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Accumulating evidence has suggested that extracellular vesicles (EVs) play a crucial role in lung cancer treatment. Thus, we aimed to investigate the modulatory role of bone marrow mesenchymal stem cell (BMSC)‐EV‐derived let‐7i and their molecular mechanism in lung cancer progression. Microarray‐based analysis was applied to predict lung cancer‐related miRNAs and their downstream genes. RT‐qPCR and Western blot analyses were conducted to determine Let‐7i, lysine demethylase 3A (KDM3A), doublecortin‐like kinase 1 (DCLK1) and FXYD domain‐containing ion transport regulator 3 (FXYD3) expressions, after which dual‐luciferase reporter gene assay and ChIP assay were used to identify the relationship among them. After loss‐ and gain‐of‐function assays, the effects of let‐7i, KDM3A, DCLK1 and FXYD3 on the biological characteristics of lung cancer cells were assessed. Finally, tumour growth in nude mice was assessed by xenograft tumours in nude mice. Bioinformatics analysis screened out the let‐7i and its downstream gene, that is KDM3A. The findings showed the presence of a high expression of KDM3A and DCLK1 and reduced expression of let‐7i and FXYD3 in lung cancer. KDM3A elevated DCLK1 by removing the methylation of H3K9me2. Moreover, DCLK1 suppressed the FXYD3 expression. BMSC‐EV‐derived let‐7i resulted in the down‐regulation of KDM3A expression and reversed its promoting role in lung cancer development. Consistently, in vivo experiments in nude mice also confirmed that tumour growth was suppressed by the BMSC‐EV‐derived let‐7i. In conclusion, our findings demonstrated that the BMSC‐EV‐derived let‐7i possesses an inhibitory role in lung cancer progression through the KDM3A/DCLK1/FXYD3 axis, suggesting a new molecular target for lung cancer treatment.

Hepatocellular cancer (HCC) has been reported to belong to one of the highly vascularized solid tumours accompanied with angiogenesis of human umbilical vein endothelial cells (HUVECs). KDM5A, an attractive drug target, plays a critical role in diverse physiological processes. Thus, this study aims to investigate its role in angiogenesis and underlying mechanisms in HCC. ChIP‐qPCR was utilized to validate enrichment of H3K4me3 and KDM5A on the promotor region of miR‐433, while dual luciferase assay was carried out to confirm the targeting relationship between miR‐433 and FXYD3. Scratch assay, transwell assay, Edu assay, pseudo‐tube formation assay and mice with xenografted tumours were conducted to investigate the physiological function of KDM5A‐miR‐433‐FXYD3‐PI3K‐AKT axis in the progression of HCC after loss‐ and gain‐function assays. KDM5A p‐p85 and p‐AKT were highly expressed but miR‐433 was down‐regulated in HCC tissues and cell lines. Depletion of KDM5A led to reduced migrative, invasive and proliferative capacities in HCC cells, including growth and a lowered HUVEC angiogenic capacity in vitro. Furthermore, KDM5A suppressed the expression of miR‐433 by demethylating H3K4me3 on its promoterregion. miR‐433 negatively targeted FXYD3. Depleting miR‐433 or re‐expressing FXYD3 restores the reduced migrative, invasive and proliferative capacities, and lowers the HUVEC angiogenic capacity caused by silencing KDM5A. Therefore, KDM5A silencing significantly suppresses HCC tumorigenesis in vivo, accompanied with down‐regulated miR‐433 and up‐regulated FXYD3‐PI3K‐AKT axis in tumour tissues. Lastly, KDM5A activates the FXYD3‐PI3K‐AKT axis to enhance angiogenesis in HCC by suppressing miR‐433.

