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  • thyrotropin releasing hormone Interestingly intermittent hig


    Interestingly, intermittent high doses of AKT inhibitors have been shown to be a more effective strategy both clinically and pre-clinically. High doses appear to be required for induction of apoptosis and intermittent schedules overcome the low therapeutic index of these compounds. This is particularly important in combination studies where toxicity is often limiting (Shimizu et al., 2012). Current preclinical data suggests intermittent dosing that inhibits AKT signalling to a greater extent is more efficacious than chronically inhibiting AKT to a lesser degree as a clinical strategy (Lopez and Banerji, 2016, Stewart et al., 2015). Interestingly due to feedback inhibition within the PI3K/AKT pathway, intermittent dosing may also delay treatment resistance. Despite the challenges, there remains intense enthusiasm in establishing AKT inhibitors within the future collection of personalised treatments for cancer and numerous clinical trials of AKT inhibitor combinations are actively recruiting.
    Conflict of interest
    Acknowledgements The Drug Development Unit of the Royal Marsden NHS Foundation Trust and The Institute of Cancer Research is supported in part by a programme grant from Cancer Research UK (C347/A18077). Support is also provided by the Experimental Cancer Medicine Centre (C12540/A15573) (programme grant) (to The ICR) and the National Institute for Health Research Biomedical Research Centre (jointly to the RMH NHS Foundation Trust and The ICR).
    Introduction Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory lung condition, which predominantly affects the small airways and lung thyrotropin releasing hormone [1,2]. Patients with COPD suffer progressive worsening of lung function, characterized by an obstructive pattern of air flow limitation, which is only partially reversible [[3], [4], [5]]. These events are a common cause of hospitalization and impose a considerable financial burden on health services. Smoking is reported to be the main etiological cause of COPD [6,7]. The disease is also expected to worsen over the next 30 years, with over 4.5 million COPD-related deaths predicted to occur in 2030 due to the increased prevalence of smoking in developing countries and aging populations [8]. Therefore, a better understanding of the molecular mechanisms underlying COPD is urgently needed to find effective therapeutic targets. Growth differentiation factor 11 (GDF11), also known as bone morphogenetic protein 11 (BMP11), was first cloned from rat incisor pulp RNA and characterized as a member of the bone morphogenetic protein/transforming growth factor-β (BMP/TGF-β) superfamily by Nakashima et al. in 1999 [9]. Like other members of the TGF-β superfamily, GDF11 binds to type II receptors, and the complex then activates type I receptors, which regulate promoter activity and positively or negatively control gene expression [10]. GDF11 plays a crucial role in metabolic disorders [11], cancers [12,13], and COPD [14]. Sinha et al. found that upregulating systemic GDF11 levels in old mice reversed age-related skeletal muscle dysfunction [15] and cardiac hypertrophy [16]. Qin et al demonstrated that GDF11 induced epithelial-mesenchymal transition (EMT), cell migration, and reactive oxygen species (ROS) in oral cancer, indicating that GDF11 may participate in metastasis of oral cancer via the EMT [12]. Moreover, Onodera et al. reported that decreased levels of plasma GDF11 in COPD patients as compared with non-COPD individuals were significantly, positively correlated with pulmonary function [14]. However, the molecular mechanism of GDF11 in COPD, including the signaling pathway involved in the pathogenesis of the disease, has not been elucidated.
    Material and methods
    Discussion Long-term inhalation of cigarette smoke is the main causal mechanism underlying persistent inflammation, which brings a serious threat to COPD occurrence [22,23]. Cigarette smoke includes oxidants, which directly damage cells and tissues, hamper defense mechanisms, and finally initiate inflammation [23], via markedly activating the AKT signaling pathway downstream of phosphatidylinositol 3-kinase (PI3K) [24,25]. Recently, Onodera et al. [14] found that the levels of plasma GDF11 in the COPD patients were decreased compared with the healthy individuals, and the mRNA expression of GDF11 in mesenchymal cells from the COPD group was decreased; chronic exposure to CSE decreased the production of GDF11; treatment with GDF11 significantly inhibited CSE-induced cellular senescence and upregulation of inflammatory mediators; daily GDF11 treatment attenuated cellular senescence and airspace enlargement in an elastase-induced mouse model of emphysema. All data suggested that CSE and GDF11 played crucial roles in COPD progression. However, the specific molecular mechanism underlying COPD was not complementally clear until now. And the findings of the present study shed light on the functions of GDF11, AKT, and smoke in the progression of COPD, and results showed that GDF11 obviously decreased in the plasma and mesenchymal cells of the COPD patients, and CSE could also reduce the expression level of GDF11 whereas make p-AKT activated, furthermore, we observed that knockdown of GDF11 promoted the activation of p-AKT, all indicating that the decreased expression of GDF11 accelerated COPD progress via activating AKT signaling pathway.