Down Regulation
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Plants ◽  
2022 ◽  
Vol 11 (2) ◽  
pp. 154
Naveed Mushtaq ◽  
Yong Wang ◽  
Junmiao Fan ◽  
Yi Li ◽  
Jing Ding

Environmental stresses negatively affect the growth and development of plants. Several previous studies have elucidated the response mechanisms of plants to drought and heat applied separately; however, these two abiotic stresses often coincide in environmental conditions. The global climate change pattern has projected that combined drought and heat stresses will tend to increase in the near future. In this study, we down-regulated the expression of a cytokinin receptor gene SlHK2 using RNAi and investigated the role of this gene in regulating plant responses to individual drought, heat, and combined stresses (drought + heat) in tomato. Compared to the wild-type (WT), SlHK2 RNAi plants exhibited fewer stress symptoms in response to individual and combined stress treatments. The enhanced abiotic stress tolerance of SlHK2 RNAi plants can be associated with increased membrane stability, osmoprotectant accumulation, and antioxidant enzyme activities. Furthermore, photosynthesis machinery was also protected in SlHK2 RNAi plants. Collectively, our results show that down-regulation of the cytokinin receptor gene SlHK2, and consequently cytokinin signaling, can improve plant tolerance to drought, heat, and combined stress.

Toxins ◽  
2022 ◽  
Vol 14 (1) ◽  
pp. 31
Jeroen L. A. Pennings ◽  
Eric Abachin ◽  
Raphaël Esson ◽  
Hennie Hodemaekers ◽  
Antoine Francotte ◽  

Background: Ensuring consistency of tetanus neurotoxin (TeNT) production by Clostridium tetani could help to ensure consistent product quality in tetanus vaccine manufacturing, ultimately contributing to reduced animal testing. The aim of this study was to identify RNA signatures related to consistent TeNT production using standard and non-standard culture conditions. Methods: We applied RNA sequencing (RNA-Seq) to study C. tetani gene expression in small-scale batches under several culture conditions. Results: We identified 1381 time-dependent differentially expressed genes (DEGs) reflecting, among others, changes in growth rate and metabolism. Comparing non-standard versus standard culture conditions identified 82 condition-dependent DEGs, most of which were specific for one condition. The tetanus neurotoxin gene (tetX) was highly expressed but showed expression changes over time and between culture conditions. The tetX gene showed significant down-regulation at higher pH levels (pH 7.8), which was confirmed by the quantification data obtained with the recently validated targeted LC-MS/MS approach. Conclusions: Non-standard culture conditions lead to different gene expression responses. The tetX gene appears to be the best transcriptional biomarker for monitoring TeNT production as part of batch-to-batch consistency testing during tetanus vaccine manufacturing.

2021 ◽  
Boyi Liao ◽  
Peiran Huang ◽  
Xiangyu Zhang ◽  
Xinyu Wang ◽  
Kaiqian Zhou ◽  

Abstract Background: Hepatocellular carcinoma (HCC) is one of the most common causes of cancer-related deaths. Recent studies have demonstrated that deregulation of long noncoding RNAs (lncRNAs), such as abnormal DNA methylation of promoter, is strongly associated with development and progression of diverse malignant tumors. This study investigated the mechanisms and changes in DNA methylation levels of promoter regions of HCC-specific lncRNAs, and alterations of downstream target genes.Methods: LncRNA expression profile data of 8 human HCC tissues and matched normal tissues were obtained. LncRNAs with aberrant methylation were identified through DNA methylation microarray. The biological functions of the lncRNAs were investigated through targeted knockdown of lncRNA-SCARF1 in vitro and in vivo. Furthermore, the downstream targets of lncRNA-SCARF1 were identified through ChIRP-MS.Results: LncRNA-SCARF1 was significantly down-regulated in HCC samples. Hypermethylation in the promoter of lnc-SCARF1 induced its down-regulation in HCC. Over-expression of lnc-SCARF1 inhibited the tumor proliferation and migration ability of HCC cells in vitro and in vivo. Furthermore, CUL9 was found to be a potential downstream target of lncRNA-SCARF1.Conclusion: LncRNA-SCARF1 regulates HCC progression by interacting with CUL9 and may serve as a prognostic biomarker or an effective therapeutic target in HCC.

