2022
Permanent URI for this collectionhttps://hdl.handle.net/1807/109466
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Item Open Access ERCC6 plays a promoting role in the progression of non-small cell lung cancer(Canadian Science Publishing, 2022-10-28) Luo, Hui; Xiao, Zhehao; Huang, Cheng; Wu, Wei; Xie, QingbinAlthough excision repair cross-complementing group 6 (ERCC6) has been reported to be associated with lung cancer risk, the specific roles of ERCC6 in non-small cell lung cancer (NSCLC) progression are inadequately studied. Thus, this study aimed to examine the potential functions of ERCC6 in NSCLC. The expression of ERCC6 in NSCLC was analyzed by immunohistochemical (IHC) staining and quantitative PCR (qPCR). Celigo cell count, colony formation, flow cytometry, wound healing and transwell assays were used to evaluate the effects of ERCC6 knockdown on the proliferation, apoptosis and migration of NSCLC cells. The effect of ERCC6 knockdown on tumor-forming ability of NSCLC cells was estimated by establishing xenograft model. ERCC6 was highly expressed in NSCLC tumor tissues and cell lines, and high ERCC6 expression was significantly associated with poor overall survival. Additionally, ERCC6 knockdown significantly suppressed cell proliferation, colony formation and migration, while accelerated cell apoptosis of NSCLC cells in vitro. Moreover, ERCC6 knockdown inhibited tumor growth in vivo. Further studies verified that ERCC6 knockdown attenuated the expression levels of Bcl-w, CCND1 and c-Myc. Altogether, these data unveil a major role of ERCC6 in the progression of NSCLC, and ERCC6 is expected to become a novel therapeutic target for NSCLC treatment.Item Open Access RNA deadenylation complexes in development and diseases(Canadian Science Publishing, 2022-12-21) Liu, Yilin; Ramkumar, Niveditha; Vu, Ly PhuongRNA deadenylation, the process of shortening of the 3’ poly(A) tail of an RNA molecule, is one of the key steps of post-transcriptional regulation of gene expression in eukaryotic cells. PAN2/3 and CCR4-NOT (CNOT) are the two dominant RNA deadenylation complexes, which play central roles in mediating mRNA decay and translation. While degradation is the final fate of virtually all RNAs in their life cycles, selection of RNA targets as well as control of the rate and timing of RNA decay, in coordination with other molecular pathways, including translation, can be modulated in certain contexts. Such regulation influences cell growth, proliferation, and differentiation at the cellular level; and contributes to establish polarity and regulate signaling at the tissue level. Dysregulation of deadenylation processes have also been implicated in human diseases ranging from cardiac diseases and neurodevelopmental disorders to cancers. In this review, we will discuss mechanisms of gene expression control mediated by the RNA deadenylation complexes and highlight relevant evidence supporting the emerging roles of RNA deadenylation and its regulatory proteins during development and in diseases. A systemic understanding of these mechanisms will be a critical foundation for development of effective strategies to therapeutically target them.Item Open Access HDAC1 overexpression promoted by METTL3-IGF2BP2 inhibits FGF21 expression in metabolic syndrome-related liver injury(Canadian Science Publishing, 2022-11-30) Chen, Yunjiang; Cai, Kaiyu; Du, Yueling; Liu, Zixiong; Gong, YanchunMetabolic syndrome (MetS) represents a cluster of diseases that include diabetes and insulin resistance. A combination of these metabolic disorders damages liver function. We hypothesized here that HDAC1 inhibits FGF21 expression through histone deacetylation, thereby accentuating liver injury in rats with MetS. MetS rats induced by a high-fat diet were monitored weekly for blood pressure and body weight. The changes of hepatic injury parameters were also measured. The pathological changes in the liver were observed by HE staining and oil red O staining. We found that HDAC1 was increased in the liver of rats with MetS, while sh-HDAC1 reduced blood pressure, body weight and hepatic injury parameters. Improvement of structural pathological alterations and reduction of lipid deposition were observed after HDAC1 inhibition. Notably, HDAC1 inhibited FGF21 expression through histone deacetylation. The hepatoprotective effects of sh-HDAC1 on rats were reversed by adenovirus-mediated knockdown