Abstract
Ischemic stroke is one of major causes of disability. In the pathological process of ischemic stroke, the up-regulation of Ras homolog gene family, member A (RhoA) and its downstream effector, Ras homolog gene family (Rho)-associated coiled coil-containing kinase (ROCK), contribute to the neuroinflammation, blood-brain barrier (BBB) dysfunction, neuronal apoptosis, axon growth inhibition and astrogliosis. Accumulating evidences have revealed that hydrogen sulphide (H2S) could reduce brain injury in animal model of ischemic stroke via inhibiting the RhoA/ROCK pathway. Recently, noncoding RNAs (ncRNAs) such as circular RNAs (circRNAs), long noncoding RNAs (lncRNAs) and microRNAs (miRNAs) have attracted much attention because of their essential role in adjusting gene expression both in physiological and pathological conditions. Numerous studies have uncovered the role of RhoA/ROCK pathway and ncRNAs in ischemic stroke. In this review, we focused on the role of H2S, RhoA/ROCK pathway and ncRNAs in ischemic stroke and aimed to reveal new strategies for preventing and treating this devastating disease.
Similar content being viewed by others
Avoid common mistakes on your manuscript.
Introduction
Hydrogen sulphide (H2S) is the third gaseous molecule, along with carbon monoxide (CO) and nitric oxide (NO) (Wu et al. 2015). Endogenous H2S is one of widely distributed gaseous neurotransmitters and mainly synthesized by cystathionine-β-synthase (CBS), cystathionine-γ lyase (CSE) and 3-mercaptopyruvate (3-MST) (Wen et al. 2019). Numerous studies have revealed that H2S mediates the variously biological effects in different ways such as inducing long-term potentiation (LTP), maintaining calcium homeostasis, inhibiting oxidative stress and regulating the neural signals under physiological condition (Kimura 2013). In addition to its biological effects, H2S also increases intracellular calcium concentration and promotes the cyclic adenosine monophosphate (cAMP) production, as well as activates ATP-dependent potassium channels (Zhang and Bian 2014). Besides, H2S is also related to the pathological process of the central diseases such as stroke, subarachnoid hemorrhage (SAH) and Alzheimer’s disease, etc. (Gong et al. 2011).We have revealed that endogenous H2S protects against the cerebral ischemia/reperfusion (I/R) injury via inhibiting RhoA/ROCK pathway (Wen et al. 2018, 2019).
Non-coding RNAs (ncRNAs) make up about 98–99% of RNAs generated from all mammalian genomes (Arraiano 2021). Although ncRNAs do not have the potential to be translated to proteins, they could function as vital regulatory molecules via actively interacting with nucleic acids or other molecules on almost all cellular processes in normal development and the pathological process of various diseases, containing ischemic stroke (Al Mamun et al. 2020). In addition, one ncRNA can directly interact with one or more target molecules within variously cellular signalling pathways such as RhoA/ROCK pathway, which make the regulation network mediated by ncRNAs be even more complicated (Sun et al. 2022). This review outlines the role of H2S, Rho/ROCK pathway and ncRNAs in ischemic stroke, which has been reported recently.
H2S-mediated anti-neuroinflammation via inhibiting the RhoA/ROCK pathway in ischemic stroke
Until now, mechanical thrombectomy and intravenous thrombolysis have been widely used to treat ischemic stroke. Nevertheless, such treatments are often limited due to potential bleeding risks, narrow time window and limited eligibility criteria (Collaborators 2017). Hence, new treatment for stroke is urgently needed. The pathological process of cerebral ischemic injury includes inflammatory response, excitatory amino acid toxicity, oxidative stress, peroxidation, brain edema, free radical production, neuronal apoptosis and death (Zhu et al. 2015). Among all the damage elements, neuroinflammation is receiving increasing attention. Although inflammation and immune responses following cerebral ischemic insult contribute to isolating the injured region, an exaggerated inflammatory response could aggravate the ischemic injury (Magnus et al. 2012). Lively S et al. have found that inflammation and immune responses are crucial factors involved in the onset and progression of ischemic stroke (Lively et al. 2016).
H2S inhibits the neuroinflammation
As one of neuromodulatory and neuroprotective molecules, H2S can freely cross the cell membrane, thereby regulates various intracellular signaling processes in vivo (Zhang and Bian 2014), for instance, H2S acts as an endogenous neuromodulator modulating Ca2+ levels in astrocytes, neurons, and microglia (Donertas Ayaz and Zubcevic 2020). Besides, CBS-produced H2S has inhibitory effects on glia-mediated neuroinflammation, thereby exerts neuroprotective effect against cerebral ischemia injury (Zhang et al. 2017). Furthermore, beneficial effects of exogenous H2S donors on glia-mediated neuroinflammation have also been found in various neurodegenerative conditions (Lee et al. 2016). In our previous study, we have found that supplement with H2S could inhibit the cerebral I/R-induced release of inflammatory factors such as IL-6 and TNF-α (Ding et al. 2022).
H2S-mediated anti-neuroinflammation via inhibiting RhoA/ROCK pathway
RhoA/ROCK pathway, widely expressed in neurons and astrocytes, is involved in the pathological process of ischemic stroke (Lu et al. 2021). Rho is active when bound to GTP while becoming inactive when bound to GDP based on the guanine exchange factors. Activated Rho-GTP activates its downstream effector, ROCK, which includes ROCK1 and ROCK2 isoforms and belongs to a serine/threonine kinases family. ROCK1 transcript is prominently expressed in non-neuronal tissues, while ROCK2 is present more abundantly in the brain and skeletal muscles (Lu et al. 2021). Besides, ROCK1 and ROCK2 can be respectively activated by caspase-3 and granzyme B via the cleavage of inhibitory C-terminal domain (Sladojevic et al. 2017).
Activated ROCK then phosphorylates its downstream effectors, including ezrin/radixin/moesin (ERM), myosin light chain (MLC), adducin, LIM kinase, collapsin response mediator protein 2 (CRMP2), and so on. As a consequence, ROCK regulates cytoskeletal rearrangement via affecting stress fiber formation, focal adhesion, smooth muscle contraction, growth cone collapse, actin filament stabilization, and actin network assembly (Amano et al. 2010). Furthermore, inhibition of ROCK could obviously lower the stress fiber formation and reduce the focal adhesion in astrocytes induced by Thy-1 (CD90), a glycosylphosphatidylinositol-anchored protein. These findings indicated the importance of the Rho/ROCK pathway in the process of neuron-glia communication (Avalos et al. 2004).
In addition, stroke-induced ROCK activation contributes to the deterioration of brain injury in the acute phase via stimulating neuronal inflammation (Laufs and Liao 1998). Inhibition of ROCK activity could mitigate the neutrophil accumulation in the ischemic area and decrease the ischemic-induced infarct volume (Satoh et al. 1999, 2001). Moreover, ROCK activation in the resident macrophages and microglias leads to the secretion of pro-inflammatory cytokine (Jin et al. 2010). ROCK inhibitor Fasudil has been found to reduce hippocampal injury by suppressing pro-inflammatory cytokine secretion from the microglial cells (Ding et al. 2010). In our previous study, we have found that CSE-derived H2S promotes neural functional recovery after cerebral I/R injury in mice via inhibiting the RhoA/ROCK pathway (Zhang et al. 2021). Combined with the above description, we conclude that H2S-mediated inhibition of the neuroinflammation following cerebral I/R is via inhibiting the RhoA/ROCK pathway (Fig. 1).
Relationship between RhoA/ROCK pathway and H2S in ischemic stroke
ROCK: Rho kinase
H2S-mediated anti-neuroinflammation and astrocytes
Astrocytes, abundant glial cells in central nervous system (CNS), have emerged as vital regulators in health such as keeping the ionic homeostasis, as well as controlling normal neurotransmission, neurotransmitter reuptake and recycling (Abeysinghe et al. 2016). Interaction between astrocytes and endothelial cells in neurovascular unit (NVU) is crucial to adjusting BBB under both normal and pathological conditions (Abbott et al. 2006). Astrocytes could connect with neurons and blood vessels through astrocytic endfeet. During the pathological process of ischemic stroke, astrocytes play multifaceted roles in the context of CNS inflammation induced by cerebral ischemia (Linnerbauer et al. 2020).
Immediately after cerebral ischemia, activation of astrocytes will happen for the oxidative stress. The activated astrocytes release excessive amounts of proinflammatory mediators, such as TNF-α, IL-6 and IL-1β, which are directly deleterious to neighboring neurons (Liu et al. 2020b; Wang et al. 2017). With the further research on distinct roles of astrocyte on neuronal injury, two distinct subtypes of reactive astrocytes, named as “A1” and “A2”, have been termed by Liddelow et al. (Liddelow et al. 2017), which is widely accepted by increasing researches (Escartin et al. 2021). Ischemia and neuroinflammatory stimuli respectively induce the formation of A2 and A1 reactive astrocytes. A1 reactive astrocytes were induced by C1q, IL-1α and TNF-α secreted by activated microglia during neuroinflammation after ischemic stroke, and contribute to the death of neurons and oligodendrocytes. By contrast, the formation of A2 reactive astrocytes was induced by cerebral ischemia and A2 astrocytes were postulated as neuroprotective subtype via up-regulating neurotrophic factors (Liddelow et al. 2017). Besides, A2 astrocytes were found to promote the expression of anti-inflammatory cytokine transforming growth factor β (Wang et al. 2021c). Furthermore, A2 astrocytes obtain the capacity to phagocytize and clear myelin debris following cerebral ischemia, the accumulating myelin debris can exacerbate the inflammatory response (Jiang et al. 2021b). Therefore, promoting the formation of A2 astrocytes is a potential therapeutic strategy for inhibition of neuroinflammation and promotion of neuronal recovery after ischemic stroke (Guo et al. 2021).
