Ischemia stroke is a highly disabling and fatal disease in China. Neuroinflammation is the predominant pathological change in ischemic stroke. Various immune cells such as microglia and T cells are involved in the process of brain tissue damage during ischemic stroke; they play different roles during the acute and chronic phases, the disruption of which may directly affect the functional prognosis of stroke in animals and humans. Therefore, a deep understanding regarding the bidirectional regulatory mechanisms of neuroinflammation is essential for developing novel therapeutic strategies. In this review, we aim to introduce the recent research progress on neuroinflammation in the pathogenesis of ischemic stroke, while elucidating the energy metabolism changed induced immunity cells activation in ischemic stroke including glycolysis, lactic acid and succinate. We also review the RNA modification on energy metabolism changed. The information in this review provides valuable insights for further transitional research on stroke.

Vascular smooth muscle cell (VSMC) phenotypic switching, followed by enhanced proliferation and migration, is a key event in the development of intimal hyperplasia in diverse vascular diseases. While tetraspanin 4 (TSPAN4) is known to be expressed in the vasculature, its function in VSMC phenotypic switching and vascular disease is currently unknown. Here, we investigated the role of TSPAN4 using an in vitro model of platelet-derived growth factor BB (PDGF-BB)-induced phenotypic switching and an in vivo carotid artery ligation model in wildtype and TSPAN4-deficient mice. Our experiments, including EdU assays, Transwell assays, western blot analysis, and immunoprecipitation, revealed that TSPAN4 expression is elevated in human atherosclerotic arteries, ligated mouse carotid arteries, and PDGF-BB-stimulated VSMCs. Additionally, TSPAN4 overexpression promoted the switch from a contractile to a synthetic phenotype, accompanied by enhanced VSMC proliferation and migration. Conversely, TSPAN4 knockdown inhibited these effects, suppressing PDGF-BB-induced phenotypic switching. Mechanistically, TSPAN4 was found to interact with and influence the expression and localization of tropomyosin-1 (TPM1). This, in turn, affected cytoskeletal organization, ultimately driving phenotypic switching and functional alterations in VSMCs. Finally, we demonstrated that TSPAN4 deficiency in mice attenuated vascular neointimal formation following carotid artery ligation. These findings suggested that TSPAN4 is a promising novel therapeutic target for vascular remodeling and proliferative vascular diseases.

Background: Angiogenesis is an important mechanism in stroke therapy. Circular RNA-DICAR is known to protect against diabetes-induced cardiomyocyte pyroptosis. In this study, we examined the effect of DICAR on angiogenesis as well as the therapeutic effect of DICAR-JP, which is its functional domain, against stroke. The mechanism involves the miR-361-5p/PRMT1 signaling pathway. Moreover, the middle cerebral artery occlusion/reperfusion (MCAO) method was used to establish a mouse stroke model in the DICAR-Tg mouse model. Methods: AAV9-DICAR-JP was constructed and injected into the cerebral ventricles. Furthermore, tube formation assays were used to evaluate the in vitro activity of DICAR-JP. The blood flow was tested by Laser Speckle Flowgraphy. The expressions of PRMT1 protein expression was evaluated by Western blotting (WB). The binding ability was evaluated by luciferase reporter. Results: Results indicated that DICAR-Tg improved neuronal function. AAV9-DICAR-JP increased blood flow in the brain following stroke. DICAR-siRNA upregulated miR-361-5p expression, and overexpression of miR-361-5p significantly reduced PRMT1 expression. Conclusion: DICAR/DICAR-JP has potential therapeutic benefits in stroke, which is mediated by the miR-361-5p/PRMT1 signaling pathway.

Background: DICAR plays a cardioprotection of diabetic models. DICAR-JP, a short sequence of DICAR, may represent DICAR’s active functional domain. NACα is necessary for the heart tissue development. Addtionally, OGDHL is a metabolism regulator. In this study, we examine a new mechanism of DICAR via NACα/OGDHL on regulating cardiomyocyte metabolism in DCM. We also sought to elucidate the function of DICAR/DICAR-JP in modulating NACα-dependent production of OGDHL nascent peptides and their mitochondrial translocation, and we also aimed to optimize the DICAR-JP sequence to be better therapy on DCM. Methods: SPR was to investigate the binding interaction between DICAR-JP and NACα. The function of DICAR-JP and DICAR-JP45 on OGDHL nascent peptide transfection was detected by in vitro translation approach. Biotin-DICAR-JP was transfected to study the function of DICAR-JP, NACα and OGDHL. Untargeted metabolomics was utilized to characterize the metabolic reprogramming of cardiomyocytes. AAV9-DICAR-JP and DICAR-JP45 were constructed and administered to db/db mice for 1-2 months to assess their cardioprotective effects detected by Echocardiography confirmed mouse cardiac function. Results: Our findings demonstrated that DICAR-JP be the functional domain that interacts with NACα to regulate OGDHL nascent peptide expression. Disruption of OGDHL expression reversed the metabolic reprogramming observed in diabetic cardiomyocytes, highlighting its crucial role in maintaining cardiac metabolic homeostasis. DICAR-JP facilitated the translocation of OGDHL nascent peptides from the cytoplasm to the mitochondria, leading us to hypothesize that DICAR-JP plays a key role in regulating ribosomal migration from the endoplasmic reticulum to the mitochondria. We refer to this process as the ‘Ribosome Migration’. In our studies using AAV9-mediated DICAR-JP and DICAR-JP45 overexpression in heart tissue. DICAR-JP and DICAR-JP45 both exhibited significant cardioprotective effects against diabetic cardiomyopathy (DCM), comparable to those observed with Empagliflozin. Conclusions: In a conclusion, we propose a new endogenous nucleic acid candidate drug library, and a new molecular framework, the ‘Ribosome Migration’, which implicates the DICAR-JP/NACα/OGDHL nascent peptide axis in metabolic reprogramming related to DCM. This theory constructs a new mitochondrion protein from nuclear original protein. Moreover, DICAR-JP45 shows strong potential as a nucleic acid-based therapeutic candidate for treating DCM. Novelty and Significance: What Is Known?: DICAR is a new protective circular noncoding RNA for diabetic cardiomyopathy. NACα is located in ribosome and regulates new peptide production, which is also a key factor in heart tissue development. OGDHL can regulate different energy metabolism in mitochondria. What New Information Does This Article Contribute?: DICAR-JP is the functional domain that interacts with NACα to regulate OGDHL nascent peptide expression. There is an interaction between DICAR-JP and NACα. DICAR-JP sequence is protected by NACα and NACα function is mediated by DICAR-JP. We called this ‘RNA functional domain’. OGDHL expression reversed the metabolic reprogramming observed in diabetic cardiomyocytes, highlighting its crucial role in maintaining cardiac metabolic homeostasis. DICAR-JP takes part in tanscription and translocation of OGDHL nascent peptides from the cytoplasm to the mitochondria via plasma ribosome. We call this process the ‘Ribosome Migration Theory’. DICAR-JP and DICAR-JP45 both exhibited significant cardioprotective effects against diabetic cardiomyopathy (DCM), comparable to those observed with Dapagliflozin (DAPA). Our study revealed a novel molecular framework, the ‘Ribosome Migration Theory’, which implicates the DICAR-JP/NACα/OGDHL nascent peptide axis in metabolic reprogramming related to DCM. Moreover, DICAR-JP45 shows strong potential as a nucleic acid-based therapeutic candidate for treating DCM.