Targeting the WNK-SPAK/OSR1 Pathway and Cation-Chloride Cotransporters for the Therapy of Stroke

Stroke is one of the major culprits responsible for morbidity and mortality worldwide, and the currently available pharmacological strategies to combat this global disease are scanty. Cation-chloride cotransporters (CCCs) are expressed in several tissues (including neurons) and extensively contribute to the maintenance of numerous physiological functions including chloride homeostasis. Previous studies have implicated two CCCs, the Na+-K+-Cl− and K+-Cl− cotransporters (NKCCs and KCCs) in stroke episodes along with their upstream regulators, the with-no-lysine kinase (WNKs) family and STE20/SPS1-related proline/alanine rich kinase (SPAK) or oxidative stress response kinase (OSR1) via a signaling pathway. As the WNK-SPAK/OSR1 pathway reciprocally regulates NKCC and KCC, a growing body of evidence implicates over-activation and altered expression of NKCC1 in stroke pathology whilst stimulation of KCC3 during and even after a stroke event is neuroprotective. Both inhibition of NKCC1 and activation of KCC3 exert neuroprotection through reduction in intracellular chloride levels and thus could be a novel therapeutic strategy. Hence, this review summarizes the current understanding of functional regulations of the CCCs implicated in stroke with particular focus on NKCC1, KCC3, and WNK-SPAK/OSR1 signaling and discusses the current and potential pharmacological treatments for stroke.

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Cytotoxic Activity of Aplykurodin A Isolated From Aplysia kurodai against AXIN1-Mutated Hepatocellular Carcinoma Cells by Promoting Oncogenic β-Catenin Degradation

Marine Drugs ◽

10.3390/md18040210 ◽

2020 ◽

Vol 18 (4) ◽

pp. 210

Author(s):

Jaehoo Lee ◽

Wei Zhou ◽

MinKyun Na ◽

Sangtaek Oh

Keyword(s):

Hepatocellular Carcinoma ◽

Therapeutic Strategy ◽

Glycogen Synthase ◽

Annexin V ◽

Carcinoma Cells ◽

Human Hepatocellular Carcinoma ◽

Human Hepatoma ◽

Sensitive Cell ◽

Novel Therapeutic ◽

Stimulation Of

Dysregulation of the Wnt/β-catenin signaling pathway is involved in the development of human hepatocellular carcinoma and has thus emerged as a therapeutic target for this malignant tumor. In this study, we employed sensitive cell-based assays to identify aplykurodin A isolated from Aplysia kurodai as an antagonist of Wnt/β-catenin signaling. Aplykurodin A inhibited β-catenin responsive transcription, which was stimulated by a Wnt3a-conditioned medium or a glycogen synthase kinase 3β inhibitor by accelerating intracellular β-catenin degradation. Aplykurodin A downregulated the level of oncogenic β-catenin and decreased the expression of β-catenin-dependent gene, leading to inhibition of human hepatoma Hep3B and SNU475 cell proliferation. Moreover, apoptosis and autophagy were elicited by aplykurodin A, as indicated by an increase the number of Annexin V-FITC-stained cells and the formation of microtubule-associated protein 1 light chain 3 puncta, respectively, in Hep3B and SNU475 cells. Our findings suggest that aplykurodin A provides a novel therapeutic strategy for human hepatocellular carcinoma via stimulation of oncogenic β-catenin degradation.

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894 A novel therapeutic strategy for patients with premature ejaculation: Possibility of electrical stimulation of dorsal penile nerves

European Urology Supplements ◽

10.1016/s1569-9056(16)60896-5 ◽

2016 ◽

Vol 15 (3) ◽

pp. e894

Author(s):

Y. Kimura ◽

C. Saitoh

Keyword(s):

Electrical Stimulation ◽

Therapeutic Strategy ◽

Premature Ejaculation ◽

Novel Therapeutic ◽

Stimulation Of

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Anti-OX40ligand treatment as a novel therapeutic strategy in a murine model of colitis

Gastroenterology ◽

10.1016/s0016-5085(01)83410-7 ◽

2001 ◽

Vol 120 (5) ◽

pp. A685-A685

Author(s):

B SINGH ◽

V MALMSTROM ◽

F POWRIE

Keyword(s):

Murine Model ◽

Therapeutic Strategy ◽

Novel Therapeutic

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Anticancer Immunotoxins, Challenges, and Approaches

Current Pharmaceutical Design ◽

10.2174/1381612826666201006155346 ◽

2020 ◽

Vol 26 ◽

Author(s):

Maryam Dashtiahangar ◽

Leila Rahbarnia ◽

Safar Farajnia ◽

Arash Salmaninejad ◽

Arezoo Gowhari Shabgah ◽

...