Ischemic injury could induce the morphological change of astrocytes via activation of RhoA/ROCK pathway, which is complied with the retractation of astrocytic endfeet, thereby leading to the breakdown of neurovascular coupling, as well as formation of reactive astrogliosis (Abeysinghe et al. 2016; LeComte et al. 2015). We previously have found that H2S could not only restrain the proliferation of reactive astrocytes induced by cerebral I/R but also promote the transformation of reactive astrocytes from A1 type to A2 type in mice hippocampal tissues (Ding et al. 2022). In addition, we have revealed that H2S-mediated transformation of astrocytes from “A1” to “A2” is related to inhibition of RhoA/ROCK pathway (Fig. 1).
The relationship between H2S-mediated inhibition of RhoA/ROCK pathway and ncRNAs in ischemic stroke
What is ncRNA and its contribution to ischemic stroke
Noncoding RNAs (ncRNAs) constitute the majority of the human transcribed genome, they initially were considered as junk. NcRNAs started to gain more and more attention for they were considered as key regulatory factors in cellular and biological processes, ranging from gene expression to genome remodeling in the early 21st century (Jae and Dimmeler 2020). Besides, the ncRNAs have been recognized as important contributors to both disorder and cellular homeostasis in CNS (Deng et al. 2022; Zhang et al. 2022). The group of ncRNAs contain microRNA (miRNA), circular RNA (circRNA), long noncoding RNA (lncRNA), and so on (DeOcesano-Pereira et al. 2020).
MiRNA
MiRNAs, consisting of 20–22 nucleotides, adjust gene expression via interacting with the 30-untranslated region (UTR) of the target mRNAs (Mirzaei et al. 2018). Primary RNA (pri-RNA) of miRNA, transcribed from genomic DNA, contains at least one hairpin loop and some long loops with several thousand base pairs. This hairpin loop of pri-RNA is cleaved by the endonuclease Drosha to generate precursor miRNA (pre-miRNA) (Basyuk et al. 2003; Han et al. 2004; Lee et al. 2002), which is transported by the intervention of exportin-5 from the nucleus to the cytoplasm. In the cytoplasm, pre-miRNAs are cleaved to form a duplex of mature miRNA strands (Chendrimada et al. 2005; Hutvagner et al. 2001; Lau et al. 2001). Mature miRNAs control various cellular functions such as neuronal development, proliferation, metabolism and differentiation, and synaptic plasticity (Bartel 2004). Previous studies have shown that miRNAs participated in pathological process of stroke via affecting the neuroinflammation, apoptosis, oxidative stress and vascular endothelial damage (Bam et al. 2018; Khoshnam et al. 2017).
MiRNAs mediate post-transcriptional gene regulation by controlling the mRNA translation into protein (O’Brien et al. 2018), thereby involve in multiple cellular functions such as injured tissue repair, neuronal development, remodeling different neuronal activities in ischemic stroke (Khoshnam et al. 2017). MiRNAs and their target genes exert a key inhibitory effect on the cerebral I/R-induced neuroinflammation, which make miRNAs as potential therapeutic targets in ischemic stroke (Khoshnam et al. 2017). Lots of miRNAs participate in controlling target genes expression of ischemic stroke risk factors. For instance, single nucleotide polymorphisms (SNPs) within the binding site of miRNA could affect miRNA-induced genetic repression, which is called miR-SNP. Mu-En Liu et al. have found that miR-SNP rs3735590 at the paraoxonase 1 (PON1) gene is associated with an elevated risk for ischemic stroke because it could affect genetic expression (Liu et al. 2013).
Afterwards, increasing circulatory miRNAs such as PC-3p-57,664, miR-211-5p, PC-5p-12,969 and miR-122-5p were successively identified as biomarkers for early diagnosis of ischemic stroke because of their up-regulation in human ischemic stroke serum samples (Vijayan et al. 2018). Furthermore, accumulated researches have revealed that miRNAs are related to neurogenesis, angiogenesis and neuroprotection after ischemic stroke (Bulygin et al. 2020). Therefore, miRNAs have recently been used as potential biomarkers for early diagnosis and prognosis, and used as a therapeutic target for ischemic stroke.
Circular RNAs
CircRNAs, containing multiple exons or a single exon, are mainly expressed from known protein coding genes, and generally locate in the cytoplasm (Memczak et al. 2013). Despite the generally lower expression than their linear counterparts, many circRNAs are the predominant transcripts. Besides, competition between back splicing and canonical splicing is likelihood to exist for the majority of loci that produce circRNAs (Hansen et al. 2013). It is well known that circRNAs are enriched in the nervous system, and affect neuronal migration and axon growth (Ostolaza et al. 2020). Besides, circRNAs interact with human RNA binding proteins and take part in neuronal development under physiological status and participate in the pathogenesis of neurological diseases. CircRNAs protect the dysfunction of BBB, and inhibit the neuroinflammation and apoptosis following cerebrovascular diseases (Wang et al. 2020c). Thus, circRNAs are gaining interest as a possible biomarker for their several functions in the onset and progression of ischemic stroke. Therefore, understanding the role of circRNAs on the ischemic stroke process will provide us new biomarkers for the diagnosis and prognosis of ischemic stroke.
CircRNAs were initially known as viroids in 1976. Subsequently, circRNAs were detected in many species such as unicellular prokaryotes, eukaryotes and mammals (Huang et al. 2020). Further researches have revealed that circRNAs could act as protein scaffolds or miRNA sponges and could be translated into polypeptides (Wang et al. 2018b). Notably, circRNAs are revealed to adjust the target genes expression at the post-transcriptional level through antagonizing the activity of miRNA through a sponge-like mechanism (Granados-Riveron and Aquino-Jarquin 2016). CircRNAs could act as competitive endogenous RNAs (ceRNAs), which contains harbors miRNA response elements (MREs) and can compete for miRNA binding.
Moreover, circRNAs have the same selective transcribed sequences which can capture the corresponding linear mRNAs and may exert specific roles via influencing the combination of other RNAs. CircRNAs affect the miRNA expression through micro-adjustment, for example, circRNAs perturb miRNA function via competing with miRNA combination, and then, blocking the posttranslational repression of target-coding RNA species and adjusting the expression levels of target genes (Rybak-Wolf et al. 2015). The combination ability of circRNAs with miRNAs is 10 times higher than other known transcriptions (Chen et al. 2015). Furthermore, circRNAs serve as a natural miRNA sponges those bind with corresponding miRNAs and then restrain the activity of them, thus regulating target genes (Shao and Chen 2016).
LncRNAs
LncRNAs, comprising more than 200 nucleotides, regulate gene expression via various mechanisms (Mercer et al. 2009) at transcriptional, epigenetic, post-transcriptional and chromatin remodeling levels (Bali and Kuner 2014). LncRNAs can activate or inhibit target genes expression by directly binding to the recruiting transcription factors or the target genes (Li et al. 2018b). LncRNAs exert the spatiotemporal regulation for cell type-specific genes expression and physiological functions via regulating the transcription at multiple levels (Li et al. 2022b). Thus, not surprisingly, lncRNAs have been shown to adjust the neural differentiation and specification, and maintain the cell identity. Furthermore, dysregulation of lncRNA function has been found to be involved in multiple neurological diseases such as ischemic stroke (Bao et al. 2018).
LncRNAs are associated with inflammation, cell apoptosis, angiogenesis and cell death in ischemic stroke (Wang et al. 2020a, b; Xiang et al. 2020; Zhang and Zhang 2020). Thus, lncRNAs are emerging as a new therapeutic target of ischemic stroke (Bao et al. 2018). X-inactive specific transcript (XIST) RNA is one of lncRNAs, which regulates X chromosome inactivation in mammals (Chen et al. 2017). During the late stage after the onset of ischemic stroke, LncRNA XIST exhibits increased expression, and the lncRNA XIST level in sera of ischemic stroke patients was obviously negatively correlated with the severity of neurological impairments. Therefore, lncRNA XIST has been regarded as a therapeutic target for stroke patients and been considered as a potential biomarker for the prognosis of ischemic stroke (Wang et al. 2021a). Silencing lncRNA XIST markedly impairs the angiogenesis and exacerbates cerebral vascular injury (Wang et al. 2021a).
What’s the relationship between H2S-mediated inhibition of RhoA/ROCK pathway and ncRNAs
MiRNA
Endogenous H2S mediates biological effects in a variety of ways in plenty of disease models. Controlling H2S content exerts a protective role on the cerebral ischemia, making it becomes a therapeutic candidate for cerebrovascular diseases. In CNS of mammals, H2S is mainly produced by CBS (Renga 2011), which is expressed in radial glial/astrocyte cell lines. The up-regulation of CBS expression in active astrocytes promotes the recovery of injured neurons, suggesting that CBS-produced H2S, mainly from astrocytes, plays important roles in a variety neuronal damages induce by I/R and oxidative stress (Campagnoli et al. 1971; Kimura et al. 2010). At present, accumulating literature reports have revealed a close relationship between miRNA and H2S, uncovered that H2S is involved in different pathophysiological processes via up-regulating the expression of miRNAs such as miR-393, miR-396 and miR-398 (Liu et al. 2011). Using miScript microRNA (miRNA) polymerase chain reaction array-based screening, Jyotirmaya et al. have identified miR‐218 as a particular miRNA, and found that H2S could up-regulate the expression of miR‐218 and then protect endothelial cells against ethanol‐induced permeability (Behera et al. 2021).
