Browsing by Subject "senescence"
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Item Aging of the Thymic Epithelial Progenitor Pool is Determined by the p63-FoxN1 Regulatory Axis(2015-05-01) Burnley, Preston I.; Dong-Ming SuThe immune system is composed of various effector cells and molecules that must work in concert in order to protect the body against infections, auto-reaction, and tumor occurrence. These responses can be divided into two categories – innate and adaptive immunity. The innate response is the host’s first line of defense towards a pathogen by providing a physical and chemical barrier against infection. Once activated, innate cells such as macrophages and dendritic cells can engulf the bacterium, degrade it, and secrete proteins to destroy the pathogen. Although this response occurs immediately after an encounter with a pathogen, the innate immunity is neither long-lasting nor specific. In contrast, the adaptive immune response is initiated when the innate immune response is unsuccessful in eliminating the infection, allowing for recognition and response tailored for a particular pathogen. The cells that make up the adaptive response all originate from a common lymphoid progenitor found in the bone marrow. From this precursor arise natural killer (NK) cells (part of the innate response) and T and B lymphocytes. The T lymphocytes originate from the bone marrow but undergo development in the thymus, hence the name T cells. B lymphocytes, on the other hand, originate and develop in the bone marrow. With the exception of NK cells, these adaptive immune cells require antigen presentation in order to become activated. Once the T and B cells have matured and become activated they can work together to clear the infection by secreting cytokines and antibodies. The most important aspect of the adaptive immune response is its ability to produce immunological memory. Memory T and B cells are able to ensure a rapid and effective response to a second encounter, providing long-last immunity. Unfortunately, this well-ordered process, specifically the development of T cells, becomes compromised during aging. This is due to the fact that thymic involution (or shrinking of the thymus) occurs at the onset of puberty and continues throughout the lifespan, which is primarily resulted from age-related defect in thymic epithelial cells (TECs). The thymus is crucial for the generation of T cells so any compromise to the organ results in changes in the T cells, which can possibly lead to immune insufficiency and autoimmunity [1]. Additionally, these conditions are exacerbated with age [2, 3]. This research project will focus on the molecular mechanism(s) responsible for thymic involution. To do so, we focused on TECS and two genes associated with the homeostatic maintenance of the thymic microenvironment, p63 and FoxN1. These genes regulate the proliferation and differentiation, respectively, of thymic epithelial cells (TECs), thereby maintaining a properly functioning thymus. For this study we will utilize our mouse model (FoxN1 conditional knockout, FC) extensively because it mimics an aged thymus. This model allows us to study the thymic microenvironment of a mouse with a defect in the FoxN1 gene.Item Akt Isoforms: A Family Affair in Breast Cancer(MDPI, 2021-07-09) Basu, Alakananda; Lambring, Christoffer B.Akt, also known as protein kinase B (PKB), belongs to the AGC family of protein kinases. It acts downstream of the phosphatidylinositol 3-kinase (PI3K) and regulates diverse cellular processes, including cell proliferation, cell survival, metabolism, tumor growth and metastasis. The PI3K/Akt signaling pathway is frequently deregulated in breast cancer and plays an important role in the development and progression of breast cancer. There are three closely related members in the Akt family, namely Akt1(PKBalpha), Akt2(PKBbeta) and Akt3(PKBgamma). Although Akt isoforms share similar structures, they exhibit redundant, distinct as well as opposite functions. While the Akt signaling pathway is an important target for cancer therapy, an understanding of the isoform-specific function of Akt is critical to effectively target this pathway. However, our perception regarding how Akt isoforms contribute to the genesis and progression of breast cancer changes as we gain new knowledge. The purpose of this review article is to analyze current literatures on distinct functions of Akt isoforms in breast cancer.Item Combining Injectable Plasma Scaffold with Mesenchymal Stem/Stromal Cells for Repairing Infarct Cavity after Ischemic Stroke(JKL International, 2017-04-01) Zhang, Hongxia; Sun, Fen; Wang, Jixian; Xie, Luokun; Yang, Chenqi; Pan, Mengxiong; Shao, Bei; Yang, Guo-Yuan; Yang, Shaohua; Zhuge, Qichuan; Jin, KunlinStroke survivors are typically left with structural brain damage and associated functional impairment in the chronic phase of injury, for which few therapeutic options exist. We reported previously that transplantation of human embryonic stem cell (hESC)-derived neural stem cells together with Matrigel scaffolding into the brains of rats after focal ischemia reduced infarct volume and improved neurobehavioral performance. Matrigel is a gelatinous protein mixture extracted from mouse sarcoma cells, thus would not be approved for use as a scaffold clinically. In this study, we generated a gel-like scaffold from plasma that was controlled