Dataset Information

Neuroprotective Effect of SCM-198 through Stabilizing Endothelial Cell Function.

ABSTRACT: Leonurine, also named SCM-198, which was extracted from Herba leonuri, displayed a protective effect on various cardiovascular and brain diseases, like ischemic stroke. Ischemic stroke which is the leading cause of morbidity and mortality, ultimately caused irreversible neuron damage. This study is aimed at exploring the possible therapeutic potential of SCM-198 in the protection against postischemic neuronal injury and possible underlying mechanisms. A transient middle cerebral artery occlusion (tMCAO) rat model was utilized to measure the protective effect of SCM-198 on neurons. TEM was used to determine neuron ultrastructural changes. The brain slices were stained with Nissl staining solution for Nissl bodies. Fluoro-Jade B (FJB) was used for staining the degenerating neurons. In the oxygen-glucose deprivation and re-oxygenation (OGD/R) model of bEnd.3 cells treated with SCM-198 (0.1, 1, 10 ?M). Then, the bEnd.3 cells were cocultured with SH-SY5Y cells. Cell viability, MDA level, CAT activity, and apoptosis were examined to evaluate the cytotoxicity of these treatments. Western blot and immunofluorescent assays were used to examine the expression of protein related to the p-STAT3/NOX4/Bcl-2 signaling pathway. Coimmunoprecipitation was performed to determine the interaction between p-STAT3 and NOX4. In the transient middle cerebral artery occlusion (tMCAO) rat model, we found that treatment with SCM-198 could ameliorate neuron morphology and reduce the degenerating cell and neuron loss. In the in vitro model of bEnd.3 cell oxygen-glucose deprivation and reoxygenation (OGD/R), treatment with SCM-198 restored the activity of catalase (CAT), improved the expression of Cu-Zn superoxide dismutase (SOD1), and decreased the malondialdehyde (MDA) production. SCM-198 treatment prevented OGD/R-induced cell apoptosis as indicated by increased cell viability and decreased the number of TUNEL-positive cells, accompanied with upregulation of Bcl-2 and Bcl-xl protein and downregulation Bax protein. The results were consistent with SH-SY5Y cells which coculture with bEnd.3 cells. The forthcoming study revealed that SCM-198 activated the p-STAT3/NOX4/Bcl-2 signaling pathway. All the data indicated that SCM-198 protected against oxidative stress and neuronal damage in in vivo and in vitro injury models via the p-STAT3/NOX4/Bcl-2 signaling pathway. Our results suggested that SCM-198 could be the potential drug for neuroprotective effect through stabilizing endothelial cell function.

SUBMITTER: Zhang QY

PROVIDER: S-EPMC6885260 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Neuroprotective Effect of SCM-198 through Stabilizing Endothelial Cell Function.

Zhang Qiu-Yan QY Wang Zhi-Jun ZJ Miao Lei L Wang Ying Y Chang Ling-Ling LL Guo Wei W Zhu Yi-Zhun YZ Zhu Yi-Zhun YZ

Oxidative medicine and cellular longevity 20191111

Leonurine, also named SCM-198, which was extracted from <i>Herba leonuri</i>, displayed a protective effect on various cardiovascular and brain diseases, like ischemic stroke. Ischemic stroke which is the leading cause of morbidity and mortality, ultimately caused irreversible neuron damage. This study is aimed at exploring the possible therapeutic potential of SCM-198 in the protection against postischemic neuronal injury and possible underlying mechanisms. A transient middle cerebral artery oc ...[more]

