Protective effect of alirocumab, a PCSK9 inhibitor, on the sciatic nerve of rats with diabetic peripheral neuropathy.

Dyslipidemia has been considered a risk factor for diabetic peripheral neuropathy. Proprotein convertase subtilisin-like/Kexin 9 inhibitor (PCSK9) inhibitors are a new type of lipid-lowering drug currently in clinical use. The role of PCSK9 in diabetic peripheral neuropathy is still unclear. In this study, the effect of alirocumab, a PCSK9 inhibitor, on the sciatic nerve in rats with diabetic peripheral neuropathy and its underlying mechanisms were investigated. The diabetic peripheral neuropathy rat model was established by using a high-fat diet combined with streptozotocin injection, and experimental subjects were divided into normal, diabetic peripheral neuropathy, and alirocumab groups. The results showed that Alirocumab improved nerve conduction, morphological changes, and small fiber deficits in rats with DPN, possibly related to its amelioration of oxidative stress and the inflammatory response.

Metabolic crosstalk between skeletal muscle cells and liver through IRF4-FSTL1 in nonalcoholic steatohepatitis.

Inter-organ crosstalk has gained increasing attention in recent times; however, the underlying mechanisms remain unclear. In this study, we elucidate an endocrine pathway that is regulated by skeletal muscle interferon regulatory factor (IRF) 4, which manipulates liver pathology. Skeletal muscle specific IRF4 knockout (F4MKO) mice exhibited ameliorated hepatic steatosis, inflammation, and fibrosis, without changes in body weight, when put on a nonalcoholic steatohepatitis (NASH) diet. Proteomics analysis results suggested that follistatin-like protein 1 (FSTL1) may constitute a link between muscles and the liver. Dual luciferase assays showed that IRF4 can transcriptionally regulate FSTL1. Further, inducing FSTL1 expression in the muscles of F4MKO mice is sufficient to restore liver pathology. In addition, co-culture experiments confirmed that FSTL1 plays a distinct role in various liver cell types via different receptors. Finally, we observed that the serum FSTL1 level is positively correlated with NASH progression in humans. These data indicate a signaling pathway involving IRF4-FSTL1-DIP2A/CD14, that links skeletal muscle cells to the liver in the pathogenesis of NASH.

Skeletal muscle-specific DJ-1 ablation-induced atrogenes expression and mitochondrial dysfunction contributing to muscular atrophy.

BACKGROUND: DJ-1 is a causative gene for Parkinson's disease. DJ-1-deficient mice develop gait-associated progressive behavioural abnormalities and hypoactive forearm grip strength. However, underlying activity mechanisms are not fully explored. METHODS: Western blotting and quantitative real-time polymerase chain reaction approaches were adopted to analyse DJ-1 expression in skeletal muscle from aged humans or mice and compared with young subjects. Skeletal muscle-specific-DJ-1 knockout (MDKO) mice were generated, followed by an assessment of the physical activity phenotypes (grip strength, maximal load capacity, and hanging, rotarod, and exercise capacity tests) of the MDKO and control mice on the chow diet. Muscular atrophy phenotypes (cross-sectional area and fibre types) were determined by imaging and quantitative real-time polymerase chain reaction. Mitochondrial function and skeletal muscle morphology were evaluated by oxygen consumption rate and electron microscopy, respectively. Tail suspension was applied to address disuse atrophy. RNA-seq analysis was performed to indicate molecular changes in muscles with DJ-1 ablation. Dual-luciferase reporter assays were employed to identify the promoter region of Trim63 and Fbxo32 genes, which were indirectly regulated by DJ-1 via the FoxO1 pathway. Cytoplasmic and nuclear fractions of DJ-1-deleted muscle cells were analysed by western blotting. Compound 23 was administered into the gastrocnemius muscle to mimic the of DJ-1 deletion effects. RESULTS: DJ-1 expression decreased in atrophied muscles of aged human (young men, n = 2; old with aged men, n = 2; young women, n = 2; old with aged women, n = 2) and immobilization mice (n = 6, P < 0.01). MDKO mice exhibited no body weight difference compared with control mice on the chow diet (Flox, n = 8; MDKO, n = 9). DJ-1-deficient muscles were slightly dystrophic (Flox, n = 7; MDKO, n = 8; P < 0.05), with impaired physical activities and oxidative capacity (n = 8, P < 0.01). In disuse-atrophic conditions, MDKO mice showed smaller cross-sectional area (n = 5, P < 0.01) and more central nuclei than control mice (Flox, n = 7; MDKO, n = 6; P < 0.05), without alteration in muscle fibre types (Flox, n = 6; MDKO, n = 7). Biochemical analysis indicated that reduced mitochondrial function and upregulated of atrogenes induced these changes. Furthermore, RNA-seq analysis revealed enhanced activity of the FoxO1 signalling pathway in DJ-1-ablated muscles, which was responsible for the induction of atrogenes. Finally, compound 23 (an inhibitor of DJ-1) could mimic the effects of DJ-1 ablation in vivo. CONCLUSIONS: Our results illuminate the crucial of skeletal muscle DJ-1 in the regulation of catabolic signals from mechanical stimulation, providing a therapeutic target for muscle wasting diseases.

