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Item Neuroprotective effects of whey and buttermilk-based formulas on a DSS-induced colitis murine model(Canadian Science Publishing, 2024-09-23) Buey, Berta; Latorre, Eva; Castro, Marta; Valero, Marta Sofía; Plaza, Miguel Ángel; Arruebo, María Pilar; Abad, Inés; Rodríguez-Largo, Ana; Sánchez, Lourdes; Mesonero, Jose EmilioInflammatory bowel disease is a gut-brain axis disorder that comprises chronic inflammatory conditions affecting the gastrointestinal tract, where alterations in the mood of patients are common. Gut-brain axis is a bidirectional communication that link gut and brain. The close association between inflammatory bowel disease and neuroinflammation has far-reaching implications, as is increasingly recognized as a contributing factor to neuropsychiatric and neurodegenerative diseases. The increasing prevalence and high economic cost, together with the loss of life quality of people suffering from these diseases, point to the need to find alternatives to alleviate them. Exploring new therapeutic avenues prompts us to consider the potential benefits of milk fractions, taking advantage of the use of dairy by-products, such as whey and buttermilk. This study examines the impact of cow’s whey- and buttermilk-based formulas supplemented with bovine lactoferrin and milk fat globule membrane on the expression of cytokines, as well as on the components of immune and serotonergic system of the brain in a murine model of DSS-induced colitis. Our results show the potential of these dairy by-products, especially whey, as functional foods in ameliorating neuroinflammation and safeguarding the central nervous system function amid the neurological complications induced or concomitant with intestinal inflammatory processes.Item Bovine lactoferrin and chimera lactoferrin prevent and destroy Salmonella Typhimurium biofilms in Caco-2 cells.(Canadian Science Publishing, 2024-07-08) Quintero-Martínez, Laura E.; Canizalez-Roman, Adrian; Angulo-Zamudio, Uriel A.; Flores-Villaseñor, Hector; Velazquez-Roman, Jorge A.; Bolscher, Jan G.M.; Nazmi, Kamran; Leon-Sicairos, NidiaSalmonellosis is a common foodborne disease caused by Salmonella bacteria. The emergence of multidrug-resistant (MDR) Salmonella serotypes, such as Typhimurium, and Salmonella's ability to form biofilms contribute to their resistance and persistence in host and non-host environments. New strategies are needed to treat or prevent Salmonella infections. This work aimed to determine the effect of the bovine lactoferrin (bLF) and lactoferrin chimera (LFchimera) in preventing or disrupting biofilms formed on abiotic surfaces or Caco-2 cells by Salmonella Typhimurium ATCC 14028 or an MDR strain. The inhibitory activity of planktonic bacteria, prevention of biofilm formation, and destruction of biofilms of S. Typhimurium (ATCC 14028 or MDR strain) on the abiotic surface and Caco-2 cells of bLF and LFchimera were quantified by CFU/ml and visualized by microscopy using Giemsa-stained samples. bLF (75-1000µM) and LFchimera (1-20µM) inhibited more than 95% of S. Typhimurium planktonic growth cultures (ATCC 14028 and MDR). In addition, bLF (600, 800, and 1000 µM) and LFchimera (10 and 20µM) prevented more than 98% of S. Typhimurium adherence and biofilm formation on Caco-2 cells. Finally, bLF (600 and 1000 µM) and LFchimera (10 and 20µM) destroyed more than 80% of S. Typhimurium biofilms established on abiotic and Caco-2 cells. In conclusion, bLF and LF chimeras have the potential to inhibit and destroy S. Typhimurium biofilms.Item Canada’s contributions to RNA research: past, present and future perspectives(Canadian Science Publishing, 2024-09-20) Lécuyer, Eric; Sauvageau, Martin; Kothe, Ute; Unrau, Peter J; Damha, Masad J.; Perreault, Jonathan; Abou Elela, Sherif; Bayfield, Mark; Claycomb, Julie; Scott, Michelle S.The field of RNA research has provided profound insights into the basic mechanisms modulating the function and adaption of biological systems. RNA has also been at the center stage in the development of transformative biotechnological and medical applications, perhaps most notably was the advent of mRNA vaccines that were critical in helping humanity through the Covid-19 pandemic. Unbeknownst to many, Canada boasts a diverse community of RNA scientists, spanning multiple disciplines and locations, whose cutting-edge