Despite the diverse target genes of miRNAs associated with ischemic stroke, RhoA/ROCK pathway related with miRNAs was only wildly reported in ischemic stroke in recent years (Kimura et al. 2021). Jiang et al. have revealed that RhoA was a direct target of miR-190 by using cerebral I/R model and found that the overexpression of miR-190 ameliorates the brain damage and apoptosis via down-regulation of RhoA/ROCK pathway (Jiang et al. 2021a). Using model of traumatic brain injury, Lilja Meissner have found that MiR-190 is down-regulated after cerebral injury (Meissner et al. 2016). Besides, RhoA/ROCK pathway is up-regulated in mice brain tissues after cerebral I/R (Ding et al. 2022). These findings confirmed that MiR-190 may be used as a biomarker for diagnosis of cerebral injury and a therapeutic target of ischemic stroke.
Along with decreased miR-431 expression, Han et al. have observed a significant increment of RhoA expression in rat middle cerebral artery occlusion
(MCAO)/R model, suggesting that RhoA was the potential target gene of miR-431. They revealed the neuroprotective effects of miR-431 and concluded that miR-431 inhibited apoptosis and promoted proliferation by negatively regulating the RhoA/ROCK pathway (Han et al. 2018). The relationship between anti-apoptotic effect of miR-335 and the RhoA/ROCK pathway has been revealed by Si et al. They have found that miR-335 promotes the formation of stress granules (SGs) by inhibiting the ROCK2 expression (Si et al. 2019). SGs generates in the cytoplasm when eukaryotic cells suffer from stress such as heat shock, acute energy starvation and endoplasmic reticulum stress (Gutierrez-Beltran et al. 2015). The formation of SGs protects the mRNA and proteins against misfolding and degradation, which enhances cellular resistance to apoptosis (Sampuda et al. 2017). Stein ES et al. have found that miR-582-5p expression decreases after cerebral I/R, while the expression of RhoA and ROCK2 increases. The over-expression of miR-582 alleviates the neuronal apoptosis via inhibiting the up-regulation of RhoA/ROCK pathway (Olson et al. 2004; Stein et al. 2015).
MiR-135, one of miRNAs, has been shown to be involved in regulation of cell regeneration and differentiation (Xie et al. 2016). Liu et al have found that miR-135a-5p is involved in the regulation of ROCK2 expression by targeting the 3’-UTR of ROCK2 mRNA to inhibit its protein translation in a mouse model for Parkinson’s disease (Liu et al. 2016). They have revealed that H2S could inhibit the up-regulation of ROCK2 expression in brain tissues but not affect the mRNA of ROCK2. Furthermore, the research demonstrated that miR-135a-5p mediated the inhibitory effect of H2S on ROCK2 expression. In a word, some miRNAs could inhibit the up-regulation of RhoA/ROCK pathway after ischemic stroke (Fig. 2). Combined with the previous description that H2S could up-regulate the expression of miRNAs such as miR-393, miR-396 and miR-398 [56], we speculate that H2S-mediated inhibition of RhoA/ROCK pathway maybe related to up-regulation of miRNAs expression, which needs further exploration.
Relationship between RhoA/ROCK pathway and miRNA in ischemic stroke
Circular RNAs
As aforementioned, circRNAs are shown to play a key role in regulating genes expression through the circRNA-miRNA-mRNA pathway via acting as miRNA sponges (Liu et al. 2017). Zhao et al. have found that circRNAs play a vital role in cerebral ischemia. They have revealed that knockdown of circRNA_0072309 can accelerate the cell apoptosis following ischemic stroke and demonstrated that the role of circRNA is via sponge miR-100 (Zhao et al. 2020). Silencing circRNA cZNF292 alleviates oxygen-glucose deprivation/reperfusion (OGD/R)-induced injury of rat neural stem cells by upregulating miR-22 (Cao et al. 2020). Furthermore, Circ_002664 has been found to participate in neuronal apoptosis following OGD/R via directly targeting miR-182–5p/Herpud1 pathway (Liu et al. 2020a). All of these studies illustrated the relationship between miRNA and circRNAs (Fig. 3).
Relationship between circRNA pathway and miRNA in ischemic stroke
Relationship among lncRNA, miRNA and RhoA/ROCK pathway in ischemic stroke
Although there is no finding about the relationship between circRNA and RhoA/ROCK pathway in the ischemic stroke, circNRIP1, one of circRNAs, has been demonstrated to enhance ROCK1 expression in gastric cancer cells, thereby promoting carcinogenesis. Overexpression of miR‑182 could significantly inhibit the luciferase activity of ROCK1‑expressing MGC‑803 in AGS cancer cells (Liang and Li 2020). ROCK1 has been founded to be upregulated in miR‑584‑3p inhibitor‑transfected SCLC cells. FLI1 exonic circRNA (FECR) silencing results in a reduction of ROCK in small cell lung cancer cells (Li et al. 2019). In addition, the researchers have found that FECR reduces the inhibitory effects of miR‑584‑3p on ROCK1 expression by sponging the miRNA away from its target (Li et al. 2019). Furthermore, in melanoma cells, ROCK1 was directly targeted by miR‑431‑5p. Circ0001591 could antagonize the miR‑431‑5p‑mediated targeting of ROCK1 (Yin et al. 2021). Circ_101141, an oncogenic circRNA has been found to block miR‑1297‑mediated inhibition of ROCK1 expression (Zhang et al. 2020).
LncRNAs
Previous studies have revealed that lncRNAs interact functionally with various miRNA molecules via competitively binding with miRNAs, thereby resulting in miRNA degradation (Siddeek et al. 2014). This interaction has been found in ischemic stroke (Yan et al. 2017). Among the predicted potential XIST targeting miRNAs, Liu et al. have found that XIST directly interacts with miR-362-5p on breast cancer cell malignant behaviors, they have revealed that miR-362-5p mediates the regulatory effects of XIST overexpression (Liu et al. 2021). MiR-362 acts as a target of lncRNAs in regulation of the development of tumors (Wei et al. 2020). However, the studies on the functional role of miR-362 in ischemic stroke are still rarely.
In the acute phase of stroke, ROCK activation leads to the deterioration of cerebral injury by stimulating neuroinflammation (Laufs and Liao 1998). Inhibition of ROCK reduces neutrophil accumulation in the ischemic region and lessened the infarct volume (Satoh et al. 2001). Wang et al. have found that ROCK2 is the candidate target of miR-362 using the TargetScan database. Using the cerebral I/R model, Wang et al. have revealed the relationship among XIST, miR-362, and ROCK2. They found that knockdown of miR-362 or over-expression of ROCK2 attenuates the effect of XIST down-regulation on OGD/R-induced neuronal impairment and inflammation injury. These findings revealed that knockdown of XIST ameliorates the ischemic stroke injury through regulation of miR-362/ROCK2 axis (Wang et al. 2021b). Using bioinformatic software combined with sequence complementation analysis, Zeng et al. have demonstrated that miR-148a-3p is an inhibitory target of lncRNA-H19. They found that miR-148a-3p is a located downstream of lncRNA-H19 that regulates cerebral ischemic processes. Besides, the researchers have revealed that miR-148a-3p directly targets the 3′UTR of ROCK2 in N2a cells and inhibits the expression of ROCK2 at both mRNA and protein levels in N2a cells. As a result, lncRNA-H19 promotes the OGD/R-induced oxidative stress by down-regulating miR-148a-3p to increase ROCK2 expression (Zeng et al. 2019).
LncRNA/miR-376a/CBS/H2S axis
H2S, an uprising gasotransmitter, is associated with stoke regulation. H2S exerts imperious role in maintaining homeostasis of cerebrovascular function under physiological condition. Not surprisingly, reduction of H2S level is related to endothelial dysfunction and pathological process of ischemic stroke (Narne et al. 2019). Cerebrovascular protection of H2S was validated by the promotion of vascular remodeling and regeneration induced by supplement with H2S (Nath et al. 2019). CBS is the main synthase for H2S production in the brain, enhancement of CBS-produced H2S concentration alleviates brain injury and exerts inhibitory effect on the inflammatory responses following mimicking ischemia stroke of mice (Zhang et al. 2017).
Bioinformatics predictions indicate the direct interaction between H2S synthase CBS and miR-376a, which is closely related to the occurrence and development of stroke (van Kralingen et al. 2019). Moreover, risk factors of ischemic stroke such as apoptosis, oxidative stress, inflammation and excitotoxity are all found to be regulated by miRNAs (Li et al. 2018a). Thus, the hypothesis is worthy discussing to explore whether miRNA can regulate the pathological process of stroke through CBS/H2S pathway.
Recent studies have indicated that lncRNA can act as competing endogenous RNAs and interact with and immobilize miRNA via conserved sequences, protecting their target genes (Zhang et al. 2016). Abnormal expression of lncRNA is also related to the occurrence of many diseases such as cerebral ischemic stroke (Yu et al. 2019). Besides, lncRNA SNHG1 can alleviate oxygen-glucose deprivation (OGD) injury of brain microvascular endothelial cells, which confirms that lncRNAs exert a key role in the pathogenesis of stroke (Yang and Zi 2019). Bioinformatics analysis have further revealed that the targeting effect of SNHG1 is via inhibiting miR-376a (Meng et al. 2021).
