NEUROCHEMICAL RESEARCH
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2025
·Vol. 50
·期 1
·1-17
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IF 3.8
Min Xiao-li,Shi Ying,Xu Ying,Li Yu-ye,Dong You-kang,Chen Fei-xiong,Chen Quan-ming,Sun Yu-long,Liao Rui,Wang Jia-ping
Objective: Post-resuscitation brain injury is a common sequela after cardiac arrest (CA). Increasing sirtuin1 (SIRT1) has been involved in neuroprotection in oxygen-glucose deprivation (OGD) neurons, and we investigated its mechanism in post-cardiopulmonary resuscitation (CPR) rat brain injury by mediating p65 deacetylation modification to mediate hippocampal neuronal ferroptosis. Methods: Sprague-Dawley rat CA/CPR model was established and treated with Ad-SIRT1 and Ad-GFP adenovirus vectors, or Erastin. Rat postoperative neurological function, and cognitive and learning abilities were assessed by neurological deficit score and Morris water maze test. Hippocampal neuronal pathological changes and injury were evaluated by H&E and TUNEL staining. Serum brain injury biomarkers and hippocampal inflammatory factors and SIRT1 mRNA levels were determined by ELISA and RT-qPCR. OGD/reoxygenation (OGD/R) rat hippocampal neuron (H19-7) model was established. Cell viability and injury, nuclear factor-kappa B (NF-κB) p65 localization, iron content, and levels of glutathione, malondialdehyde, reactive oxygen species, SIRT1, Ac NF-κB p65 (Lys310), NF-κB p65, ACSL4, glutathione peroxidase 4 and SLC7A11 were measured. Results: In CA/CPR rats, SIRT1 was down-regulated, and SIRT1 overexpression alleviated cerebral injury. SIRT1 overexpression inhibited OGD/R-induced H19-7 cell ferroptosis to ameliorate cell injury, and inactivated the NF-κB pathway by reducing p65 acetylation to hinder its entry into the nucleus. Inactivating the NF-κB pathway reduced OGD/R-induced ferroptosis and alleviated cell injury. SIRT1 alleviated cerebral injury by mediating p65 deacetylation to inhibit hippocampal neuronal ferroptosis mediated by the NF-κB pathway. Conclusions: SIRT1 inhibited the NF-κB signaling pathway-mediated hippocampal neuronal ferroptosis by mediating p65 deacetylation modification, thereby alleviating brain injury in CA/CPR rats.
研究领域:
神经科学
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分子生物学
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细胞生物学
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医学
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产品关联
DOI
PubMed
高影响因子
Antioxidants
·
2024
·Vol. 13
·期 2
·186
·
IF 6
Zhengyi Zhang,Baochen Cheng,Wenqian Du,Mengqi Zeng,Ke He,Tingyi Yin,Sen Shang,Tian Su,Dan Han,Xinyi Gan,Ziyang Wang,Meng Liu,Min Wang,Jiankang Liu,Yan Zheng
Psoriasis is one of several chronic inflammatory skin diseases with a high rate of recurrence, and its pathogenesis remains unclear. Nicotinamide mononucleotide (NMN), as an important precursor of nicotinamide adenine dinucleotide (NAD+), has been reported to be a promising agent in treating various diseases, its positive effects including those induced via its anti-inflammatory and antioxidant properties. For this reason, we have aimed to explore the possible role of NMN in the treatment of psoriasis. Psoriasis models were constructed with imiquimod (IMQ) stimulation for 5 days in vivo and with M5 treatment in keratinocyte cell lines in vitro. NMN treatment during the IMQ application period markedly attenuated excess epidermal proliferation, splenomegaly, and inflammatory responses. According to GEO databases, Sirtuin1 (SIRT1) levels significantly decreased in psoriasis patients’ lesion tissues; this was also the case in the IMQ-treated mice, while NMN treatment reversed the SIRT1 