2021 ◽  
Vol 119 (2) ◽  
pp. e2110166119
Shreya Das ◽  
Mohd Saqib ◽  
Ryan C. Meng ◽  
Sridar V. Chittur ◽  
Ziqiang Guan ◽  

Hemachromatosis (iron-overload) increases host susceptibility to siderophilic bacterial infections that cause serious complications, but the underlying mechanisms remain elusive. The present study demonstrates that oral infection with hyperyersiniabactin (Ybt) producing Yersinia pseudotuberculosis Δfur mutant (termed Δfur) results in severe systemic infection and acute mortality to hemochromatotic mice due to rapid disruption of the intestinal barrier. Transcriptome analysis of Δfur-infected intestine revealed up-regulation in cytokine–cytokine receptor interactions, the complement and coagulation cascade, the NF-κB signaling pathway, and chemokine signaling pathways, and down-regulation in cell-adhesion molecules and Toll-like receptor signaling pathways. Further studies indicate that dysregulated interleukin (IL)-1β signaling triggered in hemachromatotic mice infected with Δfur damages the intestinal barrier by activation of myosin light-chain kinases (MLCK) and excessive neutrophilia. Inhibiting MLCK activity or depleting neutrophil infiltration reduces barrier disruption, largely ameliorates immunopathology, and substantially rescues hemochromatotic mice from lethal Δfur infection. Moreover, early intervention of IL-1β overproduction can completely rescue hemochromatotic mice from the lethal infection.

2021 ◽  
Chenchen Hu ◽  
Xin Wei ◽  
Jinmin Liu ◽  
Linlin Han ◽  
Chengkun Xia ◽  

Abstract Background: Abnormal myocardial expression and function of Nav1.5 causes lethal ventricular arrhythmias during myocardial ischemia-reperfusion (I/R). PIASy mediated Caveolin-3 (Cav-3) SUMO modification affects Cav-3 binding to ligand Nav1.5. PIASy activity is increased after myocardial I/R, whether or not this may be attributable to plasma membrane Nav1.5 downregulation and ventricular arrhythmias remains unclear. Methods: Using recombinant adeno-associated virus subtype 9 (AAV9), rat cardiac PIASy was silenced by intraventricular injection of PIASy shRNA. Two weeks later, the hearts were subjected to I/R, and electrocardiography was performed to assess malignant arrhythmias. Tissues from peri-infarct areas of the left ventricle were collected for molecular biological measurement. Results: We found that PIASy was upregulated by I/R, with increased SUMO2/3 modification of Cav-3, reduced membrane Nav1.5 density, and increased ventricular arrhythmia frequency. These effects were significantly reversed by PIASy silencing. In addition, PIASy silencing enhanced Cav-3 binding to Nav1.5 and prevented I/R-induced Nav1.5 re-localization. Using in vitro models of HEK293T cells and isolated adult rat cardiomyocytes exposed to hypoxia/reoxygenation (H/R), this reserch further confirmed that PIASy promoted Cav-3 modification by SUMO2/3 and Nav1.5/Cav-3 dissociation after H/R. Mutation of the SUMO Consensus Sites Lysine in Cav-3 (K38R or K144R) alters the membrane expression levels of Nav1.5 and Cav-3 before and after H/R in HEK293T cells. Conclusions: I/R-induced cardiac PIASy activation contributes to Cav-3 SUMOylation by SUMO2/3 and dysregulated Nav1.5- related ventricular arrhythmias. Cardiac-targeted PIASy gene silencing mediates deSUMOylation of Cav-3 and prevents I/R-induced Nav1.5 down-regulation and ventricular arrhythmias in rats, identifying PIASy as a potential therapeutic target for relevant life-threatening arrhythmias in patients with ischemic heart diseases.

2021 ◽  
Shanyi Lin ◽  
Yu Miao ◽  
Xu Zheng ◽  
Yang Dong ◽  
Qingcheng Yang ◽  

Abstract BackgroundAngiopoietin-like-4 (ANGPTL4), a secreted glycoprotein that is mainly recognized as a regulator in lipid metabolism, now, is implied in the regulation of the growth and metastasis of various carcinomas. However, less is known about its functions in the progression of sarcomas, let alone osteosarcoma (OS), which is the most common malignant diagnosed in musculoskeletal system.MethodsThe expression of ANGPTL4 in clinical OS samples and cell lines paired with their controls were analyzed in both mRNA and protein levels. Cell functional analysis including proliferation and colony formation were carried out to detect the roles ANGPTL4 takes in the progress of OS using stable ANGPTL4 overexpression and knockdown HOS/MNNG cell lines. The RNA-Seq and bioinformatics analysis were then employed to discover the BCAA metabolism related signaling which is involved in ANGPTL4 functioning on HOS/MNNG cell growth. Furthermore, BCAAs content measurement, and BCATs rescue experiments were performed to confirm the BCAA/mTOR signaling axis that ANGPTL4 triggered in HOS/MNNG cells. Finally, a xenograft mouse model was carried out to further verify the ANGPTL4 /BCAA/mTOR signaling axis discovered. ResultsWe found that the expression of ANGPTL4 is reduced in clinical OS tissues and cell lines compared to cancellous bone tissues and BMSCs, respectively. The knockdown of ANGPTL4 in HOS/MNNG cells results in enhanced cell growth and clone formation. Moreover, BCAA/mTOR signaling axis were discovered to be triggered by ANGPTL4 down regulation in HOS/MNNG cell using RNA-seq. It was also verified that the accumulation of BCAAs activates the mTOR signaling pathway, and in turn promotes HOS/MNNG cell growth using BCAAs content measurement, and BCAT inhibition. Finally, the IHC results of xenograft mouse model also confirmed this ANGPTL4/BCAA/mTOR signaling axis in vivo.ConclusionsTaken together, our results demonstrate that the expression of ANGPTL4 were negatively related to OS progress. Moreover, it was found the down-regulation of ANGPTL4 promoted OS cell growth via BCAAs/mTOR axis.