Using OGD model of human cerebral microvascular endothelial cell line (HCMIEC/D3), Li et al. sought to explore whether lncRNA SNHG1 can ameliorate OGD injury of HCMIEC/D3 through CBS/H2S pathway through targeting miR-376a. They have found that SNHG1 and CBS expression at RNA level in HCMEC/D3 cells is downregulated while miR-376a is upregulated, inhibition of miR-376a blocks the apoptosis and inflammation in HCMEC/D3 cells under OGD conditions. In addition, the researchers have revealed that miR-376a exacerbates apoptosis and inflammation in OGD-induced HCMEC/D3 cells via inhibiting CBS/H2S production. While the researchers also have found that overexpression of lncRNA SNHG1 reduces the apoptosis and inflammation in OGD-induced HCMEC/D3 via inhibiting miR-376a and up-regulating CBS/H2S production (Lv et al. 2021).
The challenges of H2S and RhoA/ROCK pathway-based therapies for ischemic stroke
H2S
Although H2S has specific neuroprotection on the cerebral ischemic injury, several issues hinder the clinical translation of H2S-based therapies from the bench. First, we know very little about the effect of endogenous H2S in pathological process of stroke. Second, the neuroprotective mechanisms underlying the therapeutic effects of H2S is not complete clear. Besides, it is not clear whether the therapeutic mechanisms of H2S can be isolated from its toxic mechanisms. Until now, research mainly use the gene knockout of H2S synthases or the inhibitors of them to investigate the effect of endogenous H2S in pathological process of stroke. No clear conclusion has been obtained based on these studies (Jia et al. 2019). Third, present research almost exclusively focuses on the acute neuroprotection of H2S against cerebral ischemia. It is of great importance to examine the effect of H2S on long-term stroke outcomes.
ROCK inhibitors
In view of the evidence of increased ROCK activity in pathological conditions of ischemic stroke, it is of great importance to determine the precise effect of ROCK in ischemic stroke and stroke recovery by using ROCK inhibitors. Y-27,632 is a selective and highly potent inhibitor of ROCK. It binds intracellularly to the catalytic site of ROCK (both ROCK1 and 2), thereby inhibits its kinase activity. Y-27,632 has been shown to inhibit ROCK kinase activity in neurons, smooth muscle cells and epithelial cells (Gong and Yang 2014). Y-27,632 has been used in treating spinal cord injury, for it is known to promote neurite outgrowth and axonal regeneration in neurons (Wang et al. 2018a).
But for the important limitation of the nonselective mechanism of ROCK inhibitor and for the use of ROCK inhibitors which inhibit other serine-threonine kinases such as PKC and PKA at higher concentrations, Fasudil is the only ROCK inhibitor approved for human use in China and Japan to treat and prevent cerebral ischemia, and subarachnoid hemorrhage-induced vasospasm (Sladojevic et al. 2017). KD025 (formerly SLx2119), a selective ROCK2 inhibitor, also has neuroprotective effect and can improve the mice outcome after focal cerebral ischemia in a dose-dependent manner by improving collateral cortical blood flow. Interestingly, KD025 has been shown to be safe when compared with nonselective ROCK inhibitors in aged, diabetic, or female (Lee et al. 2014).
The challenges of ncRNA-based therapies for ischemic stroke
MiRNA
MiRNAs, enriched in brain, can regulate the expression of potentially deleterious genes in post-transcriptional manner after ischemic stroke, thereby might be potential targets. However, all the mechanisms of cerebral I/R injury are simultaneously present during ischemic stroke and it is not easy to isolate these events from each other. Neuroprotective effect of miRNAs is interlinked with inhibition of neuroinflammation (Alhadidi et al. 2022), oxidative stress damage (Zhai et al. 2022) and neurons loss, as well as promotion of neuronal recovery (Zhou and Qiao 2022). Overexpression of the miRNAs such as miR-216a (Tian et al. 2018) and miRNA-589 (Ma et al. 2020) exerts neuroprotection and improves the outcome after cerebral I/R. While some other miRNAs such as microRNA-153 (Yan et al. 2020) impair the presynaptic plasticity and injure the neurological function after cerebral I/R. Therefore, “reversing” the expression of the miRNAs (overexpression or inhibiting an overexpressed miRNA) improves the outcome and studied parameters. These findings could mean that a miRNA-centered therapeutic approach could be beneficial. It is very likely that this strategy in a clinical setting is insufficient. Further study is needed to evaluate the exact roles of miRNAs in cerebral I/R injuries and to assess the most favorable candidates as treatment options.
CircRNA
Based on mouse model subjected to transient MCAO, Mehta et al. have found that there are 283 circular RNAs altered compared with sham control by using circular RNA microarrays and real-time PCR (Mehta et al. 2017). Bai et al. have found that circRNA DLGAP4 (circDLGAP4) is increased both in the plasma of ischemic stroke patients including 13 females and 13 males and in mice plasma of stroke model. Besides, they have revealed that circDLGAP4 serves as a microRNA-143 sponge. More importantly, the research revealed that overexpression of circDLGAP4 could obviously reduce infarct area and decrease neurological deficits in mouse stroke model following transient MCAO. These data indicated that circDLGAP4 provide a novel therapeutic target for treatment of cerebral ischemic diseases (Bai et al. 2018).
LncRNA
The potential diagnostic and therapeutic roles of lncRNAs have been made in ischemic stroke. Nevertheless, there is still several challenges in the way of lncRNA-based translational research for ischemic stroke. For example, more sensitive methods for RNA detection should be established due to the lncRNAs expression is relatively low in comparison to the levels of mRNAs and proteins in the circulation system. In addition, there is still a significant challenge that the targeted lncRNAs deliver into the CNS of stroke patients. The carry ability of viral vectors, non-viral vectors, nanoparticles, exosomes, chemically modified antisense oligonucleotides, and liposomes to carry lncRNA-based drugs into the cerebral infarction area should be evaluated (Bar et al. 2016; Li et al. 2022a).
Conclusion
Cerebral ischemia-induced upregulation of RhoA/ROCK pathway is deeply involved in the pathological process of ischemic stroke in various ways such as neuroinflammation. Growing evidences have revealed that both exogenous and endogenous H2S could ameliorate cerebral I/R-induced brain injury via inhibiting of the RhoA/ROCK pathway. Here, we introduced the inhibitory effect of H2S on the neuroinflammation after ischemic stroke via inhibiting the RhoA/ROCK pathway, and discussed the relationship among H2S, Rho/ROCK pathway and ncRNAs in ischemic stroke. Besides, we also discussed the challenges of RhoA/ROCK pathway, as well as ncRNA-based therapies for ischemic stroke. Furthermore, as mentioned in this review, circRNAs, miRNA and lncRNA, have been proposed as valuable biomarkers for diagnosing ischemic stroke. Therefore, endogenous H2S, Rho/ROCK pathway and ncRNAs are worthy of further exploration as therapeutic targets for ischemic stroke.
Data Availability
Data sharing is not applicable to this review article as no new data of our own were created.
References
Abbott NJ, Ronnback L, Hansson E (2006) Astrocyte-endothelial interactions at the blood-brain barrier. Nature reviews Neuroscience 7:41–53. https://doi.10.1038/nrn1824
Abeysinghe HC, Phillips EL, Chin-Cheng H, Beart PM, Roulston CL (2016) Modulating Astrocyte Transition after Stroke to Promote Brain Rescue and Functional Recovery: Emerging Targets Include Rho Kinase. International journal of molecular sciences 17:288. https://doi.10.3390/ijms17030288
Al Mamun A, Chauhan A, Qi S, Ngwa C, Xu Y, Sharmeen R, Hazen AL, Li J, Aronowski JA, McCullough LD, Liu F (2020) Microglial IRF5-IRF4 regulatory axis regulates neuroinflammation after cerebral ischemia and impacts stroke outcomes. Proceedings of the National Academy of Sciences of the United States of America 117:1742–1752. https://doi.10.1073/pnas.1914742117
