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Nathan Goodyear

Hit-and-run epigenetic editing prevents senescence entry in primary breast cells from h... - 0 views

www.nature.com/...s41467-017-01078-2

epigenetics breast cancer cancer

shared by Nathan Goodyear on 29 Nov 17 - No Cached
  • Nathan Goodyear on 29 Nov 17
     
    Epigenetics is no longer something to observe, but is now something to seek to modify for therapeutic purposes.  Study targeted CPG islands for hypermethylation in primary breast cancer cells to arrest cell cycle and stop senescence escape.
Nathan Goodyear

Cellular senescence: a double-edged sword in cancer therapy - PMC - 0 views

www.ncbi.nlm.nih.gov/...PMC10522834

cancer senescence

shared by Nathan Goodyear on 11 Jun 24 - No Cached
  • cellular senescence has been identified in cancer patients undergoing chemotherapy and radiotherapy
Nathan Goodyear

Role of Oxidative Stress and the Microenvironment in Breast Cancer Development and Prog... - 0 views

www.ncbi.nlm.nih.gov/...PMC3950899

cancer oxidative stress warburg effect reverse warburg effect ROS

shared by Nathan Goodyear on 11 Nov 14 - No Cached
  • oxidative stress leads to HIF-1α accumulation
  • Oxidative stress generated by breast cancer cells activates HIF-1α and NFκB in fibroblasts, leading to autophagy and lysosomal degradation of Cav-1
  • increased levels of hydrogen peroxide in exhaled breath condensate from patients with localized breast malignancy, associated with increased clinical severity
  • ...18 more annotations...
  • Comparing mitochondrial metabolic activity revealed a difference between stroma and epithelial cells
  • Overexpression of NOX4 in normal breast epithelial cells results in cellular senescence, resistance to apoptosis, and tumorigenic transformation, as well as increased aggressiveness of breast cancer cells
  • metalloproteinases (MMP) such as MMP-2, MMP-3, and MMP-9 increase extracellular matrix turnover and are themselves activated by oxidative stress
  • Lowered expression of Cav-1 not only leads to myofibroblast conversion and inflammation but also seems to impact aerobic glycolysis, leading to secretion of high energy metabolites such as pyruvate and lactate that drive mitochondrial oxidative phosphorylation in cancer cells
  • Reverse Warburg Effect
  • secreted transforming growth factor β (TGFβ), insulin-like growth factor (IGF), platelet-derived growth factor (PDGF), fibroblast growth factor 2, and stromal-derived factor 1 (SDF1) are able to activate fibroblasts and increase cancer cell proliferation
  • oxidative stress has an important role in the initiation and preservation of breast cancer progression
  • cancer preventive role of healthy mitochondria
  • the cancer cells produce hydrogen peroxide and by driving the “Reverse Warburg Effect” initiate oxidative stress in fibroblasts. As a result of this process, fibroblasts exhibited reduced mitochondrial activity, increased glucose uptake, ROS, and metabolite production.
  • Oxidative stress results from an imbalance between unstable reactive species lacking one or more unpaired electrons (superoxide anion, hydrogen peroxide, hydroxyl radical, reactive nitrogen species) and antioxidants
  • cancer cells are able to induce drivers of oxidative stress, autophagy and mitophagy: HIF-1α and NFκB in surrounding stroma fibro-blasts
  • Studies show that loss of Cav-1 in adjacent breast cancer stroma fibroblasts can be prevented by treatment with N-acetyl cysteine, quercetin, or metformin
  • However, diets rich in antioxidants have fallen short in sufficiently preventing cancer
  • hydrogen peroxide is one of the main factors that can push fibroblasts and cancer cells into senescence
  • It is widely held that HIF-1α function is dependent upon its location within the tumor microenvironment. It acts as a tumor promoter in CAFs and as a tumor suppressor in cancer cells
  • It was reported that overexpression of recombinant (SOD2) (Trimmer et al., 2011) or injection of SOD, catalase, or their pegylated counterparts can block recurrence and metastasis in mice
  • obstructing oxidative stress in the tumor microenvironment can lead to mitophagy and promote breast cancer shutdown is a promising discovery for the development of future therapeutic interventions.
  • Recent studies show that in the breast cancer microenvironment, oxidative stress causes mitochondrial dysfunction
  • Nathan Goodyear on 11 Nov 14
     
    Really fascinating article on tumor signaling. The article points to a complex signaling between cancer cells and stromal fibroblasts that results in myofibroblast transformation that increases the microenvironment favorability of cancer. This article points to oxidative stress as the primary driving force.  
Nathan Goodyear

