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Precision medicine in myelodysplastic syndromes
Published in Debmalya Barh, Precision Medicine in Cancers and Non-Communicable Diseases, 2018
Advances in supportive care are connected with advances in MDS molecular biology and pathogenesis research (Gill et al., 2016). A new target has emerged in treating MDS-related anemia. Defects in erythroid differentiation lead to increased production of erythropoietin without effective hemoglobin synthesis. Growth differentiation factor GDF11, an important erythropoiesis regulator, accumulates and can be inhibited by transforming growth factor β (TGF-β) superfamily ligand trap strategies (Dussiot et al., 2014; Suragani et al., 2014). Luspatercept is an activin receptor antagonist that functions as a ligand trap for GDF11 and other TGF-β family ligands to suppress Smad2/3 activation and to increase hemoglobin synthesis (Mies et al., 2016; Almeida et al., 2017).
Aging Epigenetics
Published in Shamim I. Ahmad, Aging: Exploring a Complex Phenomenon, 2017
Vasily V. Ashapkin, Lyudmila I. Kutueva, Boris F. Vanyushin
In an experimental procedure, known as heterochronic parabiosis, a shared circulatory system between young and old mice is established, thus exposing old mice to factors present in young serum. Heterochronic parabiosis was found to restore activity of the Notch signaling pathway, and proliferation and regenerative capacity of the aged skeletal muscle satellite cells [104]. Furthermore, heterochronic parabiosis increased proliferation of the aged hepatocytes and restored their cEBP-α level to values seen in young animals. Thus, age-related decline of the progenitor cell activity could be modulated by systemic factors that change with age. The number of newly born neurons, proliferating cells, and neural progenitors in the dentate gyrus of hippocampus decreased in the young heterochronic parabiont mice and increased in the old ones [105]. A systemic environment appears to affect the biological age of cells. Most likely, its effects are caused by changes in activity of the main signaling pathways (Notch, Wnt, and TGFβ) due to changed concentrations of respective cytokines. In the adult brain, neural stem cells (NSCs) reside in a heterogeneous niche where they are in direct contact with blood vessels and the cerebrospinal fluid. The vasculature influences NSC proliferation and differentiation by providing signaling molecules secreted from endothelial cells and by delivering systemic regulatory factors. In the aging niche, the vasculature deteriorates with a consequent reduction in blood flow, and the neurogenic potential of NSCs declines, leading to reduced neuroplasticity and cognition. Systemic factors can affect these aging-associated events. In a mouse heterochronic parabiosis model, remodeling of the aged cerebral vasculature in response to young systemic factors was observed, producing a noticeably higher blood flow [106]. NSCs proliferation in the subventricular zone and olfactory neurogenesis were activated and an improvement in the olfactory function occurred. GDF11, a circulating TGF-β family member that has been reported to reverse cardiac hypertrophy in aged mice [107], also stimulated vascular remodeling and increased neurogenesis in aging mice. Thus, circulating factors have diverse positive effects in aging mice, including enhancing neurogenesis and improving the vasculature in the cortex and other parts of the brain. As regards the specific rejuvenating role of GDF11, it has been questioned in subsequent studies. First, it was shown that GDF11 levels in the serum and muscle of rats do not decrease, but rather increase with age [108]. Furthermore, GDF11 has been shown not to stimulate muscle regeneration, but rather to inhibit it in a dose-dependent manner. In humans, GDF11 levels have been found to be not statistically different between variously aged (21–93 years) subjects of both genders [109]. Furthermore, in older adults with cardiovascular disease, increased circulating GDF11 has been shown to correlate with a higher prevalence of comorbid conditions, frailty, and a larger number of adverse health outcomes following aortic valve replacement surgery.