of FGF21. Moreover, METTL3 mediated the m6A modification of HDAC1 mRNA and increased its binding to IGF2BP2. Consistently, sh-METTL3 inhibited HDAC1 and increased FGF21 expression, thereby ameliorating liver injury in MetS rats. This study discovered that HDAC1 is capable of managing liver injury in MetS. Targeting HDAC1 may be an optimal treatment for MetS-related liver injury.Item Open Access Evaluation of drug-free methods for the detection of gene silencing in S. cerevisiae(Canadian Science Publishing, 2022-10-27) Shaban, Kholoud; Sauty, Safia Mahabub; Fisher, Ashley; Cheng, Ashley; Yankulov, KrassimirMultiple studies in S. cerevisiae have measured the levels of gene silencing by inserting the URA3 gene at various loci and selecting against URA3 expressing cells by 5-flouro-orotic acid (5-FOA). However, 5-FOA affects the cellular pools of dNTPs and can produce side effects. To circumvent this issue, we and others have introduced drug-free techniques to detect silent and active gene states. In this study we compared three drug-free methods based on the expression of fluorescent reporters in the VIIL telomere of S. cerevisiae. Our results point out that only one of these methods is suitable for large scale drug-free analyses of gene silencing.Item Open Access GSK126 an Inhibitor of Epigenetic Regulator EZH2 Suppresses Cardiac Fibrosis by Regulating EZH2-PAX6-CXCL10 Pathway(Canadian Science Publishing, 2022-11-23) Aziz, Shireen; Yalan, Li; Raza, Muhammad Ahmer; Lemin, Jiao; Akram, Hafiz Muhammad Bilal; Zhao, WenMyocardial fibrosis is a common pathological companion of various cardiovascular diseases. To date, the role of enhancer of zeste homolog 2 (EZH2) in cancer has been well demonstrated including in renal carcinoma and its inhibitors have entered the stage of phase I/II clinical trials. However, the precise mechanism of EZH2 in cardiac diseases is largely unclear. In the current study, we first found that EZH2 expression was increased in Ang-II treated cardiac fibroblasts (CFs) and mouse heart homogenates following isoproterenol (ISO) administration for 21 days, respectively. Ang-II induces CFs activation and increased collagen-I, collagen-III, α-SMA, EZH2, and trimethylates lysine 27 on histone 3 (H3K27me3) expressions can be reversed by EZH2 inhibitor (GSK126) and EZH2 siRNA. The ISO induced-cardiac hypertrophy, and fibrosis in vivo which were also related to the upregulation of EZH2 and its downstream target, H3K27me3, could be recovered by GSK126. Furthermore, the upregulation of EZH2 induces the decrease of paired box 6 (PAX6) and C-X-C motif ligand 10 (CXCL10) “which” was also reversed by GSK126 treatment. In summary, the present evidence strongly suggests that GSK126 could be a therapeutic intervention blunting the development and progression of myocardial fibrosis in an EZH2-PAX6-CXCL10-dependent manner.Item Open Access Hyperglycemia enhances generation of ROS and RNS that impair antioxidant power and cause oxidative damage in human erythrocytes(Canadian Science Publishing, 2022-10-24) Qasim, Neha; Arif, Amin; Mahmood, RiazHyperglycemia is a state in which excess glucose circulates in blood. Erythrocytes are in direct contact with this high glucose concentration and are greatly affected by it. We examined the effect of hyperglycemic condition on isolated human erythrocytes under in vitro conditions. Erythrocytes were incubated with different concentrations of glucose (5, 15, 30, 45 mM) for 24 h and several biochemical parameters were determined. Treatment with high glucose concentrations increased heme degradation and methemoglobin level, while methemoglobinreductase activity was decreased. Significant increase in protein oxidation, lipid hydroperoxides with decrease in total sulfhydryl content was seen. This suggested generation of oxidative stress which was confirmed by enhanced production of reactive oxygen and nitrogen species.Hyperglycemia led to significant decline in the antioxidant power of erythrocytes lowering their ability to quench free radicals and reduce metal ions to lower oxidation states. The plasma membrane redox system was up-regulated while ascorbate free radical reductase activity was lowered. Glucose exposure inhibited enzymes of glycolysis and hexose monophosphate shunt. Electron microscopy showed morphological changes resulting in the formation of echinocytes. Thus hyperglycemic condition generates reactive species