Keyword(s):

Therapeutic Strategy ◽

Antibody Fragment ◽

Clinical Use ◽

Multiple Cancer ◽

Main Obstacle ◽

Cancer Types ◽

Recombinant Immunotoxins ◽

Cancerous Cells ◽

High Immunogenicity ◽

Novel Therapeutic

: The development of recombinant immunotoxins (RITs) as a novel therapeutic strategy has made a revolution in the treatment of cancer. RITs are resulting from the fusion of antibodies to toxin proteins for targeting and eliminating cancerous cells by inhibiting protein synthesis. Despite indisputable outcomes of RITs regarding inhibiting multiple cancer types, high immunogenicity has been known as the main obstacle in the clinical use of RITs. Various strategies have been proposed to overcome these limitations, including immunosuppressive therapy, humanization of the antibody fragment moiety, generation of immunotoxins originated from endogenous human cytotoxic enzymes, and modification of the toxin moiety to escape the immune system. This paper devoted to reviewing recent advances in the design of immunotoxins with lower immunogenicity.

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Targeting ferroptosis: A novel therapeutic strategy for the treatment of mitochondrial disease-related epilepsy

PLoS ONE ◽

10.1371/journal.pone.0214250 ◽

2019 ◽

Vol 14 (3) ◽

pp. e0214250 ◽

Cited By ~ 10

Author(s):

Amanda H. Kahn-Kirby ◽

Akiko Amagata ◽

Celine I. Maeder ◽

Janet J. Mei ◽

Steve Sideris ◽

...

Keyword(s):

Mitochondrial Disease ◽

Therapeutic Strategy ◽

Novel Therapeutic

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A novel therapeutic strategy for hepatocellular carcinoma: Immunomodulatory mechanisms of selenium and/or selenoproteins on a shift towards anti-cancer

International Immunopharmacology ◽

10.1016/j.intimp.2021.107790 ◽

2021 ◽

Vol 96 ◽

pp. 107790

Author(s):

Bao-Kang Wu ◽

Qian-Hui Chen ◽

Dan Pan ◽

Bing Chang ◽

Li-Xuan Sang

Keyword(s):

Hepatocellular Carcinoma ◽

Therapeutic Strategy ◽

Anti Cancer ◽

Novel Therapeutic

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Apohemoglobin-haptoglobin complex attenuates the pathobiology of circulating acellular hemoglobin and heme

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00136.2020 ◽

2020 ◽

Vol 318 (5) ◽

pp. H1296-H1307 ◽

Cited By ~ 2

Author(s):

Carlos J. Munoz ◽

Ivan S. Pires ◽

Jin Hyen Baek ◽

Paul W. Buehler ◽

Andre F. Palmer ◽

...

Keyword(s):

Therapeutic Strategy ◽

Capillary Density ◽

Microvascular Blood Flow ◽

Systemic Hypertension ◽

Proof Of Concept ◽

Heme Transfer ◽

Ligand Transfer ◽

Novel Therapeutic

This study highlights the apoHb-Hp complex as a novel therapeutic strategy to attenuate the adverse systemic and microvascular responses to intravascular Hb and heme exposure. In vitro and in vivo Hb exchange and heme transfer experiments demonstrated proof-of-concept Hb/heme ligand transfer to apoHb-Hp. The apoHb-Hp complex reverses Hb- and heme-induced systemic hypertension and microvascular vasoconstriction, preserves microvascular blood flow, and functional capillary density. In summary, the unique properties of the apoHb-Hp complex prevent adverse systemic and microvascular responses to Hb and heme-albumin exposure and introduce a novel therapeutic approach to facilitate simultaneous removal of extracellular Hb and heme.

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