Effect of growth differentiation factor 11 expression after peripheral nerve injury in Sprague-Dawley rats
Published in Neurological Research, 2023
Yi Zhang, Peiwen Bai, Jiamin Lu, Koon Hei Winson Lui, Tianjiao Zhao, Di Wen, Bo He, Zhaowei Zhu
The role of GDF11 in nervous system development and function has been investigated in many studies. GDF11 is a member of the transforming growth factor beta 1 (TGF-β1) superfamily. TGF-β family was widely reported to be expressed throughout the body and has been reported to take part in regulating numerous biological behaviors, such as embryonic development, extracellular matrix (ECM) formation and remodeling, epithelial–mesenchymal transition (EMT), inflammation, immune response and wound healing [13,14]. Studies also reported GDF11 to play an important part in central nerve injury and peripheral nerve injury. It has been reported, TGF-β1 expression was elevated following both peripheral and central nerve damage [15,16]. It was found during peripheral nerve injury (PNI), mRNA and proteins of TGF-β1 were elevated, and this protein was mainly localized in the regions containing infiltrating macrophages [16–18]. Einheber S et al. and Guenard V et al. demonstrated that TGF-β1 assisted in the transition of Schwann cells to its non-myelinating phenotype. The resulting cells were capable of inhabiting the production of myelin-related molecules, P0, myelin-associated glycoprotein (MAG), and myelin basic protein (MBP) thus resulting in faster regenerative response in PNI [19,20]. This information indicated that TGF-β1 family played a critical role in the PNI regenerative process.
CircNUFIP2 overexpression induces GDF11 to ameliorate oxygen-glucose deprivation-induced hippocampal neuron cell apoptosis and oxidative stress after cerebral ischemia
Published in Neurological Research, 2023
Zhujun Mei, LinLing Huang, Wei Rao
GDF11 is also termed bone morphogenetic protein 11 and is closely associated with the transforming growth factor-β superfamily that can regulate the cardiac function and neurogenesis of mice [23,24]. GDF11 treatment decreased cognitive deficits and amyloid deposition, as revealed in an animal model of Alzheimer’s Disease [25]. In addition, the protein could weaken inflammatory response and inhibit oxidative stress and apoptosis [26]. Also, GDF11 supplementation improved the survival of aged mice after ischemic stroke [27]. In this study, GDF11 was identified as a target of miR-1224-5p and negatively regulated by miR-1224-5p. OGD-stimulated HT22 cells displayed a low expression of GDF11. In addition, the loss-of-function assay indicated that GDF11 protected against OGD-caused HT22 cell injury. GDF11 participated in the regulation of miR-1224-5p toward OGD-triggered cell damage. Furthermore, circNUFIP2-induced GDF11 production by reducing miR-1224-5p expression.
Decline of stress resilience in aging rats: Focus on choroid plexus-cerebrospinal fluid-hippocampus
Published in The World Journal of Biological Psychiatry, 2023
Kaige Liu, Huizhen Li, Ningxi Zeng, Wenjun Lu, Xiaofeng Wu, Hanfang Xu, Can Yan, Lili Wu
CP has both secretion and transport functions, and once changed, it will affect the CSF composition. Variations in CSF components may include increased harmful substances (e.g. pro-inflammatory cytokines, excessive neurotransmitters) and decreased beneficial substances (e.g. neurotrophins, anti-inflammatory cytokine, and antioxidants). Given CON-CSF exerted a supportive and protective effect on hippocampal NSCs, we focussed more on nutrients in CSF. In this study, we mainly found the following components decreased in ACUMS-CSF, (1) Axon guidance proteins: Neurexins are a set of synapse adhesion molecules, whose molecular diversity are considered basis of synaptic plasticity and specificity (Treutlein et al. 2014). Sema3G plays an essential role in regulating hippocampal synaptic plasticity and cognition (Chao et al. 2019). Ncam is important in sustaining axon growth, neurogenesis, and learning and memory function (Yang et al. 2020). (2) Growth factors: GDF11 is a potential anti-ageing factor in blood, which can promote vasculogenesis and neurogenesis in brain and reverse age-related cognitive decline (Loffredo et al. 2013). IGF-1 exerts neurotrophic and neuroprotective effects in neurodegenerative disorders, such as AD and PD (Montivero et al. 2021). (3) 5-MTHF: Folate deficiency is a key risk factor for developmental abnormalities and neurodegenerative disorders (Guo et al. 2017). The development and progression of AD and LOD are associated with folate supply and metabolic status (Ghasemzadeh and Riazi 2020). Our results proposed there was a high positive correlation of 5-MTHF between CSF and hippocampus, which illustrated low-concentration 5-MTHF in hippocampus might be caused by 5-MTHF transport dysfunction in CP. Besides, we found a positive correlation between 5-MTHF in CSF and hippocampal neurogenesis proteins. Together, 5-MTHF decline in CSF and hippocampus might be an influential factor for severer hippocampal neurogenesis dysfunction in ACUMS rats. Certainly, there are other substances in CSF that affect brain parenchyma, which requires further studies.