The Contributions of Thrombospondin-1 to Epilepsy Formation.

Epilepsy is a neural network disorder caused by uncontrolled neuronal hyperexcitability induced by an imbalance between excitatory and inhibitory networks. Abnormal synaptogenesis plays a vital role in the formation of overexcited networks. Recent evidence has confirmed that thrombospondin-1 (TSP-1), mainly secreted by astrocytes, is a critical cytokine that regulates synaptogenesis during epileptogenesis. Furthermore, numerous studies have reported that TSP-1 is also involved in other processes, such as angiogenesis, neuroinflammation, and regulation of Ca2+ homeostasis, which are closely associated with the occurrence and development of epilepsy. In this review, we summarize the potential contributions of TSP-1 to epilepsy development.

Increased thrombospondin-1 levels contribute to epileptic susceptibility in neonatal hyperthermia without seizures via altered synaptogenesis.

Childhood febrile seizures (FS) represent one of the most common types of seizures and may lead to severe neurological damage and an increased risk of epilepsy. However, most children with fevers do not show clinical manifestations of convulsions, and the consequences of hyperthermia without seizures remain elusive. This study focused on hyperthermia not reaching the individual's seizure threshold (sub-FS stimulus). Changes in thrombospondin-1 (TSP-1) levels, synapses, seizure susceptibility, and seizure severity in subsequent FS were investigated in rats exposed to sub-FS stimuli. Pharmacological and genetic interventions were used to explore the role of TSP-1 in sub-FS-induced effects. We found that after sub-FS stimuli, the levels of TSP-1 and synapses, especially excitatory synapses, were concomitantly increased, with increased epilepsy and FS susceptibility. Moreover, more severe neuronal damage was found in subsequent FS. These changes were temperature dependent. Reducing TSP-1 levels by genetic intervention or inhibiting the activation of transforming growth factor-ß1 (TGF-ß1) by Leu-Ser-Lys-Leu (LSKL) led to lower synapse/excitatory synapse levels, decreased epileptic susceptibility, and attenuated neuronal injury after FS stimuli. Our study confirmed that even without seizures, hyperthermia may promote synaptogenesis, increase epileptic and FS susceptibility, and lead to more severe neuronal damage by subsequent FS. Inhibition of the TSP-1/TGF-ß1 pathway may be a new therapeutic target to prevent detrimental sub-FS sequelae.

Inhibition of PTEN-induced kinase 1 autophosphorylation may assist in preventing epileptogenesis induced by pentylenetetrazol.

PTEN-induced kinase 1 (PINK1) autophosphorylation-triggered mitophagy is the main mitophagic pathway in the nervous system. Moreover, multiple studies have confirmed that mitophagy is closely related to the occurrence and development of epilepsy. Therefore, we speculated that the PINK1 autophosphorylation may be involved in epileptogenesis by mediating mitophagic pathway. This study aimed to explore the contribution of activated PINK1 to epileptogenesis induced by pentylenetetrazol (PTZ) in Sprague‒Dawley rats. During PTZ-induced epileptogenesis, the levels of phosphorylated PINK1 were increased, accompanied by elevated mitophagy, mitochondria oxidative stress and neuronal damage. After microRNA intervention targeting translocase outer mitochondrial membrane 7 (TOM7) or overlapping with the m-AAA protease 1 homolog (OMA1), the levels of PINK1 phosphorylation, mitophagy, mitochondrial oxidative stress, neuronal injury were observed in the rats with induced epileptogenesis. Furthermore, inhibiting of the expression of TOM7, a positive regulator of PINK1 autophosphorylation, reversed the increase in PINK1 phosphorylation and alleviated mitophagy, neuronal injury, thereby preventing epileptogenesis. In contrast, reducing the levels of OMA1, a negative regulator of PINK1 autophosphorylation, led to increased phosphorylation of PINK1, accompanied by aggravated neuronal injury and ultimately, epileptogenesis. This study confirmed the contribution of activated PINK1 to PTZ-induced epileptogenesis and suggested that the inhibition of PINK1 autophosphorylation may assist in preventing epileptogenesis.

Xenon inhalation attenuates neuronal injury and prevents epilepsy in febrile seizure Sprague-Dawley pups.

