Figure 6 - available via license: Creative Commons Attribution 4.0 International
Content may be subject to copyright.
Effects of bilobalide on the expression of ERK1/2, JNK1/2, and p38 MAPK in ischemic penumbra after MCAO/R. (A) Pretreatment with bilobalide (5, 10 mg/kg) did not change p-ERK1/2 concentration, (B) significantly reduced p-JNK1/2 concentration, (C) and remarkably decreased p-p38 MAPK concentration in the ischemic penumbra compared with the MCAO/R group. There were no obvious differences in the levels of total ERK1/2, total JNK1/2, and total p38 MAPK among all experimental groups. Mean values ± standard error of the mean for six rats per group. * P < 0.05, ** P < 0.01 versus sham; ## P < 0.01 versus MCAO/R. BB, bilobalide; MCAO/R, middle cerebral artery occlusion and reperfusion; NMP, nimodipine.
Source publication
Background
Mitogen-activated protein kinase (MAPK) signaling pathways are implicated in inflammatory and apoptotic processes of cerebral ischemia and reperfusion (I/R) injury. Hence, MAPK pathways represent a promising therapeutic target. Exploring the full potential of inhibitors of MAPK pathways is a useful therapeutic strategy for ischemic strok...
Citations
... Bilobalide's lack of convulsant activity may be due to suppression of glutamate release, which reduces synaptic excitement and outweighs reductions in synaptic inhibition (Johnston et al. 2009). There is evidence that bilobalide can reduce inflammation, boost mitochondrial function, and protect against cerebral ischemia-induced damage (Jiang et al. 2014). Recent research shows that bilobalide has anti-inflammatory impacts on chondrocytes via reducing IL-17-induced inflammatory damage to ATDC5 cells by down-regulation of micro-RNA-125a through the JNK and NF-κB signaling pathways. ...
Chronic inflammation is a common underlying factor in many major diseases, including heart disease, diabetes, cancer, and autoimmune disorders, and is responsible for up to 60% of all deaths worldwide. Metformin, statins, and corticosteroids, and NSAIDs (non-steroidal anti-inflammatory drugs) are often given as anti-inflammatory pharmaceuticals, however, often have even more debilitating side effects than the illness itself. The natural product-based therapy of inflammation-related diseases has no adverse effects and good beneficial results compared to substitute conventional anti-inflammatory medications. In this review article, we provide a concise overview of present pharmacological treatments, the pathophysiology of inflammation, and the signaling pathways that underlie it. In addition, we focus on the most promising natural products identified as potential anti-inflammatory therapeutic agents. Moreover, preclinical studies and clinical trials evaluating the efficacy of natural products as anti-inflammatory therapeutic agents and their pragmatic applications with promising outcomes are reviewed. In addition, the safety, side effects and technical barriers of natural products are discussed. Furthermore, we also summarized the latest technological advances in the discovery and scientific development of natural products-based medicine.
... The activity of superoxide dismutase (SOD) was evaluated by the xanthine oxidase method (19) . Briefly, after the cells were completely lysed, the cell supernatant was incubated with the working solution at 37℃ for 30 min. ...
Purpose
The regulatory effect of microRNA on diseases has been confirmed. This study aimed to evaluate the expression of microRNA-210-3p in age-related cataracts and assess the effect of abnormal miR-210-3p expressions on H2O2-induced SAR01/04 cells.
Methods
Reverse-transcription quantitative polymerase chain reaction method was performed to assess the levels of miR-210-3p in aqueous humor samples. Receiver operating characteristic analysis was employed to assess the discrimination ability of miR-210-3p between patients with age-related cataracts and healthy people, and Pearson correlation analysis was used to identify the correlation between miR-210-3p and oxidative stress indices such as superoxide dismutase, glutathione peroxidase, malonaldehyde. Cell counting kit-8 assay and Transwell assay were used to estimate the biological function of H2O2-induced age-related cataract cell model. The levels of oxidative stress indices such as superoxide dismutase, glutathione peroxidase, and malonaldehyde were measured to evaluate the degree of oxidative stress damage in the age-related cataract cell model. The relationship between miR-210-3p and its target gene was verified by luciferase reporter gene analysis.
Results
The miR-210-3p expression was elevated in the aqueous humor of patients with age-related cataracts. A high miR-210-3p expression showed a high diagnostic value for age-related cataracts and was significantly associated with the level of oxidative stress markers in patients with age-related cataracts. The inhibition of miR-210-3p can reverse oxidative stress stimulation and adverse effects on H2O2-induced cell function.
