MYB proteins are a superfamily of transcription factors that play regulatory roles in developmental processes and defense responses in plants. We identified 198 genes in the MYB superfamily from an analysis of the complete Arabidopsis genome sequence, among them, 126 are R2R3-MYB, 5 are R1R2R3-MYB, 64 are MYB-related, and 3 atypical MYB genes. Here we report the expression profiles of 163 genes in the Arabidopsis MYB superfamily whose full-length open reading frames have been isolated. This analysis indicated that the expression for most of the Arabidopsis MYB genes were responsive to one or multiple types of hormone and stress treatments. A phylogenetic comparison of the members of this superfamily in Arabidopsis and rice suggested that the Arabidopsis MYB superfamily underwent a rapid expansion after its divergence from monocots but before its divergence from other dicots. It is likely that the MYB-related family was more ancient than the R2R3-MYB gene family, or had evolved more rapidly. Therefore, the MYB gene superfamily represents an excellent system for investigating the evolution of large and complex gene families in higher plants. Our comprehensive analysis of this largest transcription factor superfamily of Arabidopsis and rice may help elucidate the possible biological roles of the MYB genes in various aspects of flowering plants.

Here we demonstrate biallelic mutations in sorbitol dehydrogenase (SORD) as the most frequent recessive form of hereditary neuropathies. We identified 45 cases from 38 families across multiple ethnicities, carrying a particular nonsense mutation in SORD, c.753delG; p.Ala253GlnfsTer27, either in homozygous or compound heterozygous state with a second variant. With an allele frequency of 0.004 in healthy controls, the p.Ala253GlnfsTer27 variant represents one of the most common pathogenic alleles in humans. SORD is an enzyme that converts sorbitol into fructose, in the two-step polyol pathway that has been implicated in diabetic neuropathy. In patient-derived fibroblasts, we find a complete loss of SORD protein as well as increased intracellular sorbitol. Also, serum fasting sorbitol level was over 100 times higher in patients homozygous for the p.Ala253GlnfsTer27 mutation compared to healthy individuals. In Drosophila, we show that loss of SORD orthologues causes synaptic degeneration and progressive motor impairment. Reducing the polyol influx by treatment with aldose reductase inhibitors normalized intracellular sorbitol levels in patient fibroblasts and in Drosophila, and also dramatically ameliorated motor and eye phenotypes. Together, these findings establish a potentially treatable cause in a significant fraction of patients with inherited neuropathies and may contribute to a better understanding of the pathophysiology of diabetic neuropathy.

Myofibroblasts characterized by alpha smooth muscle actin(alpha-SMA) expression play a key role in pulmonary fibrosis. Transforming growth factor-beta1 (TGF-beta1) is likely to be involved in the emergence of myofibroblasts, but the intracellular signal pathways for this process have not been well determined. The aim of the present study was to investigate the role of mitogen-activated protein kinase (MAPK)/activator protein-1 (AP-1) signaling pathways in TGF-beta1-induced alpha-SMA expression in human fetal lung fibroblasts (HLF-02). We found that TGF-beta1 treatment activated p38 kinase and extracellular signal-regulated kinase (Erk) in HLF-02 cells. The induction of alpha-SMA by TGF-beta1 was suppressed by p38 kinase inhibitor (SB203580) and Erk inhibitor (PD98059). AP-1 inhibitor curcumin also inhibited TGF-beta1-induced alpha-SMA expression. In addition, dominant negative mutant c-Jun (TAM67) downregulated TGF-beta1-induced AP-1 transactivation and alpha-SMA expression. In additional, PD98059 but not SB203580 inhibited the AP-1 DNA binding activity induced by TGF-beta1. Based on these findings, we conclude that p38 kinase, Erk, and AP-1 are responsible for the alpha-SMA expression induced by TGF-beta1 in human fetal lung fibroblasts. Erk is involved in inducing alpha-SMA expression via AP-1 activation.