Background: Febrile seizures (FS) usually occur in childhood and may cause irreversible neuronal damage, cognitive functional defects, and an increase in the risk of epilepsy later in life. Anti-epileptic drugs (AEDs), currently used to treat FS in children, can relieve seizures. However, their effects in preventing the risk of developing epilepsy in later life are unsatisfactory. Moreover, AEDs may damage child brain development. Here, we evaluated the efficiency of xenon in treating prolonged FS (PFS) and preventing epilepsy in Sprague-Dawley pups. Methods: Prolonged FS was induced by hyperthermic treatment. After 90 min of PFS, the pups in the xenon treatment group were immediately treated with 70% xenon/21% oxygen/9% nitrogen for 60 min. The levels of glutamate, mitochondrial oxidative stress, mitophagy, and neuronal injury, seizures, learning, and memory functions were measured at specific time points. Results: Neonatal period PFS led to spontaneous seizure, learning and memory dysfunction, accompanied by increased levels of glutamate, mitochondrial oxidative stress, mitophagy, and neuronal injury. Xenon treatment alleviated the changes caused by PFS and reduced the risk of PFS developing into epilepsy later. Conclusion: Our results suggest that xenon inhalation could be a potential therapeutic strategy to attenuate neuronal injury and prevent epilepsy in patients with FS.

The REM microarousal and REM duration as the potential indicator in paradoxical insomnia.

OBJECTIVE: Although paradoxical insomnia is a prevalent subtype of chronic insomnia, the etiology of it is unclear. Contrary to complaints of little or no sleep, polysomnography (PSG) findings show that paradoxical insomnia patients have near normal sleep macrostructure. The purpose of this study is to determine the changes of microstructure and explore the etiology of paradoxical insomnia. METHODS: The PSG findings of 89 paradoxical insomnia patients were compared with those of 41 gender balanced healthy controls without sleep complaints. All subjects underwent nocturnal PSG recordings. Conventional PSG measures and microarousals were quantified and statistically analyzed. Receiver operating characteristic curve and correlation analysis were used to evaluate the potential of REM sleep microarousals and REM duration as indicators of paradoxical insomnia. RESULTS: Compared with the controls, paradoxical insomnia patients had no significant differences in sleep macrostructures. Statistical analysis showed that non-rapid eye movement (NREM) microarousals revealed no significant differences between paradoxical insomnia patients and controls. Noticeably, more spontaneous microarousals appeared in rapid eye movement (REM) stage for paradoxical insomnia patients. Based on receiver operating characteristic curve (ROC), the optimal cutoff value of REM sleep microarousals could predict paradoxical insomnia. Furthermore, a positive correlation between microarousals in REM sleep and the duration of REM sleep was presented in paradoxical insomnia patients. CONCLUSIONS: The frequency of REM microarousals and the duration of REM sleep could reflect the real sleep state of paradoxical insomnia patients. That suggested PSG investigation extended to microarousal could be helpful to understand the etiology in paradoxical insomnia.

Attenuated iron stress and oxidative stress may participate in anti-seizure and neuroprotective roles of xenon in pentylenetetrazole-induced epileptogenesis.

The previous studies have demonstrated the excellent neuroprotective effects of xenon. In this study, we verified the anti-seizure and neuroprotective roles of xenon in epileptogenesis and evaluated the involvement of oxidative stress and iron accumulation in the protective roles of xenon. Epileptogenesis was induced by pentylenetetrazole (PTZ) treatment in Sprague-Dawley rats. During epileptogenesis, we found increased levels of iron and oxidative stress accompanied by elevated levels of divalent metal transporter protein 1 and iron regulatory protein 1, which are closely associated with iron accumulation. Meanwhile, the levels of autophagy and mitophagy increased, alongside significant neuronal damage and cognitive deficits. Xenon treatment reversed these effects: oxidative stress and iron stress were reduced, neuronal injury and seizure severity were attenuated, and learning and memory deficits were improved. Thus, our results confirmed the neuroprotective and anti-seizure effects of xenon treatment in PTZ-induced epileptogenesis. The reduction in oxidative and iron stress may be the main mechanisms underlying xenon treatment. Thus, this study provides a potential intervention strategy for epileptogenesis.

IGH/BCL2 Status Better Predicts Clinico-Pathological Behavior in Primary Splenic Follicular Lymphoma than Histological Grade and Other Molecular Markers.