Conclusions
The results suggested that miR-210-3p could promote cell viability, cell migration, and oxidative stress by targeting autophagy-related gene 7 in in vitro age-related cataract cell model.
Keywords:
Cataract; Age factors; Aqueous humor; MiR-210-3p; Oxidative stress; Autophagy-related protein 7
... Several studies have validated oxidative stress results in neural damage via MAPK signal cascades [43,44]. For example, a significant increase in the phosphorylation of ERK1/2, JNK1/2, and p38 MAPK protein was detected in the ischemic penumbra rat model with middle cerebral artery occlusion and reperfusion [45]. Consistent with the previous findings, the present study has proven that H 2 O 2 promoted apoptosis through upregulating the phosphorylation of p-Erk1/2, p-JNK1/2, and p-p38 in SH-SY5Y cells. ...
Background. Oxidative stress is implicated in the progression of many neurological diseases, which could be induced by various chemicals, such as hydrogen peroxide (H 2 O 2) and acrylamide. Triphala is a well-recognized Ayurvedic medicine that possesses different therapeutic properties (e.g., antihistamine, antioxidant, anticancer, anti-inflammatory, antibacterial, and anticariogenic effects). However, little information is available regarding the neuroprotective effect of Triphala on oxidative stress. Materials and Methods. An in vitro H 2 O 2-induced SH-SY5Y cell model and an in vivo acrylamide-induced zebrafish model were established. Cell viability, apoptosis, and proliferation were examined by MTT assay, ELISA, and flow cytometric analysis, respectively. The molecular mechanism underlying the antioxidant activity of Triphala against H 2 O 2 was investigated dose dependently by Western blotting. The in vivo neuroprotective effect of Triphala on acrylamide-induced oxidative injury in Danio rerio was determined using immunofluorescence staining. Results. The results indicated that Triphala plays a neuroprotective role against H 2 O 2 toxicity in inhibiting cell apoptosis and promoting cell proliferation. Furthermore, Triphala pretreatment suppressed the phosphorylation of the mitogen-activated protein kinase (MARK) signal pathway (p-Erk1/2, p-JNK1/2, and p-p38), whereas it restored the activities of antioxidant enzymes (superoxide dismutase 1 (SOD1) and catalase) in the H 2 O 2-treated SH-SY5Y cells. Consistently, similar protective effects of Triphala were observed in declining neuroapoptosis and scavenging free radicals in the zebrafish central neural system, possessing a critical neuroprotective property against acrylamide-induced oxidative stress. Conclusion. In summary, Triphala is a promising neuroprotective agent against oxidative stress in SH-SY5Y cells and zebrafishes with significant antiapoptosis and antioxidant activities.
... 177,178 In cases of brain damage, ginkgo biloba can act as a neuroprotective medication and a reinforcing antidepressant.179 ...
Traditional medicine has received more attention in recent years. Numerous plants have been employed in medicine to treat neurological disorders like AD and other memory-related problems. Traditional uses for dietary, spice, and food additive medicinal purposes included the use of, Nigella sativa, Crocus sativus, Ferula assafoetida, Coriandrum sativum, Zataria multiflora, Thymus vulgaris Cats Claw, and Carotenoids, monoterpenes, and polyphenol chemicals, which are the main ingredients in these plants, improved neurological processes. These healing plants improved antioxidant production, reduced oxidative stress, and prevented the neurological system's acetylcholinesterase enzyme from working. Reduced production of proinflammatory cytokines such IL-6, TNF-an ,IL-1b, NF-Kβ, Bax Protein, Bcl-2,Caspase-3 and total nitrite is another way that plants are neuroprotective. As a result, the effects of the aforementioned medications and their active ingredients improved neurodegenerative diseases, indicating their therapeutic promise in diseases like AD and depression that are linked to neuro-inflammation and neurotransmitter deficit.
... The standardized extract of Ginkgo biloba (EGb) usually contains 6% terpene trilactones (TTLs), and bilobalide (BB) is the only sesquiterpene trilactone found in TTLs (van Beek and Montoro, 2009). Several studies have suggested that the neuroprotective properties of the Ginkgo biloba extract might be attributable to the presence of BB (Defeudis, 2002;Huang et al., 2003;Jiang et al., 2014). By antagonizing the GABA receptor, BB could increase the levels of glutamic acid decarboxylase (GAD) in the brain, reducing the transmission of GABA in the brain and resulting in an anticonvulsant effect (Sasaki et al., 1999). ...