Background and Purpose— Early presentation is critical for receiving effective reperfusion therapy for acute ischemic stroke, therefore, we undertook a national survey of awareness and responses to acute stroke symptoms in China. Methods— We undertook a cross-sectional community-based study of 187 723 adults (age ≥40 years) presenting to 69 administrative areas across China between January 2017 and May 2017 to determine the national stroke recognition rate and the correct action rate. Multivariable logistic regression models were used to identify factors associated with stroke recognition and intention-to-avail emergency medical services. Results— Estimates of stroke recognition rate and correct action rate were 81.9% (153 675/187 723) and 60.9% (114 380/187 723), respectively, but these rates varied widely by sociodemographic status, region, and stroke risk. Approximately one-third of participants who recognized a stroke failed to call emergency medical service. Low likelihood of emergency medical service use was associated with younger age (40–59 years), being male, rural location, (regions of east, south, and northwest China), high body mass index (≥24), low education (primary school or below), low personal income (<US $731 per annum), living with immediate family, having multiple children (≥2), having a friend with stroke, exposure to less avenues to learn about stroke, nonsmoking, regular exercise, unknown family history, and no history of cardiovascular disease. Intention of calling emergency medical service was strongly related to awareness of stroke (odds ratio 2.05; 95% CI, 2.00–2.10; P <0.001). Conclusions— Substantial discrepancies exist between stroke recognition and correct action and not all stroke patients know the appropriate responses. Further, national stroke educational programs with specific plans targeting different groups are needed, which do not solely focus on stroke recognition, but also on the appropriate responses at the time of a stroke.

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BACKGROUND: In human pancreatic adenocarcinoma, nuclear factor-kappa-B (NF-kB) transcription factor is constitutively activated that contributes to the resistance of the tumour cells to induced apoptosis. In our earlier studies, we have shown that brucein D (BD) mediated apoptosis through activation of the p38-mitogen-activated protein kinase (MAPK) signalling pathway in pancreatic cancer cells. This study investigated the function of reactive oxygen species (ROS) in BD-mediated p38-MAPK and NF-kB signalling pathways in PANC-1 cells. METHODS: Glutathione and dihydroethidium assays were used to measure the antioxidant and superoxide levels, respectively. The protein expression of p22 phox , p67 phox and p38-MAPK were examined by western blot. The NF-kB activity was evaluated by electrophoretic mobility shift assay. RESULTS: Treatment with BD depleted the intracellular glutathione levels in PANC-1 cells. Brucein D triggered the activation of NADPH oxidase isoforms, p22 phox and p67 phox while enhancing the generation of superoxide. Increases in both intracellular ROS and NADPH oxidase activity were inhibited by an antioxidant, N-acetylcysteine (NAC). Brucein D-mediated activation of p38-MAPK was also inhibited by NAC. However, inhibition of NF-kB activity in BD-treated cells was independent of ROS. In vivo studies showed that BD treatment effectively reduced the rate of xenograft human pancreatic tumour in nude mice with no significant toxicity. CONCLUSION: These data suggest that BD is an apoptogenic agent for pancreatic cancer cells through activation of the redox-sensitive p38-MAPK pathway and inhibition of NF-kB anti-apoptotic activity in pancreatic cancer cells.

Uncaria rhynchophylla is a component herb of many Chinese herbal formulae for the treatment of neurodegenerative diseases. Previous study in our laboratory has demonstrated that an ethanol extract of Uncaria rhynchophylla ameliorated cognitive deficits in a mouse model of Alzheimer's disease induced by D-galactose. However, the active ingredients of Uncaria rhynchophylla responsible for the anti-Alzheimer's disease activity have not been identified. This study aims to identify the active ingredients of Uncaria rhynchophylla by a bioassay-guided fractionation approach and explore the acting mechanism of these active ingredients by using a well-established cellular model of Alzheimer's disease, beta-amyloid- (Aβ-) induced neurotoxicity in PC12 cells. The results showed that six alkaloids, namely, corynoxine, corynoxine B, corynoxeine, isorhynchophylline, isocorynoxeine, and rhynchophylline were isolated from the extract of Uncaria rhynchophylla. Among them, rhynchophylline and isorhynchophylline significantly decreased Aβ-induced cell death, intracellular calcium overloading, and tau protein hyperphosphorylation in PC12 cells. These results suggest that rhynchophylline and isorhynchophylline are the major active ingredients responsible for the protective action of Uncaria rhynchophylla against Aβ-induced neuronal toxicity, and their neuroprotective effect may be mediated, at least in part, by inhibiting intracellular calcium overloading and tau protein hyperphosphorylation.

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