The copper transporter, SLC31A1, transcriptionally activated by ELF3, imbalances copper homeostasis to exacerbate cisplatin-induced acute kidney injury through mitochondrial dysfunction.

Acute kidney injury (AKI) is a common complication of cisplatin chemotherapy, which greatly limits its clinical effect and application. This study explored the function of solute Carrier Family 31 Member 1 (SLC31A1) in cisplatin-induced AKI and its possible mechanism. Mice and HK-2 cells were exposed to cisplatin to establish the in vivo and in vitro AKI models. Cell viability was detected by CCK-8. Mitochondrial and oxidative damage was determined by Mito-Tracker Green staining, mtROS level, ATP production, mitochondrial membrane potential, MDA content and CAT activity. AKI was evaluated by renal function and histopathological changes. Apoptosis was detected by TUNEL and caspase-3 expression. Molecule expression was measured by RT-qPCR, Western blotting, and immunohistochemistry. Molecular mechanism was studied by luciferase reporter assay and ChIP. SLC31A1 level was predominantly increased by cisplatin exposure in AKI models. Notably, copper ion (Cu+) level was enhanced by cisplatin challenge. Moreover, Cu+ supplementation intensified cisplatin-induced cell death, mitochondrial dysfunction, and oxidative stress in HK-2 cells, indicating the involvement of cuproptosis in cisplatin-induced AKI, whereas these changes were partially counteracted by SLC31A1 knockdown. E74 like ETS transcription factor 3 (ELF3) could directly bind to SLC31A1 promoter and promote its transcription. ELF3 was up-regulated and positively correlated with SLC31A1 expression upon cisplatin-induced AKI. SLC31A1 silencing restored renal function, alleviated mitochondrial dysfunction, and apoptosis in cisplatin-induced AKI mice. ELF3 transcriptionally activated SLC31A1 to trigger cuproptosis that drove cisplatin-induced AKI through mitochondrial dysfunction, indicating that SLC31A1 might be a promising therapeutic target to mitigate AKI during cisplatin chemotherapy.

The effectiveness and safety of electromyography biofeedback therapy for motor dysfunction of children with cerebral palsy: A protocol for systematic review and meta-analysis.

INTRODUCTION: To investigate the effectiveness and safety of electromyography (EMG) biofeedback therapy in improving motor dysfunction among children with cerebral palsy (CP). METHODS AND ANALYSIS: The following databases will be searched: PubMed, EMBASE, ScienceDirect, the Cochrane Library, China National Knowledge infrastructure (CNKI), Technology Periodical Database (VIP), WanFang Data and China Biology Medicine (CBM) from inception to June 2019. All relevant randomized controlled trials (RCTs) utilizing EMG biofeedback therapy for CP will be included. The main outcome is the Gross Motor Function Measure (GMFM). Additional outcomes such as the Modified Ashworth Scale (MAS), Integral Electromyogram (iEMG), Composite Spasticity Scale (CSS), passive range of motion (PROM) or other related outcomes will be included, adverse effects of EMG biofeedback therapy and comparators will also be included. Two reviewers will screen studies, extract data and assess quality independently. Review Manager 5.3 will be used to assess the risk of bias, data synthesis, and subgroup analysis. ETHICS AND DISSEMINATION: This systematic review does not require formal ethical approval because all data will be analyzed anonymously. Results will provide a general overview and evidence concerning the effectiveness and safety of EMG biofeedback therapy for children with CP. The findings of this systematic review will be disseminated through peer-reviewed publications or conference presentations.