Muscle PARP1 inhibition extends lifespan through AMPKα PARylation and activation in Drosophila.

Poly(ADP-ribose) polymerase-1 (PARP1) has been reported to play an important role in longevity. Here, we showed that the knockdown of the PARP1 extended the lifespan of Drosophila, with particular emphasis on the skeletal muscle. The muscle-specific mutant Drosophila exhibited resistance to starvation and oxidative stress, as well as an increased ability to climb, with enhanced mitochondrial biogenesis and activity at an older age. Mechanistically, the inhibition of PARP1 increases the activity of AMP-activated protein kinase alpha (AMPKα) and mitochondrial turnover. PARP1 could interact with AMPKα and then regulate it via poly(ADP ribosyl)ation (PARylation) at residues E155 and E195. Double knockdown of PARP1 and AMPKα, specifically in muscle, could counteract the effects of PARP1 inhibition in Drosophila. Finally, we showed that increasing lifespan via maintaining mitochondrial network homeostasis required intact PTEN induced kinase 1 (PINK1). Taken together, these data indicate that the interplay between PARP1 and AMPKα can manipulate mitochondrial turnover, and be targeted to promote longevity.

Transcriptomics Dissection of Calorie Restriction and Exercise Training in Brown Adipose Tissue and Skeletal Muscle.

Calorie restriction (CR) and exercise training (EX) are two critical lifestyle interventions for the prevention and treatment of metabolic diseases, such as obesity and diabetes. Brown adipose tissue (BAT) and skeletal muscle are two important organs for the generation of heat. Here, we undertook detailed transcriptional profiling of these two thermogenic tissues from mice treated subjected to CR and/or EX. We found transcriptional reprogramming of BAT and skeletal muscle as a result of CR but little from EX. Consistent with this, CR induced alterations in the expression of genes encoding adipokines and myokines in BAT and skeletal muscle, respectively. Deconvolution analysis showed differences in the subpopulations of myogenic cells, mesothelial cells and endogenic cells in BAT and in the subpopulations of satellite cells, immune cells and endothelial cells in skeletal muscle as a result of CR or EX. NicheNet analysis, exploring potential inter-organ communication, indicated that BAT and skeletal muscle could mutually regulate their fatty acid metabolism and thermogenesis through ligands and receptors. These data comprise an extensive resource for the study of thermogenic tissue molecular responses to CR and/or EX in a healthy state.

Obese Skeletal Muscle-Expressed Interferon Regulatory Factor 4 Transcriptionally Regulates Mitochondrial Branched-Chain Aminotransferase Reprogramming Metabolome.