decline in the mouse model. Moreover, NMN supplementation also improved the prognoses of the mice after IMQ stimulation, compared to the untreated group with elevated SIRT1 levels. In HEKa and HaCaT cells, the co-culturing of NMN and M5 significantly decreased the expression levels of proinflammation factors, the phosphorylation of NF-κB, stimulator of interferon genes (STING) levels, and reactive oxygen species levels. NMN treatment also recovered the decrease in mitochondrial membrane potential and respiration ability and reduced mtDNA in the cytoplasm, leading to the inhibition of autoimmune inflammation. The knockdown ofSIRT1in vitro eliminated the protective and therapeutic effects of NMN against M5. To conclude, our results indicate that NMN protects against IMQ-induced psoriatic inflammation, oxidative stress, and mitochondrial dysfunction by activating the SIRT1 pathway.Keywords:nicotinamide mononucleotide;psoriasis;inflammation;SIRT1;ROS;mitochondria
研究领域:
皮肤病学
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药理学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
FASEB JOURNAL
·
2025
·Vol. 39
·期 5
·e70420
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IF 4.2
Min Zhu,Xiaofang Fan,Nan Zhang,Hui Wang,Jianshe Ma,Xianghong Yin,Junyan Cai,Linjing Cong,Ran Chen,Junming Fan,Xiaoxia Kong,Bin Geng,Yongsheng Gong,Congkuo Du
Endothelial pyroptosis, a pro-inflammatory programmed cell death, promotes endothelial inflammation and is a pivotal process in the initial stage of acute lung injury (ALI). Hydrogen sulfide (H 2 S), a gasotransmitter primarily dependent on cystathionine γ-lyase (CSE) in the cardiovascular and respiratory systems, plays a protective role during ALI. Nonetheless, the modulatory role and precise molecular mechanism of endothelial endogenous CSE/H 2 S in the pathogenesis of ALI remain elusive. Herein, we prepared an ALI mouse model using intratracheal administration of LPS (5 mg/kg), and lung injury was assessed by evaluating pulmonary edema, inflammatory response, and endothelial pyroptosis. In this model, H 2 S production from pulmonary tissues declined in a time-dependent manner, accompanied by a compensatory elevation of CSE protein levels. Treatment with the H 2 S donor (NaHS) attenuated pulmonary edema, inflammatory cell infiltration, endothelial pyroptosis, and reduced serum levels of tumor necrosis factor-alpha (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6). Meanwhile, the inducible deletion of CSE in endothelial cells exacerbated these changes. The blocking effect of CSE/H 2 S on endothelial pyroptosis (evidenced by caspase-11 activation and GSDMD-NT formation) was also confirmed in cultured pulmonary microvascular endothelial cells (PMECs). Mechanistically, H 2 S-mediated regulation of sirtuin-1 (SIRT1) expression and activation (via sulfhydration) contributed to the modulatory process. Collectively, we uncovered that endothelial endogenous CSE/H 2 S alleviates endothelial pyroptosis by activating SIRT1, thereby preventing LPS-induced acute lung injury. Graphical In the LPS-induced ALI model, caspase-1-independent pyroptosis was activated. The expression of activated caspase-11 and GSDMD-NT was increased, accompanied by pulmonary edema and inflammatory infiltration. Endothelial CSE/H 2 S deficiency aggravated endothelial pyroptosis and acute lung injury. Mechanistically, endothelial endogenous CSE/H 2 S mediated the expression and activation of sirtuin-1 (SIRT1) via sulfhydration, one of the post-translational modifications. Activated SIRT1 inhibited the activation of caspase-11 and GSDMD-NT to inhibit endothelial pyroptosis, thereby alleviating acute lung injury.
