Histone Deacetylase Inhibitor (SAHA) Reduces Mortality in an Endotoxemia Mouse Model by Suppressing Glycolysis.
Histone Deacetylase Inhibitor (SAHA) Reduces Mortality in an Endotoxemia Mouse Model by Suppressing Glycolysis.
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DOI：
10.3390/ijms241512448
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发表时间：
2023-08-04
影响因子：
5.6
通讯作者：
Xing, Shaojun
中科院分区：
文献类型：
--
作者：
Wu, Yunchen;He, Yudan;Liu, Chen;Ehle, Charlotte;Iyer-Bierhoff, Aishwarya;Liu, Bing;Heinzel, Thorsten;Xing, Shaojun
败血症是一种危及生命的医疗紧急情况，由对感染的过度炎症引发。高死亡率和有限的治疗选择对败血症的治疗提出了重大挑战。组蛋白去乙酰化酶抑制剂（HDACi），如亚酰苯胺羟肟酸（SAHA），已被提出作为治疗炎症性疾病的有效抗炎剂。然而，脓毒症治疗的潜在机制仍然知之甚少。在这项研究中，我们研究了SAHA治疗对脂多糖（LPS）诱导的内毒素血症小鼠模型的影响，因为它非常接近于脓毒症的系统性炎症的早期阶段。我们的研究结果表明，炎症介质分泌减少，提高了小鼠的存活率。通过定量乙酰组学，我们发现SAHA增加了乳酸脱氢酶（LDHA）的乙酰化，从而抑制LDHA的活性。值得注意的是，LDHA酶活性的降低导致糖酵解速率的降低。此外，我们对骨髓源性巨噬细胞（bmdm）的实验表明，SAHA可降低氧化应激和细胞外ATP浓度，最终减弱炎性体的激活。总的来说，我们的研究提供了SAHA在脓毒症治疗中的治疗作用机制的见解，并强调LDHA是开发新型脓毒症治疗的潜在靶点。
Sepsis is a life-threatening medical emergency triggered by excessive inflammation in response to an infection. High mortality rates and limited therapeutic options pose significant challenges in sepsis treatment. Histone deacetylase inhibitors (HDACi), such as suberoylanilide hydroxamic acid (SAHA), have been proposed as potent anti-inflammatory agents for treating inflammatory diseases. However, the underlying mechanisms of sepsis treatment remain poorly understood. In this study, we investigated the effects of SAHA treatment in the lipopolysaccharide (LPS)-induced endotoxemia mouse model as it closely mimics the early stages of the systemic inflammation of sepsis. Our results demonstrate a reduced inflammatory mediator secretion and improved survival rates in mice. Using quantitative acetylomics, we found that SAHA administration increases the acetylation of lactate dehydrogenase (LDHA), and consequently inhibits LDHA activity. Notably, the reduced enzyme activity of LDHA results in a reduced rate of glycolysis. Furthermore, our experiments with bone marrow-derived macrophages (BMDMs) show that SAHA administration reduced oxidative stress and extracellular ATP concentrations, ultimately blunting inflammasome activation. Overall, our study provides insights into the mechanism underlying SAHA’s therapeutic effects in sepsis treatment and highlights LDHA as a potential target for developing novel sepsis treatment.
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DOI：
10.5539/gjhs.v8n3p72
发表时间：
2015-06-25
期刊：
Global journal of health science
影响因子：
--
作者：
Alturkistani HA;Tashkandi FM;Mohammedsaleh ZM
通讯作者：
Mohammedsaleh ZM
影响因子：
3.9
作者：
Guarino, Matteo;Perna, Benedetta;Cesaro, Alice Eleonora;Maritati, Martina;Spampinato, Michele Domenico;Contini, Carlo;De Giorgio, Roberto
通讯作者：
De Giorgio, Roberto
DOI：
10.1186/cc7157
发表时间：
2008
期刊：
Critical care (London, England)
影响因子：
--
作者：
Blanco J;Muriel-Bombín A;Sagredo V;Taboada F;Gandía F;Tamayo L;Collado J;García-Labattut A;Carriedo D;Valledor M;De Frutos M;López MJ;Caballero A;Guerra J;Alvarez B;Mayo A;Villar J;Grupo de Estudios y Análisis en Cuidados Intensivos
通讯作者：
Grupo de Estudios y Análisis en Cuidados Intensivos
DOI：
10.3390/medsci11020041
发表时间：
2023-06-12
期刊：
Medical sciences (Basel, Switzerland)
影响因子：
--
作者：
通讯作者：
--
影响因子：
32.4
作者：
Sheng, Jianpeng;Ruedl, Christiane;Karjalainen, Klaus
通讯作者：
Karjalainen, Klaus