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Cardiac ischemia, hypoxia, arrhythmias, and heart failure share the common electrophysiological changes featured by the elevation of intracellular Ca2+ (Ca2+ overload) and inhibition of the inward rectifier potassium (IK1) channel. IK1 channel agonists have been considered a new type of anti‐arrhythmia and cardioprotective agents. We predicted using a drug repurposing strategy that tetramisole (Tet), a known anthelminthic agent, was a new IK1 channel agonist. The present study aimed to experimentally identify the above prediction and further demonstrate that Tet has cardioprotective effects. Results of the whole‐cell patch clamp technique showed that Tet at 1–100 μmol/L enhanced IK1 current, hyperpolarized resting potential (RP), and shortened action potential duration (APD) in isolated rat cardiomyocytes, while without effects on other ion channels or transporters. In adult Sprague–Dawley (SD) rats in vivo, Tet showed anti‐arrhythmia and anticardiac remodeling effects, respectively, in the coronary ligation‐induced myocardial infarction model and isoproterenol (Iso, i.p., 3 mg/kg/day, 10 days) infusion‐induced cardiac remodeling model. Tet also showed anticardiomyocyte remodeling effect in Iso (1 μmol/L) infused adult rat ventricular myocytes or cultured H9c2 (2‐1) cardiomyocytes. Tet at 0.54 mg/kg in vivo or 30 μmol/L in vitro showed promising protections on acute ischemic arrhythmias, myocardial hypertrophy, and fibrosis. Molecular docking was performed and identified the selective binding of Tet with Kir2.1. The cardioprotection of Tet was associated with the facilitation of IK1 channel forward trafficking, deactivation of PKA signaling, and inhibition of intracellular calcium overload. Enhancing IK1 may play dual roles in anti‐arrhythmia and antiventricular remodeling mediated by restoration of Ca2+ homeostasis. [ABSTRACT FROM AUTHOR]

Cardiomyocyte apoptosis is an important cause of trauma-induced secondary cardiac injury (TISCI), in which the endoplasmic reticulum stress (ERS)-mediated apoptosis signaling pathway is known to be first activated, but the mechanism remains unclear. In this study, rat models of traumatic injury are established by using the Noble-Collip trauma device. The expression of glucose-regulating protein 78 (GRP78, a molecular chaperone of the cardiomyocyte ER), acetylation modification of GRP78 and apoptosis of cardiomyocytes are determined. The results show that ERS-induced GRP78 elevation does not induce cardiomyocyte apoptosis in the early stage of trauma. However, with prolonged ERS, the GRP78 acetylation level is elevated, and the apoptosis of cardiomyocytes also increases significantly. In addition, in the early stage of trauma, the expression of histone acetyl-transferase (HAT) P300 is increased and that of histone deacetylase 6 (HDAC6) is decreased in cardiomyocytes. Inhibition of HDAC function could induce the apoptosis of traumatic cardiomyocytes by increasing the acetylation level of GRP78. Our present study demonstrates for the first time that post-traumatic protracted ERS can promote cardiomyocyte apoptosis by increasing the acetylation level of GRP78, which may provide an experimental basis for seeking early molecular events of TISCI.

Laryngeal squamous cell carcinoma (LSCC) is the second most common head and neck cancer. Previously, we discovered that miR-1207-5p was downregulated in LSCC. In this study, the clinical significance, function, and mechanism of miR-1207-5p in LSCC were investigated. Downregulation of miR-1207-5p was found to be strongly linked to the malignant progression of LSCC. Functional studies revealed that miR-1207-5p upregulation suppressed LSCC cell proliferation, invasion, migration, and xenograft tumor growth. Bioinformatics analysis revealed that miR-1207-5p target genes were involved in cell cycle regulation, proliferation, adhesion, and the phosphatidylinositol 3-kinase (PI3K)/Akt pathway. Mechanistic studies revealed that miR-1207-5p interacts directly with the 3' untranslated region of spindle and kinetochore associated complex subunit 3 (SKA3) and downregulates SKA3 expression. Furthermore, SKA3 was found to be overexpressed in LSCC, and its high expression was associated with tumor progression and a poor prognosis. Rescue experiments demonstrated that miR-1207-5p inhibited the malignant phenotypes of LSCC via SKA3. Furthermore, miR-1207-5p upregulation or knockdown of SKA3 inhibited the epithelial-mesenchymal transition (EMT). Collectively, miR-1207-5p inhibited LSCC malignant progression by downregulating SKA3 and preventing EMT. These findings provide new insights into the mechanism of LSCC progression, as well as new potential biomarkers and therapeutic targets for LSCC diagnosis and treatment., Competing Interests: The authors declare no competing interests., (© 2021 The Author(s).)