which oxidize proteins, hemoglobin and lipids, impair the total antioxidant capacity and alter cell morphology in human erythrocytes.Item Open Access HSPB8 facilitates prostate cancer progression via activating JAK/STAT3 signaling pathway(Canadian Science Publishing, 2022-09-23) Zhang, Kan; Yin, Weiqi; Ma, Luping; Liu, Zhili; Li, QiangProstate cancer (PC) is a clinically and biologically heterogeneous disease that lacks effective treatment. Heat shock protein B8 (HSPB8) is an important factor in the progression of various types of cancer. However, the clinical significance and biological role of HSPB8 in PC is still unclear. In this study, we determined HSPB8 expression in PC tissues by immunohistochemical (IHC) staining, explored the in vitro functions of HSPB8 using HSPB8 knockdown DU145 and LNcap PC cell lines. The in vivo effect of HSPB8 was explored by subcutaneous xenograft mice model. The Human Phospho-kinase Array and STAT3 activator were utilized to explore potential mechanism of HSPB8 induced PC progression. As a result, we found that HSPB8 was abundantly expressed in PC tissues and cell lines. HSPB8 knockdown inhibited cell proliferation and migration, promoted apoptosis and cycle repression, as well as weaken tumorigenesis ability. Mechanistically, we demonstrated that HSPB8 facilitate the malignant phenotypes of PC by activating the JAK/STAT3 signaling pathway. These results proposed that HSPB8 seems to be an attractive therapeutic target for PC patients.Item Open Access Single cell genomics illustrate heterogeneous phenotypes of myocardial fibroblasts under ischemic insults(Canadian Science Publishing, 2022-10-25) Thankam, Finosh G; La, Vy; Agrawal, Devendra KMyocardial regenerative strategies are promising where the choice of ideal cell population is crucial for successful translational applications. Herein, we aim to explore the regenerative/repair responses of infarct zone cardiac fibroblasts (CF) by unveiling their phenotype heterogeneity at single cell resolution. CF were isolated from the infarct zone of Yucatan mini swine which suffered myocardial infarction (MI), cultured under simulated ischemic and reperfusion, and grouped into Control, Ischemia (ISC), and Ischemia/reperfusion (ISC/R). scRNAseq analysis revealed 19 unique cell clusters suggesting distinctive sub-populations. The status of gene expression (Log2 fold change (FC)>2 and Log2 FCItem Open Access NCAPG2 contributes to progression of malignant melanoma through regulating proliferation and metastasis(Canadian Science Publishing, 2022-09-28) Feng, Zhang; Zhang, Linfeng; Liu, Yanxin; Zhang, WeiMalignant melanoma is a highly aggressive cutaneous neoplasm with increasing incidence worldwide. Non-SMC condensin II complex subunit G2 (NCAPG2) exerts import biological function in the pathogenesis of several tumors. In this study, the functional roles of NCAPG2 knockdown in malignant melanoma were revealed in vitro and in vivo experiments. In vitro study demonstrated that NCAPG2 depletion could inhibit proliferation and migration, and promote apoptosis of malignant melanoma cells. Our in vivo date further confirmed that NCAPG2 knockdown attenuated tumor growth of malignant melanoma. Interestingly, NCAPG2 drove tumor development of malignant melanoma through activating the STAT3. In conclusion, this study elaborated the tumor-promoting effects of NCAPG2 on malignant melanoma and NCAPG2 may be a potential therapeutic target for malignant melanoma therapy.Item Open Access How to Become a Successful Scientist: the 2022 CSMB Arthur Wynne Gold Medal Lecture(Canadian Science Publishing, 2022-07-21) Reithmeier, Reinhart A.F.There are many pathways to success. Mine followed a traditional one to an academic faculty position, but this pathway is not the one most life sciences PhD graduates will follow today. We have all had time during the COVID-19 Pandemic to reflect on our personal pathway -where we are and where we are going. In this reflection I outline five steps on my pathway to success: 1.Train with the best 2.Discover something 3.Mentor others 4.Go beyond 5.Promote science. I will provide examples from my personal journey that I hope will resonant with the reader as they create their pathway to success.Item Open Access Community-led risk analysis of direct-to-consumer whole-genome sequencing(Canadian Science Publishing, 2022-07-08) Samlali, Kenza; Thornbury, Mackenzie; Venter, AndreiDirect-to-consumer (DTC) genetic testing is cheaper and more accessible than ever before. What is generally hidden from the consumer is the intention to combine, reuse, and resell this genetic information as powerful datasets. This financial gain is creating a competitive DTC market, reducing the price of whole genome sequencing (WGS) down to USD 299. Entering this transition from SNP based DTC testing to WGS DTC testing, individuals looking for access to their whole-genomic information face new privacy and security risks. We studied the ownership question of whole genomic data for 30 weeks, by conducting weekly community discussions and seminar series. Differences between WGS and other methods of consumer genetic tests are left unexplored by regulation, leading to the application of legal data anonymization methods on whole genome data, and questionable consent methods. Large representative genomic datasets are important for research and improve the standard of medicine and personalized care. However, this data can also be used by market players, law enforcement, and governments for surveillance, population analyses, marketing purposes, and discrimination. Here, we present a summary of the state of WGS DTC genetic testing and its current regulation, through community-based methods to expose dual-use risks in consumer facing biotechnologies.Item Open Access 43rd International Asilomar Chromatin, Chromosomes, and Epigenetics Conference(Canadian Science Publishing, 2022-06-13) Brown, Joshua A. R.; Cui, Jieying Hazel; Ling, Maggie Y.M.; Gao, Ellia X.C.; Howe, LeAnn J; Teves, Sheila S.The 43rd Asilomar Chromatin, Chromosomes, and Epigenetics Conference was held in an entirely online format from December 9-11, 2021. The conference enabled presenters at various career stages to share promising new findings, and presentations covered modern chromatin research across an array of model systems. Topics ranged from the fundamental principles of nuclear organization and transcription regulation to key mechanisms underlying human disease. The meeting featured five keynote speakers from diverse backgrounds and was organized by: Juan Ausió, University of Victoria (British Columbia, Canada), James Davie, University of Manitoba (Manitoba, Canada), Philippe T. Georgel, Marshall University (West Virginia, USA), Michael Goldman, San Francisco State University (California, USA), LeAnn Howe, University of British Columbia (British Columbia, Canada), Jennifer A. Mitchell, University of Toronto (Ontario, Canada), and Sally G. Pasion, San Francisco State University (California, USA).Item Open Access Cholecalciferol induces apoptosis via autocrine metabolism in epidermoid cervical cancer cells(Canadian Science Publishing, 2022-06-10) Bhoora, Sachin; Pillay, Tahir S.; Punchoo, RivakThe anti-cancer effects of vitamin D are of fundamental interest. Cholecalciferol is sequentially hydroxylated endogenously to calcidiol and calcitriol. Here, SiHa epidermoid cervical cancer cells were treated with cholecalciferol (10 - 2600 nM). Cell count and viability were assayed using crystal violet and trypan blue, respectively. Apoptosis was assessed using flow cytometry for early and late biomarkers along with brightfield microscopy and transmission electron microscopy. Autocrine vitamin D metabolism was analysed by qPCR and immunoblotting for activating enzymes; 25-hydroxylases (CYP2R1 and CYP27A1) and 1α-hydroxylase (CYP27B1); the catabolic 24-hydroxylase (CYP24A1); and the vitamin D receptor (VDR). Data were analysed using one-way ANOVA and Bonferroni post hoc test, and pItem Open Access Decursin ameliorates carbon tetrachloride-induced liver fibrosis by facilitating ferroptosis of hepatic stellate cells(Canadian Science Publishing, 2022-06-28) Que, Renye; Cao, Mengxing; Dai, Yancheng; Zhou, Yi; Chen, Yirong; Lin, LiubingDecursin possesses the potential to alleviate transforming growth factor (TGF)-β-induced hepatic stellate cells (HSCs) activation. However, the mechanisms by which decursin alleviates hepatic fibrosis remain not fully understood. Our aim is to explore the function of decursin on regulating HSCs activation and hepatic fibrosis. The anti-fibrotic effect of decursin was evaluated by Masson and Sirius red staining, and immunohistochemical (IHC) and quantitative real-time PCR (qRT-PCR) analysis for alpha-smooth muscle actin (α-SMA) and collagen types I (Col1a1) expression. Ferroptosis