by changing the concentration of CaCl2. In vitro study confirmed that 10-20 mM CaCl2 and 10-40% plasma did not affect the viability and proliferation of human and rat bone marrow mesenchymal stem/stromal cells (BMSCs) and neural stem cells (NSCs). We transplanted plasma scaffold in combination of BMSCs into the cystic cavity after focal cerebral ischemia, and found that the atrophy volume was dramatically reduced and motor function was significantly improved in the group transplanted with scaffold/BMSCs compared with the groups treated with vehicle, scaffold or BMSCs only. Our data suggest that plasma-derived scaffold in combination of BMSCs is feasible for tissue engineering approach for the stroke treatment.Item Key Signaling Pathways in Aging and Potential Interventions for Healthy Aging(MDPI, 2021-03-16) Yu, Mengdi; Zhang, Hongxia; Wang, Brian; Zhang, Yinuo; Zheng, Xiaoying; Shao, Bei; Zhuge, Qichuan; Jin, KunlinAging is a fundamental biological process accompanied by a general decline in tissue function. Indeed, as the lifespan increases, age-related dysfunction, such as cognitive impairment or dementia, will become a growing public health issue. Aging is also a great risk factor for many age-related diseases. Nowadays, people want not only to live longer but also healthier. Therefore, there is a critical need in understanding the underlying cellular and molecular mechanisms regulating aging that will allow us to modify the aging process for healthy aging and alleviate age-related disease. Here, we reviewed the recent breakthroughs in the mechanistic understanding of biological aging, focusing on the adenosine monophosphate-activated kinase (AMPK), Sirtuin 1 (SIRT1) and mammalian target of rapamycin (mTOR) pathways, which are currently considered critical for aging. We also discussed how these proteins and pathways may potentially interact with each other to regulate aging. We further described how the knowledge of these pathways may lead to new interventions for antiaging and against age-related disease.Item Lifelong vs. Late Life Tocopherol on Learning and Memory in Mice(2004-05-01) McDonald, Shelley R.; Michael Forster; Glenn DillonMcDonald, Shelley R., Lifelong vs. late life tocopherol on learning and memory in mice. Doctor of Philosophy (Biomedical Sciences), May, 2004, 132 pp., 1 table, 14 figures, bibliography, 122 titles. The purpose of these studies was to determine if vitamin E supplementation, a well-studied antioxidant, could improve the cognitive functions of old mice either by preventing age-dependent impairments or reversing age-related dysfunction. Cellular oxidative stress is believed to be a causal factor in senescence, and the brain appears to be particularly susceptible to oxidative damage because of a relatively high rate of reactive oxygen species generation without commensurate levels of antioxidant defenses. If oxidative stress indeed plays a role in age-related brain dysfunction, then it can be predicted that experimental interventions capable of lowering oxidative stress would either prevent or restore function. This was tested using apolipoprotein E-deficient mice, which have an increased susceptibility to neuronal oxidative damage, maintained on 3 different doses (2 mg/kg, 20 mg/kg, or 200 mg/kg/day) of dl-α-tocopheryl acetate (vitamin E) via supplemented food pellets from 8 weeks of age throughout behavioral testing when 6 or 18 mo of age. A separate experiment used wild type mice 24 months of age to examine whether or not a combination of vitamin E (123 mg/kg/day) with coenzyme Q10 (200 mg/kg/day) which leads to higher tissue levels of vitamin E, could improve brain functions in old mice. Mice were tested on multiple behavioral tasks that required utilization of various components of memory and learning, as well as sensorimotor testing. The highest dose of vitamin E prevented the decline of spatial memory in old apolipoprotein E-deficient mice, but did not prevent age-related impairments in learning and memory for discriminated escape. When old wild type mice were treated with the combined vitamin E and coenzyme W10, the mice learned and remembered to avoid a preemptive shock significantly more than old mice treated with vitamin E or coenzyme Q10 alone. A followup experiment with higher doses of coenzyme Q10 alone (250 or 500 mg/kg/day) resulted in no cognitive improvements. No treatments improved sensorimotor performance.Item The Enigmatic Protein Kinase C-eta(MDPI, 2019-02-13) Basu, AlakanandaProtein kinase C (PKC), a multi-gene family, plays critical roles in signal transduction and cell regulation. Protein kinase C-eta (PKCeta) is a unique member of the PKC family since its regulation is distinct from other PKC isozymes. PKCeta was shown to regulate cell proliferation, differentiation and cell death. It was also shown to contribute to chemoresistance in several cancers. PKCeta has been associated with several cancers, including renal cell carcinoma, glioblastoma, breast cancer, non-small cell lung cancer, and acute myeloid leukemia. However, mice lacking PKCeta were more susceptible to tumor formation in a two-stage carcinogenesis model, and it is downregulated in hepatocellular carcinoma. Thus, the role of PKCeta in cancer remains controversial. The purpose of this review article is to discuss how PKCeta regulates various cellular processes that may contribute to its contrasting roles in cancer.