The integrated stress response (ISR) is a vital signaling pathway initiated by four kinases, PERK, GCN2, HRI and PKR, that ensure cellular resilience and protect cells from challenges. Here, we investigated whether increasing ISR signaling could rescue diabetes-like phenotypes in a mouse model of diet-induced obesity (DIO). We show that the orally available and clinically approved GCN2 activator halofuginone (HF) can activate the ISR in mouse tissues. We found that daily oral administration of HF increases glucose tolerance whilst reducing weight gain, insulin resistance, and serum insulin in DIO mice. Conversely, the ISR inhibitor GSK2656157, used at low doses to optimize its selectivity, aggravates glucose intolerance in DIO mice. Whilst loss of function mutations in mice and humans have revealed that PERK is the essential ISR kinase that protects from diabetes, our work demonstrates the therapeutic value of increasing ISR signaling by activating the related kinase GCN2 to reduce diabetes phenotypes in a DIO mouse model.

01 Oct 2024·Journal of Investigative Medicine

Astragaloside IV ameliorated neuroinflammation and improved neurological functions in mice exposed to traumatic brain injury by modulating the PERK-eIF2α-ATF4 signaling pathway

Article

Author: Sun, Guozhu ; Feng, Shiyao ; Zhao, Jianfei ; Lang, Jiadong ; Zhao, Gengshui ; Li, Dongsheng ; Sun, Boyu

Increasing evidence suggests that endoplasmic reticulum stress (ER stress) and neuroinflammation are involved in the complex pathological process of traumatic brain injury (TBI). However, the pathological mechanisms of their interactions in TBI remain incompletely elucidated. Therefore, investigating and ameliorating neuroinflammation and ER stress post-TBI may represent effective strategies for treating secondary brain injury. Astragaloside IV (AS-IV) has been reported as a potential neuroprotective and anti-inflammatory agent in neurological diseases. This study utilized a mouse TBI model to investigate the pathological mechanisms and crosstalk of ER stress, neuroinflammation, and microglial cell morphology in TBI, as well as the mechanisms and potential of AS-IV in improving TBI. The research revealed that post-TBI, inflammatory factors IL-6, IL-1β, and TNF-α increased, microglial cells were activated, and the specific inhibitor of PERK phosphorylation, GSK2656157, intervened to alleviate neuroinflammation and inhibit microglial cell activation. Post-TBI, levels of ER stress-related proteins (p-PERK, p-eIF2a, ATF4, ATF6, and p-IRE1a) increased. Following AS-IV treatment, neurological dysfunction in TBI mice improved. Levels of p-PERK, p-eIF2a, and ATF4 decreased, along with reductions in inflammatory factors IL-6, IL-1β, and TNF-α. Changes in microglial/macrophage M1/M2 polarization were observed. Additionally, the PERK activator CCT020312 intervention eliminated the impact of AS-IV on post-TBI inflammation and ER stress-related proteins p-PERK, p-eIF2a, and ATF4. These results indicate that AS-IV alleviates neuroinflammation and brain damage post-TBI through the PERK pathway, offering new directions and theoretical insights for TBI treatment.

01 Aug 2024·Environmental Toxicology

Luteolin, apigenin, and chrysin inhibit lipotoxicity–induced NLRP3 inflammasome activation and autophagy damage in macrophages by suppressing endoplasmic reticulum stress

Article

Author: Liu, Kai-Li ; Lii, Chong-Kuei ; Chen, Haw-Wen ; Li, Chien-Chun ; Lo, Chia-Wen ; Lin, Kuan-Shuan ; Yang, Ya-Chen

AbstractLipotoxicity leads to numerous metabolic disorders such as nonalcoholic steatohepatitis. Luteolin, apigenin, and chrysin are three flavones with known antioxidant and anti‐inflammatory properties, but whether they inhibit lipotoxicity‐mediated NLRP3 inflammasome activation was unclear. To address this question, we used J774A.1 macrophages and Kupffer cells stimulated with 100 μM palmitate (PA) in the presence or absence of 20 μM of each flavone. PA increased p‐PERK, p‐IRE1α, p‐JNK1/2, CHOP, and TXNIP as well as p62 and LC3‐II expression and induced autophagic flux damage. Caspase‐1 activation and IL‐1β release were also noted after 24 h of exposure to PA. In the presence of the PERK inhibitor GSK2656157, PA‐induced CHOP and TXNIP expression and caspase‐1 activation were mitigated. Compared with PA treatment alone, Bcl‐2 coupled to beclin‐1 was elevated and autophagy was reversed by the JNK inhibitor SP600125. With luteolin, apigenin, and chrysin treatment, PA‐induced ROS production, ER stress, TXNIP expression, autophagic flux damage, and apoptosis were ameliorated. Moreover, TXNIP binding to NLRP3 and IL‐1β release in response to LPS/PA challenge were reduced. These results suggest that luteolin, apigenin, and chrysin protect hepatic macrophages against PA‐induced NLRP3 inflammasome activation and autophagy damage by attenuating endoplasmic reticulum stress.

100 Deals associated with GSK-2656157

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Indication	Highest Phase	Country/Location	Organization	Date
Viral Myocarditis	Preclinical	US	Houston Methodist Research Institute	25 Apr 2024
Neoplasms	Discovery	US	GSK Plc	12 Aug 2013

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