTRgene was demonstrated using 28 and 24 time-series sample gene expression data measured under cold and heat stress in Arabidopsis. HTRgene analysis successfully reproduced known biological mechanisms of cold and heat stress in Arabidopsis. Also, HTRgene showed higher accuracy in detecting the documented stress response genes than existing tools. Conclusions HTRgene, a method to find the ordering of response time of genes that are commonly observed among multiple time-series samples, successfully integrated multiple heterogeneous time-series gene expression datasets. It can be applied to many research problems related to the integration of time series data analysis.This work, including publication costs, was supported by National Research Foundation of Korea(NRF) funded by the Ministry of Science, ICT (No.NRF-2017M3C4A7065887). This work was also supported by the Collaborative Genome Program for Fostering New Post-Genome Industry of the National Research Foundation (NRF) funded by the Ministry of Science and ICT (MSIT) (No. NRF-2014M3C9A3063541), and a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HI15C3224). This work was supported for W.J. by the Agenda program (No.PJ012465032019), Rural Development of dministration of Republic of Korea

Venous Blood Derivatives as FBSSubstitutes for Mesenchymal Stem Cells: A Systematic Scoping Review

Although the biological properties of mesenchymal stem cells (MSC) are well-characterized in vitro, MSC clinical application is still far away to be achieved, mainly due to the need of xenogeneic substances for cell expansion, such as fetal bovine serum (FBS). FBS presents risks regarding pathogens transmissions and internalization of animal’s proteins, which can unleash antigenic responses in patients after MSC implantation. A wide range of venous blood derivatives (VBD) has been reported as FBS substitutes showing promising results. Thus, the aim of this study was to conduct a systematic scoping review to analyze whether VBD are effective FBS substitutes for MSC ex vivo expansion. The search was performed in SciVerse ScopusTM, PubMed, Web of ScienceTM, BIREME, Cochrane library up to January 2016. The keywords were selected using MeSH and entry terms. Two independent reviewers scrutinized the records obtained considering specific inclusion criteria. The included studies were evaluated in accordance with a modified Arksey and O’ Malley’s framework. From 184 found studies, 90 were included. Bone marrow mesenchymal stem cells (BMMSC) were presented in most of these studies. Overall, VBD allowed for either, maintenance of MCS’s fibroblast-like morphology, high proliferation, high colony-formation ability and maintenance of multipotency. Besides. MSC expanded in VBD supplements presented higher mitogen activity than FBS. VBD seems to be excellent xeno-free serum for ex vivo expansion of mesenchymal stem cells. However, an accentuated heterogeneity was observed between the carried out protocols for VBD isolation did not allowing for direct comparisons between the included studies