Alhadidi QM, Xu L, Sun X, Althobaiti YS, Almalki A, Alsaab HO, Stary CM (2022) MiR-182 Inhibition Protects Against Experimental Stroke in vivo and Mitigates Astrocyte Injury and Inflammation in vitro via Modulation of Cortactin Activity. Neurochemical research. https://doi.10.1007/s11064-022-03718-6
Amano M, Nakayama M, Kaibuchi K (2010) Rho-kinase/ROCK: A key regulator of the cytoskeleton and cell polarity. Cytoskeleton 67:545–554. https://doi.10.1002/cm.20472
Arraiano CM (2021) Regulatory noncoding RNAs: functions and applications in health and disease. The FEBS journal 288:6308–6309. https://doi.10.1111/febs.16027
Avalos AM, Arthur WT, Schneider P, Quest AF, Burridge K, Leyton L (2004) Aggregation of integrins and RhoA activation are required for Thy-1-induced morphological changes in astrocytes. The Journal of biological chemistry 279:39139–39145. https://doi.10.1074/jbc.M403439200
Bai Y, Zhang Y, Han B, Yang L, Chen X, Huang R, Wu F, Chao J, Liu P, Hu G, Zhang JH, Yao H (2018) Circular RNA DLGAP4 Ameliorates Ischemic Stroke Outcomes by Targeting miR-143 to Regulate Endothelial-Mesenchymal Transition Associated with Blood-Brain Barrier Integrity. The Journal of neuroscience: the official journal of the Society for Neuroscience 38:32–50. https://doi.10.1523/JNEUROSCI.1348-17.2017
Bali KK, Kuner R (2014) Noncoding RNAs: key molecules in understanding and treating pain. Trends in molecular medicine 20:437–448. https://doi.10.1016/j.molmed.2014.05.006
Bam M, Yang X, Sen S, Zumbrun EE, Dennis L, Zhang J, Nagarkatti PS, Nagarkatti M (2018) Characterization of Dysregulated miRNA in Peripheral Blood Mononuclear Cells from Ischemic Stroke Patients. Molecular neurobiology 55:1419–1429. https://doi.10.1007/s12035-016-0347-8
Bao MH, Szeto V, Yang BB, Zhu SZ, Sun HS, Feng ZP (2018) Long non-coding RNAs in ischemic stroke. Cell death & disease 9:281. https://doi.10.1038/s41419-018-0282-x
Bar C, Chatterjee S, Thum T (2016) Long Noncoding RNAs in Cardiovascular Pathology, Diagnosis, and Therapy. Circulation 134:1484–1499. https://doi.10.1161/CIRCULATIONAHA.116.023686
Bartel DP (2004) MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116:281–297. https://doi.10.1016/s0092-8674(04)00045-5
Basyuk E, Suavet F, Doglio A, Bordonne R, Bertrand E (2003) Human let-7 stem-loop precursors harbor features of RNase III cleavage products. Nucleic acids research 31:6593–6597. https://doi.10.1093/nar/gkg855
Behera J, Kelly KE, Tyagi N (2021) Hydrogen sulfide prevents ethanol-induced ZO-1 CpG promoter hypermethylation-dependent vascular permeability via miR-218/DNMT3a axis. J Cell Physiol 236:6852–6867. https://doi.10.1002/jcp.30382
Bulygin KV, Beeraka NM, Saitgareeva AR, Nikolenko VN, Gareev I, Beylerli O, Akhmadeeva LR, Mikhaleva LM, Torres Solis LF, Solis Herrera A, Avila-Rodriguez MF, Somasundaram SG, Kirkland CE, Aliev G (2020) Can miRNAs Be Considered as Diagnostic and Therapeutic Molecules in Ischemic Stroke Pathogenesis?-Current Status. International journal of molecular sciences 21. https://doi.10.3390/ijms21186728
Campagnoli M, Durand D, Calcagno L, Cella G, Porro P (1971) [Fibrosarcoma of the kidney]. Pathologica 63:313–319
Cao Y, Liu H, Zhang J, Dong Y (2020) Circular RNA cZNF292 silence alleviates OGD/R-induced injury through up-regulation of miR-22 in rat neural stem cells (NSCs). Artificial cells, nanomedicine, and biotechnology 48:594–601. https://doi.10.1080/21691401.2020.1725536
Chen DL, Chen LZ, Lu YX, Zhang DS, Zeng ZL, Pan ZZ, Huang P, Wang FH, Li YH, Ju HQ, Xu RH (2017) Long noncoding RNA XIST expedites metastasis and modulates epithelial-mesenchymal transition in colorectal cancer. Cell death & disease 8:e3011. https://doi.10.1038/cddis.2017.421
Chen I, Chen CY, Chuang TJ (2015) Biogenesis, identification, and function of exonic circular RNAs. Wiley interdisciplinary reviews RNA 6:563–579. https://doi.10.1002/wrna.1294
Chendrimada TP, Gregory RI, Kumaraswamy E, Norman J, Cooch N, Nishikura K, Shiekhattar R (2005) TRBP recruits the Dicer complex to Ago2 for microRNA processing and gene silencing. Nature 436:740–744. https://doi.10.1038/nature03868
Collaborators GBDCoD (2017) Global, regional, and national age-sex specific mortality for 264 causes of death, 1980–2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet 390:1151–1210. https://doi.10.1016/S0140-6736(17)32152-9
Deng L, Jiang J, Chen S, Lin X, Zuo T, Hu Q, Wu Y, Fan X, Dong Z (2022) Long Non-coding RNA ANRIL Downregulation Alleviates Neuroinflammation in an Ischemia Stroke Model via Modulation of the miR-671-5p/NF-kappaB Pathway. Neurochemical research. https://doi.10.1007/s11064-022-03585-1
DeOcesano-Pereira C, Machado RAC, Chudzinski-Tavassi AM, Sogayar MC (2020) Emerging Roles and Potential Applications of Non-Coding RNAs in Glioblastoma. International journal of molecular sciences 21. https://doi.10.3390/ijms21072611
Ding J, Li QY, Wang X, Sun CH, Lu CZ, Xiao BG (2010) Fasudil protects hippocampal neurons against hypoxia-reoxygenation injury by suppressing microglial inflammatory responses in mice. Journal of neurochemistry 114:1619–1629. https://doi.10.1111/j.1471-4159.2010.06876.x
Ding Y, Liu B, Zhang Y, Fang F, Li X, Wang S, Wen J (2022) Hydrogen sulphide protects mice against the mutual aggravation of cerebral ischaemia/reperfusion injury and colitis. Eur J Pharmacol 914:174682. https://doi.10.1016/j.ejphar.2021.174682
Donertas Ayaz B, Zubcevic J (2020) Gut microbiota and neuroinflammation in pathogenesis of hypertension: A potential role for hydrogen sulfide. Pharmacological research 153:104677. https://doi.10.1016/j.phrs.2020.104677
Escartin C, Galea E, Lakatos A, O’Callaghan JP, Petzold GC, Serrano-Pozo A, Steinhauser C, Volterra A, Carmignoto G, Agarwal A, Allen NJ, Araque A, Barbeito L, Barzilai A, Bergles DE, Bonvento G, Butt AM, Chen WT, Cohen-Salmon M, Cunningham C, Deneen B, De Strooper B, Diaz-Castro B, Farina C, Freeman M, Gallo V, Goldman JE, Goldman SA, Gotz M, Gutierrez A, Haydon PG, Heiland DH, Hol EM, Holt MG, Iino M, Kastanenka KV, Kettenmann H, Khakh BS, Koizumi S, Lee CJ, Liddelow SA, MacVicar BA, Magistretti P, Messing A, Mishra A, Molofsky AV, Murai KK, Norris CM, Okada S, Oliet SHR, Oliveira JF, Panatier A, Parpura V, Pekna M, Pekny M, Pellerin L, Perea G, Perez-Nievas BG, Pfrieger FW, Poskanzer KE, Quintana FJ, Ransohoff RM, Riquelme-Perez M, Robel S, Rose CR, Rothstein JD, Rouach N, Rowitch DH, Semyanov A, Sirko S, Sontheimer H, Swanson RA, Vitorica J, Wanner IB, Wood LB, Wu J, Zheng B, Zimmer ER, Zorec R, Sofroniew MV, Verkhratsky A (2021) Reactive astrocyte nomenclature, definitions, and future directions. Nature neuroscience 24:312–325. https://doi.10.1038/s41593-020-00783-4
Gong H, Yang CY (2014) Morphological and hydrodynamic correlations with increasing outflow facility by rho-kinase inhibitor Y-27632. J Ocul Pharmacol Ther 30:143–153. https://doi.10.1089/jop.2013.0192
Gong QH, Shi XR, Hong ZY, Pan LL, Liu XH, Zhu YZ (2011) A new hope for neurodegeneration: possible role of hydrogen sulfide. Journal of Alzheimer’s disease: JAD 24 Suppl 2:173–182. https://doi.10.3233/JAD-2011-110128
Granados-Riveron JT, Aquino-Jarquin G (2016) The complexity of the translation ability of circRNAs. Biochimica et biophysica acta 1859:1245–1251. https://doi.10.1016/j.bbagrm.2016.07.009
Guo H, Fan Z, Wang S, Ma L, Wang J, Yu D, Zhang Z, Wu L, Peng Z, Liu W, Hou W, Cai Y (2021) Astrocytic A1/A2 paradigm participates in glycogen mobilization mediated neuroprotection on reperfusion injury after ischemic stroke. Journal of neuroinflammation 18:230. https://doi.10.1186/s12974-021-02284-y
Gutierrez-Beltran E, Moschou PN, Smertenko AP, Bozhkov PV (2015) Tudor staphylococcal nuclease links formation of stress granules and processing bodies with mRNA catabolism in Arabidopsis. Plant Cell 27:926–943. https://doi.10.1105/tpc.114.134494
