Last update 01 Nov 2024

NHE2

Last update 01 Nov 2024

Basic Info

Synonyms

Na(+)/H(+) exchanger 2, NHE-2, NHE2

+ [7]

Introduction

Plasma membrane Na(+)/H(+) antiporter. Mediates the electroneutral exchange of intracellular H(+) ions for extracellular Na(+) (PubMed:10444453). Major apical Na(+)/H(+) exchanger in the base of the colonic crypt. Controls in the colonic crypt intracellular pH (pHi) to direct colonic epithelial cell differentiation into the absorptive enterocyte lineage at the expense of the secretory lineage (By similarity).

Drugs associated with NHE2

d9A-2

Target

NHE1 x NHE2 x SLC9A4 x SLC9A7 x SLC9B1

Mechanism

NHE1 inhibitors [+4]

Active Org.

Das CeMM - Forschungszentrum für Molekulare Medizin GmbH

Originator Org.-

Active Indication

Neoplasms

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with NHE2

100 Translational Medicine associated with NHE2

0 Patents (Medical) associated with NHE2

1,127

Literatures (Medical) associated with NHE2

01 Sep 2024·Journal of Hazardous Materials

Exacerbated interfacial impacts of nanoplastics and 6:2 chlorinated polyfluorinated ether sulfonate by natural organic matter in adult zebrafish: Evidence through histopathology, gut microbiota, and transcriptomic analysis

Article

Author: Liu, Shulin ; Yue, Qiang ; Wang, Jun ; Junaid, Muhammad

Nanoplastics (NPs) interact with cooccurring chemicals and natural organic matter (NOM) in the environment, forming complexes that can change their bioavailability and interfacial toxicity in aquatic organisms. This study aims to elucidate the single and combined impacts of 21-day chronic exposure to low levels of polystyrene NPs (size 80 nm) at 1 mg/L and 6:2 chlorinated polyfluorinated ether sulfonate (Cl-PFAES or F53B) at 200 μg/L in the presence and absence of NOM (humic acid-HA and bovine serum albumin-BSA at 10 mg/L) in adult zebrafish (Danio rerio). Our findings through multiple bioassays, revealed that the mixture group (M), comprising of NPs, F53B, HA, and BSA, caused a higher level of toxicity compared to the single NPs (AN), single F53B (AF), and combined NPs+F53B (ANF) groups. The mixture exposure caused the highest level of vacuolization and nuclear condensation in hepatocytes, and most of the intestinal villi were fused and highly reduced in villi length and crypt depth. Further, the T-AOC levels were significantly lower (p < 0.05), while the MDA levels in the liver and intestine were significantly higher (p < 0.05) in the M group with downregulation of nfkbiaa, while upregulation of prkcda, csf1ra, and il1b apoptosis genes in the liver. Pairwise comparison of gut microbiota showed significantly higher (p < 0.05) abundances of various genera in the M group, including Gordonia, Methylobacterium, Tundrisphaera, GKS98, Pedomicrobium, Clostridium, Candidatus and Anaerobacillus, as well as higher abundance of genera including pathogenic strains, while control group showed higher abundance of probiotic genus ZOR0006 than exposed group (p < 0.01). The transcriptomic analysis revealed highest number of DEGs in the M group (2815), followed by the AN group (506) and ANF group (206) with the activation of relaxin signaling pathway-RSP (slc9a1, slc9a2) and AMP-activated protein kinase (AMPK) pathway (plin1), and suppression of the toll-like receptor (TLR) pathway (tlr4a, tlr2, tlr1), cytokine-cytokine receptor interaction (CCRI) pathway (tnfb, il21r1, il21, ifng1), and peroxisome proliferator-activated receptors (PPAR) pathway (pfkfb3). Overall, toxicity in the M group was higher, indicating that the HA and BSA elevated the interfacial impacts of NPs and F53B in adult zebrafish after chronic environmentally relevant exposure, implying the revisitation of the critical interaction of NOM with co-occurring chemicals and associated impacts.

01 Aug 2024·Acta Physiologica

Striatin knock out induces a gain of function of I_Na and impaired Ca²⁺ handling in mESC‐derived cardiomyocytes

Article

Author: Rocchetti, M. ; Gennaccaro, L. ; Rossini, A. ; Cappelletti, G. ; Calogero, A. ; Pramstaller, P. P. ; Leibbrandt, A. ; Mazzetti, S. ; Bucchi, A. ; Foco, L. ; Baruscotti, M. ; Suffredini, S. ; Piubelli, C. ; Benzoni, P. ; Elling, U. ; Metallo, A. ; Rosato‐Siri, M. D. ; Volani, C. ; Prevostini, R. ; Cospito, A. ; Penninger, J. M. ; Arici, M. ; Barbuti, A. ; Giannetti, F. ; Broso, F. ; Fassina, L.

