Prostaglandin D2 Synthase Secreted in the Caput Epididymidis Displays Spatial and Temporal Delay Between Messenger RNA and Protein Expression During Postnatal Development1

: Ulcerative colitis (UC) is one of the main subtypes of inflammatory bowel disease. UC has a negative effect on patients’ quality of life, and it is an important risk factor for the development of colitis-associated cancer. Patients with UC need to take medications for their entire life because no permanent cure is available. Therefore, approaches that target messenger RNA (mRNA) of proinflammatory cytokines or anti-inflammatory cytokines are needed to improve the safety of UC therapy and promote intestinal mucosa recovery. The major challenge facing RNA interference-based therapy is the delivery of RNA molecules to the intracellular space of target cells. Moreover, nonspeciﬁc and systemic protein expression inhibition can result in adverse effects and less therapeutic beneﬁts. Thus, it is important to develop an efficient delivery strategy targeting the cytoplasm of target cells to avoid side effects caused by off-target protein expression inhibition. This review focuses on the most recent advances in the targeted nano delivery systems of siRNAs and mRNA that have shown in vivo efficacy.

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Prostaglandin D2 synthase/prostaglandin D2/TWIST2 signaling inhibits breast cancer proliferation

Anti-Cancer Drugs ◽

10.1097/cad.0000000000001111 ◽

2021 ◽

Vol Publish Ahead of Print ◽

Author(s):

Jun Pan ◽

Leyi Zhang ◽

Jian Huang

Keyword(s):

Breast Cancer ◽

Prostaglandin D2 ◽

Cancer Proliferation ◽

Prostaglandin D2 Synthase

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Prognostic implications of programmed death ligand 1 expression in resected lung adenocarcinoma: a systematic review and meta-analysis

European Journal of Cardio-Thoracic Surgery ◽

10.1093/ejcts/ezaa172 ◽

2020 ◽

Vol 58 (5) ◽

pp. 888-898

Author(s):

Donglai Chen ◽

Yiming Mao ◽

Qifeng Ding ◽

Wei Wang ◽

Feng Zhu ◽

...

Keyword(s):

Gene Expression ◽

Protein Expression ◽

Lung Adenocarcinoma ◽

Messenger Rna ◽

Disease Free Survival ◽

Pooled Analysis ◽

The Cancer Genome Atlas ◽

Free Survival ◽

L1 Protein ◽

Disease Free

Abstract OBJECTIVES Conflicting results have been reported about the prognostic value of programmed death ligand 1 (PD-L1) protein and gene expression in lung adenocarcinoma. METHODS We performed a comprehensive online search to explore the association between PD-L1 expression (protein and messenger RNA) and overall survival (OS) or disease-free survival. Outcomes also included pooled rates of high PD-L1 protein expression in different cell types, per threshold used and per antibody used. A pooled gene expression analysis was also performed on 3 transcriptomic data sets that were obtained from The Cancer Genome Atlas database and the Gene Expression Omnibus database. RESULTS A total of 6488 patients from 25 studies were included. The pooled results suggested that high PD-L1 expression was associated with shorter OS [hazard ratio (HR) 1.57; P < 0.001] and disease-free survival (HR 1.341; P = 0.037) in the overall population. The overall pooled rate of high PD-L1 protein expression was 29% (95% confidence interval 23–34%) in tumour cells. In subgroup analysis, high PD-L1 protein expression in tumour cells predicted worse OS and disease-free survival. A pooled analysis of The Cancer Genome Atlas and Gene Expression Omnibus data sets revealed that higher levels of PD-L1 messenger RNA predicted poorer OS in the entire population. CONCLUSIONS This study is, to our knowledge, the largest pooled analysis on the subject to shed light on the high expression rate of PD-L1 and the prognostic value of high PD-L1 expression in resected lung adenocarcinomas. PD-L1 gene expression is a promising prognostic factor for patients with surgically resected lung adenocarcinoma. Standardization of staining should be underscored prior to routine implementation.