Splenic lymphoma may be primary or secondary. Primary splenic lymphoma's are rare and usually of follicular cell origin representing <1% of Non-Hodgkin's Lymphoma's. Most are secondary with 35% representing Marginal Cell sub-type with the rest being Diffuse Large B-Cell Lymphoma's. Unlike the uniformly aggressive clinical course of Diffuse Large B-Cell Lymphoma's, biological behavior of Primary Splenic CD10-Positive Small B-Cell Lymphoma/Follicular Lymphoma remains less well defined. We present here a solitary splenic mass confirmed as Primary Splenic CD10-Positive Small B-Cell Lymphoma/Follicular Lymphoma after a diagnostic splenectomy. Biopsy revealed monomorphic small lymphoid cells with low grade mitotic activity. Flow cytometry showed a lambda restricted population of B-Cells displaying dim CD19 and CD10. The cells were negative for CD5, CD11c, and CD103. FISH was negative for IGH/BCL2 fusion unlike nodal Follicular Lymphoma's which are usually positive for this translocation. Evidence from this case and a review of literature support the finding that Primary Splenic CD10-Positive Small B-Cell Lymphoma/Follicular Lymphoma is less likely to have the classic IGH-BCL2 fusion and the associated chromosomal 14;18 translocation. This profile is associated with less aggressive clinical behavior even when histopathology represents a high-grade pattern. In such cases splenectomy alone is adequate for localized disease when negative for IGH/BCL2 fusion regardless of histological grade.

Celastrol inhibits rheumatoid arthritis by inducing autophagy via inhibition of the PI3K/AKT/mTOR signaling pathway.

OBJECTIVE: Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disorder of the synovial joints. Celastrol (Cel) is a quinone-methylated triterpenoid extracted from Tripterygium wilfordii Hook F (TwHF) that has been proven to be effective in treating RA. However, the underlying molecular mechanism of celastrol in the treatment of RA remains unknown. This study explored the protective effect of celastrol against RA and the specific mechanisms of celastrol in vitro and in vivo. METHODS: A chicken type II collagen (CII)-induced arthritis (CIA) mouse model was used to explore the anti-arthritic effects of celastrol, and paw swelling degree, the poly-arthritis index score and serum cytokine levels were determined. Pathological morphology was observed using hematoxylin and eosin (H&E) staining. The influences of celastrol on the proliferation of tumor necrosis factor-α (TNF-α)-induced fibroblast-like synoviocytes (FLSs) were tested by Cell Counting Kit-8 (CCK-8) assays and5-ethynyl-2'-deoxyuridine (EdU) staining assays. The level of autophagy was detected by transmission electron microscopy (TEM). Furthermore, the PI3K/AKT/mTOR pathway and the status of autophagy in the CIA model and FLSs were also detected by western blot and immunofluorescence staining. RESULTS: The results showed that celastrol decreased arthritis severity and inhibited TNF-α-induced FLSs proliferation. Additionally, celastrol decreased the secretion of pro-inflammatory cytokines. Moreover, celastrol increased autophagosome levels and LC3B protein expression in TNF-α-treated FLSs. Furthermore, celastrol increased the protein expression of LC3-II and Beclin-1 and decreased the phosphorylation degree of mTOR and AKT. CONCLUSION: In conclusion, our findings confirmed that celastrol ameliorates RA via the up-regulation of autophagy by inhibiting the PI3K/AKT/mTOR axis.

Anti-Seizure and Neuronal Protective Effects of Irisin in Kainic Acid-Induced Chronic Epilepsy Model with Spontaneous Seizures.

An increased level of reactive oxygen species is a key factor in neuronal apoptosis and epileptic seizures. Irisin reportedly attenuates the apoptosis and injury induced by oxidative stress. Therefore, we evaluated the effects of exogenous irisin in a kainic acid (KA)-induced chronic spontaneous epilepsy rat model. The results indicated that exogenous irisin significantly attenuated the KA-induced neuronal injury, learning and memory defects, and seizures. Irisin treatment also increased the levels of brain-derived neurotrophic factor (BDNF) and uncoupling protein 2 (UCP2), which were initially reduced following KA administration. Furthermore, the specific inhibitor of UCP2 (genipin) was administered to evaluate the possible protective mechanism of irisin. The reduced apoptosis, neurodegeneration, and spontaneous seizures in rats treated with irisin were significantly reversed by genipin administration. Our findings indicated that neuronal injury in KA-induced chronic epilepsy might be related to reduced levels of BDNF and UCP2. Moreover, our results confirmed the inhibition of neuronal injury and epileptic seizures by exogenous irisin. The protective effects of irisin may be mediated through the BDNF-mediated UCP2 level. Our results thus highlight irisin as a valuable therapeutic strategy against neuronal injury and epileptic seizures.