PI3K/Akt, an essential signaling pathway widely present in cells, has been shown to be relevant to neurological disorders. As an important class of natural products, terpenoids exist in large numbers and have diverse backbones, so they have a great chance to be identified as neuroprotective agents. In this review, we described and summarized recent research for a range of terpenoid natural products associated with the PI3K/Akt pathway by classifying their basic chemical structures of the terpenes, identified by electronic searches on PubMed, Web of Science for research, and Google Scholar websites. Only articles published in English were included. Our discussion here concerned 16 natural terpenoids and their mechanisms of action, the associated diseases, and the methods of experimentation used. We also reviewed the discovery of their chemical structures and their derivatives, and some compounds have been concluded for their structure–activity relationships (SAR). As a result, terpenoids are excellent candidates for research as natural neuroprotective agents, and our content will provide a stepping stone for further research into these natural products. It may be possible for more terpenoids to serve as neuroprotective agents in the future.
... The concentration of inflammatory mediator TNF-α in peripheral blood in the acute stage of cerebral infarction is closely related to the activation of inflammatory cells in the central nervous system, which is similar to a reference index that can reflect the inflammatory course in the central nervous system and is regarded as a typical representative of inflammatory injury cytokines. [12] A large number of studies have confirmed that the activation of EGFR is related to the activation of the MAPK family and PI3K family. [13] Some studies have shown that the EGFR/ERK pathway plays a crucial role in cell proliferation, apoptosis and neuroprotection after cerebral infarction by affecting the cell cycle. ...
To explore the mechanism of action of colchicine in the treatment of acute cerebral infarction (ACI) based on network pharmacology. The Swiss Target Prediction Database and CTD database were used to predict the target information of colchicine. ACI-related targets were retrieved using the GeneCards database, and the target protein interaction network (PPI) and active ingredient-target network were obtained by combining Cytoscape 3.7.1 software and R language. Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis and gene function analysis (GO) enrichment analysis were performed using R language to preliminarily explore the multiple pharmacological mechanisms of action of colchicine. There were 200 targets identified by network parameter analysis; 958 ACI targets were identified. Overlapping comparisons allowed the extraction of 143 overlapping targets, and the top 30 targets were screened according to the topological isomerization parameters. Component-target networks were constructed. A PPI of overlapping targets was established to identify key targets. In addition, Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis and GO functional enrichment analysis were performed to explore the multiple mechanisms of action of colchicine in the treatment of ACI. Colchicine treatment of ACI is characterized by multi-component, multi-target and multi-pathway, and can exert complex network regulation through the interaction between different targets, providing a new idea and new basis for further exploration of the mechanism of action of colchicine in the treatment of ACI.
... Thus, according to the docking results, the Z isomer, which should be abundant in the case of the more active Li + salt, has better binding affinity for JNK3 than (E)-IQ-1. Although JNK3 is relatively specifically expressed in brain [62], JNK1 is also an important molecular target for stroke treatment [63,64]. Previously, we also conducted a molecular docking of IQ-1 into structure of JNK1 and found that docking of the Z isomer gave the best pose, which was almost identical to that of the co-crystallized JNK inhibitor Although JNK3 is relatively specifically expressed in brain [62], JNK1 is also an important molecular target for stroke treatment [63,64]. ...
... Although JNK3 is relatively specifically expressed in brain [62], JNK1 is also an important molecular target for stroke treatment [63,64]. Previously, we also conducted a molecular docking of IQ-1 into structure of JNK1 and found that docking of the Z isomer gave the best pose, which was almost identical to that of the co-crystallized JNK inhibitor Although JNK3 is relatively specifically expressed in brain [62], JNK1 is also an important molecular target for stroke treatment [63,64]. Previously, we also conducted a molecular docking of IQ-1 into structure of JNK1 and found that docking of the Z isomer gave the best pose, which was almost identical to that of the co-crystallized JNK inhibitor SP600125 and in contrast to that of the E isomer [33]. ...