Han J, Lee Y, Yeom KH, Kim YK, Jin H, Kim VN (2004) The Drosha-DGCR8 complex in primary microRNA processing. Genes Dev 18:3016–3027. https://doi.10.1101/gad.1262504
Han XR, Wen X, Wang YJ, Wang S, Shen M, Zhang ZF, Fan SH, Shan Q, Wang L, Li MQ, Hu B, Sun CH, Wu DM, Lu J, Zheng YL (2018) Protective effects of microRNA-431 against cerebral ischemia-reperfusion injury in rats by targeting the Rho/Rho-kinase signaling pathway. Journal of cellular physiology 233:5895–5907. https://doi.10.1002/jcp.26394
Hansen TB, Jensen TI, Clausen BH, Bramsen JB, Finsen B, Damgaard CK, Kjems J (2013) Natural RNA circles function as efficient microRNA sponges. Nature 495:384–388. https://doi.10.1038/nature11993
Huang A, Zheng H, Wu Z, Chen M, Huang Y (2020) Circular RNA-protein interactions: functions, mechanisms, and identification. Theranostics 10:3503–3517. https://doi.10.7150/thno.42174
Hutvagner G, McLachlan J, Pasquinelli AE, Balint E, Tuschl T, Zamore PD (2001) A cellular function for the RNA-interference enzyme Dicer in the maturation of the let-7 small temporal RNA. Science 293:834–838. https://doi.10.1126/science.1062961
Jae N, Dimmeler S (2020) Noncoding RNAs in Vascular Diseases. Circulation research 126:1127–1145. https://doi.10.1161/CIRCRESAHA.119.315938
Jia J, Li J, Cheng J (2019) H2S-based therapies for ischaemic stroke: opportunities and challenges. Stroke and vascular neurology 4:63–66. https://doi.10.1136/svn-2018-000194
Jiang C, Dong N, Feng J, Hao M (2021a) MiRNA-190 exerts neuroprotective effects against ischemic stroke through Rho/Rho-kinase pathway. Pflugers Archiv: European journal of physiology 473:121–130. https://doi.10.1007/s00424-020-02490-2
Jiang T, Luo J, Pan X, Zheng H, Yang H, Zhang L, Hu X (2021b) Physical exercise modulates the astrocytes polarization, promotes myelin debris clearance and remyelination in chronic cerebral hypoperfusion rats. Life sciences 278:119526. https://doi.10.1016/j.lfs.2021.119526
Jin R, Yang G, Li G (2010) Inflammatory mechanisms in ischemic stroke: role of inflammatory cells. J Leukoc Biol 87:779–789. https://doi.10.1189/jlb.1109766
Khoshnam SE, Winlow W, Farbood Y, Moghaddam HF, Farzaneh M (2017) Emerging Roles of microRNAs in Ischemic Stroke: As Possible Therapeutic Agents. Journal of stroke 19:166–187. https://doi.10.5853/jos.2016.01368
Kimura H (2013) Physiological role of hydrogen sulfide and polysulfide in the central nervous system. Neurochemistry international 63:492–497. https://doi.10.1016/j.neuint.2013.09.003
Kimura T, Horikoshi Y, Kuriyagawa C, Niiyama Y (2021) Rho/ROCK Pathway and Noncoding RNAs: Implications in Ischemic Stroke and Spinal Cord Injury. International journal of molecular sciences 22. https://doi.10.3390/ijms222111573
Kimura Y, Goto Y, Kimura H (2010) Hydrogen sulfide increases glutathione production and suppresses oxidative stress in mitochondria. Antioxidants & redox signaling 12:1–13. https://doi.10.1089/ars.2008.2282
Lau NC, Lim LP, Weinstein EG, Bartel DP (2001) An abundant class of tiny RNAs with probable regulatory roles in Caenorhabditis elegans. Science 294:858–862. https://doi.10.1126/science.1065062
Laufs U, Liao JK (1998) Post-transcriptional regulation of endothelial nitric oxide synthase mRNA stability by Rho GTPase. The Journal of biological chemistry 273:24266–24271. https://doi.10.1074/jbc.273.37.24266
LeComte MD, Shimada IS, Sherwin C, Spees JL (2015) Notch1-STAT3-ETBR signaling axis controls reactive astrocyte proliferation after brain injury. Proceedings of the National Academy of Sciences of the United States of America 112:8726–8731. https://doi.10.1073/pnas.1501029112
Lee JH, Zheng Y, von Bornstadt D, Wei Y, Balcioglu A, Daneshmand A, Yalcin N, Yu E, Herisson F, Atalay YB, Kim MH, Ahn YJ, Balkaya M, Sweetnam P, Schueller O, Poyurovsky MV, Kim HH, Lo EH, Furie KL, Ayata C (2014) Selective ROCK2 Inhibition In Focal Cerebral Ischemia. Annals of clinical and translational neurology 1:2–14. https://doi.10.1002/acn3.19
Lee M, McGeer EG, McGeer PL (2016) Sodium thiosulfate attenuates glial-mediated neuroinflammation in degenerative neurological diseases. Journal of neuroinflammation 13:32. https://doi.10.1186/s12974-016-0488-8
Lee Y, Jeon K, Lee JT, Kim S, Kim VN (2002) MicroRNA maturation: stepwise processing and subcellular localization. Embo J 21:4663–4670. https://doi.10.1093/emboj/cdf476
Li G, Morris-Blanco KC, Lopez MS, Yang T, Zhao H, Vemuganti R, Luo Y (2018a) Impact of microRNAs on ischemic stroke: From pre- to post-disease. Progress in neurobiology 163–164:59–78. https://doi.10.1016/j.pneurobio.2017.08.002
Li L, Li W, Chen N, Zhao H, Xu G, Zhao Y, Pan X, Zhang X, Zhou L, Yu D, Li A, Hu JF, Cui J (2019) FLI1 Exonic Circular RNAs as a Novel Oncogenic Driver to Promote Tumor Metastasis in Small Cell Lung Cancer. Clin Cancer Res 25:1302–1317. https://doi.10.1158/1078-0432.CCR-18-1447
Li Y, Liu B, Chen Y, Quan X, Han Y, Zheng Y, Zhao Y (2022a) Extracellular Vesicle Application as a Novel Therapeutic Strategy for Ischemic Stroke. Translational stroke research 13:171–187. https://doi.10.1007/s12975-021-00915-3
Li Y, Wu J, Lu Q, Liu X, Wen J, Qi X, Liu J, Lian B, Zhang B, Sun H, Tian G (2022b) GA&HA-Modified Liposomes for Co-Delivery of Aprepitant and Curcumin to Inhibit Drug-Resistance and Metastasis of Hepatocellular Carcinoma. International journal of nanomedicine 17:2559–2575. https://doi.10.2147/IJN.S366180
Li Z, Li X, Chen C, Li S, Shen J, Tse G, Chan MTV, Wu WKK (2018b) Long non-coding RNAs in nucleus pulposus cell function and intervertebral disc degeneration. Cell Prolif 51:e12483. https://doi.10.1111/cpr.12483
Liang L, Li L (2020) Down-Regulation of circNRIP1 Promotes the Apoptosis and Inhibits the Migration and Invasion of Gastric Cancer Cells by miR-182/ROCK1 Axis. Onco Targets Ther 13:6279–6288. https://doi.10.2147/OTT.S221633
Liddelow SA, Guttenplan KA, Clarke LE, Bennett FC, Bohlen CJ, Schirmer L, Bennett ML, Munch AE, Chung WS, Peterson TC, Wilton DK, Frouin A, Napier BA, Panicker N, Kumar M, Buckwalter MS, Rowitch DH, Dawson VL, Dawson TM, Stevens B, Barres BA (2017) Neurotoxic reactive astrocytes are induced by activated microglia. Nature 541:481–487. https://doi.10.1038/nature21029
Linnerbauer M, Wheeler MA, Quintana FJ (2020) Astrocyte Crosstalk in CNS Inflammation. Neuron 108:608–622. https://doi.10.1016/j.neuron.2020.08.012
Liu B, Luo C, Lin H, Ji X, Zhang E, Li X (2021) Long Noncoding RNA XIST Acts as a ceRNA of miR-362-5p to Suppress Breast Cancer Progression. Cancer Biother Radiopharm 36:456–466. https://doi.10.1089/cbr.2019.3481
Liu C, Xu X, Huang C, Zhang L, Shang D, Cai W, Wang Y (2020a) Circ_002664/miR-182-5p/Herpud1 pathway importantly contributes to OGD/R-induced neuronal cell apoptosis. Mol Cell Probes 53:101585. https://doi.10.1016/j.mcp.2020.101585
Liu C, Zhang C, Yang J, Geng X, Du H, Ji X, Zhao H (2017) Screening circular RNA expression patterns following focal cerebral ischemia in mice. Oncotarget 8:86535–86547. https://doi.10.18632/oncotarget.21238
Liu J, Hao DD, Zhang JS, Zhu YC (2011) Hydrogen sulphide inhibits cardiomyocyte hypertrophy by up-regulating miR-133a. Biochemical and biophysical research communications 413:342–347. https://doi.10.1016/j.bbrc.2011.08.101
Liu M, Xu Z, Wang L, Zhang L, Liu Y, Cao J, Fu Q, Liu Y, Li H, Lou J, Hou W, Mi W, Ma Y (2020b) Cottonseed oil alleviates ischemic stroke injury by inhibiting the inflammatory activation of microglia and astrocyte. Journal of neuroinflammation 17:270. https://doi.10.1186/s12974-020-01946-7
Liu ME, Liao YC, Lin RT, Wang YS, Hsi E, Lin HF, Chen KC, Juo SH (2013) A functional polymorphism of PON1 interferes with microRNA binding to increase the risk of ischemic stroke and carotid atherosclerosis. Atherosclerosis 228:161–167. https://doi.10.1016/j.atherosclerosis.2013.01.036
Liu Y, Liao S, Quan H, Lin Y, Li J, Yang Q (2016) Involvement of microRNA-135a-5p in the Protective Effects of Hydrogen Sulfide Against Parkinson’s Disease. Cellular physiology and biochemistry: international journal of experimental cellular physiology, biochemistry, and pharmacology 40:18–26. https://doi.10.1159/000452521