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Aerosolizable Lipid Nanoparticles for Pulmonary Delivery of mRNA through Design of Experiments

Pharmaceutics ◽

10.3390/pharmaceutics12111042 ◽

2020 ◽

Vol 12 (11) ◽

pp. 1042

Author(s):

Hairui Zhang ◽

Jasmim Leal ◽

Melissa R. Soto ◽

Hugh D. C. Smyth ◽

Debadyuti Ghosh

Keyword(s):

Design Of Experiments ◽

Protein Expression ◽

Messenger Rna ◽

Pulmonary Delivery ◽

Lipid Nanoparticles ◽

In Vivo Studies ◽

Molar Ratio ◽

Mouse Lung ◽

Intracellular Protein ◽

Before And After

Messenger RNA is a class of promising nucleic acid therapeutics to treat a variety of diseases, including genetic diseases. The development of a stable and efficacious mRNA pulmonary delivery system would enable high therapeutic concentrations locally in the lungs to improve efficacy and limit potential toxicities. In this study, we employed a Design of Experiments (DOE) strategy to screen a library of lipid nanoparticle compositions to identify formulations possessing high potency both before and after aerosolization. Lipid nanoparticles (LNPs) showed stable physicochemical properties for at least 14 days of storage at 4 °C, and most formulations exhibited high encapsulation efficiencies greater than 80%. Generally, upon nebulization, LNP formulations showed increased particle size and decreased encapsulation efficiencies. An increasing molar ratio of poly-(ethylene) glycol (PEG)-lipid significantly decreased size but also intracellular protein expression of mRNA. We identified four formulations possessing higher intracellular protein expression ability in vitro even after aerosolization which were then assessed in in vivo studies. It was found that luciferase protein was predominately expressed in the mouse lung for the four lead formulations before and after nebulization. This study demonstrated that LNPs hold promise to be applied for aerosolization-mediated pulmonary mRNA delivery.

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Methylphenidate causes cytotoxicity on photoreceptor cells via autophagy

Human & Experimental Toxicology ◽

10.1177/0960327120940357 ◽

2020 ◽

Vol 40 (1) ◽

pp. 71-80

Author(s):

N Kong ◽

Y Bao ◽

H Zhao ◽

X Kang ◽

X Tai ◽

...

Keyword(s):

Oxidative Stress ◽

Protein Expression ◽

Messenger Rna ◽

Cell Damage ◽

Photoreceptor Cells ◽

Cell Toxicity ◽

Hyperactivity Disorder ◽

Increased Risk ◽

Gene And Protein Expression ◽

Underlying Mechanisms

Methylphenidate (MPH) is used as the first-line treatment for attention-deficit hyperactivity disorder. However, there are concerns that this treatment may be associated with increased risk of retinal damage. This study was to investigate cytotoxicity of MPH on photoreceptor cells and explore its underlying mechanisms. MPH-caused cell toxicity was established in 661 W cells. Cytotoxicity was evaluated by 3-(4,5-dimethylthiazol)-2,5-diphenyltetrazolium-bromid and lactate dehydrogenase assays. Oxidative stress was measured by the markers: glutathione (GSH) reductase, catalase, and superoxide dismutase activities as well as GSH, reactive oxygen species, and malondialdehyde levels. Gene and protein expression was detected by real-time polymerase chain reaction (PCR) and western blot, respectively. Results showed that MPH decreased 661 W cell viability, increased caspase-3/9 activities, and induced oxidative stress. Furthermore, MPH treatment increased messenger RNA (mRNA) expression of Beclin-1 and microtubule-associated protein 1A/1B-light chain 3B (LC3B) protein expression in 661 W cells, suggesting autophagy was induced. MPH treatment also upregulated p-JAK1/p-STAT1 protein expression. These data demonstrated that MPH could increase oxidative stress in photoreceptor cells to cause cell toxicity via autophagy, providing the scientific rationale for the photoreceptor cell damage caused by the MPH administration.

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