The c-Jun N-terminal kinases (JNKs) regulate many physiological processes, including inflammatory responses, morphogenesis, cell proliferation, differentiation, survival, and cell death. Therefore, JNKs represent attractive targets for therapeutic intervention. In an effort to develop improved JNK inhibitors, we synthesized the lithium salt of 11H-indeno[1,2-b]quinoxaline-11-one oxime (IQ-1L) and evaluated its affinity for JNK and biological activity in vitro and in vivo. According to density functional theory (DFT) modeling, the Li+ ion stabilizes the six-membered ring with the 11H-indeno[1,2-b]quinoxaline-11-one (IQ-1) oximate better than Na+. Molecular docking showed that the Z isomer of the IQ-1 oximate should bind JNK1 and JNK3 better than (E)-IQ-1. Indeed, experimental analysis showed that IQ-1L exhibited higher JNK1-3 binding affinity in comparison with IQ-1S. IQ-1L also was a more effective inhibitor of lipopolysaccharide (LPS)-induced nuclear factor-κB/activating protein 1 (NF-κB/AP-1) transcriptional activity in THP-1Blue monocytes and was a potent inhibitor of proinflammatory cytokine production by MonoMac-6 monocytic cells. In addition, IQ-1L inhibited LPS-induced c-Jun phosphorylation in MonoMac-6 cells, directly confirming JNK inhibition. In a rat model of focal cerebral ischemia (FCI), intraperitoneal injections of 12 mg/kg IQ-1L led to significant neuroprotective effects, decreasing total neurological deficit scores by 28, 29, and 32% at 4, 24, and 48 h after FCI, respectively, and reducing infarct size by 52% at 48 h after FCI. The therapeutic efficacy of 12 mg/kg IQ-1L was comparable to that observed with 25 mg/kg of IQ-1S, indicating that complexation with Li+ improved efficacy of this compound. We conclude that IQ-1L is more effective than IQ-1S in treating cerebral ischemia injury and thus represents a promising anti-inflammatory compound.
... ERK consists of ERK1 (44 kDa) and ERK2 (42 kDa), referred to as ERK1/2. The role of JNK and p-38 in cerebral ischemia injury has been largely clarified, and both of them lead to cell death after activation (13,(36)(37)(38)(39). However, the role of ERK1/ 2 in cerebral ischemia injury has not been determined. ...
Background
Hyperglycemia is one of the major risk factors for stroke and stroke recurrence, leading to aggravated neuronal damage after cerebral ischemia/reperfusion (I/R). ERK1/2 signaling pathway plays a vital role in cerebral ischemic injury. However, the role of the ERK1/2 pathway in hyperglycemia-aggravated ischemic brain damage is not clear.
Methods
Streptozotocin (STZ; 50 mg/kg)-induced diabetes (blood glucose ≥12 mmol/L) or control groups in adult Sprague-Dawley rats were further subdivided into I/R (carotid artery/vein clamping), I/R + PD98059 (I/R plus ERK1/2 inhibitor), and Sham-operated groups (n = 10 each). Neurobehavioral status (Neurological behavior scores) and the volume of the cerebral infarction (TTC staining); brain mitochondrial potential (JCI ratio test) and cell apoptosis (TUNEL assay); RAS protein expression, phosphorylated/total ERK1/2 and Drp-1 (Dynamic-related protein 1) protein levels (Western blotting); mitochondrial fusion-related proteins mitofusin-1/2 (Mfn1/2), optic atrophy (OPA-1) and mitochondrial fission 1 (Fis1), and autophagy-associated proteins Beclin-1, LC3-I/II and P62 (Western blotting and immunohistochemistry) were analyzed.
Results
The I/R + PD98059 group demonstrated better neurobehavior on the 1 st (p < 0.05) and the 3 rd day (p < 0.01) than the I/R group. Compared to the Sham group, cerebral ischemia/reperfusion brought about neuronal damage in the I/R group (p <0.01). However, treatment with PD98059 showed an improved situation with faster recovery of mitochondrial potential and less apoptosis of neuronal cells in the I/R + PD98059 group (p < 0.01). The I/R group had a higher-level expression of RAS and phosphorylated ERK1/2 and Drp-1 than the diabetes mellitus (DM) group (p < 0.01). The PD98059 treated group showed decreased expression of p-ERK1/2, p-Drp-1, Fis1, and Beclin-1, LC3-I/II and P62, but increased Mfn1/2 and OPA-1 than the I/R group (p < 0.01).
Conclusion
Hyperglycemia worsens cerebral ischemia/reperfusion-induced neuronal damage via ERK1/2 activated cell autophagy and mitochondrial fission.
... The inflammatory cells in the brain upregulate pro-inflammatory factors and excessively activate the P38-MAPK pathways in the neurons, increasing the number of apoptotic neurons [41]. The application of the pro-inflammatory factor inhibitor weakens the degree of phosphorylation and brain tissue damage and decreases nerve cell apoptosis [39,42]. After the P38-MAPK inhibitor was applied to rats with vascular dementia, the amount of hippocampal neuron apoptosis reduced and the memory function was significantly improved [28], which fully indicated that P38-MAPK was involved in the CNS nerve cell injury [43]. ...
