Resolvin D1 ameliorates cognitive impairment following traumatic brain injury via protecting astrocytic mitochondria.

Cognitive impairment is one of the most common and devastating neuropsychiatric sequelae after traumatic brain injury (TBI), and hippocampal neuronal survival plays a causal role in this pathological process. Resolvin D1 (RvD1), an important endogenous specialized pro-resolving mediator, has recently been reported to exert a potent protective effect on mitochondria. This suggests that RvD1 may suppress neuroinflammation and protect astrocytic mitochondria at the same time to play further neuroprotective roles. C57BL/6 mice subjected to TBI using a controlled cortical impact device were used for in vivo experiments. Cultured primary mouse astrocytes and an N2a mouse neuroblastoma cell line were used for in vitro experiments. In TBI mice, RvD1 significantly ameliorated cognitive impairment, suppressed gliosis and alleviated neuronal loss in the hippocampus. To explore the mechanism underlying this activity, we verified that RvD1 can induce a higher level of mitophagy to remove damaged mitochondria and eliminate extra mitochondria-derived reactive oxygen species (mitoROS) by activating ALX4/FPR2 receptors in astrocytes. In an in vitro model, we further confirmed that RvD1 can protect mitochondrial morphology and membrane potential in astrocytes and thereby enhance the survival of neurons. Meanwhile, RvD1 was also shown to increase the expression of brain-derived neurotrophic factor and glutamate aspartate transporter in the hippocampus following TBI, which indicates a possible way by which RvD1 increases the supportive function of astrocytes. These findings suggest that RvD1 may be a potent therapeutic option for ameliorating cognitive impairment following TBI by controlling neuroinflammation and protecting astrocytic mitochondria.

Tetramerization of PKM2 Alleviates Traumatic Brain Injury by Ameliorating Mitochondrial Damage in Microglia.

Traumatic brain injury (TBI) is a leading cause of death and disability worldwide. Microglial activation and neuroinflammation are key cellular events that determine the outcome of TBI, especially neuronal and cognitive function. Studies have suggested that the metabolic characteristics of microglia dictate their inflammatory response. The pyruvate kinase isoform M2 (PKM2), a key glycolytic enzyme, is involved in the regulation of various cellular metabolic processes, including mitochondrial metabolism. This suggests that PKM2 may also participate in the regulation of microglial activation during TBI. Therefore, the present study aimed to evaluate the role of PKM2 in regulating microglial activation and neuroinflammation and its effects on cognitive function following TBI. A controlled cortical impact (CCI) mouse model and inflammation-induced primary mouse microglial cells in vitro were used to investigate the potential effects of PKM2 inhibition and regulation. PKM2 was significantly increased during the acute and subacute phases of TBI and was predominantly detected in microglia rather than in neurons. Our results demonstrate that shikonin and TEPP-46 can inhibit microglial inflammation, improving mitochondria, improving mouse behavior, reducing brain defect volume, and alleviating pathological changes after TBI. There is a difference in the intervention of shikonin and TEPP-46 on PKM2. Shikonin directly inhibits General PKM2; TEPP-46 can promote the expression of PKM2 tetramer. In vitro experiments, TEPP-46 can promote the expression of PKM2 tetramer, enhance the interaction between PKM2 and MFN2, improve mitochondria, alleviate neuroinflammation. General inhibition and tetramerization activation of PKM2 attenuated cognitive function caused by TBI, whereas PKM2 tetramerization exhibited a better treatment effect. Our experiments demonstrated the non-metabolic role of PKM2 in the regulation of microglial activation following TBI. Both shikonin and TEPP-46 can inhibit pro-inflammatory factors, but only TEPP-46 can promote PKM2 tetramerization and upregulate the release of anti-inflammatory factors from microglia.

The outcomes of intra-aortic balloon pump usage in patients with acute myocardial infarction: a comprehensive meta-analysis of 33 clinical trials and 18,889 patients.

BACKGROUND: The effects of intra-aortic balloon pump (IABP) usage in patients with acute myocardial infarction remain controversial. This study sought to evaluate the outcomes of IABP usage in these patients. METHODS: Medline, EMBASE, and other internet sources were searched for relevant clinical trials. The primary efficacy endpoints (in-hospital, midterm, and long-term mortality) and secondary endpoints (reinfarction, recurrent ischemia, and new heart failure in the hospital) as well as safety endpoints (severe bleeding requiring blood transfusion and stroke in-hospital) were subsequently analyzed. RESULTS: Thirty-three clinical trials involving 18,889 patients were identified. The risk of long-term mortality in patients suffering from acute myocardial infarction was significantly decreased following IABP use (odds ratio [OR] 0.66, 95% confidence interval [CI]: 0.48-0.91, P=0.010). Both in-hospital and midterm mortality did not differ significantly between the IABP use group and no IABP use group (in-hospital: OR 0.87, 95% CI: 0.59-1.28, P=0.479; midterm: OR 1.12, 95% CI: 0.53-2.38, P=0.768). IABP insertion was not associated with the risk reduction of reinfarction, recurrent ischemia, or new heart failure. However, IABP use increased the risk of severe bleeding requiring blood transfusion (OR 2.05, 95% CI: 1.29-3.25, P=0.002) and stroke (OR 1.71, 95% CI: 1.04-2.82, P=0.035). In the thrombolytic therapy and cardiogenic shock subgroups, reduced mortality rates following IABP use were observed. CONCLUSION: IABP insertion is associated with feasible benefits with respect to long-term survival rates in patients suffering from acute myocardial infarction, particularly those suffering from cardiogenic shock and receiving thrombolytic therapy, but at the cost of higher incidence of severe bleeding and stroke.