In addition to the significant role in physical activity, skeletal muscle also contributes to health through the storage and use of macronutrients associated with energy homeostasis. However, the mechanisms of regulating integrated metabolism in skeletal muscle are not well-defined. Here, we compared the skeletal muscle transcriptome from obese and lean control subjects in different species (human and mouse) and found that interferon regulatory factor 4 (IRF4), an inflammation-immune transcription factor, conservatively increased in obese subjects. Thus, we investigated whether IRF4 gain of function in the skeletal muscle predisposed to obesity and insulin resistance. Conversely, mice with specific IRF4 loss in skeletal muscle showed protection against the metabolic effects of high-fat diet, increased branched-chain amino acids (BCAA) level of serum and muscle, and reprogrammed metabolome in serum. Mechanistically, IRF4 could transcriptionally upregulate mitochondrial branched-chain aminotransferase (BCATm) expression; subsequently, the enhanced BCATm could counteract the effects caused by IRF4 deletion. Furthermore, we demonstrated that IRF4 ablation in skeletal muscle enhanced mitochondrial activity, BCAA, and fatty acid oxidation in a BCATm-dependent manner. Taken together, these studies, for the first time, established IRF4 as a novel metabolic driver of macronutrients via BCATm in skeletal muscle in terms of diet-induced obesity.

Neuropeptide Y Plays an Important Role in the Relationship Between Brain Glucose Metabolism and Brown Adipose Tissue Activity in Healthy Adults: A PET/CT Study.

Introduction: Brown adipose tissue (BAT) becomes the favorite target for preventing and treating metabolic diseases because the activated BAT can produce heat and consume energy. The brain, especially the hypothalamus, which secretes Neuropeptide Y (NPY), is speculated to regulate BAT activity. However, whether NPY is involved in BAT activity's central regulation in humans remains unclear. Thus, it's essential to explore the relationship between brain glucose metabolism and human BAT activity. Methods: A controlled study with a large sample of healthy adults used Positron emission tomography/computed tomography (PET/CT) to noninvasively investigate BAT's activity and brain glucose metabolism in vivo. Eighty healthy adults with activated BAT according to the PET/CT scan volunteered to be the BAT positive group, while 80 healthy adults without activated BAT but with the same gender, similar age, and BMI, scanning on the same day, were recruited as the control (BAT negative). We use Statistical parametric mapping (SPM) to analyze the brain image data, Picture Archiving & Communication System (PACS), and PET/CT Viewer software to calculate the semi-quantitative values of brain glucose metabolism and BAT activity. ELISA tested the levels of fasting plasma NPY. The multiple linear regression models were used to analyze the correlation between brain glucose metabolism, the level of NPY, and the BAT activity in the BAT positive group. Results: (1) Compared with controls, BAT positive group showed significant metabolic decreases mainly in the right Insula (BA13a, BA13b) and the right claustrum (uncorrected P <0.01, adjusted BMI). (2) The three brain regions' semi-quantitative values in the BAT positive group were significantly lower than the negative group (all P values < 0.05). (3) After adjusting for age, gender, BMI, and outside temperature, there was a negative correlation between brain metabolic values and BAT activity (all P values < 0.05). However, after further adjusting for NPY level, there were no significant differences between the BA13b metabolic values and BAT activity (P>0.05), while the correlation between the BA13a metabolic values and BAT activity still was significant (P< 0.05). Conclusions: Regional brain glucose metabolism is closely related to healthy adults' BAT activity, which may be mediated by NPY.

Advances with Long Non-Coding RNAs in Diabetic Peripheral Neuropathy.

Long non-coding RNAs (lncRNAs) are a group of non-coding RNAs longer than 200 nucleotides, which are defined as transcripts. The lncRNAs are involved in regulating gene expression at epigenetic, transcriptional, and post-transcriptional levels. Recent studies have found that lncRNA is closely related to many diseases like neurological diseases, endocrine and metabolic disorders. Diabetic peripheral neuropathy (DPN) is one of the most common chronic complications of diabetes mellitus. In this review, we highlight the latest research related to lncRNAs in DPN.

