Brain and Behavior
·
2023
·Vol. 13
·期 5
·e2980
·
IF 3.1
Yunchao Shi,Ying Fang,Peng Shen,He Liu,Longsheng Xu,Liyan Wang,Maoxian Yang
Purpose Cognitive impairment is a critical complication of acute respiratory distress syndrome (ARDS). However, effective interventions are lacking. Growing evidence demonstrates that c-Jun N-terminal kinase (JNK)-mediated neuroinflammation is involved in the development of ARDS. Therefore, we hypothesized that the JNK pathway is involved in ARDS-induced cognitive impairment. Methods An in vivo rat model of ARDS was established by treating it with lipopolysaccharide. The cognitive function was assessed by behavioral tests. The levels of pro-inflammatory cytokines, JNK and NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) were analyzed by enzyme-linked immunosorbent assay, western blot, or immunohistochemical analysis. Results We found that JNK inhibitor 8 (JNK-IN-8) alleviated cognitive impairment, neuroinflammation, and NLRP3 inflammasome activation in the ARDS rat model. Additionally, an in vivo study showed that the protective effect of JNK-IN-8 on cognitive impairment was blocked by nigericin, an NLRP3 activator. Conclusions Our data suggest that JNK-IN-8 treatment improves ARDS-induced cognitive impairment by inhibiting the JNK/nuclear factor-κB-mediated NLRP3 inflammasome.
研究领域:
药理学
·
神经科学
·
免疫学
·
呼吸医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF BIOLOGICAL CHEMISTRY
·
2020
·Vol. 295
·期 20
·6958-6971
·
IF 4.238
Chunyan Liao,Binxiang Cai,Yufeng Feng,Jingmeng Chen,Yiping Wu,Jingbin Zhuang,Zuguo Liu,Yalin Wu
Disrupted clearance of all-trans-retinal (atRAL), a component of the visual (retinoid) cycle in the retina, may cause photoreceptor atrophy in autosomal recessive Stargardt disease (STGD1) and dry age-related macular degeneration (AMD). However, the mechanisms underlying atRAL-induced photoreceptor loss remain elusive. Here, we report that atRAL activates c-Jun N-terminal kinase (JNK) signaling at least partially through reactive oxygen species production, which promoted mitochondria-mediated caspase- and DNA damage-dependent apoptosis in photoreceptor cells. Damage to mitochondria in atRAL-exposed photoreceptor cells resulted from JNK activation, leading to decreased expression of Bcl2 apoptosis regulator (Bcl2), increased Bcl2 antagonist/killer (Bak) levels, and cytochrome c (Cyt c) release into the cytosol. Cytosolic Cyt c specifically provoked caspase-9 and caspase-3 activation and thereby initiated apoptosis. Phosphorylation of JNK in atRAL-loaded photoreceptor cells induced the appearance of γH2AX, a sensitive marker for DNA damage, and was also associated with apoptosis onset. Suppression of JNK signaling protected photoreceptor cells against atRAL-induced apoptosis. Moreover, photoreceptor cells lacking Jnk1 and Jnk2 genes were more resistant to atRAL-associated cytotoxicity. The Abca4−/− Rdh8−/− mouse model displays defects in atRAL clearance that are characteristic of STGD1 and dry AMD. We found that JNK signaling was activated in the neural retina of light-exposed Abca4−/−Rdh8−/− mice. Of note, intraperitoneal administration of JNK–IN-8, which inhibits JNK signaling, effectively ameliorated photoreceptor degeneration and apoptosis in light-exposed Abca4−/−Rdh8−/− mice. We propose that pharmacological inhibition of JNK signaling may represent a therapeutic strategy for preventing photoreceptor loss in retinopathies arising from atRAL overload.
研究领域:
眼科学
·
细胞生物学
·
分子生物学
·
神经科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Cell Reports Medicine
·
2025
·
IF 10.6
Shuai Yang,Xinyao Qiu,Yingcheng Yang,Jing Wu,Shan Wang,Bo Zheng,Jianmin Wu,Tao Zhou,Yangqianwen Zhang,Mixue Bai,Shuowu Liu,Zihan Zhao,Yani Zhang,Yixian Wang,Jinxia Bao,Mengye Wu,Dongdong Xue,Meiyu Bao,Ji Hu,Siyun Shen,Hongyang Wang,Lei Chen
Leukotriene A4 hydrolase (LTA4H), an inflammatory mediator, has garnered attention for its role in the development of chronic lung diseases and various cancers. Our study highlights the protective role of LTA4H in hepatocellular carcinoma (HCC) occurrence and progression. LTA4H is downregulated in clinical and mouse HCC tumors. LTA4H deficiency exacerbates hepatocyte damage by restraining JNK activation and promotes CD206 + macrophage polarization through the upregulation of LTBP1 expression and downstream transforming growth factor β (TGF-β) secretion and activation. Mechanistically, LTA4H induces heterogeneous nuclear ribonucleoprotein A1 (HNRNPA1) phosphorylation, enhancing their interaction and leading to the functional inhibition of HNRNPA1 in regulating Ltbp1 mRNA maturation and processing in the nucleus. LTA4H-deficient patients exhibit poor prognosis and immunotherapy resistance. Combination therapy targeting TGF-β and PD-1 significantly improves the immunotherapy resistance of LTA4H-knockout Hepa1-6 tumors. Our findings reveal the previously unreported role of LTA4H in regulating the tumor microenvironment and provide insights into potential diagnostic and therapeutic strategies for patients with LTA4H-deficient HCC.
研究领域:
肿瘤学
·
分子生物学
·
免疫学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
iScience
·
2026
·Vol. 29
·期 4
·
IF 4.5
Peng Zhang,Jianfeng Zhong,Ting Zhou,Depei Jiang,Zijing Wang,Meifang Ye,Lekun Fang,Huizhen Xiong,Honglei Chen
The role of spindle and kinetochore-associated complex subunit 2 (SKA2) in gastric cancer (GC) pathogenesis remains largely undefined. Here, we report that SKA2 is overexpressed in GC and correlates with poor prognosis. Functionally, SKA2 silencing inhibits tumor growth, induces G2/M arrest, and promotes apoptosis both in vitro and in vivo . Mechanistically, SKA2 upregulates the glycine transporter SLC6A9, enhancing glycine uptake and glutathione (GSH) synthesis to maintain redox homeostasis. Consequently, SKA2 depletion disrupts this metabolic balance, leading to reactive oxygen species (ROS) accumulation and DNA damage. This oxidative stress activates the ATM/Chk2 pathway to trigger cell-cycle arrest and the ATM/JNK pathway to induce apoptosis. Our findings identify SKA2 as a critical driver of metabolic reprogramming that shields GC cells from oxidative stress-induced death, highlighting the SKA2-SLC6A9-GSH-ROS axis as a promising therapeutic target.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）