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  • niclosamide mg Fujimoto et al pointed out that RPN knockout


    Fujimoto et al. pointed out that RPN2 knockout alleviated the resistance of GC niclosamide mg (MKN74 and KATO III) to docetaxel and DDP [23]. Yuan et al. demonstrated that the depletion of RPN2 resulted in the reduction in resistance of GC cells to drugs such as irinotecan, docetaxel, doxorubicin, oxaliplatin, and DDP [24]. Moreover, better clinical and pathological responses to docetaxel and DDP combination chemotherapy were observed in RPN2-negative GC tissues than those in RPN2-positive group [23], indicating the clinical correlation of RPN2 and MDR in GC. Hence, the roles and molecular mechanisms of RPN2 in the development of MDR were further explored in GC. Our data showed that RPN2 was highly expressed in SGC7901/DDP and SGC7901/VCR cells as compared to that in parental cells SGC7901. Knockdown of RPN2 resulted in the reduction of MDR1 and ABCG2 expressions in SGC7901/DDP and SGC7901/VCR cells. Inversely, the ectopic expression of RPN2 induced P-gp and ABCG2 protein expressions in SGC7901/DDP and SGC7901/VCR cells. The depletion of RPN2 weakened MDR in SGC7901/DDP and SGC7901/VCR cells. However, some reports pointed out that RPN2 knockdown had no effect on the responsiveness of MKN-45 cells to some drugs such as oxaliplatin, irinotecan, 5-Fu, docetaxel, DDP, doxorubicin [24,39]. Fujimoto et al. showed that RPN2 expression was associated with P-gp expression, but not related with ABCG2 and multidrug resistance-associated protein 1 (MRP1) expressions niclosamide mg in GC tissues [23]. Previous studies showed that the activation of MEK/ERK pathway could enhance MDR in cancer cells [40,41]. Katayama et al. unveiled that P-gp level was positively regulated by ERK pathway and the blockage of ERK pathway could inhibit P-gp expression [42]. Lmai et al. disclosed that ABCG2 level was differentially regulated by MEK/ERK pathway with upregulated ABCG2 expression by the inhibition of the MEK/ERK/RSK pathway and reduced ABCG2 expression through the inhibition of MEK/ERK/non-RSK pathway [43]. The ERK pathway is typically triggered by the activation of cell surface receptors, such as the epidermal growth factor receptor (EGFR) [44]. As a component of an oligosaccharyltransferase (OST) complex, RPN2 is crucial for N‑glycosylation development [45]. EGFR is highly N‑glycosylated and N‑glycosylation affects EGFR functional properties and expression level [46,47]. Therefore, RPN2 downregulation may affect OST activity, leading to weakening the glycosylation of EGFR and decreasing its activation and expression level, and ultimately inactivating the ERK pathway [18]. Consequently, the effect of RPN2 silence on MEK/ERK pathway was tested in SGC7901/DDP and SGC7901/VCR cells in the current study. Results showed that RPN2 knockdown resulted in the inactivation of MEK/ERK pathway in SGC7901/DDP and SGC7901/VCR cells. Moreover, the loss of ERK abrogated RPN2-induced P-gp and ABCG2 upregulation in SGC7901/DDP and SGC7901/VCR cells, hinting the key roles of ERK pathway in RPN2-mediated MDR in GC. However, Guo et al. disclosed that p38 mitogen-activated protein kinase (p38-MAPK) pathway but not ERK and JNK pathways is responsible for MDR in SGC7901/VCR cells [36].
    Conflict of interest
    Introduction Accelerating interests in skeletal muscle in uremic patients are fueled by clinical presentations of exercise intolerance [1], higher mortality associated with muscle mass loss [2], and histological features of type II fiber atrophy with increased glycogen deposits [3]. Above functional and morphological alterations are collectively attributed to uremic sarcopenia [4]. The pathophysiology of muscle wasting in chronic kidney disease (CKD) involves inflammatory cytokines (e.g. TNF-α, IL-6 and TGF-β1) [5] and protein-bound toxins, including indoxyl sulfate (IS), indole acetic acid, p-cresyl sulfate [6]. Among those, IS is speculated as the major trigger that substantially accumulates in muscle tissue due to limited dialysis clearance [7]. Previous studies have been gradually revealed that IS induces profound oxidative stress and aggravates ROS production in skeletal muscle [8]. Following disruption of redox homeostasis, muscle cells shift toward proteolysis status and away from protein synthesis [9]. Multiple signaling transduction are reported to involve in ROS-mediated muscle catabolism, including, peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), the AMP-activated protein kinase (AMPK), and mitogen-activated protein kinase (MAPK) pathway [10]. Elucidation of the dominant signaling molecules provides druggable targets to alleviate skeletal muscle dysfunction in CKD patients.