Lively S, Hutchings S, Schlichter LC (2016) Molecular and Cellular Responses to Interleukin-4 Treatment in a Rat Model of Transient Ischemia. J Neuropathol Exp Neurol 75:1058–1071. https://doi.10.1093/jnen/nlw081
Lu W, Chen Z, Wen J (2021) RhoA/ROCK signaling pathway and astrocytes in ischemic stroke. Metab Brain Dis 36:1101–1108. https://doi.10.1007/s11011-021-00709-4
Lv L, Xi HP, Huang JC, Zhou XY (2021) LncRNA SNHG1 alleviated apoptosis and inflammation during ischemic stroke by targeting miR-376a and modulating CBS/H2S pathway. Int J Neurosci 131:1162–1172. https://doi.10.1080/00207454.2020.1782904
Ma GP, Yang BZ, Zhang YS, Wang B, Wei XH, Zhang RF, Jia KH, Gao JP (2020) Protective effects of miRNA-589 on cerebral ischemia-reperfusion injury. J Biol Regul Homeost Agents 34:1269–1275. https://doi.10.23812/20-52-A
Magnus T, Wiendl H, Kleinschnitz C (2012) Immune mechanisms of stroke. Curr Opin Neurol 25:334–340. https://doi.10.1097/WCO.0b013e328352ede6
Mehta SL, Pandi G, Vemuganti R (2017) Circular RNA Expression Profiles Alter Significantly in Mouse Brain After Transient Focal Ischemia. Stroke 48:2541–2548. https://doi.10.1161/STROKEAHA.117.017469
Meissner L, Gallozzi M, Balbi M, Schwarzmaier S, Tiedt S, Terpolilli NA, Plesnila N (2016) Temporal Profile of MicroRNA Expression in Contused Cortex after Traumatic Brain Injury in Mice. J Neurotrauma 33:713–720. https://doi.10.1089/neu.2015.4077
Memczak S, Jens M, Elefsinioti A, Torti F, Krueger J, Rybak A, Maier L, Mackowiak SD, Gregersen LH, Munschauer M, Loewer A, Ziebold U, Landthaler M, Kocks C, le Noble F, Rajewsky N (2013) Circular RNAs are a large class of animal RNAs with regulatory potency. Nature 495:333–338. https://doi.10.1038/nature11928
Meng F, Liu J, Lu T, Zang L, Wang J, He Q, Zhou A (2021) SNHG1 knockdown upregulates miR-376a and downregulates FOXK1/Snail axis to prevent tumor growth and metastasis in HCC. Molecular therapy oncolytics 21:264–277. https://doi.10.1016/j.omto.2021.02.002
Mercer TR, Dinger ME, Mattick JS (2009) Long non-coding RNAs: insights into functions. Nat Rev Genet 10:155–159. https://doi.10.1038/nrg2521
Mirzaei H, Momeni F, Saadatpour L, Sahebkar A, Goodarzi M, Masoudifar A, Kouhpayeh S, Salehi H, Mirzaei HR, Jaafari MR (2018) MicroRNA: Relevance to stroke diagnosis, prognosis, and therapy. J Cell Physiol 233:856–865. https://doi.10.1002/jcp.25787
Narne P, Pandey V, Phanithi PB (2019) Role of Nitric Oxide and Hydrogen Sulfide in Ischemic Stroke and the Emergent Epigenetic Underpinnings. Molecular neurobiology 56:1749–1769. https://doi.10.1007/s12035-018-1141-6
Nath N, Prasad HK, Kumar M (2019) Cerebroprotective effects of hydrogen sulfide in homocysteine-induced neurovascular permeability: Involvement of oxidative stress, arginase, and matrix metalloproteinase-9. Journal of cellular physiology 234:3007–3019. https://doi.10.1002/jcp.27120
O’Brien J, Hayder H, Zayed Y, Peng C (2018) Overview of MicroRNA Biogenesis, Mechanisms of Actions, and Circulation. Frontiers in endocrinology 9:402. https://doi.10.3389/fendo.2018.00402
Olson EE, Lyuboslavsky P, Traynelis SF, McKeon RJ (2004) PAR-1 deficiency protects against neuronal damage and neurologic deficits after unilateral cerebral hypoxia/ischemia. Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism 24:964–971. https://doi.10.1097/01.WCB.0000128266.87474.BF
Ostolaza A, Blanco-Luquin I, Urdanoz-Casado A, Rubio I, Labarga A, Zandio B, Roldan M, Martinez-Cascales J, Mayor S, Herrera M, Aymerich N, Gallego J, Munoz R, Mendioroz M (2020) Circular RNA expression profile in blood according to ischemic stroke etiology. Cell & bioscience 10:34. https://doi.10.1186/s13578-020-00394-3
Renga B (2011) Hydrogen sulfide generation in mammals: the molecular biology of cystathionine-beta- synthase (CBS) and cystathionine-gamma-lyase (CSE). Inflammation & allergy drug targets 10:85–91. https://doi.10.2174/187152811794776286
Rybak-Wolf A, Stottmeister C, Glazar P, Jens M, Pino N, Giusti S, Hanan M, Behm M, Bartok O, Ashwal-Fluss R, Herzog M, Schreyer L, Papavasileiou P, Ivanov A, Ohman M, Refojo D, Kadener S, Rajewsky N (2015) Circular RNAs in the Mammalian Brain Are Highly Abundant, Conserved, and Dynamically Expressed. Mol Cell 58:870–885. https://doi.10.1016/j.molcel.2015.03.027
Sampuda KM, Riley M, Boyd L (2017) Stress induced nuclear granules form in response to accumulation of misfolded proteins in Caenorhabditis elegans. BMC Cell Biol 18:18. https://doi.10.1186/s12860-017-0136-x
Satoh S, Kobayashi T, Hitomi A, Ikegaki I, Suzuki Y, Shibuya M, Yoshida J, Asano T (1999) Inhibition of neutrophil migration by a protein kinase inhibitor for the treatment of ischemic brain infarction. Jpn J Pharmacol 80:41–48. https://doi.10.1254/jjp.80.41
Satoh S, Utsunomiya T, Tsurui K, Kobayashi T, Ikegaki I, Sasaki Y, Asano T (2001) Pharmacological profile of hydroxy fasudil as a selective rho kinase inhibitor on ischemic brain damage. Life sciences 69:1441–1453. https://doi.10.1016/s0024-3205(01)01229-2
Shao Y, Chen Y (2016) Roles of Circular RNAs in Neurologic Disease. Front Mol Neurosci 9:25. https://doi.10.3389/fnmol.2016.00025
Si W, Ye S, Ren Z, Liu X, Wu Z, Li Y, Zhou J, Zhang S, Li Y, Deng R, Chen D (2019) miR335 promotes stress granule formation to inhibit apoptosis by targeting ROCK2 in acute ischemic stroke. International journal of molecular medicine 43:1452–1466. https://doi.10.3892/ijmm.2019.4073
Siddeek B, Inoubli L, Lakhdari N, Rachel PB, Fussell KC, Schneider S, Mauduit C, Benahmed M (2014) MicroRNAs as potential biomarkers in diseases and toxicology. Mutation research Genetic toxicology and environmental mutagenesis 764–765:46–57. https://doi.10.1016/j.mrgentox.2014.01.010
Sladojevic N, Yu B, Liao JK (2017) ROCK as a therapeutic target for ischemic stroke. Expert review of neurotherapeutics 17:1167–1177. https://doi.10.1080/14737175.2017.1395700
Stein ES, Itsekson-Hayosh Z, Aronovich A, Reisner Y, Bushi D, Pick CG, Tanne D, Chapman J, Vlachos A, Maggio N (2015) Thrombin induces ischemic LTP (iLTP): implications for synaptic plasticity in the acute phase of ischemic stroke. Scientific reports 5:7912. https://doi.10.1038/srep07912
Sun P, Hamblin MH, Yin KJ (2022) Non-coding RNAs in the regulation of blood-brain barrier functions in central nervous system disorders. Fluids and barriers of the CNS 19:27. https://doi.10.1186/s12987-022-00317-z
Tian YS, Zhong D, Liu QQ, Zhao XL, Sun HX, Jin J, Wang HN, Li GZ (2018) Upregulation of miR-216a exerts neuroprotective effects against ischemic injury through negatively regulating JAK2/STAT3-involved apoptosis and inflammatory pathways. J Neurosurg 130:977–988. https://doi.10.3171/2017.5.JNS163165
van Kralingen JC, McFall A, Ord ENJ, Coyle TF, Bissett M, McClure JD, McCabe C, Macrae IM, Dawson J, Work LM (2019) Altered Extracellular Vesicle MicroRNA Expression in Ischemic Stroke and Small Vessel Disease. Translational stroke research 10:495–508. https://doi.10.1007/s12975-018-0682-3
Vijayan M, Kumar S, Yin X, Zafer D, Chanana V, Cengiz P, Reddy PH (2018) Identification of novel circulatory microRNA signatures linked to patients with ischemic stroke. Human molecular genetics 27:2318–2329. https://doi.10.1093/hmg/ddy136
Wang C, Dong J, Sun J, Huang S, Wu F, Zhang X, Pang D, Fu Y, Li L (2021a) Silencing of lncRNA XIST impairs angiogenesis and exacerbates cerebral vascular injury after ischemic stroke. Molecular therapy Nucleic acids 26:148–160. https://doi.10.1016/j.omtn.2021.06.025
Wang H, Zheng X, Jin J, Zheng L, Guan T, Huo Y, Xie S, Wu Y, Chen W (2020a) LncRNA MALAT1 silencing protects against cerebral ischemia-reperfusion injury through miR-145 to regulate AQP4. J Biomed Sci 27:40. https://doi.10.1186/s12929-020-00635-0
Wang J, Fu Z, Wang M, Lu J, Yang H, Lu H (2021b) Knockdown of XIST Attenuates Cerebral Ischemia/Reperfusion Injury Through Regulation of miR-362/ROCK2 Axis. Neurochemical research 46:2167–2180. https://doi.10.1007/s11064-021-03354-6