Long Non­Coding RNAs Regulate Inflammation in Diabetic Peripheral Neuropathy by Acting as ceRNAs Targeting miR-146a-5p.

BACKGROUND: Long non-coding RNAs (lncRNAs), as competing endogenous RNAs (ceRNAs), can regulate various pathophysiological processes by binding competitively to microRNAs at the post-transcription level. Our previous work demonstrated that miR-146a-5p was lowly expressed in diabetic peripheral neuropathy (DPN) rats. However, the ceRNA network in DPN mediated by lncRNAs and miR-146a-5p remains to be explored. METHODS: Two groups of rats (n=4 per group), a type 2 diabetes (T2DM) group and a DPN group, were used in this study. Sciatic nerve conduction velocity (NCV) of each rat was determined at the 6th and the 12th week. LncRNA microarray analysis was performed in the sciatic nerve of DPN and T2DM rats. Based on the TargetScan algorithm and the miRanda database, we determined the differentially expressed (DE) lncRNAs bound to miR-146a-5p. Furthermore, we verified the DE lncRNAs potentially bound to miR-146a-5p by qRT-PCR. The genes targeted by miR-146a-5p were identified by bioinformatics prediction and experimental techniques. RESULTS: We found 413 DE lncRNAs between DPN and T2DM rats (|log2FC| ≥ 2 and adjust P ≤ 0.05). Eight DE lncRNAs were predicted to bind to miR-146a-5p by both algorithms, of which four were verified by qRT-PCR. TRAF6, IRAK1, and SMAD4 were identified as miR-146a-5p targeted genes and were predominantly enriched in the inflammatory signaling pathway. CONCLUSION: LncRNAs may contribute to the pathogenesis of DPN by regulating inflammation through functioning as ceRNAs of miR-146a-5p.

MicroRNA-146a-5p Downregulates the Expression of P-Glycoprotein in Rats with Lithium-Pilocarpine-Induced Status Epilepticus.

Increasing evidence supports that the efflux transporters, especially P-glycoprotein (P-gp), have vital roles on drug resistance in epilepsy. Overexpression of P-gp in the brain could reduce the anti-epileptic drugs (AEDs) concentration in the epileptogenic zone, resulting in drug resistance. Studies have demonstrated that recurrent seizures induce the expression of P-gp and status epilepticus (SE) could upregulate the expression of P-gp, resulting in drug resistance. MicroRNAs (miRNAs), as endogenous regulators, represent small regulatory RNA molecules that have been shown to act as negative regulators of gene expression in different biological processes. We investigated the impact of miR-146a-5p on the expression of P-gp in status epilepticus rat model. The expression of miR-146a-5p in rat cortex and hippocampus was measured by quantitative RT-PCR at 2 weeks after induction of SE. Meanwhile, we detected the expression of P-gp in the brain of SE rats using Western blotting and immunohistochemistry. Upregulation of miR-146a-5p and overexpression of P-gp were evident at 2 weeks after SE. Moreover, the expression of P-gp was downregulated by injection of miR-146a mimic into the hippocampus. We also detected the expression of interleukin-1 receptor-associated protein kinases-1 (IRAK1) and tumor necrosis factor receptor-associated factor 6 (TRAF6) and nuclear factor-kappaB (NF-κB) p65 using Western blotting and immunohistochemistry, which indicated the expression of IRAK1, TRAF6 and NF-κB p-p65/p65 increased in the brain of SE rats, and overexpression of miR-146a-5p could downregulate the expression of IRAK1, TRAF6, NF-κB p-p65/p65 and P-gp. Our study indicated that miR-146a-5p may decrease the expression of P-gp in status epilepticus rats via NF-κB signaling pathway.