PMID: 31827699

Similar Datasets

Project description:BackgroundEndometriosis (EMS), an endocrine-related inflammatory disease, is characterized by estrogen and progesterone imbalance in ectopic lesions. However, its pathogenic mechanism has not been fully elucidated. While SCM-198 is the synthetic form of leonurine and has multiple pharmacological activities such as antioxidation and anti-inflammation, it remains unknown whether it could inhibit the progress of EMS by regulating estrogen signaling and inflammation.MethodsThe therapeutic effects of SCM-198 on EMS and its potential mechanism were analyzed by establishing EMS mouse models and performing an RNA sequencing (RNA-seq) assay. ELISA was performed to detect estrogen and tumor necrosis factor (TNF) -α concentrations in normal endometrial stromal cells (nESCs) and ectopic endometrial stromal cells (eESCs) with or without SCM-198 treatment. Western blotting, RNA silencing, and plasmid overexpression were used to analyze the relationship between inflammation, endocrine factors, and autophagy and the regulatory activity of SCM-198 on the inflammation-endocrine-autophagy axis.ResultsIncreased estrogen-estrogen receptor (ER) α signaling and decreased progesterone receptor isoform B (PRB) expression synergistically led to a hypo-autophagy state in eESCs, which further inhibited the apoptosis of eESCs. The high expression of TNF-α in eESCs enhanced the antiapoptotic effect mediated by low autophagy through the activation of the aromatase-estrogen-ERα signaling pathway. SCM-198 inhibited the growth of ectopic lesions in EMS mice and promoted the apoptosis of eESCs both in vivo and in vitro. The apoptotic effect of SCM-198 on eESCs was attained by upregulating the autophagy level via the inhibition of the TNF-α-activated aromatase-estrogen-ERα signal and the increase in PRB expression.ConclusionInflammation facilitated the progress of EMS by disrupting the estrogen regulatory axis. SCM-198 inhibited EMS progression by regulating the inflammation-endocrine-autophagy axis.

Project description:BackgroundNeuroinflammation mediated by overactivated microglia plays a key role in many neurodegenerative diseases, including Alzheimer's disease (AD). In this study, we investigated for the first time the anti-neuroinflammatory effects and possible mechanisms of SCM-198 (an alkaloid extracted from Herbaleonuri), which was previously found highly cardioprotective, both in vitro and in vivo.MethodsFor in vitro experiments, lipopolysaccharide (LPS) or β-amyloid(1-40) (Aβ(1-40)) was applied to induce microglial overactivation. Proinflammatory mediators were measured and activations of NF-κB and mitogen-activated protein kinases' (MAPKs) pathways were investigated. Further protective effect of SCM-198 was evaluated in microglia-neuron co-culture assay and Sprague-Dawley (SD) rats intrahippocampally-injected with Aβ(1-40).ResultsSCM-198 reduced expressions of nitric oxide (NO), TNF-α, IL-1β and IL-6 possibly via, at least partially, inhibiting c-Jun N-terminal kinase (JNK) and NF-κB signaling pathways in microglia. Co-culture assay showed that activated microglia pretreated with SCM-198 led to less neuron loss and decreased phosphorylation of tau and extracellular signal-regulated kinase (ERK) in neurons. Besides, SCM-198 also directly protected against Aβ(1-40)-induced neuronal death and lactate dehydrogenase (LDH) release in primary cortical neurons. For in vivo studies, SCM-198 significantly enhanced cognitive performances of rats 12 days after intrahippocampal injections of aged Aβ(1-40) peptides in the Morris water maze (MWM), accompanied by less hippocampal microglial activation, decreased synaptophysin loss and phosphorylation of ERK and tau. Co-administration of donepezil and SCM-198 resulted in a slight cognitive improvement in SD rats 50 days after intrahippocampal injections of aged Aβ(1-40) peptides as compared to only donepezil or SCM-198 treated group.ConclusionsOur findings are the first to report that SCM-198 has considerable anti-neuroinflammatory effects on inhibiting microglial overactivation and might become a new potential drug candidate for AD therapy in the future.