Wang J, Li H, Yao Y, Ren Y, Lin J, Hu J, Zheng M, Song X, Zhao T, Chen YY, Shen Y, Zhu YJ, Wang LL (2018a) beta-Elemene Enhances GAP-43 Expression and Neurite Outgrowth by Inhibiting RhoA Kinase Activation in Rats with Spinal Cord Injury. Neuroscience 383:12–21. https://doi.10.1016/j.neuroscience.2018.04.045
Wang L, Liu W, Zhang Y, Hu Z, Guo H, Lv J, Du H (2020b) Dexmedetomidine had neuroprotective effects on hippocampal neuronal cells via targeting lncRNA SHNG16 mediated microRNA-10b-5p/BDNF axis. Mol Cell Biochem 469:41–51. https://doi.10.1007/s11010-020-03726-6
Wang L, Yao Y, He R, Meng Y, Li N, Zhang D, Xu J, Chen O, Cui J, Bian J, Zhang Y, Chen G, Deng X (2017) Methane ameliorates spinal cord ischemia-reperfusion injury in rats: Antioxidant, anti-inflammatory and anti-apoptotic activity mediated by Nrf2 activation. Free radical biology & medicine 103:69–86. https://doi.10.1016/j.freeradbiomed.2016.12.014
Wang Q, Liu X, Zhao J, Zhu R (2020c) Circular RNAs: novel diagnostic and therapeutic targets for ischemic stroke. Expert review of molecular diagnostics 20:1039–1049. https://doi.10.1080/14737159.2020.1826313
Wang SW, Liu Z, Shi ZS (2018b) Non-Coding RNA in Acute Ischemic Stroke: Mechanisms, Biomarkers and Therapeutic Targets. Cell Transplant 27:1763–1777. https://doi.10.1177/0963689718806818
Wang X, Zhang Z, Zhu Z, Liang Z, Zuo X, Ju C, Song Z, Li X, Hu X, Wang Z (2021c) Photobiomodulation Promotes Repair Following Spinal Cord Injury by Regulating the Transformation of A1/A2 Reactive Astrocytes. Frontiers in neuroscience 15:768262. https://doi.10.3389/fnins.2021.768262
Wei X, Wang B, Wang Q, Yang X, Yang Y, Fang Z, Yi C, Shi L, Fan X, Tao J, Guo Y, Song D (2020) MiR-362-5p, Which Is Regulated by Long Non-Coding RNA MBNL1-AS1, Promotes the Cell Proliferation and Tumor Growth of Bladder Cancer by Targeting QKI. Front Pharmacol 11:164. https://doi.10.3389/fphar.2020.00164
Wen JY, Gao SS, Chen FL, Chen S, Wang M, Chen ZW (2019) Role of CSE-Produced H2S on Cerebrovascular Relaxation via RhoA-ROCK Inhibition and Cerebral Ischemia-Reperfusion Injury in Mice. ACS Chem Neurosci 10:1565–1574. https://doi.10.1021/acschemneuro.8b00533
Wen JY, Wang M, Li YN, Jiang HH, Sun XJ, Chen ZW (2018) Vascular Protection of Hydrogen Sulfide on Cerebral Ischemia/Reperfusion Injury in Rats. Frontiers in neurology 9:779. https://doi.10.3389/fneur.2018.00779
Wu D, Wang J, Li H, Xue M, Ji A, Li Y (2015) Role of Hydrogen Sulfide in Ischemia-Reperfusion Injury. Oxidative medicine and cellular longevity 2015:186908. https://doi.10.1155/2015/186908
Xiang Y, Zhang Y, Xia Y, Zhao H, Liu A, Chen Y (2020) LncRNA MEG3 targeting miR-424-5p via MAPK signaling pathway mediates neuronal apoptosis in ischemic stroke. Aging 12:3156–3174. https://doi.10.18632/aging.102790
Xie Q, Wang Z, Zhou H, Yu Z, Huang Y, Sun H, Bi X, Wang Y, Shi W, Gu P, Fan X (2016) The role of miR-135-modified adipose-derived mesenchymal stem cells in bone regeneration. Biomaterials 75:279–294. https://doi.10.1016/j.biomaterials.2015.10.042
Yan H, Rao J, Yuan J, Gao L, Huang W, Zhao L, Ren J (2017) Long non-coding RNA MEG3 functions as a competing endogenous RNA to regulate ischemic neuronal death by targeting miR-21/PDCD4 signaling pathway. Cell death & disease 8:3211. https://doi.10.1038/s41419-017-0047-y
Yan ML, Zhang S, Zhao HM, Xia SN, Jin Z, Xu Y, Yang L, Qu Y, Huang SY, Duan MJ, Mao M, An XB, Mishra C, Zhang XY, Sun LH, Ai J (2020) MicroRNA-153 impairs presynaptic plasticity by blocking vesicle release following chronic brain hypoperfusion. Cell communication and signaling: CCS 18:57. https://doi.10.1186/s12964-020-00551-8
Yang X, Zi XH (2019) LncRNA SNHG1 alleviates OGD induced injury in BMEC via miR-338/HIF-1alpha axis. Brain research 1714:174–181. https://doi.10.1016/j.brainres.2018.11.003
Yin D, Wei G, Yang F, Sun X (2021) Circular RNA has circ 0001591 promoted cell proliferation and metastasis of human melanoma via ROCK1/PI3K/AKT by targeting miR-431-5p. Hum Exp Toxicol 40:310–324. https://doi.10.1177/0960327120950014
Yu S, Yu M, He X, Wen L, Bu Z, Feng J (2019) KCNQ1OT1 promotes autophagy by regulating miR-200a/FOXO3/ATG7 pathway in cerebral ischemic stroke. Aging cell 18:e12940. https://doi.10.1111/acel.12940
Zeng J, Zhu L, Liu J, Zhu T, Xie Z, Sun X, Zhang H (2019) Metformin Protects against Oxidative Stress Injury Induced by Ischemia/Reperfusion via Regulation of the lncRNA-H19/miR-148a-3p/Rock2 Axis. Oxidative medicine and cellular longevity 2019:8768327. https://doi.10.1155/2019/8768327
Zhai Y, Liu B, Wu L, Zou M, Mei X, Mo X (2022) Pachymic acid prevents neuronal cell damage induced by hypoxia/reoxygenation via miR155/NRF2/HO1 axis. Acta Neurobiol Exp (Wars) 82:197–206. https://doi.10.55782/ane-2022-018
Zhang L, Li Z, Mao L, Wang H (2022) Circular RNA in Acute Central Nervous System Injuries: A New Target for Therapeutic Intervention. Front Mol Neurosci 15:816182. https://doi.10.3389/fnmol.2022.816182
Zhang M, Wu X, Xu Y, He M, Yang J, Li J, Li Y, Ao G, Cheng J, Jia J (2017) The cystathionine beta-synthase/hydrogen sulfide pathway contributes to microglia-mediated neuroinflammation following cerebral ischemia. Brain, behavior, and immunity 66:332–346. https://doi.10.1016/j.bbi.2017.07.156
Zhang T, Zhang L, Han D, Tursun K, Lu X (2020) Circular RNA hsa_Circ_101141 as a Competing Endogenous RNA Facilitates Tumorigenesis of Hepatocellular Carcinoma by Regulating miR-1297/ROCK1 Pathway. Cell Transplant 29:963689720948016. https://doi.10.1177/0963689720948016
Zhang X, Bian JS (2014) Hydrogen sulfide: a neuromodulator and neuroprotectant in the central nervous system. ACS chemical neuroscience 5:876–883. https://doi.10.1021/cn500185g
Zhang Y, Li K, Wang X, Ding Y, Ren Z, Fang J, Sun T, Guo Y, Chen Z, Wen J (2021) CSE-Derived H2S Inhibits Reactive Astrocytes Proliferation and Promotes Neural Functional Recovery after Cerebral Ischemia/Reperfusion Injury in Mice Via Inhibition of RhoA/ROCK2 Pathway. ACS chemical neuroscience 12:2580–2590. https://doi.10.1021/acschemneuro.0c00674
Zhang Y, Xu Y, Feng L, Li F, Sun Z, Wu T, Shi X, Li J, Li X (2016) Comprehensive characterization of lncRNA-mRNA related ceRNA network across 12 major cancers. Oncotarget 7:64148–64167. https://doi.10.18632/oncotarget.11637
Zhang Y, Zhang Y (2020) lncRNA ZFAS1 Improves Neuronal Injury and Inhibits Inflammation, Oxidative Stress, and Apoptosis by Sponging miR-582 and Upregulating NOS3 Expression in Cerebral Ischemia/Reperfusion Injury. Inflammation 43:1337–1350. https://doi.10.1007/s10753-020-01212-1
Zhao Y, Li J, Li J, Xu L, Lian W (2020) The decreased circular RNA hsa_circ_0072309 promotes cell apoptosis of ischemic stroke by sponging miR-100. European review for medical and pharmacological sciences 24:4420–4429. https://doi.10.26355/eurrev_202004_21024
Zhou X, Qiao B (2022) Inhibition of HDAC3 and ATXN3 by miR-25 prevents neuronal loss and ameliorates neurological recovery in cerebral stroke experimental rats. J Physiol Biochem 78:139–149. https://doi.10.1007/s13105-021-00848-3
Zhu L, He D, Han L, Cao H (2015) Stroke Research in China over the Past Decade: Analysis of NSFC Funding. Translational stroke research 6:253–256. https://doi.10.1007/s12975-015-0404-z
Funding
This study was supported by Natural Science Foundation of Colleges and Universities of Anhui Province in 2020 (No. KJ2020A0976).
Author information
Authors and Affiliations
Contributions
WZL had the main idea of the article; WZL was a major contributor in writing the manuscript; JYW organized the sequence of the whole manuscript, and thoroughly revised the manuscript.
Corresponding author
Ethics declarations
Ethical approval
This review article does not contain any studies with human participants or animals performed by any of the authors.
Conflict of interest
All authors declare that there is no conflict of interest.
Additional information
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Lu, W., Wen, J. H2S-mediated inhibition of RhoA/ROCK pathway and noncoding RNAs in ischemic stroke. Metab Brain Dis 38, 163–176 (2023). https://doi.org/10.1007/s11011-022-01130-1
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11011-022-01130-1