The Neuroprotective Effect of Astaxanthin on Pilocarpine-Induced Status Epilepticus in Rats.

Cognitive dysfunction is one of the serious complications induced by status epilepticus (SE), which has a significant negative impact on patients' quality of life. Previous studies demonstrated that the pathophysiological changes after SE such as oxidative stress, inflammatory reaction contribute to neuronal damage. A recent study indicated that preventive astaxanthin (AST) alleviated epilepsy-induced oxidative stress and neuronal apoptosis in the brain. In the present study, rats were treated with vehicle or AST 1 h after SE onset and were injected once every other day for 2 weeks (total of seven times). The results showed that the cognitive function in SE rats was significantly impaired, and AST treatment improved cognitive function in the Morris water maze (MWM). Magnetic resonance imaging (MRI), hematoxylin-eosin (HE) staining and TdT-mediated dUTP Nick-End Labeling (TUNEL) staining showed obvious damage in the hippocampus of SE rats, and AST alleviated the damage. Subsequently, we evaluated the effect of AST on relative pathophysiology to elucidate the possible mechanisms. To evaluate the oxidative stress, the expression of malondialdehyde (MDA) and superoxide dismutase (SOD) in plasma were detected using commercially available kits. NADPH oxidase-4 (Nox-4), p22phox, NF-E2-related factor 2 (Nrf-2), heme oxygenase 1 (Ho-1) and sod1 in the parahippocampal cortex and hippocampus were detected using western blot and real-time polymerase chain reaction (RT-PCR). The levels of MDA in plasma and Nox-4 and p22phox in the brain increased in SE rats, and the levels of SOD in plasma and Nrf-2, Ho-1 and sod1 in the brain decreased. Treatment with AST alleviated these changes. We also detected the levels of inflammatory mediators like cyclooxygenase-2 (cox-2), interleukin-1ß (IL-1ß), tumor necrosis factor-α (TNF-α) and NF-κB phosphorylation p65 (p-p65)/p65 in the brain. The inflammatory reaction was significantly activated in the brain of SE rats, and AST alleviated neuroinflammation. We detected the levels of p-Akt, Akt, B-cell lymphoma-2 (Bcl-2), Bax, cleaved caspase-3, and caspase-3 in the parahippocampal cortex and hippocampus using western blot. The levels of p-Akt/Akt and Bcl-2 decreased in SE rats, Bax and cleaved caspase-3/caspase-3 increased, while AST alleviated these changes. The present study indicated that AST exerted an reobvious neuroprotective effect in pilocarpine-induced SE rats.

Nanoparticle-microRNA-146a-5p polyplexes ameliorate diabetic peripheral neuropathy by modulating inflammation and apoptosis.

Nontoxic and nonimmunogenic nanoparticles play an increasingly important role in the application of pharmaceutical nanocarriers. The pathogenesis of diabetic peripheral neuropathy (DPN) has been extensively studied. However, the role of microRNAs in DPN remains to be clarified. We verified in vitro that miR-146a-5p mimics inhibited the expression of proinflammatory cytokines and apoptosis. Then, we explored the protective effect of nanoparticle-miRNA-146a-5p polyplexes (nano-miR-146a-5p) on DPN rats. We demonstrated that nano-miR-146a-5p improved nerve conduction velocity and alleviated the morphological damage and demyelination of the sciatic nerve of DPN rats. The expression of the inflammatory cytokines, caspase-3, and cleaved caspase-3 in the sciatic nerve was inhibited by nano-miR-146a-5p. Additionally, nano-miR-146a-5p increased the expression of myelin basic protein. These results all indicated that nano-miR-146a-5p had a protective effect on peripheral nerves in the DPN rat model, which may occur through the regulation of the inflammatory response and apoptosis.

The Protective Effect of Astaxanthin on Cognitive Function via Inhibition of Oxidative Stress and Inflammation in the Brains of Chronic T2DM Rats.