This historical review traces key discoveries regarding K+ and Na+ ions in skeletal muscle at rest and with exercise, including contents and concentrations, Na+,K+-ATPase (NKA) and exercise effects on plasma [K+] in humans. Following initial measures in 1896 of muscle contents in various species, including humans, electrical stimulation of animal muscle showed K+ loss and gains in Na+, Cl− and H20, then subsequently bidirectional muscle K+ and Na+ fluxes. After NKA discovery in 1957, methods were developed to quantify muscle NKA activity via rates of ATP hydrolysis, Na+/K+ radioisotope fluxes, [3H]-ouabain binding and phosphatase activity. Since then, it became clear that NKA plays a central role in Na+/K+ homeostasis and that NKA content and activity are regulated by muscle contractions and numerous hormones. During intense exercise in humans, muscle intracellular [K+] falls by 21 mM (range − 13 to − 39 mM), interstitial [K+] increases to 12–13 mM, and plasma [K+] rises to 6–8 mM, whilst post-exercise plasma [K+] falls rapidly, reflecting increased muscle NKA activity. Contractions were shown to increase NKA activity in proportion to activation frequency in animal intact muscle preparations. In human muscle, [3H]-ouabain-binding content fully quantifies NKA content, whilst the method mainly detects α2 isoforms in rats. Acute or chronic exercise affects human muscle K+, NKA content, activity, isoforms and phospholemman (FXYD1). Numerous hormones, pharmacological and dietary interventions, altered acid–base or redox states, exercise training and physical inactivity modulate plasma [K+] during exercise. Finally, historical research approaches largely excluded female participants and typically used very small sample sizes.

Epithelial ovarian cancer is aggressive and lacks effective prognostic indicators or therapeutic targets. In the present study, using immunohistochemistry and bioinformatics analysis on ovarian cancer tissue data from The Obstetrics and Gynecology Hospital of Fudan University and The Cancer Genome Atlas database, it was identified that FXYD domain-containing ion transport regulator 5 (FXYD5) expression was upregulated in the SKOV3-IP cell line compared with its parental cell line, SKOV3, and in ovarian cancer tissues compared with in normal tissues. In addition, FXYD5 upregulation was predictive of poor patient survival. Furthermore, through various in vitro (Transwell assay, clonogenic assay and western blot analysis) and in vivo (nude mouse model) experiments, it was demonstrated that FXYD5 promoted the metastasis of ovarian cancer cells. Mechanistically, RNA sequencing, western blot analysis, a luciferase reporter assay and chromatin immunoprecipitation were performed to reveal that FXYD5 dispersed the SMAD7-SMAD specific E3 ubiquitin protein ligase 2-TGF-β receptor 1 (TβR1) complex, deubiquitinated and stabilized TβR1, and subsequently enhanced transforming growth factor-β (TGF-β) signaling and sustained TGF-β-driven epithelial-mesenchymal transition (EMT). The TGF-β-activated SMAD3/SMAD4 complex was in turn directly recruited to the FXYD5 promoter region, interacted with specific SMAD-binding elements, and then promoted FXYD5 transcription. In brief, FXYD5 positively regulated TGF-β/SMADs signaling activities, which in turn induced FXYD5 expression, creating a positive feedback loop to drive EMT in the process of ovarian cancer progression. Collectively, the findings of the present study suggested a mechanism through which FXYD5 serves a critical role in the constitutive activation of the TGF-β/SMADs signaling pathways in ovarian cancer, and provided a promising therapeutic target for human ovarian cancer.

Background The FXYD family of ion transport regulators have emerged as important modulators of cancer progression and metastasis. However, their expression and roles in ovarian cancer (OCa) have not been systematically investigated. Methods The expression of FXYD genes in OCa was analyzed using data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO), as well as independent clinical samples. The prognostic values of FXYD genes were evaluated by Kaplan–Meier and Cox regression analysis. To explore potential mechanisms, bioinformatics approaches including Gene Ontology, KEGG pathway analysis, GSEA and drug sensitivity correlation analysis were performed. OCa cell lines overexpressing FXYD1, FXYD5 or FXYD7 were also generated and their impacts on proliferation, migration and invasion were assessed. Results FXYD1 and FXYD6 were significantly downregulated while FXYD3, FXYD4 and FXYD5 were upregulated in OCa tissues compared to normal tissues. FXYD1, FXYD5 and FXYD7 were independent adverse prognostic factors for OCa patients. Pathway and drug correlation analysis revealed that FXYD1, FXYD5 and FXYD7 genes regulated diverse oncogenic signaling cascades and modulated the response to various chemotherapeutic agents. Overexpression of FXYD1, FXYD5 or FXYD7 enhanced OCa cell motility and invasiveness in vitro. Conclusion Our results demonstrate aberrant expression patterns, prognostic values, and oncogenic activities of FXYD genes in OCa. FXYD1, FXYD5 and FXYD7 may serve as biomarkers and therapeutic targets for this disease. Targeting FXYD-mediated signaling represents a promising therapeutic strategy against OCa.

