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Aim: Highly prevalent diseases such as insulin resistance and heart failure are characterized by reduced metabolic flexibility and reserve. We tested whether Na/K-ATPase (NKA)-mediated regulation of Src kinase, which requires two NKA sequences specific to the α1 isoform, is a regulator of metabolic capacity that can be targeted pharmacologically. Methods: Metabolic capacity was challenged functionally by Seahorse metabolic flux analyses and glucose deprivation in LLC-PK1-derived cells expressing Src binding rat NKA α1, non-Src-binding rat NKA α2 (the most abundant NKA isoform in the skeletal muscle), and Src binding gain-of-function mutant rat NKA α2. Mice with skeletal muscle-specific ablation of NKA α1 (skα1−/−) were generated using a MyoD:Cre-Lox approach and were subjected to treadmill testing and Western diet. C57/Bl6 mice were subjected to Western diet with or without pharmacological inhibition of NKA α1/Src modulation by treatment with pNaKtide, a cell-permeable peptide designed by mapping one of the sites of NKA α1/Src interaction. Results: Metabolic studies in mutant cell lines revealed that the Src binding regions of NKA α1 are required to maintain metabolic reserve and flexibility. Skα1−/− mice had decreased exercise endurance and mitochondrial Complex I dysfunction. However, skα1−/− mice were resistant to Western diet-induced insulin resistance and glucose intolerance, a protection phenocopied by pharmacological inhibition of NKA α1-mediated Src regulation with pNaKtide. Conclusions: These results suggest that NKA α1/Src regulatory function may be targeted in metabolic diseases. Because Src regulatory capability by NKA α1 is exclusive to endotherms, it may link the aerobic scope hypothesis of endothermy evolution to metabolic dysfunction.

A highly flexible symmetrical supercapacitor based on a δ-MnO2nanofiber/SWCNT hybrid film showed an energy density of 31.8 μW h cm−2at a power density of 0.815 mW cm−2.

Colorectal cancer (CRC) is the third most common type of diagnosed cancer and the fourth leading cause of cancer‑associated mortalities worldwide. Increasing studies have demonstrated that the deregulation of microRNAs (miRNAs or miRs) is associated with the occurrence and development of multiple types of human cancer, including CRC. miR‑329 has been identified to be downregulated in various types of cancer; however, its expression pattern, functions and mechanisms in CRC remain unclear. The present study demonstrated that miR‑329 was lowly expressed in CRC tissue samples and cell lines. Low expression of miR‑329 was correlated with tumor‑node‑metastasis stage and lymph node metastasis in patients with CRC. In vitro experiments revealed that resumption expression of miR‑329 suppressed cell proliferation and invasion in CRC. Furthermore, the results of the present study indicated that miR‑329 targets transforming growth factor‑β1 (TGF‑β1) directly in vitro. TGF‑β1 was demonstrated to be upregulated in CRC tissue samples and inversely correlated with miR‑329 expression. Upregulation of TGF‑β1 was able to partially counteract the antitumor roles of miR‑329 on CRC cell proliferation and invasion. The results of the current study revealed that miR‑329 suppresses CRC cell proliferation and invasion through targeting TGF‑β1, thus suggesting that targeting miR‑329/TGF‑β1 may provide a novel effective therapeutic approach for the treatment of patients with CRC.

An all-solid-state Cu/RGO/MnO2 fiber supercapacitor showed excellent capacitance and flexibility, and could serve as electrical cable and as energy storage device.

The N-terminal caveolin binding motif (CBM) in Na/K-ATPase (NKA) α1 subunit is essential for cell signaling and somitogenesis in animals. To further investigate the molecular mechanism, we have generated CBM mutant human induced pluripotent stem cells (iPSCs) through CRISPR/Cas9 genome editing and examined their ability to differentiate into skeletal muscle (Skm) cells. Compared to the parental wild type human iPSCs, the CBM mutant cells lost their ability of Skm differentiation, which was evidenced by the absence of spontaneous cell contraction, marker gene expression, and subcellular myofiber banding structures in the final differentiated iSkm (induced Skm) cells. Another NKA functional mutant, A420P, which lacks NKA/Src signaling function, did not produce a similar defect. Indeed, A420P mutant iPSCs retained intact pluripotency and ability of Skm differentiation. Mechanistically, the myogenic transcription factor MYOD was greatly suppressed by the CBM mutation. Overexpression of a mouse Myod cDNA through lentiviral delivery restored the CBM mutant cells’ ability to differentiate into Skm. Upstream of MYOD, Wnt signaling was demonstrated from the TOPFlash assay to have a similar inhibition. This effect on Wnt activity was further confirmed functionally by defective induction of the presomitic mesoderm marker genes BRACHYURY (T) and MESOGENIN1 (MSGN1) by Wnt3a ligand or the GSK3 inhibitor/Wnt pathway activator CHIR. Further investigation through immunofluorescence imaging and cell fractionation revealed a shifted membrane localization of β-catenin in CBM mutant iPSCs, revealing a novel molecular component of NKA-Wnt regulation. This study sheds light on a genetic regulation of myogenesis through the CBM of NKA and control of Wnt/β-catenin signaling.

The nitric oxide (NO) signaling pathway plays a critical role in auditory signal conversion and transduction. Cyclic nucleotide phosphodiesterase (PDE), an important component of the NO signaling pathway, has not been identified in the cochlea. Using cross-species comparison, homologous sequences of human and mouse Pde coding sequences were searched in a guinea pig genomic database and conserved homologous exons were found between human and mouse homologous sequences. Based on reverse-transcription PCR of these conserved regions, six partial Pde cDNAs were detected in the cochlea: CpPde3a, CpPde4d, CpPde8a, CpPde8b, CpPde9a, and CpPde11a. The identity rates of the six partial Pde cDNA sequences between guinea pig and human range from 83.8 to 95.5% and those of the peptide sequences range from 85.6 to 100%. The identity rates of the six Pde cDNA sequences between guinea pig and mouse range from 80.6 to 93.0% and those of peptide sequences range from 79.5 to 99.2%. The results demonstrate that multiple Pde genes are expressed in the cochlea, suggesting a NO pathway in the auditory system. Insights into this pathway will help to develop new therapeutic drugs on auditory abnormalities.

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