研究领域:
医学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
WORLD JOURNAL OF GASTROENTEROLOGY
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2024
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IF 4.3
Kai-Di Chen,Kui-Ling Wang,Chen Chen,Yi-Jia Zhu,Wen-Wen Tang,Yu-Ji Wang,Ze-Peng Chen,Lin-Hai He,Yu-Gen Chen,Wei Zhang
BACKGROUND Constipation, a highly prevalent functional gastrointestinal disorder, induces a significant burden on the quality of patients' life and is associated with substantial healthcare expenditures. Therefore, identifying efficient therapeutic modalities for constipation is of paramount importance. Oxidative stress is a pivotal contributor to colonic dysmotility and is the underlying pathology responsible for constipation symptoms. Consequently, we postulate that hydrogen therapy, an emerging and promising intervention, can serve as a safe and efficacious treatment for constipation. AIM To determine whether hydrogen-rich water (HRW) alleviates constipation and its potential mechanism. METHODS Constipation models were established by orally loperamide to Sprague-Dawley rats. Rats freely consumed HRW, and were recorded their 24 h total stool weight, fecal water content, and charcoal propulsion rate. Fecal samples were subjected to 16S rDNA gene sequencing. Serum non-targeted metabolomic analysis, malondialdehyde, and superoxide dismutase levels were determined. Colonic tissues were stained with hematoxylin and eosin, Alcian blue-periodic acid-Schiff, reactive oxygen species (ROS) immunofluorescence, and immunohistochemistry for cell growth factor receptor kit (c-kit), PGP 9.5, sirtuin1 (SIRT1), nuclear factor-erythroid-2-related factor 2 (Nrf2), and heme oxygenase-1 (HO-1). Quantitative real-time PCR and western blot analysis were conducted to determine the expression level of SIRT1, Nrf2 and HO-1. A rescue experiment was conducted by intraperitoneally injecting the SIRT1 inhibitor, EX527, into constipated rats. NCM460 cells were induced with H 2 O 2 and treated with the metabolites to evaluate ROS and SIRT1 expression. RESULTS HRW alleviated constipation symptoms by improving the total amount of stool over 24 h, fecal water content, charcoal propulsion rate, thickness of the intestinal mucus layer, c-kit expression, and the number of intestinal neurons. HRW modulated intestinal microbiota imbalance and abnormalities in serum metabolism. HRW could also reduce intestinal oxidative stress through the SIRT1/Nrf2/HO-1 signaling pathway. This regulatory effect on oxidative stress was confirmed via an intraperitoneal injection of a SIRT1 inhibitor to constipated rats. The serum metabolites, β-leucine (β-Leu) and traumatic acid, were also found to attenuate H 2 O 2 -induced oxidative stress in NCM460 cells by up-regulating SIRT1. CONCLUSION HRW attenuates constipation-associated intestinal oxidative stress via SIRT1/Nrf2/HO-1 signaling pathway, modulating gut microbiota and serum metabolites. β-Leu and traumatic acid are potential metabolites that upregulate SIRT1 expression and reduce oxidative stress.
研究领域:
胃肠病学
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药理学
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分子生物学
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微生物学
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代谢组学
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产品关联
DOI
PubMed
高影响因子
Acta Biomaterialia
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2023
·
IF 9.7
Mengjie Kong,Yan Peng,Liyan Qiu
Non-alcoholic fatty liver disease (NAFLD) is currently a common chronic liver disease worldwide. By now, however, there isn't any FDA-approved specific drug for NAFLD treatment. It has been noticed that farnesoid X receptor (FXR), miR-34a and Sirtuin1 (SIRT1) is related to the occurrence and development of NAFLD. A oligochitosan-derivated nanovesicle (UBC) with esterase responsive degradability was designed to co-encapsulate FXR agonist (obeticholic acid, OCA) and miR-34a antagomir (anta-miR-34a) into the hydrophobic membrane and the center aqueous lumen of nanovesicles, respectively, by dialysis method. The action of UBC/OCA/anta-miR-34a loop on the regulation of lipid deposition via nanovesicles was evaluated on high-fat HepG2 cells and HFD-induced mice. The obtained dual drug-loaded nanovesicles UBC/OCA/anta-miR-34a could enhance the cellular uptake and intracellular release of OCA and anta-miR-34a, leading to the reduced lipid deposition in high-fat HepG2 cells. In NAFLD mice models, UBC/OCA/anta-miR-34a achieved the best curative effect on the recovery of body weight and hepatic function. Meanwhile, in vitro and vivo experiments validated that UBC/OCA/anta-miR-34a effectively activated the expression level of SIRT1 by enhancing the FXR/miR-34a/SIRT1 regulatory loop. This study provides a promising strategy for constructing oligochitosan-derivated nanovesicles to co-deliver OCA and anta-miR-34a for NAFLD treatment. Statement of significance This study proposed a strategy to construct oligochitosan-derivated nanovesicles to co-deliver obeticholic acid and miR-34a antagomir for NAFLD treatment. Based on the FXR/miR-34a/SIRT1 action loop, this nanovesicle effectively exerted a synergetic effect of OCA and anta-miR-34a to significantly regulate lipid deposition and recover liver function in NAFLD mice.
研究领域:
药学
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分子生物学
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肝病学
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纳米技术
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DOI
PubMed
高影响因子
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