research has established a rich track-record of contributions across various aspects of RNA science over many decades. Through this position paper, we seek to highlight key contributions made by Canadian investigators to the RNA field, via both thematic and historical viewpoints. We also discuss initiatives underway to organize and enhance the impact of the Canadian RNA research community, particularly focusing on the creation of the not-for-profit organization RNA Canada ARN. Considering the strategic importance of RNA research in biology and medicine, and its considerable potential to help address major challenges facing humanity, sustained support of this sector will be critical to help Canadian scientists play key roles in the ongoing RNA revolution and the many benefits this could bring about to Canada.Item Neurodevelopmental functions and activities of the KAT3 class of lysine acetyltransferases(Canadian Science Publishing, 2024-09-09) Shahib, Ashraf K; Rastegar, Mojgan; van Wijnen, Andre J; Davie, James R.The human lysine acetyltransferases KAT3A (CREBBP) and KAT3B (EP300) are essential enzymes in gene regulation in the nucleus. Their ubiquitous expression in metazoan cell types controls cell proliferation and differentiation during development. This comprehensive review delves into the biological roles of KAT3A and KAT3B in neurodevelopment, shedding light on how alterations in their regulation or activity can potentially contribute to a spectrum of neurodegenerative diseases (e.g. Huntington's and Alzheimer's). We explore the pathophysiological implications of KAT3 function loss in these disorders, considering their conserved protein domains and biochemical functions in chromatin regulation. The discussion also underscores the crucial role of KAT3 proteins and their substrates in supporting the integration of key cell signaling pathways. Furthermore, the narrative highlights the interdependence of KAT3-mediated lysine acetylation with lysine methylation and arginine methylation. From a cellular perspective, KAT3-dependent signal integration at subnuclear domains is mediated by liquid-liquid phase separation in response to KAT3-mediated lysine acetylation. The disruption of these finely tuned regulatory processes underscores their pathological roles in neurodegeneration. This review also points to the exciting potential for future research in this field, inspiring further investigation and discovery in the area of neurodevelopment and neurodegenerative diseases.Item Pathophysiological Relevance and Therapeutic Outlook of GPR43 in Atherosclerosis(Canadian Science Publishing, 2024-07-08) Tang, Mu-Yao; Xie, Hao; Tao, Jin-Tao; Zhang, Chun; Luo, Yao-Hua; Zhang, Cong; Peng, Si-Qin; Xie, Lin-Xi; Lv, Wen-Bo; Zhang, Chi; Huang, LiangAtherosclerosis (AS) is an inflammatory arterial disorder that occurs due to the deposition of the excessive lipoprotein under the artery intima, mainly including low-density lipoprotein (LDL) and other apolipoprotein B-containing lipoproteins. G protein-coupled receptors (GPCRs) play a crucial role in transmitting signals in physiological and pathophysiological conditions. GPCRs recognize inflammatory mediators, thereby serving as important players during chronic inflammatory processes. It has been demonstrated that free fatty acids can function as ligands for various GPCRs, such as free fatty acid receptor (FFAR)1/GPR40, FFAR2/GPR43, FFAR3/GPR41, FFAR4/GPR120, and the lipid metabolite binding glucose-dependent insulinotropic receptor (GPR119). This review discusses GPR43 and its ligands in the pathogenesis of AS, especially focusing on its distinct role in regulating chronic vascular inflammation, inhibiting oxidative stress, ameliorating endothelial dysfunction and improving dyslipidemia. It is hoped that this review may provide guidance for further studies aimed at GPR43 as a promising target for drug development in the prevention and therapy of AS.Item The Importance of Prion Research(Canadian Science Publishing, 2024-06-28) Eid, Shehab; Lee, Seojin; Verkuyl, Claire E.; Almanza, Dustin; Hanna, Joseph; Shenouda, Sandra; Belotserkovsky, Ari; Zhao, Wenda; Watts, JoelOver the past four decades, prion diseases have received considerable research attention owing to their potential to be transmitted within and across species as well as their consequences for human and animal health. The unprecedented nature of prions has led to the discovery of a paradigm of templated protein misfolding that underlies a diverse range of both disease-related and normal biological processes. Indeed, the “prion-like” misfolding and propagation of protein aggregates is now recognized as a common underlying disease mechanism in human neurodegenerative disorders such as Alzheimer’s and Parkinson’s disease and the prion principle has led to the development of novel diagnostic and therapeutic strategies for these illnesses. Despite these advances, research into the fundamental biology of prion diseases has declined, likely due to their rarity and the absence of an acute human health crisis. Given the past translational influence, continued research on the etiology, pathogenesis, and transmission of prion disease should remain a priority. In this review we highlight several important “unsolved mysteries” in the prion disease research field and how solving them may be crucial for the development of effective therapeutics, preventing future outbreaks of prion disease, and understanding the pathobiology of more common human neurodegenerative disorders.Item miR-520e and its promoter region DNA methylation as potential biomarkers in atherosclerosis(Canadian Science Publishing, 2024-06-11) Mu, Mimi; Liu, Gao; Ding, Xiaoyu; Xue, Lijun; Li, Dandan; Zhu, Yunhua; Zhang, Nan; Wu, Jia; Wang, JunjunIn atherosclerosis, DNA methylation plays a key regulatory role in the expression of related genes. However, the molecular mechaism of these processes in HUVECs are unclear. Here, using high-throughput sequencing from the Infinium HumanMethylation450 assay, we manifested that the cg19564375 methylation of miR-520e promoter region in the peripheral blood of acute coronary syndrome (ACS) patients was higher than that of healthy controls. As shown by RQ-MSP, the upstream DNA methylation level of the miR-520e promoter region was considerably increased in ACS patients. miR-520e was markedly down-regulated in ACS patients compared with healthy controls. In the ox-LDL-induced HUVECs injury model, DNA methylation of the upstream region of miR-520e was significantly increased. With increasing concentrations of the methylase inhibitor 5-Aza, miR-520e expression was upregulated. The silence of methyltransferase DNMT1, rather than DNMT3a or DNMT3b, abolished the influence of miR-520e expression by ox-LDL treatment in HUVECs. A dual luciferase reporter assay revealed that miR-520e regulated the TGFBR2 3’-UTR region. After silencing TGFBR2, the promoting effect of miR-520e inhibitor on cell proliferation and migration may be attenuated. In conclusion, the expression of miR-520e is modified by its promoter region DNA methylation, and miR520e and its promoter region DNA methylation may be potential biomarkers in atherosclerosis.Item Review: Interconnected roles of fungal nuclear and intron encoded maturases: At the crossroads of mitochondrial intron splicing.(Canadian Science Publishing, 2024-05-21) Mukhopadhyay, Jigeesha; Hausner, GeorgGroup I and II introns are large catalytic RNAs (ribozymes) that are frequently encountered in fungal mitochondrial genomes. The discovery of respiratory mutants linked to intron splicing defects demonstrated that for the efficient removal of organellar introns there appears to be a requirement of protein splicing factors. These splicing factors can be intron-encoded proteins with maturase activities that usually promote the splicing of the introns that encode them (cis-acting) and/or nuclear-encoded factors that can promote the splicing of a range of different introns (trans-acting). Compared to plants organellar introns, fungal mitochondrial intron splicing is still poorly explored, especially in terms of the synergy of nuclear factors with intron-encoded maturases that has direct impact on splicing through their association with intron RNA. In addition, nuclear-encoded accessory factors might drive the splicing impetus through translational activation, mitoribosome assembly, and phosphorylation-mediated RNA turnover. This review explores protein-assisted splicing of introns by nuclear and mitochondrial-encoded maturases as a means of mitonuclear interplay that could respond to environmental and developmental factors promoting phenotypic adaptation and potentially speciation. It also highlights key evolutionary events that have led to changes in structure and ATP-dependence to accommodate the dual-functionality of nuclear and organellar splicing factors.Item Chromatin and Nucleosome-Associated Features in Liquid Biopsy: Implications for Cancer Biomarker Discovery(Canadian Science Publishing, 2024-03-03) Penny, Lucas; Main, Sasha; De Michino, Steven; Bratman, ScottCell-free DNA (cfDNA) from the bloodstream has been studied for cancer biomarker discovery, and chromatin-derived epigenetic features have come into the spotlight for their potential to expand clinical applications. Methylation, fragmentation, and nucleosome positioning patterns of cfDNA have previously been shown to reveal epigenomic and inferred transcriptomic information. More recently, histone modifications have emerged as a tool to further identify tumor-specific chromatin variants in plasma. A number of sequencing methods have been developed to analyze these epigenetic markers, offering new insights into tumor biology. Features within the cfDNA allow for cancer detection, subtype and tissue of origin classification, inference of gene expression, and improve the differentiation of cancer status and types. These methods provide insights into uncovering the complexity of cancer genetics and the dynamic nature of its progression. In this review, we highlight the array of features that can be extracted from chromatin- and nucleosome-associated organization for cancer classification.Item The journey from bench to bedside – it takes a science village(Canadian Science Publishing, 2024-04-15) Mes-Masson, Anne-MarieI was fortunate enough to start my career at what was the dawn of modern-day molecular biology and to apply it to an important health problem. While my early work focused on fundamental science, the desire to understand human disease better and to find practical applications for research discoveries resulted, over the following decades, in creating a stream of translational research directed specifically towards epithelial cancers. This could only have been possible through multiple collaborations. This type of team science would eventually become a hallmark of my career. With the development of higher throughput molecular techniques, the pace of research and discovery have quickened, and the concept of personalized medicine based on genomics is now coming to fruition. I hope my legacy will not just reflect my published works, but will also include the impact I have had on the development of the next generation of scientist and clinician scientists who inspired me with their dedication, knowledge and enthusiasm.Item Decreased NMIIA heavy chain phosphorylation at S1943 promotes mitoxantrone resistance by upregulating BCRP and N-cadherin expression in breast cancer cells(Canadian Science Publishing, 2024-01-03) li, kemin; li, tian; niu, yanan; gao, yu; shi, yifan; he, yifan; zhang, xuanping; wang, yan; cao, jing; hu, xiaoling; Chen, Min; shi, zan ruiMitoxantrone (MX) is an effective treatment for breast cancer; however, high efflux of MX that is accomplished by breast cancer resistance protein (BCRP) leads to acquired multidrug resistance (MDR), reducing MX’s therapeutic efficacy in breast cancer. Non-muscle myosin IIA (NMIIA) and its heavy phosphorylation at S1943 have been revealed to play key roles in tumor metastasis and progression, including in breast cancer; however, their molecular function in BCRP-mediated MDR in breast cancer remains unknown. In this study, we revealed that the expression of NMIIA heavy chain phosphorylation at S1943 was downregulated in BCRP-overexpressing breast cancer MCF‐7/MX cells, and stable expression of NMIIA-S1943A mutant increased BCRP expression and promoted the resistance of MCF‐7/MX cells to MX. Meanwhile, NMIIA S1943 phosphorylation induced by epidermal growth factor (EGF) was accompanied by the downregulation of BCRP in MCF-7/MX cells. Furthermore, stable expression of NMIIA-S1943A in MCF-7/MX cells resulted in upregulation of N-cadherin and the accumulation of β-catenin on the cell surface, which inhibited the nucleus translocation of β-catenin and Wnt/β-catenin-based proliferative signaling. EGF stimulation of MCF-7/MX cells showed the downregulaton of N-cadherin and β-catenin. Our results suggest that decreased NMIIA heavy phosphorylation at S1943 increases BCRP expression and promotes MX resistance in breast cancer cells via upregulating N-cadherin expression.