was assessed by measuring iron concentration, glutathione peroxidase 4 (Gpx4) and Prostaglandin endoperoxide synthase 2 (Ptgs2) expression, glutathione (GSH) level, lipid peroxidation, and reactive oxygen species (ROS) level. We found that decursin treatment decreased CCl4-induced liver fibrosis. The primary HSCs isolated from decursin-treated group showed an increased Fe2+, lipid ROS level, and decreased Gpx4 and GSH levels compared with HSCs from model group. Moreover, decursin promoted ferroptosis in activated HSCs in vitro, as evidenced by declined Gpx4 and GSH levels, increased Fe2+, ROS, and Ptgs2 levels compared with control. More important, ferroptosis inhibitor destroyed the anti-fibrosis effect of decursin on HSCs. In summary, these data suggest that decursin has potential to treat hepatic fibrosis.Item Open Access The search for genetic dark matter and lessons learned from the journey(Canadian Science Publishing, 2022-06-03) Borden, KatherineIn this review, I describe our scientific journey to unearth the impact of RNA metabolism in cancer using the eukaryotic translation initiation factor eIF4E as an exemplar. This model allowed us to discover new structural, biochemical, and molecular features of RNA processing, and to reveal their substantial impact on cell physiology. This led us to develop proof-of-principle strategies to target these pathways in cancer patients leading to clinical benefit. I discuss the important role that the unexpected plays in research and the necessity of embracing the data even when it clashes with dogma. I also touch on the importance of equity, diversity and inclusion to the success of the scientific enterprise.Item Open Access Establishing an incentive-based multi-stakeholder approach to Dual Use DNA screening(Canadian Science Publishing, 2022-03-07) Isaac, Christopher RFast, accessible, and high-quality DNA is fundamental to advancement in the life sciences that will drive forward fields like agriculture, energy, and medicine. Despite their importance in accelerating global progress, bioscience research and biotechnologies can also be misused, endangering humans, animals, and the environment. The ability to accidentally or deliberately endow or enhance pathogenicity of biological systems is of particular concern. Access to DNA sequences with a clear potential for Dual Use should be limited to responsible and identifiable groups with legitimate uses. Yet, none of the 195 countries party to the International Health Regulations have national laws that mandate this type of screening. Many DNA providers voluntarily screen orders and absorb increased costs, but this practice is not universally adopted for a variety of reasons. This article explores the incentives and regulatory structures that can bring the screening coverage of DNA orders towards 100%, which may include: expedited orders for approved customers, better tools and technology for more efficient screening, funding requirements that grantees use screened DNA, and early education in biosecurity aimed at researchers and students. Ultimately, an incentive-based multi-stakeholder approach to DNA screening can benefit researchers, industry, and global health security.Item Open Access Alloimperatorin activates apoptosis, ferroptosis and oxeiptosis to inhibit the growth and invasion of breast cancer cells in vitro(Canadian Science Publishing, 2022-02-15) Zhang, Jing; Gao, Run-fang; Li, Jie; Yu, Ke-da; Bi, Kai-xinBreast cancer is the most common malignant tumour in women. Our research on alloimperatorin from Angelica dahurica showed that alloimperatorin inhibited breast cancer cell viability in a concentration- and time-dependent manner; it also showed that apoptosis and ferroptosis inhibitors significantly weakened the anti-survival effect of alloimperatorin. Alloimperatorin clearly induced breast cancer cell apoptosis and increased the activities of Caspase-3, Caspase-8, Caspase-9 and PARP; it also caused significant mitochondrial shrinkage, promoted the accumulation of Fe2+, ROS and MDA, and significantly reduced mRNA and protein expression levels of SLC7A11 and GPX4, indicating that alloimperatorin induces ferroptosis. In addition, alloimperatorin significantly promoted Keap1 expression; although it did not affect the expression of PGAM5 and AIFM1, it significantly reduced the phosphorylation level of AIFM1. After downregulating the expression of Keap1, PGAM5 or