In Vivo ◽  
2021 ◽  
Vol 36 (1) ◽  
pp. 227-232

2021 ◽  
Mishal Cohen-Rengifo ◽  
Morgane Danion ◽  
Anne-Alicia Gonzalez ◽  
Marie-Laure Bégout ◽  
Lauriane Madec ◽  

Abstract Background Progressive climate-induced ocean acidification (OA) impacts marine life in ways that are difficult to predict but are likely to become exacerbated over generations. Although marine fishes can balance internal acid-base homeostasis efficiently, indirect ionic regulation effects that alter neurosensory systems can result in behavioural abnormalities. In marine invertebrates, OA can also affect immune system function, but whether this is the case in marine fishes of ecological and commercial importance is not yet understood. Farmed fish are highly susceptible to disease outbreak yet strategies for overcoming such threats in the wake of OA are wanting. Here, we exposed two generations of the European sea bass (Dicentrarchus labrax) to end-of-century predicted CO2 levels (IPCC RCP8.5), with parents being exposed for four years and their offspring for two years. Our design included a transcriptomic analysis of the olfactory rosette (collected from the F1 offspring) and a viral challenge (exposing F1 offspring to betanodavirus) where we assessed survival rates. Results We discovered long-term intergenerational molecular trade-offs in both sensory and immune systems. Specifically, RNA-Seq analysis of the olfactory rosette, the peripheral olfactory organ, from two-year-old F1 offspring revealed extensive regulation in genes involved in ion transport and neuronal signalling, including GABAergic signalling. We also detected extensive OA-induced intergenerational up-regulation of genes associated with odour transduction, synaptic plasticity, neuron excitability and wiring and down-regulation of genes involved in energy metabolism. In addition, intergenerational exposure to OA induced up-regulation of genes involved in innate antiviral immunity (pathogen recognition receptors and interferon-stimulated genes) in combination with down-regulation of the protein biosynthetic machinery. Consistently, OA-exposed F1 fish challenged with betanodavirus, which causes damage to the nervous system of marine fish, had acquired improved resistance. Conclusion F1 exposed to OA-intergenerational acclimation showed superior viral resistance, though as their metabolic and odour transduction programs were altered, odour-mediated behaviours might be consequently altered. Our results reveal that trade-offs in adaptive plastic responses is a core feature of the olfactory epithelium transcriptome in OA-exposed fish, suggesting that intergenerational plasticity propagate with progressive exposure to OA and will have important consequences for how cultured and wild fish interacts with its environment.

2021 ◽  
Oliver J. Ziff ◽  
Benjamin E. Clarke ◽  
Doaa M. Taha ◽  
Hamish Crerar ◽  
Nicholas M. Luscombe ◽  

Astrocytes contribute to motor neuron death in amyotrophic lateral sclerosis (ALS), but whether they adopt deleterious features consistent with inflammatory reactive states remains incompletely resolved. To identify inflammatory reactive features in ALS human induced pluripotent stem cell (hiPSC)–derived astrocytes, we examined transcriptomics, proteomics, and glutamate uptake in VCP-mutant astrocytes. We complemented this by examining other ALS mutations and models using a systematic meta-analysis of all publicly-available ALS astrocyte sequencing data, which included hiPSC-derived astrocytes carrying SOD1, C9orf72, and FUS gene mutations as well as mouse ALS astrocyte models with SOD1G93A mutation, Tardbp deletion, and Tmem259 (also known as membralin) deletion. ALS astrocytes were characterized by up-regulation of genes involved in the extracellular matrix, endoplasmic reticulum stress, and the immune response and down-regulation of synaptic integrity, glutamate uptake, and other neuronal support processes. We identify activation of the TGFB, Wnt, and hypoxia signaling pathways in both hiPSC and mouse ALS astrocytes. ALS changes positively correlate with TNF, IL1A, and complement pathway component C1q-treated inflammatory reactive astrocytes, with significant overlap of differentially expressed genes. By contrasting ALS changes with models of protective reactive astrocytes, including middle cerebral artery occlusion and spinal cord injury, we uncover a cluster of genes changing in opposing directions, which may represent down-regulated homeostatic genes and up-regulated deleterious genes in ALS astrocytes. These observations indicate that ALS astrocytes augment inflammatory processes while concomitantly suppressing neuronal supporting mechanisms, thus resembling inflammatory reactive states and offering potential therapeutic targets.

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