Biology subjects

Cheng, W.-Y.

Publications and source records attributed to Cheng, W.-Y..

3 recordsLinked to original sources

bioRxiv2023

The Role of PKR on Modulating Neuroinflammation and Cognitive Dysfunctions in a Peripheral Inflammation Model

Systemic inflammation may promote neuroinflammation and neurodegeneration. The double-stranded RNA-dependent protein kinase (PKR) is a key signaling molecule that regulates immune responses. This study aims to examine the role of PKR in regulating systemic inflammation-induced neuroinflammation and cognitive dysfunctions using a laparotomy mouse model. In the first part, wild-type C57BL/6J and C57BL/6-Tg(CD68-EGFP)1Drg/J mice were assigned to undergo either laparotomy with sevoflurane anesthesia or sevoflurane alone to examine effects of systemic inflammation on neuroinflammation and cognition. In the second part, PKR-/- mice were used to study the role of PKR in modulating laparotomy-induced systemic inflammation, neuroinflammation, and cognition. For the third part, PKR was inhibited selectively in cholinergic neurons of ChAT-IRES-Cre-eGFP mice via intracerebroventricular injection of rAAV-DIO-PKR-K296R. This examined the effects of inhibiting PKR in cholinergic neurons on glucose metabolism and cognition in the laparotomy model. Our study revealed that genetic deletion of PKR in mice potently attenuated the laparotomy-induced peripheral and neural inflammation and cognitive deficits. Furthermore, inhibiting PKR in the cholinergic neurons rescued the laparotomy-induced brain glucose hypometabolism and cognitive impairment. Our results demonstrated the critical role of PKR in regulating neuroinflammation and cognitive dysfunctions in a peripheral inflammation model. PKR could be a pharmacological target for treating systemic inflammation-induced neuroinflammation and cognitive dysfunctions.

neuroscience↗

bioRxiv2022

Inflammation in the tumor-adjacent lung as a predictor of clinical outcome in lung adenocarcinoma

Early-stage lung adenocarcinoma is typically treated by surgical resection of the tumor. While in the majority of cases surgery can lead to cure, approximately 30% of patients progress. Despite intense efforts to map the genetic landscape of early-stage lung tumors, there has been limited success in discovering accurate biomarkers that can predict clinical outcomes. Meanwhile, the role of the tumor-adjacent tissue in cancer progression has been largely ignored. To test whether tumor-adjacent tissue can be informative of progression-free survival and to probe the underlying molecular pathways involved, we designed a multi-omic study in both tumor and matched tumor-adjacent histologically normal lung tissue from the same patient. Our study includes 143 treatment naive stage I cases with long-term patient follow-up and is, to our knowledge, the largest such study with the longest follow-up. We performed a comprehensive histologic characterization of all tumors, mapped the mutational landscape and probed the transcriptome of both tumor and adjacent normal tissue. We evaluated the predictive power of each data modality and showed that the transcriptome of tumor-adjacent histologically normal lung tissue is the only reliable predictor of clinical outcome. Unbiased discovery of co-expressed gene modules revealed that inflammatory pathways are upregulated in the tumor-adjacent tissue of patients at high risk for disease progression. Furthermore, single-cell transcriptome analysis in the tumor-adjacent lung demonstrated that progression-associated inflammatory signatures were broadly expressed by both immune and non-immune cells including mesothelial cells, alveolar type 2 cells and fibroblasts, CD1 dendritic cells and MAST cells. Collectively, our studies suggest that molecular profiling of tumor-adjacent tissue can identify patients that are at high risk for disease progression.

bioinformatics↗

bioRxiv2019

Reducing expression of dynamin-related protein 1 increases radiation sensitivity of glioblastoma cells

BackgroundDynamin-related protein 1 (DRP1) is a GTPase involved in mitochondrial fission, mitochondrial protein imports, and drug sensitivity, suggesting an association with cancer progression. This study is to evaluate the prognostic significance of DRP1 in glioblastoma multiforme (GBM).\n\nMaterial and MethodsDRP1 expression was measured by immunohistochemistry and Western blotting. Correlations between DRP1 expression and clinicopathological parameters were analyzed by statistical analysis. Differences in survival were compared by a log-rank test.\n\nResultsDRP1 expression was detected in 87.2% (41/47) patients with GBM. Patients with higher DRP1 levels had worse survival (p = 0.0398). In vitro, silencing of DRP1 reduced cell proliferation, metastatic potential, and radiation resistance. The addition of shikonin inhibited DRP1 expression and increased drug uptake. Moreover, shikonin reduced the nuclear entry of DNA repair-associated enzymes and increased radiation sensitivity, suggesting that to reduce DRP1 expression could inhibit DNA repair and increase the radiation sensitivity of GBM cells.\n\nConclusionOur results indicate that DRP1 overexpression is a prospective radio-resistant phenotype in GBM. Therefore, DRP1 could be a potential target for improving the effectiveness of radiation therapy.\n\nAbbreviations used are: ATAD3A, the ATPase family, AAA domain containing 3A; CIM, confocal immunofluorescence microscopy; DRP1, dynamin-related protein 1; ER, endoplasmic reticulum; GBM, glioblastoma multiforme; hHR23A, human homolog of yeast Rad23 protein A; IDH1, isocitrate dehydrogenase 1; MAM, mitochondria-associated membrane; MGMT, O6-methylguanine-DNA-methyltransferase; SAHA, suberoylanilide hydroxamic acid (vorinostat); TMZ, temozolomide\n\nTranslational RelevanceThis study shows that dynamin-related protein 1 (DRP1), an essential 80-kDa GTPase, which is involved in mitochondrial fission, and mitochondrial protein imports, is highly expressed in glioblastoma multiforme (GBM). Moreover, we demonstrate that DRP1 expression is closely associated with radiation sensitivity, cancer progression, and patients cumulative survival. In vitro, inhibition of DRP1 expression reduced the nuclear entry of DNA repair-associated enzymes, such as ATM, but increased radiation sensitivity and nuclear drug uptakes of glioblastoma cells. More importantly, the silencing of DRP1 induced cellular autophagy. These results indicate that DRP1 overexpression could be a prospective radio-resistant phenotype in GBM and a clinically important target for improving the effectiveness of radiation therapy.

cancer biology↗