AIFM1, the inhibitory effect of alloimperatorin on cell viability was significantly weakened, indicating that alloimperatorin regulates the Keap1/PGAM5/AIFM1 pathway to promote oxeiptosis. Alloimperatorin significantly inhibited the invasion of breast cancer cells, while Keap1 siRNA or GPX4 overexpression vectors significantly enhanced cell invasion and effectively reversed the anti-invasive effect of alloimperatorin. Therefore, alloimperatorin induces breast cancer cell apoptosis, ferroptosis and oxeiptosis, thereby inhibiting cell growth and invasion.Item Open Access The CSP Special Edition “Dual Use in life science research”(Canadian Science Publishing, 2022-03-25) Rohden, Fabian; Wieden, Hans-JoachimBiotechnological approaches are expanding into most areas of the economy. Especially the interface of Omics technologies and Artificial Intelligence is promising to revolutionize the production of food, medicine, materials, and energy. The increasing integration of life sciences approaches into industrial processes forms the foundation for a fast emerging bioeconomy. The bioeconomy promises green growth, enabling economies to continue to grow in an environmentally sustainable manner and is increasingly perceived as an industrial revolution with disruptive potential similar to the last industrial revolution that created the digital economy by introducing Information Technology and computers into most areas of our economy and daily lives.Item Open Access Curcumin attenuates intracerebral hemorrhage-induced neuronal apoptosis and neuroinflammation by suppressing the JAK1/STAT1 pathway(Canadian Science Publishing, 2022-03-16) Wang, Fei; Xia, Jian-jun; Shen, Li-juan; Jiang, Ting-ting; Li, Wu-lin; You, Da-li; Chang, Qing; Hu, Shan-you; Wang, Li; Wu, XiaoTo date, there is no effective treatment strategy for Intracerebral hemorrhage (ICH). Curcumin, a major active ingredient of curcuma longa L, possesses a potential anti-inflammatory activity in many types of disease. In the current study, the mechanism underlying curcumin attenuates ICH-induced neuronal apoptosis and neuroinflammation was explored. Herein, we studied curcumin decreased brain edema and improved neurological function by using brain edema measurement, assessment of neurological-deficient score, immunofluorescence, and western blotting analyses after ICH. The results showed that curcumin improved ICH-induced neuronal apoptosis and neuroinflammation. Functionally, the polarization of microglia was assessed by immunofluorescence and western blotting analyses after ICH in the absence or presence of curcumin. The results suggested that the M1-type microglia were activated after ICH, while the effect was blocked by curcumin treatment, suggesting that curcumin alleviates the neuroinflammation and apoptosis of neurons by suppressing the M1-type polarization of microglia. Mechanically, M1 polarization of microglia was regulated by JAK1/STAT1 and the activation of JAK1/STAT1 was blocked by curcumin. Meanwhile, the protective function of curcumin can be blocked by RO8191, an activator of JAK1. Taken together our study suggests that curcumin improved the ICH-induced brain injury through alleviating M1 polarization of microglia/macrophage and neuroinflammation via suppressing JAK1/STAT1 pathway.Item Open Access The Biological Relevance of PCSK9: When Less Is Better…(Canadian Science Publishing, 2022-01-22) MBIKAY, Majambu; CHRÉTIEN, MichelProprotein Convertase Subtilisin/Kexin-type 9 (PCSK9) is a circulating negative regulator of hepatic low-density lipoprotein receptor (LDLR) which clears cholesterol from blood. Gain-of-function genetic mutations which amplify PCSK9 activity have been found to cause potentially lethal familial hypercholesterolemia. Inversely, reduction of its activity through loss-of-function genetics or with pharmaceuticals was shown to increase hepatic LDLR, to lower blood cholesterol, and to protect against cardiovascular diseases. New epidemiological and experimental evidence suggests that this reduction could also attenuate inflammation, reinforce cancer immunity, provide resistance to infections, and protect against liver pathologies. In this review, we question the relevance of this protein under normal physiology. We propose that PCSK9 is an important, but non-essential, modulator of cholesterol metabolism and immunity, and that its pathogenicity results from its chronic overexpression.