AbstractAimStriatin (Strn) is a scaffold protein expressed in cardiomyocytes (CMs) and alteration of its expression are described in various cardiac diseases. However, the alteration underlying its pathogenicity have been poorly investigated.MethodsWe studied the role(s) of cardiac Strn gene (STRN) by comparing the functional properties of CMs, generated from Strn‐KO and isogenic WT mouse embryonic stem cell lines.ResultsThe spontaneous beating rate of Strn‐KO CMs was faster than WT cells, and this correlated with a larger fast INa conductance and no changes in If. Paced (2–8 Hz) Strn‐KO CMs showed prolonged action potential (AP) duration in comparison with WT CMs and this was not associated with changes in ICaL and IKr. Motion video tracking analysis highlighted an altered contraction in Strn‐KO CMs; this was associated with a global increase in intracellular Ca2+, caused by an enhanced late Na+ current density (INaL) and a reduced Na+/Ca2+ exchanger (NCX) activity and expression. Immunofluorescence analysis confirmed the higher Na+ channel expression and a more dynamic microtubule network in Strn‐KO CMs than in WT. Indeed, incubation of Strn‐KO CMs with the microtubule stabilizer taxol, induced a rescue (downregulation) of INa conductance toward WT levels.ConclusionLoss of STRN alters CMs electrical and contractile profiles and affects cell functionality by a disarrangement of Strn‐related multi‐protein complexes. This leads to impaired microtubules dynamics and Na+ channels trafficking to the plasma membrane, causing a global Na+ and Ca2+ enhancement.

01 Aug 2024·Journal of Advanced Research

Short-chain fatty acid butyrate against TMAO activating endoplasmic-reticulum stress and PERK/IRE1-axis with reducing atrial arrhythmia

Article

Author: Li, Shao-Jung ; Chen, Yao-Chang ; Kao, Yu-Hsun ; Chen, Pao-Huan ; Lee, Ting-I ; Lee, Ting-Wei ; Chen, Yi-Jen ; Cheng, Tzu-Yu ; Higa, Satoshi

INTRODUCTIONThe accumulation of microbiota-derived trimethylamine N-oxide (TMAO) in the atrium is linked to the development and progression of atrial arrhythmia. Butyrate, a major short-chain fatty acid, plays a crucial role in sustaining intestinal homeostasis and alleviating systemic inflammation, which may reduce atrial arrhythmogenesis.OBJECTIVESThis study explored the roles of butyrate in regulating TMAO-mediated atrial remodeling and arrhythmia.METHODSWhole-cell patch clamp experiments, Western blotting, and immunocytochemistry were used to analyze electrical activity and signaling, respectively, in TMAO-treated HL-1 atrial myocytes with or without sodium butyrate (SB) administration. Telemetry electrocardiographic recording and echocardiography and Masson's trichrome staining and immunohistochemistry were employed to examine atrial function and histopathology, respectively, in mice treated with TMAO with and without SB administration.RESULTSCompared with control cells, TMAO-treated HL-1 myocytes exhibited reduced action potential duration (APD), elevated sarcoplasmic reticulum (SR) calcium content, larger L-type calcium current (I_Ca-L), increased Na⁺/Ca²⁺ exchanger (NCX) current, and increased potassium current. However, the combination of SB and TMAO resulted in similar APD, SR calcium content, I_Ca-L, transient outward potassium current (I_to), and ultrarapid delayed rectifier potassium current (I_Kur) compared with controls. Additionally, TMAO-treated HL-1 myocytes exhibited increased activation of endoplasmic reticulum (ER) stress signaling, along with increased PKR-like ER stress kinase (PERK)/IRE1α axis activation and expression of phospho-IP3R, NCX, and Kv1.5, compared with controls or HL-1 cells treated with the combination of TMAO and SB. TMAO-treated mice exhibited atrial ectopic beats, impaired atrial function, increased atrial fibrosis, and greater activation of ER stress signaling with PERK/IRE1α axis activation compared with controls and mice treated with TMAO combined with SB.CONCLUSIONTMAO administration led to PERK/IRE1α axis activation, which may increase atrial remodeling and arrhythmogenesis. SB treatment mitigated TMAO-elicited ER stress. This finding suggests that SB administration is a valuable strategy for treating TMAO-induced atrial arrhythmia.

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NHE2

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