BACKGROUNDFerroptosis plays a key role in the development of chronic obstructive pulmonary disease (COPD). Whether ginsenoside Rg1 improves cigarette smoke-induced COPD or whether ginsenoside Rg1 improves COPD by inhibiting ferroptosis remains unknown.METHODSBEAS-2B cells were exposed to cigarette solution (CSE) for 24 h and treated with ginsenoside Rg1, the ferroptosis inhibitor Fer-1, and the PERK inhibitor GSK. Cell viability, endoplasmic reticulum stress, mitochondrial morphology, membrane potential, reactive oxygen species (ROS), iron levels, and the expression of related proteins were detected using corresponding methods. A COPD mouse model was constructed using cigarette smoke (CS). Ginsenoside Rg1 and GSK were administered via tube feeding 15 days after successful modeling. Mouse lung tissues were evaluated by HE staining. The expression of inflammatory markers, ROS, iron content, and related proteins was detected using corresponding methods.RESULTSThe results demonstrated that in the CSE-exposed BEAS-2B cell model and CS-induced mouse COPD model, the expression levels of endoplasmic reticulum stress (ERS)-related factors such as GRP78 were increased, while those of the antioxidant markers GPX4 and GSH were significantly decreased. Ginsenoside Rg1 improved emphysema and inflammation by inhibiting ferroptosis in vivo and in vitro. Using a PERK inhibitor, we found that ginsenoside Rg1 inhibited ferroptosis in vivo and in vitro by regulating ERS.CONCLUSIONThis study showed that ginsenoside Rg1 alleviates cigarette smoke-induced COPD by regulating the PERK/ATF4 axis to inhibit ERS and ferroptosis.

2024-10-01·Stroke

Time-Dependent Potentiation of the PERK Branch of UPR by GPR68 Offers Protection in Brain Ischemia

Article

作者: Jonchhe, Sarun ; Davis, Grace ; Zha, Xiangming ; Zhou, Guokun ; Sun, Wenyan ; Tiwari, Virendra

BACKGROUND:In ischemia, acidosis occurs in/around injured tissue and parallels disease progression. Therefore, targeting an acid-sensitive receptor offers unique advantages in achieving the spatial and temporal specificity required for therapeutic interventions. We previously demonstrated that increased expression of GPR68 (G protein-coupled receptor 68), a proton-sensitive G protein-coupled receptor, mitigates ischemic brain injury. Here, we investigated the mechanism underlying GPR68-dependent protection.METHODS:We performed biochemical and molecular analyses to examine poststroke signaling. We used in vitro brain slice cultures and in vivo mouse transient middle cerebral artery occlusion (tMCAO) models to investigate ischemia-induced injuries.RESULTS:GPR68 deletion reduced PERK (protein kinase R-like ER kinase) expression in mouse brain. Compared with the wild-type mice, the GPR68-/- (knockout) mice exhibited a faster decline in eIF2α (eukaryotic initiation factor-2α) phosphorylation after tMCAO. Ogerin, a positive modulator of GPR68, stimulated eIF2α phosphorylation at 3 to 6 hours after tMCAO, primarily in the ipsilateral brain tissue. Consistent with the changes in eIF2α phosphorylation, Ogerin enhanced tMCAO-induced reduction in protein synthesis in ipsilateral brain tissue. In organotypic cortical slices, Ogerin reduced pH 6 and oxygen-glucose deprivation–induced neurotoxicity. Following tMCAO, intravenous delivery of Ogerin reduced brain infarction in wild-type but not knockout mice. Coapplication of a PERK inhibitor abolished Ogerin-induced protection. Delayed Ogerin delivery at 5 hours after tMCAO remained protective, and Ogerin has a similar protective effect in females. Correlated with these findings, tMCAO induced GPR68 expression at 6 hours, and Ogerin alters post-tMCAO proinflammatory/anti-inflammatory cytokine/chemokine expression profile.CONCLUSIONS:These data demonstrate that GPR68 potentiation leads to neuroprotection, at least in part, through enhancing PERK-eIF2α activation in ischemic tissue but has little impact on healthy tissue.

2024-09-12·Journal of Medicinal Chemistry

Selective Degradation of MLK3 by a Novel CEP1347-VHL-02 PROTAC Compound Limits the Oncogenic Potential of TNBC

Article

作者: Marusiak, Anna A. ; Sabbasani, Venkata R. ; Truong, Vi Nguyen-Phuong ; Swenson, Rolf E. ; Serwa, Remigiusz ; Łomiak, Michał ; Brognard, John ; Torres-Ayuso, Pedro ; Mehlich, Dawid ; Karpińska, Kamila ; Wróbel, Katarzyna

Triple-negative breast cancer (TNBC) is associated with poor prognosis because of the lack of effective therapies. Mixed-lineage protein kinase 3 (MLK3) is a protein that is often upregulated in TNBC and involved in driving the tumorigenic potential of cancer cells. Here, we present a selective MLK3 degrader, CEP1347-VHL-02, based on the pan-MLK inhibitor CEP1347 and a ligand for E3 ligase von Hippel-Lindau (VHL) by employing proteolysis-targeting chimera (PROTAC) technology. Our compound effectively targeted MLK3 for degradation via the ubiquitin-proteasome system in several cell line models but did not degrade other MLK family members. Furthermore, we showed that CEP1347-VHL-02 robustly degraded MLK3 and inhibited its oncogenic activity in TNBC, measured as a reduction of clonogenic and migratory potential, cell cycle arrest, and the induction of apoptosis in MDA-MB-468 cells. In conclusion, we present CEP1347-VHL-02 as a novel MLK3 degrader that may be a promising new strategy to target MLK3 in TNBC.

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适应症	最高研发状态	国家/地区	公司	日期
青光眼	临床前	美国	Johns Hopkins Technology Ventures	-
青光眼	临床前	美国	The Johns Hopkins University	-
神经系统变性病	临床前	美国	Johns Hopkins Technology Ventures	-
神经系统变性病	临床前	美国	The Johns Hopkins University	-
视神经疾病	临床前	美国	The Johns Hopkins University	-
视神经疾病	临床前	美国	Johns Hopkins Technology Ventures	-