Background
Heat stroke (HS) is a serious disease accompany with central nervous system (CNS) injury, such as delirium, convulsion, and coma. Currently, mesenchymal stem cells (MSCs) have been demonstrated novel neuroprotective effects, and thereofre it becomes the aim of the present research to explore the neuroprotective effects and mechanisms of MSCs against HS injury.
Methods
HS rat models were induced in a 40℃ and 65% humidity environment until the rectal temperature reached to 42℃. The verified HS injury model rats were divided into HS group and MSCs-treated group. Each rat in the treated group was infused with 1x106 MSCs suspended in 0.3 ml physiological saline via the tail vein. The rats in the HS- or MSCs-treated groups were further divided into early stage (3d) and late stage (28d). At the set timepoint, the mortality was analyzed and levels of liver and kidney function indicators in blood were measured by automatic biochemical analyzer. The neurons morphologic changes were observed through Nissl staining, and neurological deficit score were performed. Moreover, the levels of inflammatory factors in brain tissue were measured by using a multi-cytokine detection platform, and expression of BDNF, phosphorylated TrkB and P38 were detected by Western Bolt.
Results
MSCs injection significantly reduced the mortality and alleviated the liver and kidney function. Moreover, the neurological deficit and neuronic edema of the hippocampus caused by HS both at 3d and 28d were significantly ameliorated by MSCs administration. Specifically, the injection of MSCs inhibited the high levels of interleukin (IL)-1β, IL-6, tumor necrosis factor-α (TNF-α) and IL-17A caused by HS but elevated the levels of IL-10 and IL-13 in the early period (3d); while in the later period (28d), MSCs significantly increased the levels of IL-10 and IL-13 continuously and inhibited the high level of IL-17A. Furthermore, MSCs injection increased the expressions of BDNF and phosphorylated TrkB (BDNF receptor), meanwhile inhibited the expression of phosphorylated P38 (inflammatory factor) in the brains of HS rats in the early period (3d) but had no significant influence in the later period (28d).
Conclusions
These results suggested that MSCs injection may provide therapeutic effects in HS of rats by improving the liver and kidney function, reducing the CNS damage. Moreover, MSCs injection inhibited the brain inflammatory response of HS rats, and the BDNF-TrkB and P38/MAPK signal pathways may be involved.which may provide a potential mechanism for HS therapy by MSCs administration.
... There is accumulating evidence that inflammatory response cascades are stimulated, leading to further apoptosis and necrosis of cells [36]. Inflammation and apoptosis are involved in the mechanisms of cerebral I/R injury [7,[37][38][39]. ...
The pathogenesis of cerebral ischemia–reperfusion (I/R) injury is complex and does not exhibit an effective strategy. Maternal inflammation represents one of the most important factors involved in the etiology of brain injury in newborns. We aimed to investigate the effect of maternal inflammation on offspring susceptibility to cerebral I/R injury and the mechanisms by which it exerts its effects. Pregnant SD rats were intraperitoneally injected with LPS (300 μg/kg/day) at gestational days 11, 14, and 18. Pups were subjected to MCAO/R on postnatal day 60. Primary neurons were obtained from postnatal day 0 SD rats and subjected to OGD/R. Neurological deficits, brain injury, neuronal viability, neuronal damage, and neuronal apoptosis were assessed. Oxidative stress and inflammation were evaluated, and the expression levels of COX-2/PGD2/DP pathway-related proteins and apoptotic proteins were detected. Maternal LPS exposure significantly increased the levels of oxidative stress and inflammation, significantly activated the COX-2/PGD2/DP2 pathway, and increased proapoptotic protein expression. However, maternal LPS exposure significantly decreased the antiapoptotic protein expression, which subsequently increased neurological deficits and cerebral I/R injury in offspring rats. The corresponding results were observed in primary neurons. Moreover, these effects of maternal LPS exposure were reversed by a COX-2 inhibitor and DP1 agonist but exacerbated by a DP2 agonist. In conclusion, maternal inflammatory exposure may increase offspring susceptibility to cerebral I/R injury. Moreover, the underlying mechanism might be related to the activation of the COX-2/PGD2/DP2 pathway. These findings provide a theoretical foundation for the development of therapeutic drugs for cerebral I/R injury.