Telomerase reactivation reverses tissue degeneration in aged telomerase deficient mice - 0 views

www.ncbi.nlm.nih.gov/...PMC3057569

telomerase telomerase activator telomere aging

shared by Nathan Goodyear on 18 May 16 - No Cached
  • age-progressive loss of telomere function in mice has been shown to provoke widespread p53 activation resulting in activation of cellular checkpoints of apoptosis, impaired proliferation and senescence, compromised tissue stem cell and progenitor function, marked tissue atrophy and physiological impairment in many organ systems
  • Despite chromosomal instability, the brief course of telomerase reactivation was not sufficient to promote carcinogenesis (data not shown), a finding consistent with a role for telomerase in promoting progression of established neoplasms
  • Nathan Goodyear on 18 May 16
     
    another mouse study that found that increasing telomerase activity in shortened telomere mice improved tissue regeneration.
Nathan Goodyear

Telomerase at the intersection of cancer and aging - 0 views

www.ncbi.nlm.nih.gov/...PMC3896987

telomere telomeres telomerase telomerase activator aging disease cancer

shared by Nathan Goodyear on 18 May 16 - No Cached
  • The anti-aging role of telomerase has been demonstrated to be largely mediated by its canonical role in elongating telomeres, which prevents the accumulation of critically short telomeres and loss of tissue homeostasis
  • Short telomeres, and subsequent DDR activation, could occur both in cancer and aging
  • increased abundance of short telomeres correlates with higher genomic instability and decreased longevity in various organisms, including mice, zebrafish, and yeast
  • ...15 more annotations...
  • mice deficient for telomerase or for telomere binding proteins are characterized by accelerated age-related defects
  • In humans, short telomeres are considered good indicators of an individual’s health status and correlate with both genetic and environmental factors
  • Although recent findings strongly support the idea that short telomeres drive several age-related diseases 38 we cannot exclude the possibility that in some situations short telomeres may be a consequence of the disease itself.
  • the current view is that telomerase deficiency may contribute to the early steps of cancer development by fueling chromosomal instability, while subsequent activation of telomerase may be necessary to allow tumor growth and tumor progression towards more malignant states
  • telomerase activation can be an early event in cancer, it is not necessary for cancer initiation
  • telomerase can stimulate tumor progression by ensuring maintenance of telomeres above a critically short length, thus preventing induction of cellular senescence or apoptosis
  • Almost all human cancers present activation of telomerase as a hallmark, most likely as a mechanism to allow unlimited cell proliferation of tumor cells
  • recent evidence demonstrated that short telomeres alone could lead to genomic instability and cancer
  • Getting rid of telomerase can also be problematic; the lack of telomerase could lead to increased chromosomal instability, which in turn could be at the basis for cancer initiation when tumor suppressor barriers are bypassed
  • telomerase activation is a potential therapeutic strategy for the treatment of age-related diseases
  • telomerase activation in adult or old mice by means of a gene therapy strategy was shown to be sufficient to improve metabolic fitness, neuromuscular capacity, and prevent bone loss, as well as significantly increase both median and maximum longevity, without increased cancer incidence
  • These studies suggest that telomerase expression could be considered a feasible approach to reverse tissue dysfunction and extend healthy lifespan without increasing cancer incidence
  • humans almost completely lose telomerase activity from somatic tissues in the adulthood
  • a change of paradigm seems to be occurring in telomerase biology, with a switch from viewing telomerase as fueling cancer to reversing aging
  • Telomerase expression in a background of high levels of tumor suppressors or in aged organisms seems to prevent its expected pro-cancer activity and yet it still functions as an anti-aging factor
  • Nathan Goodyear on 18 May 16
     
    Telomerase activity and longer telomere length is shown to correlated inversely with many chronic diseases of aging.  In contrast, telomerase activity is found to be involved in carcinogenesis.  Increased carcinogenic potential of telomerase activity has not borne out in studies.  In addition, increased CD8 cell activity as a result of telomerase activation will actually decrease carcinogenic potential via NK activation.
Nathan Goodyear

Resveratrol reduces endothelial progenitor cells senescence through augmentation of tel... - 0 views

www.ncbi.nlm.nih.gov/...PMC2567879

resveratrol EPCs ageing endothelial progenitor cells Telomere Telomerase activity

shared by Nathan Goodyear on 11 Jul 12 - No Cached
  • Nathan Goodyear on 11 Jul 12
     
    Resveratrol reduces EPC ageining through increased Telomerase activity, and thus increasing telomere length.  Estradiol has been shown to do the same.
Nathan Goodyear

Artesunate enhances the therapeutic response of glioma cells to temozolomide by inhibit... - 0 views

www.ncbi.nlm.nih.gov/...PMC5341871

Cancer artesunate temodar glioblastoma glioblastoma multiforme

shared by Nathan Goodyear on 19 Dec 18 - No Cached
  • Nathan Goodyear on 19 Dec 18
     
    Artesunate augments Temodar in animal model of glioblastoma.
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