Na + K + ATPase (NKA) is crucial to branchial ion transport as it uses the energy from ATP to move Na + against its electrochemical gradient. When fish encounter extremely dilute environments the energy available from ATP hydrolysis may not be sufficient to overcome thermodynamic constraints on ion transport. Yet many fish species—including zebrafish—are capable of surviving in dilute environments. Despite much study, the physiological mechanisms by which this occurs remain poorly understood. Here, we demonstrate that zebrafish acclimated to less than 10 µM Na + water exhibit upregulation of a specific NKA α subunit ( zatp1a1a.5 ) that, unlike most NKA heterotrimers, would result in transfer of only a single Na + and K + per ATP hydrolysis reaction. Thermodynamic models demonstrate that this change is sufficient to reduce the activation energy of NKA, allowing it to overcome the adverse electrochemical gradient imposed by dilute freshwater. Importantly, upregulation of zatp1a1a.5 also coincides with the recovery of whole body Na + post-transfer, which occurs within 24 h. While these structural modifications are crucial for allowing zebrafish to survive in ion-poor environments, phylogenetic and structural analysis of available α subunits from a range of teleosts suggests this adaptation is not widely distributed.

Na+/K+ ATPase (NKA) comprises several subunits to provide isozyme heterogeneity in a tissue-specific manner. An abundance of NKA α, β, and FXYD1 subunits is well-described in human skeletal muscle, but not much is known about FXYD5 (dysadherin), a regulator of NKA and β1 subunit glycosylation, especially with regard to fibre-type specificity and influence of sex and exercise training. Here, we investigated muscle fibre-type specific adaptations in FXYD5 and glycosylated NKAβ1 to high-intensity interval training (HIIT), as well as sex differences in FXYD5 abundance. In nine young males (23.8 ± 2.5 years of age) (mean ± SD), 3 weekly sessions of HIIT for 6 weeks enhanced muscle endurance (220 ± 102 vs. 119 ± 99 s, p < 0.01) and lowered leg K+ release during intense knee-extensor exercise (0.5 ± 0.8 vs. 1.0 ± 0.8 mmol·min–1, p < 0.01) while also increasing cumulated leg K+ reuptake 0–3 min into recovery (2.1 ± 1.5 vs. 0.3 ± 0.9 mmol, p < 0.01). In type IIa muscle fibres, HIIT lowered FXYD5 abundance (p < 0.01) and increased the relative distribution of glycosylated NKAβ1 (p < 0.05). FXYD5 abundance in type IIa muscle fibres correlated inversely with the maximal oxygen consumption (r = –0.53, p < 0.05). NKAα2 and β1 subunit abundances did not change with HIIT. In muscle fibres from 30 trained males and females, we observed no sex (p = 0.87) or fibre type differences (p = 0.44) in FXYD5 abundance. Thus, HIIT downregulates FXYD5 and increases the distribution of glycosylated NKAβ1 in type IIa muscle fibres, which is likely independent of a change in the number of NKA complexes. These adaptations may contribute to counter exercise-related K+ shifts and enhance muscle performance during intense exercise.

