AKG Attenuates Cerebral Ischemia-Reperfusion Injury through c-Fos/IL-10/Stat3 Signaling Pathway

Abstract

Inflammation is dominant in the pathogenesis of ischemic stroke (IS). Alpha-ketoglutarate (AKG), according to previous studies, has demonstrated a variety of pharmacological effects such as antioxidation and inhibitive inflammation activities. However, whether AKG ameliorates cerebral ischemic injury, as well as the underlying molecular events, is still unclear. Therefore, the effect and underlying mechanisms of AKG on ischemic brain injury should be identified. The study established a cerebral ischemia-reperfusion (I/R) model in mice as well as an oxygen-glucose deprivation/reperfusion (OGD/R) model in SH-SY5Y cells, respectively. It was observed that AKG markedly suppressed infarction volume and neuronal injuries and improved the neurological score in vivo. Moreover, AKG reduced the inflammatory response and lowered the expression of proinflammatory cytokines. In vitro, AKG treatment strongly inhibited OGD/R-induced neuronal injury and the proinflammatory factors. It was also found that the increased SOD and GSH levels, as well as the lower ROS levels, showed that AKG reduced oxidative stress in OGD/R-treated SY-SY5Y cells. Mechanistically, AKG largely promoted IL-10 expression in ischemic brain injury and OGD/R-induced neuronal injury. Furthermore, IL-10 silencing neutralized the protective effect of AKG on inflammation. Notably, it was discovered that AKG could upregulate IL-10 expression by promoting the translocation of c-Fos from the cytoplasm to the nucleus. The results indicated that AKG demonstrated neuroprotection on cerebral ischemia while inhibiting inflammation through c-Fos/IL-10/stat3 pathway.

WITHDRAWN: Exploring Pathogenesis and Biomarkers Through Establishment of a Rat Model of Male Infertility with Liver Depression and Kidney Deficiency

“…When an excessive accumulation of ROS occurs in the body, it can lead to oxidative damage to sperm, potentially resulting in conditions like oligozoospermia or even azoospermia [30] . Key antioxidants, including SOD and GSH-Px, play essential roles in safeguarding cells against oxidative stress [31] . MDA is a product of lipid peroxidation triggered by ROS, and its content serves as an indicator of the extent of oxidative damage to cell membranes [32] .…”

Exploring pathogenesis and biomarkers through establishment of a rat model of male infertility with liver depression and kidney deficiency

“…When an excessive accumulation of ROS occurs in the body, it can lead to oxidative damage to sperm, potentially resulting in conditions like oligozoospermia or even azoospermia [ 45 ]. Key antioxidants, including SOD and GSH-Px, play essential roles in safeguarding cells against oxidative stress [ 46 ]. MDA is a product of lipid peroxidation triggered by ROS, and its content serves as an indicator of the extent of oxidative damage to cell membranes [ 47 ].…”

Identification of hypoxia- and immune-related biomarkers in patients with ischemic stroke

“…Some studies have shown that activation of the STAT3 pathway after cerebral ischemia can change the microglial phenotype from pro-inflammatory to anti-inflammatory, partially improving brain injury [ 44 , 45 ]. Huang et al have demonstrated that the FOS/IL-10/STAT3 pathway can play a neuroprotective role in cerebral ischemia [ 46 ]. Additionally, as previously reported, the activated STAT3/NFIL3 pathway and STAT3–NFkB/DDIT3/CEBPβ axis play regulatory roles in chemotherapy resistance [ 47 , 48 ], and lipopolysaccharide can induce the expression of DUSP1 and regulate macrophages through MAPK-STAT3 axis [ 49 ].…”