Project description:In acute liver failure (ALF), liver regeneration deficiency is frequently observed, which is the leading cause of ALF and has a high mortality rate. If not treated promptly, ALF may lead to the need for a liver transplant due to limited treatment options. Here, we report the discovery of a 4-guanidino-n-butyl syringate (Leonurine), which has a hepatoprotective effect and can promote regeneration in mouse liver and human embryonic stem cell-induced liver organoids after acute liver injury (ALI). Leonurine demonstrated excellent safety and pharmacokinetics in vivo and was able to significantly reduce mortality in mice after administration of a lethal 24-hour dose of thioacetamide (TAA) or acetaminophen (APAP), which is fully protective compared to treatment with N-acetyl cysteine (NAC) loss of protection. We have synthesized a Leonurine biotinylation probe and have identified adiponectin receptor 2 (AdipoR2), a progesterone and adiponectin receptor family member, as a selective binding partner of Leonurine with a dissociation constant at micromolar levels. Depleting nitric oxide (NO) levels in hepatocytes is the leading cause of liver regeneration deficiency following ALI. The reduction of AdipoR2-Calmodulin (CaM)-endothelial nitric oxide synthase (NOS3) complex activity decreased NO production in hepatocytes, a significant contributor to the ALF phenotype induced by liver regeneration deficiency. Leonurine can form a guanidine-arginine pairing with the AdipoR2 arginine 335 (R335) site to enhance the activity level of AdipoR2 and increase the NO content in hepatocytes, promoting liver regeneration, and quickly antagonize ALF. The oxygen atom of AdipoR2 tyrosine 274 (Y274) interacts with the oxygen atom of Leonurine through hydrogen bonds, significantly enhancing the hydrophobicity of AdipoR2 arginine 275 (R275) residue, thereby activating its surface activity, reducing the molecular switch stability of R275 and aspartate 117 (D117) configurations, which increased the hydrophilic effect, thus regulating Ca2+ inflow but not significantly affecting the AMP level of hepatocytes and finally increasing CaM activity to upregulate the activity of the AdipoR2-CaM-eNOS complex, resulting in increased NO production. In vitro, the knockdown of AdipoR2 or the introduction of a mutant that does not bind to Leonurine blunts the effect of Leonurine's up-regulation of AdipoR2-CaM-eNOS complex activity. In vivo, the knock-out of AdipoR2 or NOS3 eliminated liver protection and regeneration, which Leonurine mediates. The evidence suggests that Leonurine possesses therapeutic benefits for patients without significant adverse effects. Our findings indicate that Leonurine possesses the potential to provide a rapid-acting treatment for the exercise of therapeutic benefits in ALF.

Project description:PurposeDegenerative mechanisms of retinal neurodegenerative diseases (RND) share common cellular and molecular signalization pathways. Curative treatment does not exist and cell-based therapy, through the paracrine properties of mesenchymal stem cells (MSC), is a potential unspecific treatment for RND. This study aimed to evaluate the neuroprotective capability of human bone marrow (bm) MSC secretome and its potential to modulate retinal responses to neurodegeneration.MethodsAn in vitro model of spontaneous retinal neurodegeneration was used to compare three days of monocultured neuroretina (NR), NR cocultured with bmMSC, and NR cultured with bmMSC secretome. We evaluated retinal morphology markers (Lectin peanut agglutinin, rhodopsin, protein kinase C α isoform, neuronal-specific nuclear protein, glial fibrillary acidic protein, TdT-mediated dUTP nick-end labeling, and vimentin) and proteins involved in apoptosis (apoptosis-inductor factor, caspase-3), necroptosis (MLKL), and autophagy (p62). Besides, we analyzed the relative mRNA expression through qPCR of genes involved in apoptosis (BAX, BCL2, CASP3, CASP8, CASP9), necroptosis (MLKL, RIPK1, RIPK3), autophagy (ATG7, BCLIN1, LC3B, mTOR, SQSTM1), oxidative stress (COX2, CYBA, CYBB, GPX6, SOD1, TXN2, TXNRD1) and inflammation (IL1, IL6, IL10, TGFb1, TNFa).ResultsThe bmMSC secretome preserves retinal morphology, limits pro-apoptotic- and pro-necroptotic-related gene and protein expression, modulates autophagy-related genes and proteins, and stimulates the activation of antioxidant-associated genes.ConclusionsThe neuroprotective ability of the bmMSC secretome is associated with activation of antioxidant machinery, modulation of autophagy, and inhibition of apoptosis and necroptosis during retinal degeneration. The neuroprotective effect of bmMSC secretomes in the presence/absence of MSC looks similar. Our current results reinforce the hypothesis that the human bmMSC secretome slows retinal neurodegeneration and may be a therapeutic option for treating RND.

Dataset Information

Neuroprotective Effect of SCM-198 through Stabilizing Endothelial Cell Function.

Publications

Neuroprotective Effect of SCM-198 through Stabilizing Endothelial Cell Function.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets