Age‐related cognitive decline in neurodegenerative diseases, such as Alzheimer's disease (AD), is associated with the deficits of synaptic plasticity. Therefore, exploring promising targets to ...enhance synaptic plasticity in neurodegenerative disorders is crucial. It has been demonstrated that methyl‐CpG binding protein 2 (MeCP2) plays a vital role in neuronal development and MeCP2 malfunction causes various neurodevelopmental disorders. However, the role of MeCP2 in neurodegenerative diseases has been less reported. In the study, we found that MeCP2 expression in the hippocampus was reduced in the hippocampus of senescence‐accelerated mice P8 (SAMP8) mice. Overexpression of hippocampal MeCP2 could elevate synaptic plasticity and cognitive function in SAMP8 mice, while knockdown of MeCP2 impaired synaptic plasticity and cognitive function in senescence accelerated‐resistant 1 (SAMR1) mice. MeCP2‐mediated regulation of synaptic plasticity may be associated with CREB1 pathway. These results suggest that MeCP2 plays a vital role in age‐related cognitive decline by regulating synaptic plasticity and indicate that MeCP2 may be promising targets for the treatment of age‐related cognitive decline in neurodegenerative diseases.
Decreased hippocampal MeCP2 expression contributes to age‐related cognitive decline by impairing synaptic plasticity. Upregulation of hippocampal MeCP2 could prevent age‐related decline in cognitive function and synaptic plasticity. MeCP2‐mediated regulation of synaptic plasticity may be associated with CREB1 pathway.
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DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
Astaxanthin is a kind of tetraterpene and has strong antioxygenic property. The biosynthesis of astaxanthin in engineered microbial chassis has greater potential than its chemical synthesis and ...extraction from natural producers in an environmental-friendly way. However, the cost-offsetting production of astaxanthin in engineered microbes is still constrained by the poor efficiency of astaxanthin synthesis pathway as a heterologous pathway.
To address the bottleneck of limited production of astaxanthin in microbes, we developed in vitro and in vivo recombination methods respectively in engineered yeast chassis to optimize the combination of heterologous β-carotene ketolase (crtW) and hydroxylase (crtZ) modules that were selected from different species. As a result, the in vitro and in vivo recombination methods enhanced the astaxanthin yield respectively to 2.11-8.51 folds and 3.0-9.71 folds compared to the initial astaxanthin pathway, according to the different combination of particular genes. The highest astaxanthin producing strain yQDD022 was constructed by in vivo method and produced 6.05 mg g
DCW of astaxanthin. Moreover, it was proved that the in vivo recombination method showed higher DNA-assembling efficiency than the in vitro method and contributed to higher stability to the engineered yeast strains.
The in vitro and in vivo recombination methods of heterologous modules provide simple and efficient ways to improve the astaxanthin yield in yeast. Both the two methods enable high-throughput screening of heterologous pathways through recombination of certain crtW and crtZ derived from different species. This study not only exploited the underlying optimal combination of crtZ and crtW for astaxanthin synthesis, but also provided a general approach to evolve a heterologous pathway for the enhanced accumulation of desired biochemical products.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
In this study, 40 phospholipase D (PLD) genes were identified from allotetraploid cotton Gossypium hirsutum, and 20 PLD genes were examined in diploid cotton Gossypium raimondii. Combining with 19 ...previously identified Gossypium arboreum PLD genes, a comparative analysis was performed among the PLD gene families among allotetraploid and two diploid cottons. Based on the orthologous relationships, we found that almost each G. hirsutum PLD had a corresponding homolog in the G. arboreum and G. raimondii genomes, except for GhPLDβ3A, whose homolog GaPLDβ3 may have been lost during the evolution of G. arboreum after the interspecific hybridization. Phylogenetic analysis showed that all of the cotton PLDs were unevenly classified into six numbered subgroups: α, β/γ, δ, ε, ζ and φ. An N-terminal C2 domain was found in the α, β/γ, δ and ε subgroups, while phox homology (PX) and pleckstrin homology (PH) domains were identified in the ζ subgroup. The subgroup φ possessed a single peptide instead of a functional domain. In each phylogenetic subgroup, the PLDs showed high conservation in gene structure and amino acid sequences in functional domains. The expansion of GhPLD and GrPLD gene families were mainly attributed to segmental duplication and partly attributed to tandem duplication. Furthermore, purifying selection played a critical role in the evolution of PLD genes in cotton. Quantitative RT-PCR documented that allotetraploid cotton PLD genes were broadly expressed and each had a unique spatial and developmental expression pattern, indicating their functional diversification in cotton growth and development. Further analysis of cis-regulatory elements elucidated transcriptional regulations and potential functions. Our comparative analysis provided valuable information for understanding the putative functions of the PLD genes in cotton fiber.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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•Yifei Sanjie formula (YFSJF) reduces the inflammatory injuring and collagen deposition in BLM-induced PF mice.•Autophagy is triggered by YFSJF and inhibition of autophagy may ...contribute to the promotion of lung fibrosis.•YFSJF inhibits the PI3K-AKT-mTOR signaling pathway in BLM-induced PF mice.•Crippling of PI3K-AKT-mTOR signaling pathway induces autophagy and reduces the expression of collagens.
Pulmonary fibrosis (PF) is a crippling disease characterized by progressive dyspnea and associated with a high mortality rate, but its origin is unknown and there is no effective treatment. Yifei Sanjie formula (YFSJF) is a Chinese medicine that is widely used for treatment of respiratory systems disease. However, the molecular basis for the function of YFSJF has not been determined. Here we investigate the contribution of YFSJF in BLM-induced PF mice. Administration with YFSJF significantly alleviated the degree of BLM-induced collagen I and III deposition and the inflammatory injuring in the lungs and suppressed hydroxyproline release in PF animals. The active components of YFSJF are comprised with flavonoid, amino acids, saponins, oligosaccharide, organic acid, vitamin, esters, purine nucleosides. Additionally, there was a significant increase in autophagosomes, after treatment with YFSJF in PF animals. Interestingly, autophagy dysfunction by the blocker chloroquine (CQ) resulted in collagen deposition and inducing the expression of fibrosis-related genes. In addition, YFSJF-induced autophagy is mediated by the PI3K-AKT-mTOR pathway, and knockdown of PI3K by siRNA up-regulated the expression of autophagy-related genes and down-regulated the expression of collagen in human lung fibroblasts (HLF). Our findings provide a detailed understanding that YFSJF-antifibrotic effects are mainly mediated by triggering autophagy, and suppressing phosphorylation of the PI3K-AKT-mTOR pathway is required for YFSJF-curative effect.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
MicroRNA in Lung Cancer Metastasis Wu, Shang-Gin; Chang, Tzu-Hua; Liu, Yi-Nan ...
Cancers,
02/2019, Volume:
11, Issue:
2
Journal Article
Peer reviewed
Open access
Tumor metastasis is a hallmark of cancer, with distant metastasis frequently developing in lung cancer, even at initial diagnosis, resulting in poor prognosis and high mortality. However, available ...biomarkers cannot reliably predict cancer spreading sites. The metastatic cascade involves highly complicated processes including invasion, migration, angiogenesis, and epithelial-to-mesenchymal transition that are tightly controlled by various genetic expression modalities along with interaction between cancer cells and the extracellular matrix. In particular, microRNAs (miRNAs), a group of small non-coding RNAs, can influence the transcriptional and post-transcriptional processes, with dysregulation of miRNA expression contributing to the regulation of cancer metastasis. Nevertheless, although miRNA-targeted therapy is widely studied in vitro and in vivo, this strategy currently affords limited feasibility and a few miRNA-targeted therapies for lung cancer have entered into clinical trials to date. Advances in understanding the molecular mechanism of metastasis will thus provide additional potential targets for lung cancer treatment. This review discusses the current research related to the role of miRNAs in lung cancer invasion and metastasis, with a particular focus on the different metastatic lesions and potential miRNA-targeted treatments for lung cancer with the expectation that further exploration of miRNA-targeted therapy may establish a new spectrum of lung cancer treatments.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Intergenic transcription by RNA Polymerase II (Pol II) is widespread in plant and animal genomes, but the functions of intergenic transcription or the resulting noncoding transcripts are poorly ...understood. Here, we show that Arabidopsis Pol II is indispensable for endogenous siRNA-mediated transcriptional gene silencing (TGS) at intergenic low-copy-number loci, despite the presence of two other polymerases-Pol IV and Pol V-that specialize in TGS through siRNAs. We show that Pol II produces noncoding scaffold transcripts that originate outside of heterochromatic, siRNA-generating loci. Through these transcripts and physical interactions with the siRNA effector protein ARGONAUTE4 (AGO4), Pol II recruits AGO4/siRNAs to homologous loci to result in TGS. Meanwhile, Pol II transcription also recruits Pol IV and Pol V to different locations at heterochromatic loci to promote siRNA biogenesis and siRNA-mediated TGS, respectively. This study establishes that intergenic transcription by Pol II is required for siRNA-mediated TGS, and reveals an intricate collaboration and division of labor among the three polymerases in gene silencing.
Immune imbalance of T lymphocyte subsets is a hallmark of psoriasis, but the molecular mechanisms underlying this aspect of psoriasis pathology are poorly understood. Here, we report that ...microRNA-210 (miR-210), a miR that is highly expressed in both psoriasis patients and mouse models, induces helper T (Th) 17 and Th1 cell differentiation but inhibits Th2 differentiation through repressing STAT6 and LYN expression, contributing to several aspects of the immune imbalance in psoriasis. Both miR-210 ablation in mice and inhibition of miR-210 by intradermal injection of antagomir-210 blocked the immune imbalance and the development of psoriasis-like inflammation in an imiquimod-induced or IL-23-induced psoriasis-like mouse model. We further showed that TGF-β and IL-23 enhance miR-210 expression by inducing HIF-1α, which recruits P300 and promotes histone H3 acetylation in the miR-210 promoter region. Our results reveal a crucial role for miR-210 in the immune imbalance of T lymphocyte subsets in psoriasis and suggest a potential therapeutic avenue.
Graphite phase carbon nitride (g-C
3
N
4
) is a promising catalyst for artificial photocatalytic carbon dioxide (CO
2
) reduction. However, the fast carrier recombination and the inadequacy of the CO
...2
reduction active site in g-C
3
N
4
block the escalation of the performance. In this work, NiCo layered double hydroxide (NiCo LDH) nanoflowers were self-assembled with ultrathin graphite phase carbon nitride (g-C
3
N
4
) by an ultrasonic stirring strategy utilizing the Zeta potential difference. The formed NiCo LDH/ultrathin g-C
3
N
4
nanosheets (LDH-CN) photocatalysts own the merits of rich active sites and Z-scheme heterojunction, which lead to the enhanced CO
2
reduction activity and selectivity. The highest yields of CO and CH
4
were 114.24 and 26.48 μmol·h
−1
·g
−1
, which were much greater than those of g-C
3
N
4
and LDH. Meanwhile, the enhanced selectivity for CO confirmed the strong redox ability in the LDH-CN caused by the Z-scheme. The heterojunction-induced built-in electrical field can promote the separation and migration of photoinduced electrons and holes. This study provides a theoretical basis for designing high-performance photocatalysts.
