Lipidomic analysis identifies long-chain acylcarnitine as a target for ischemic stroke.

INTRODUCTION: Lipid metabolism dysfunction is widely involved in the pathological process of acute ischemic stroke (AIS). The coordination of lipid metabolism between neurons and astrocytes is of great significance. However, the full scope of lipid dynamic changes and the function of key lipids during AIS remain unknown. Hence, identifying lipid alterations and characterizing their key roles in AIS is of great importance. METHODS: Untargeted and targeted lipidomic analyses were applied to profile lipid changes in the ischemic penumbra and peripheral blood of transient middle cerebral artery occlusion (tMCAO) mice as well as the peripheral blood of AIS patients. Infarct volume and neurological deficits were assessed after tMCAO. The cell viability and dendritic complexity of primary neurons were evaluated by CCK8 assay and Sholl analysis. Seahorse, MitoTracker Green, tetramethyl rhodamine methyl ester (TMRM), 2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA) and MitoSOX were used as markers of mitochondrial health. Fluorescent and isotopic free fatty acid (FFA) pulse-chase assays were used to track FFA flux in astrocytes. RESULTS: Long-chain acylcarnitines (LCACs) were the lipids with the most dramatic changes in the ischemic penumbra and peripheral blood of tMCAO mice. LCACs were significantly elevated on admission in AIS patients and associated with poor outcomes in AIS patients. Increasing LCACs through a bolus administration of palmitoylcarnitine amplified stroke injury, while decreasing LCACs by overexpressing carnitine palmitoyltransferase 2 (CPT2) ameliorated stroke injury. Palmitoylcarnitine aggravated astrocytic mitochondrial damage after OGD/R, while CPT2 overexpression in astrocytes ameliorated cocultured neuron viability. Further study revealed that astrocytes stimulated by OGD/R liberated FFAs from lipid droplets into mitochondria to form LCACs, resulting in mitochondrial damage and lowered astrocytic metabolic support and thereby aggravated neuronal damage. CONCLUSION: LCACs could accumulate and damage neurons by inducing astrocytic mitochondrial dysfunction in AIS. LCACs play a crucial role in the pathology of AIS and are novel promising diagnostic and prognostic biomarkers for AIS.

Resolvin D1 reprograms energy metabolism to promote microglia to phagocytize neutrophils after ischemic stroke.

Neutrophil aggregation and clearance are important factors affecting neuroinflammatory injury during acute ischemic stroke. Emerging evidence suggests that energy metabolism is essential for microglial functions, especially microglial phagocytosis, which determines the degree of brain injury. Here, we demonstrate that Resolvin D1 (RvD1), a lipid mediator derived from docosahexaenic acid (DHA), promotes the phagocytosis of neutrophils by microglia, thereby reducing neutrophil accumulation in the brain and alleviating neuroinflammation in the ischemic brain. Further studies reveal that RvD1 reprograms energy metabolism from glycolysis to oxidative phosphorylation (OXPHOS), providing sufficient energy for microglial phagocytosis. Moreover, RvD1 enhances microglial glutamine uptake and stimulates glutaminolysis to support OXPHOS to boost ATP production depending on adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) activation. Overall, our results reveal that RvD1 reprograms energy metabolism to promote the microglial phagocytosis of neutrophils after ischemic stroke. These findings may guide perspectives for stroke therapy from modulating microglial immunometabolism.

Oridonin prevents oxidative stress-induced endothelial injury via promoting Nrf-2 pathway in ischaemic stroke.

Oridonin, a natural diterpenoid compound extracted from a Chinese herb, has been proved to exert anti-oxidative stress effects in various disease models. The aim of the present study was to investigate the protective effects of oridonin on oxidative stress-induced endothelial injury in ischaemic stroke. We found oridonin repaired blood-brain barrier (BBB) integrity presented with upregulation of tight junction proteins (TJ proteins) expression, inhibited the infiltration of periphery inflammatory cells and neuroinflammation and thereby reduced infarct volume in ischaemic stroke mice. Furthermore, our results showed that oridonin could protect against oxidative stress-induced endothelial injury via promoting nuclear translocation of nuclear factor-erythroid 2 related factor 2 (Nrf-2). The specific mechanism could be the activation of AKT(Ser473)/GSK3ß(Ser9)/Fyn signalling pathway. Our findings revealed the therapeutic effect and mechanism of oridonin in ischaemic stroke, which provided fundamental evidence for developing the extracted compound of Chinese herbal medicine into an innovative drug for ischaemic stroke treatment.

TMEM100 mediates inflammatory cytokines secretion in hepatic stellate cells and its mechanism research.

Recent studies have shown that Transmembrane protein 100 (TMEM100) is a gene at locus 17q32 encoding a 134-amino acid protein with two hypothetical transmembrane domainsa, and first identified as a transcript from the mouse genome. As a downstream target gene of bone morphogenetic protein (BMP)-activin receptor-like kinase 1 (ALK1) signaling, it was activated to participate in inducing arterial endothelium differentiation, maintaining vascular integrity, promoting cell apoptosis, inhibiting metastasis and proliferation of cancer cells. However, evidence for the function of TMEM100 in inflammation is still limited. In this study, we explore the role of TMEM100 in inflammatory cytokine secretion and the role of MAPK signaling pathways in tumor necrosis factor-alpha (TNF-α)-induced TMEM100 expression in LX-2 cells. We found that the expression of TMEM100 was decreased markedly in human liver fibrosis tissues, and its expression was also inhibited in LX-2 cells induced by TNF-α, suggesting that it might be associated with the development of inflammation. Therefore, we demonstrated that overexpression of TMEM100 by transfecting pEGFP-C2-TMEM100 could lead to the down-regulation of IL-1ß and IL-6 secretion. Moreover, we found that expression changes of TMEM100 could be involved in inhibition or activation of MAPK signaling pathways accompanied with regulating phosphorylation levels of ERK and JNK protein in response to TNF-α. These results suggested that TMEM100 might play an important role in the secretion of inflammatory cytokines (IL-1ß and IL-6) of LX-2 cells induced by TNF-α, and MAPK (ERK and JNK) signaling pathways might participate in its induction of expression.

Pathological bases and clinical impact of long noncoding RNAs in prostate cancer: a new budding star.

Long non-coding RNAs (lncRNAs) are functional RNAs longer than 200 nucleotides. Recent advances in the non-protein coding part of human genome analysis have discovered extensive transcription of large RNA transcripts that lack coding protein function, termed non-coding RNA (ncRNA). It is becoming evident that lncRNAs may be an important class of pervasive genes involved in carcinogenesis and metastasis. However, the biological and molecular mechanisms of lncRNAs in diverse diseases are not yet fully understood. Thus, it is anticipated that more efforts should be made to clarify the lncRNA world. Moreover, accumulating evidence has demonstrated that many lncRNAs are dysregulated in prostate cancer (PC) and closely related to tumorigenesis, metastasis, and prognosis or diagnosis. In this review, we will briefly outline the regulation and functional role of lncRNAs in PC. Finally, we discussed the potential of lncRNAs as prospective novel targets in PC treatment and biomarkers for PC diagnosis.