Purpose Recurrent miscarriage (RM) is a distressing and complicated adverse pregnancy outcome. It is commonly recognized that insufficient decidualization could result in RM, but the molecular mechanisms of decidual impairment are still not fully understood. Thus, this study aimed to identify novel key genes potentially involved in RM and explore their roles played in endometrial decidualization. Methods Initially, a combinative analysis of decidual and mid-secretory endometrial transcriptomes was performed to discover hub genes involved in the etiology of RM. And the expression levels of hub genes were evaluated in both primary decidual stromal cells (DSCs) and decidual tissues. Subsequently, the immortalized human endometrial cell line, T-HESCs, was used to investigate whether FXYD1 overexpression affects decidualization by regulating Na/K-ATPase activity. Results FXYD domain containing ion transport regulator 1 (FXYD1) was identified as a hub gene in the pathogenesis of RM through various bioinformatic methods. Abnormally increased FXYD1 expression was observed in DSCs and decidual tissues from RM patients compared to that of the normal group. Furthermore, in vitro decidualization was obviously inhibited by the overexpression of FXYD1. Additionally, Na/K-ATPase activity was significantly elevated during decidualization, whereas overexpression of FXYD1 reduced Na/K-ATPase activity. Bufalin, a Na/K-ATPase inhibitor, showed an effectively inhibitory effect on decidualization. Conclusions Collectively, FXYD1 was discovered as a hub gene associated with RM, and its expression levels in RM patients were significantly upregulated. Increased FXYD1 expression might lead to decidualization defects by reducing Na/K-ATPase activity, of which presented a novel prospective treatment target for RM.

In cardiac muscle, the sarcolemmal sodium/potassium ATPase is the principal quantitative means of active transport at the myocyte cell surface, and its activity is essential for maintaining the trans-sarcolemmal sodium gradient that drives ion exchange and transport processes that are critical for cardiac function. The 72-residue phosphoprotein phospholemman regulates the sodium pump in the heart: unphosphorylated phospholemman inhibits the pump, and phospholemman phosphorylation increases pump activity. Phospholemman is subject to a remarkable plethora of post-translational modifications for such a small protein: the combination of three phosphorylation sites, two palmitoylation sites, and one glutathionylation site means that phospholemman integrates multiple signaling events to control the cardiac sodium pump. Since misregulation of cytosolic sodium contributes to contractile and metabolic dysfunction during cardiac failure, a complete understanding of the mechanisms that control the cardiac sodium pump is vital. This review explores our current understanding of these mechanisms.

It is known that increased inflammation and extracellular matrix (ECM) degradation in chondrocytes can promote the development of osteoarthritis (OA). The FXYD domain containing ion transport regulator 5 (Fxyd5) has been found to promote chronic inflammatory responses. The present study aimed to investigate the role of Fxyd5 in OA. Murine ATDC5 chondrocytes were transfected with short hairpin RNAs specifically targeting Fxyd5 to silence its expression. Subsequently, cells were induced with lipopolysaccharide (LPS). The protein expression levels of Fxyd5, MMPs and proteins related to ECM, apoptosis and NF-κB signaling were detected using western blot analysis. In addition, cell viability was assessed using a Cell Counting Kit-8 assay, while the secretion of the proinflammatory factors and those of the oxidative stress-related markers were measured using the corresponding kits. Finally, cells were treated with the NF-κB activator, betulinic acid (BA) and the above experiments were repeated. The results demonstrated that Fxyd5 was significantly upregulated in ATDC5 cells treated with LPS. Additionally, Fxyd5 knockdown increased cell viability, enhanced the protein expression of Bcl-2, Aggrecan and collagen II, while reduced the expression of Bax, cleaved caspase-3/caspase-3, MMP3 and MMP13 in LPS-induced ATDC5 cells. The production of IL-1β, IL-6 and IL-18 as well as reactive oxygen species and malondialdehyde, and the reduction of superoxide dismutase caused by LPS in ATDC5 cells, were also reversed by Fxyd5 silencing. Fxyd5 silencing inhibited the phosphorylation of p65 and IκBα induced by LPS. Finally, BA reversed the protective effect of Fxyd5 silencing on LPS induced chondrocytes injury. In conclusion, Fxyd5 could enhance chondrocyte inflammation and ECM degradation via activating the NF-κB signaling.