Currently, there are no effective treatments for diabetes-related cognitive dysfunction. Astaxanthin (AST), the most powerful antioxidant in nature, exhibits diverse biological functions. In this study, we tried to explore whether AST would ameliorate cognitive dysfunction in chronic type 2 diabetes mellitus (T2DM) rats. The T2DM rat model was induced via intraperitoneal injection of streptozotocin. Forty Wistar rats were divided into a normal control group, an acute T2DM group, a chronic T2DM group, and an AST group (treated with AST at a dose of 25 mg/kg three times a week). The Morris water maze test showed that the percentage of time spent in the target quadrant of the AST group was identical to that of the chronic T2DM group, while the escape latency of the AST group was decreased in comparison to that of the chronic T2DM group. Histology of the hippocampus revealed that AST ameliorated the impairment in the neurons of diabetic rats. Western blot showed that AST could upregulate nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase 1 (HO-1) expression and inhibit nuclear transcription factor kappa B (NF-κB) p65 activation in the hippocampus. We found that AST increased the level of superoxide dismutase (SOD) and decreased the level of malondialdehyde (MDA) in the hippocampus. In addition, the levels of interleukin 1 beta (IL-1ß) and interleukin 6 (IL-6) were reduced in the AST group compared with those in the chronic T2DM group. The findings of this research imply that AST might inhibit oxidative stress and inflammatory responses by activating the Nrf2-ARE signaling pathway.

MicroRNA-146a: A Comprehensive Indicator of Inflammation and Oxidative Stress Status Induced in the Brain of Chronic T2DM Rats.

Objective: It was demonstrated that inflammation and oxidative stress induced by hyperglycemia were closely associated with alteration of miR-146a. Here, we investigated the role of miR-146a in mediating inflammation and oxidative stress in the brain of chronic T2DM rats. Methods: The chronic T2DM (cT2DM) models were induced by intraperitoneal administration of STZ (35 mg/kg) after being fed a high-fat, high-sugar diet for 6 weeks. H&E staining was conducted to observe the morphological impairment of the rat hippocampus. The expressions of inflammatory mediators (COX-2, TNF-α, IL-1ß) and antioxidant proteins (Nrf2, HO-1) were measured by western blot. The levels of MDA and SOD were detected by the respective activity assay kit. The levels of p22phox and miR-146a were examined by quantitative real-time PCR (qRT-PCR). The expressions of IRAK1, TRAF6 and NF-κB p65 were measured by western blot and qRT-PCR. Pearson correlation analysis was performed to investigate the correlations between miR-146a and inflammatory mediators as well as oxidative stress indicators. Results: The expression of miR-146a was negatively correlated with inflammation and oxidative stress status. In the brain tissues of cT2DM rats, it was observed that the expressions of inflammatory mediators (COX-2, TNF-α, IL-1ß) and oxidative stress indicators including MDA and p22phox were elevated, which were negatively correlated with the expression of miR-146a. While, the antioxidant proteins (Nrf2, HO-1, SOD) levels decreased in the brain of cT2DM rats, which were positively correlated with the miR-146a level. The expressions of NF-κB p65 and its specific modulators (IRAK1&TRAF6) were elevated in the brain of cT2DM rats, which might be inhibited by miR-146a. Conclusion: Our results implied that increased inflammation and oxidative stress status were associated with brain impairment in cT2DM rats, which were negatively correlated with miR-146a expression. Thus, miR-146a may serve as a negative comprehensive indicator of inflammation and oxidative stress status in the brain of chronic T2DM rats.

Involvement of microRNA-146a in diabetic peripheral neuropathy through the regulation of inflammation.

PURPOSE: Recent evidence has shown the involvement of inflammation in the development of diabetic peripheral neuropathy (DPN). MicroRNA-146a (miR-146a) is closely involved in the inflammatory response. However, the role of miR-146a in the inflammatory reaction in DPN has not been clarified. This study was designed to explore the role of miR-146a in the regulation of inflammatory responses in DPN. METHODS: Rats were randomly divided into three groups (n=6 per group): control group, type 2 diabetes mellitus (T2DM) group and DPN group. T2DM and DPN rats were intraperitoneally injected with streptozotocin. Sciatic nerve conduction velocity (NCV) was determined at the 6th week and the 12th week in each group. The expression of microRNAs was detected by quantitative real-time polymerase chain reaction in three sciatic nerves for each group of rats. Expression of inflammatory cytokines in nerve tissues and plasma was measured by Western blot and Bio-Plex Pro™ assays. RESULTS: The NCV and expression levels of miR-146a in the DPN group were significantly decreased (P<0.01) compared to the other two groups. Expression of tumor necrosis factor alpha (TNF-α), interleukin 1 beta (IL-1ß) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) in the DPN group was significantly increased compared with the control and T2DM groups (P<0.01). Pearson's correlation analysis showed that the expression level of miR-146a was negatively correlated with the levels of IL-1ß, TNF-α and NF-κB. CONCLUSION: miR-146a is involved in the pathogenesis of DPN, and its expression level is closely related to the inflammatory responses that aggravate sciatic nerve injuries.

Involvement of microRNA-146a in the Inflammatory Response of S tatus Epilepticus Rats.

BACKGROUND: Status epilepticus (SE), is characterized by high mortality and morbidity, which can cause neuronal injury, neuronal death and alteration of neuronal networks, Recently, inflammation was shown to play a significant role in SE pathogenesis. And miRNA-146a has been shown to be involved in inflammation and to inhibit inflammatory cytokines through NF-κB pathway. In our study, we investigated the relationship between inflammation and miR-146a expression. METHOD: The SE rat model was induced by lithium-pilocarpine. Hematoxylin and eosin staining (H&E) was performed to observe the histopathology of the rat hippocampus. The expression of COX-2, TNF-α, IL-6 and IL-1ß were respectively measured by Western blot and Bio-Plex ProTM Assays. The miR-146a expression in hippocampus tissue was measured by Quantitative real-time PCR. RESULTS: microRNA-146a was highly expressed in the hippocampus of SE rats coupled with increased level of inflammatory cytokines than the normal group. And TQ can attune the expression of inflammatory cytokines, meanwhile, miR-146a was lower in TQ group. The expression of miRNA-146a were positively correlated with the level of inflammatory reaction. CONCLUSION: TQ may alleviate the inflammatory reaction by inhibiting the NF-κB signaling pathway. Our study shows that miRNA-146a was involved in the inflammatory response and indicated inflammation severity in SE rats. Therefore, miRNA-146a may serve as a potential biomarker or a therapeutic target in SE.

Protective Effects of Thymoquinone Against Convulsant Activity Induced by Lithium-Pilocarpine in a model of Status Epilepticus.

Inflammation plays a pivotal role in status epilepticus (SE). Thymoquinone (TQ) is a bioactive monomer extracted from black seed (Nigella sativa) oil, which has anti-inflammatory properties in the context of various diseases. This study explored the protective effects of TQ in SE and used a lithium-pilocarpine model of SE to investigate the underlying mechanism, which was related to inflammation mediated by the NF-κB signaling pathway. In the present study, latency to SE increased in the TQ-pretreated group compared with the SE group, and the incidence of SE was significantly reduced. The seizure severity score measured on the Racine scale was significantly decreased in the TQ group compared with the SE group. Moreover, the results of the behavioral tests suggested that TQ may also have a protective effect on learning and memory functions. Finally, we further investigated the protective mechanism of TQ. The results showed that TQ-pretreatment significantly downregulated the protein levels of COX-2 and TNF-α in the brain, in a manner mediated by the NF-κB signaling pathway. These findings demonstrate that TQ attenuates convulsant activity via an anti- inflammation signaling pathway in a model of SE.