Graphical abstract
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Manipulation of monoterpene synthases to maximize flux towards targeted products from GPP (geranyl diphosphate) is the main challenge for heterologous monoterpene overproduction, in addition to cell ...toxicity from compounds themselves. In our study, by manipulation of the key enzymes geraniol synthase (GES) and farnesyl diphosphate synthase (Erg20), geraniol (a valuable acyclic monoterpene alcohol) overproduction was achieved in Saccharomyces cerevisiae with truncated 3-hydroxy-3-methylglutaryl-coenzyme reductase (tHMGR) and isopentenyl diphosphate isomerase (IDI1) overexpressed. The expressions of all above engineered genes were under the control of Gal promoter for alleviating product toxicity. Geraniol production varied from trace amount to 43.19mg/L (CrGES, GES from Catharanthus roseus) by screening of nine GESs from diverse species. Further through protein structure analysis and site-directed mutation in CrGES, it was firstly demonstrated that among the high-conserved amino acid residues located in active pocket, Y436 and D501 with strong affinity to diphosphate function group, were critical for the dephosphorylation (the core step for geraniol formation). Moreover, the truncation position of the transit peptide from the N-terminus of CrGES was found to influence protein expression and activity significantly, obtaining a titer of 191.61mg/L geraniol in strain with CrGES truncated at S43 (t3CrGES). Furthermore, directed by surface electrostatics distribution of t3CrGES and Erg20WW (Erg20F96W-N127W), co-expression of the reverse fusion of Erg20ww/t3CrGES and another copy of Erg20WW promoted the geraniol titer to 523.96mg/L at shakes flask level, due to enhancing GPP accessibility led by protein interaction of t3CrGES-Erg20WW and the free Erg20WW. Eventually, a highest reported titer of 1.68g/L geraniol in eukaryote cells was achieved in 2.0L fed-batch fermentation under carbon restriction strategy. Our research opens large opportunities for other microbial production of monoterpenes. It also sets a good reference for desired compounds overproduction in microorganisms in terms of manipulation of key enzymes by protein engineering and metabolic engineering.
•Geraniol overproduction was obtained by manipulation of the key enzymes GES and Erg20WW in S.cerevisiae.•CrGES was the best enzyme for geraniol overproduction. Two essential amino acid residues Y436 and D501 located in active pocket of CrGES were firstly identified to be critical for the dephosphorylation (the core step for GES function).•Geraniol production was further enhanced by tailoring the trunction of CrGES via balancing its catalytic actitity and functional expression level.•Guided by protein surface electrostatics distribution, co-expression of the reverse fusion of Erg20WW/t3CrGES and another copy of Erg20WW presented the best GPP accessibility for geraniol accumulation.•A highest reported titer of 1.68g/L geraniol in eucaryote cells was achieved.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Epidemiologic studies have shown that chronic short sleep may be associated with the development of hypertension; however, the results are controversial. This meta-analysis was conducted to determine ...whether the duration of sleep is associated with hypertension.
Reference databases (PubMed, EmBase, the Cochrane Library, Chinese Biological Medicine database) were searched for studies related to sleep duration and hypertension. Sleep duration categories (≤ 5 h, 6 h, 7 h, 8 h, ≥ 9 h) and prevalence or incidence of hypertension in each sleep category were extracted. A general analysis and subgroup analyses stratified by gender, age, study design, and different definitions of sleep duration were conducted to evaluate the relationship between sleep duration and hypertension.
Thirteen articles out of a total of 1,628 articles involving 347,759 participants met the inclusion criteria. A U-shaped change in pooled odds ratios (ORs) for hypertension due to the change of sleep duration was observed. The unadjusted OR for hypertension of individuals who slept ≤ 5 h vs. 7 h was 1.61, 95% CI = 1.28-2.02; those who slept ≥ 9 h vs. 7 h was 1.29, 95% CI = 0.97-1.71. The pooled ORs were still significant after adjusted by age and gender. Women deprived of sleep (sleep time ≤ 5 h vs. 7 h, OR = 1.68, 95% CI = 1.39-2.03) had a higher risk of hypertension than men (OR = 1.30, 95% CI = 0.93-1.83).
Excessively longer and shorter periods of sleep may both be risk factors for high blood pressure; these associations are stronger in women than men.
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