Metabolic diseases caused by disorders in amino acids, glucose, lipid metabolism, and other metabolic risk factors show high incidences in young people, and current treatments are ineffective. N 6 -methyladenosine (m 6 A) RNA modification is a post-transcriptional regulation of gene expression with several effects on physiological processes and biological functions. Recent studies report that m 6 A RNA modification is involved in various metabolic pathways and development of common metabolic diseases, making it a potential disease-specific therapeutic target. This review explores components, mechanisms, and research methods of m 6 A RNA modification. In addition, we summarize the progress of research on m 6 A RNA modification in metabolism-related human diseases, including diabetes, obesity, non-alcoholic fatty liver disease, osteoporosis, and cancer. Furthermore, opportunities and the challenges facing basic research and clinical application of m 6 A RNA modification in metabolism-related human diseases are discussed. This review is meant to enhance our understanding of the molecular mechanisms, research methods, and clinical significance of m 6 A RNA modification in metabolism-related human diseases., Competing Interests: The authors declare no competing interests., (© 2021 The Author(s).)

Fascin actin-bundling protein 1 (FSCN1) is a highly conserved actin-bundling protein that cross links F-actin microfilaments into tight, parallel bundles. Elevated FSCN1 levels have been reported in many types of human cancers and have been correlated with aggressive clinical progression, poor prognosis, and survival outcomes. The overexpression of FSCN1 in cancer cells has been associated with tumor growth, migration, invasion, and metastasis. Currently, FSCN1 is recognized as a candidate biomarker for multiple cancer types and as a potential therapeutic target. The aim of this study was to provide a brief overview of the FSCN1 gene and protein structure and elucidate on its actin-bundling activity and physiological functions. The main focus was on the role of FSCN1 and its upregulatory mechanisms and significance in cancer cells. Up-to-date studies on FSCN1 as a novel biomarker and therapeutic target for human cancers are reviewed. It is shown that FSCN1 is an unusual biomarker and a potential therapeutic target for cancer., Competing Interests: The authors declare no competing interests., (© 2021 The Author(s).)

Inward rectifier potassium channels (I K1 , Kir) are known to play critical roles in arrhythmogenesis. Thus, how I K1 agonist affects reperfusion arrhythmias needs to be clarified, and its underlying mechanisms should be determined. Reperfusion arrhythmias were modeled by coronary ligation (ischemia, 15 minutes) and release (reperfusion, 15 minutes). Zacopride (1.5-50 μg/kg in vivo, or 0.1-10 μmol/Lex vivo) was applied in the settings of pretreatment (3 minutes before coronary ligation) and posttreatment (5 minutes after coronary ligation). Hypoxia (45 minutes) /reoxygenation (30 minutes) model was established in cultured H9c2 (2-1) cardiomyocytes. Zacopride or KN93 was applied before hypoxia (pretreatment). In the setting of pre- or posttreatment, zacopride at 15 μg/kg in vivo or 1 μmol/Lin vitro exhibited superlative protections on reperfusion arrhythmias or intracellular calcium overload. Western blot data from ex vivo hearts or H9c2 (2-1) cardiomyocytes showed that I/R (H/R) induced the inhibition of Kir2.1 (the dominant subunit of I K1 channel in ventricle), phosphorylation and oxidation of CaMKII, downregulation of SERCA2, phosphorylation of phospholamban (at Thr17), and activation of caspase-3. Zacopride treatment (1 μmol/L) was noted to strikingly restore the expression of Kir2.1 and SERCA2 and decrease the activity of CaMKII, phospholamban, and caspase-3. These effects were largely eliminated by co-application of I K1 blocker BaCl 2 . CaMKII inhibitor KN93 attenuated calcium overload and p-PLB (Thr17) in an I K1 -independent manner. I K1 -depedent inhibition of CaMKII activity is found to be a key cardiac salvage signaling under Ca 2+ dyshomeostasis and reactive oxygen species (ROS) stress. I K1 might be a novel target for pharmacological conditioning of reperfusion arrhythmia, especially for the application after unpredictable ischemia.

With the expanded application of heavy metal cadmium, soil cadmium pollution is more and more serious. In this study, using Salix matsudana as a phytoremediation candidate, we observed changes of gene expression and metabolic pathway after 1, 7 and 30 days under 2.5 mg/L and 50 mg/L cadmium stress. The result of transcriptome sequencing showed that we obtained 102 595 Unigenes; 26 623 and 32 154 differentially expressed genes (DEG) in the same concentration and different stress time; 8 550, 3 444 and 11 428 DEG with different concentrations at the same time; 25 genes closely related to cadmium stress response were screened. The changes of genes expression (such as metallothionein, ABC transporter, zinc and manganese transporter) depended on both concentration of cadmium and exposure time. The expression of several genes was obviously up-regulated after cadmium stress, for example 3,6-deoxyinosinone ketolase (ROT3) in brassinolide synthesis pathway and flavonoid synthase (FLS), flavanone-3-hydroxylase (F3H) in the synthesis pathway of brassinolide. In addition, GO analysis shows that GO entries were mainly enriched in metabolic processes including cellular processes, membranes, membrane fractions, cells, cellular fractions, catalytic activation and binding proteins in response to cadmium stress, whose number would increase along with cadmium concentration and exposure time. The reliability of transcriptome information was verified by qPCR and physiological experimental data. Response mechanisms of S. matsudana after cadmium stress were analyzed by transcriptome sequencing, which provided theoretical guidance for remediation of cadmium pollution in soil by S. matsudana.