Attenuated succinate accumulation relieves neuronal injury induced by hypoxia in neonatal mice.

Hypoxia causes neonatal neuronal damage. However, the underlying mechanism remains unclear. This study aimed to explore the changes in succinate levels and identify the mechanisms underlying their contribution to hypoxia-induced damage in newborn mice. The neonatal C57BL/6J mouse hypoxia model was used in our study. We evaluated the levels of succinate, iron, reactive oxygen species (ROS), and mitochondrial ROS, and assessed mitophagy, neuronal damage, and learning and memory function, after hypoxia treatment. The neonatal mice showed increased succinate levels in the early hypoxia stage, followed by increased levels of oxidative stress, iron stress, neuronal damage, and cognitive deficits. Succinate levels were significantly reduced following treatment with inhibitors of succinate dehydrogenase (SDH), purine nucleotide cycle (PNC), and malate/aspartate shuttle (MAS), with the corresponding attenuation of oxidative stress, iron stress, neuronal damage, and cognitive impairment. Reversal catalysis of SDH through fumarate from the PNC and MAS pathways might be involved in hypoxia-induced succinate accumulation. Succinate accumulation in the early period after hypoxia may crucially contribute to oxidative and iron stress. Relieving succinate accumulation at the early hypoxia stage could prevent neuronal damage and cognitive impairment in neonatal hypoxia.

Mechanism of SMND-309 against lung injury induced by chronic intermittent hypoxia.

INTRODUCTION: Obstructive sleep apnea-hypopnea syndrome (OSAHS) is a common sleep disorder that causes severe physiological disturbance. Evidence showed that OSAHS is an important associated comorbidity that can affect the survival of patients with pulmonary fibrosis. Until now, the potential mechanisms by which OSAHS accelerates the progression of lung fibrosis remain unclear. By constructing a pathological model of chronic intermittent hypoxia (CIH), the present study aimed to explore the pathological progress and potential mechanism of lung injury caused by OSAHS. Meanwhile, SMND-309 was given for treatment to evaluate its potential therapeutic role in CIH-induced lung injury. METHODS: Mice were randomly divided into (C57BL/6 wild-type) WT+(room air) RA, WT + CIH, SMND-309 + RA, and SMND-309 + CIH groups. The WT + CIH and SMND-309 + CIH groups were exposed to CIH condition for 12 weeks, while the other groups were processed in normal oxygen at the same time. The SMND-309 + RA and SMND-309 + CIH groups were intraperitoneally injected with SMND-309 at the last week of the modeling period. After 12 weeks of treatment, three mice from each group were perfused through the heart. Lung tissues were isolated, fixed, sectioned, and stained with H&E, Masson, and immunofluorescence stain. The rest of the lung tissues were harvested for Western blot and ELISA assays. RESULTS: CIH treatment increased the expression of pro-inflammatory factors (TNF-α and IL-6), resulting in lung tissue structure disorder, inflammatory cell infiltration, increased pulmonary capillary permeability, and pulmonary edema. The activation of the NF-κB signaling pathway played a crucial role in the process of inflammation. Noticeably, we observed M2 macrophage accumulation in the lung after CIH exposure, which promoted epithelial-mesenchymal transition (EMT) and pulmonary tissue fibrosis. ELISA assays showed the increased expression of TGF-ß, IL-10, and IL-4 in the CIH group. SMND-309 inhibited pulmonary inflammation, reduced the accumulation of M2 macrophage, alleviated collagen deposition andlung damage. CONCLUSION: CIH could induce chronic lung inflammation, promote the activation of M2 macrophages, trigger the occurrence of EMT, and accelerate the deposition of lung collagen, eventually leading to lung tissue damage. This study presents a possible explanation by which interstitial lung diseases, particularly idiopathic pulmonary fibrosis (IPF) with OSAHS, are usually associated with fast progress and poor prognosis. SMND-309 showed a good protective effect on CIH-induced lung damage.

The anti-tumor efficacy of 20(S)-protopanaxadiol, an active metabolite of ginseng, according to fasting on hepatocellular carcinoma.

BACKGROUND: 20(S)-protopanaxadiol (20(S)-PPD), one of the main active metabolites of ginseng, performs a broad spectrum of anti-tumor effects. Our aims are to search out new strategies to enhance anti-tumor effects of natural products, including 20(S)-PPD. In recent years, fasting has been shown to be multi-functional on tumor progression. Here, the effects of fasting combined with 20(S)-PPD on hepatocellular carcinoma growth, apoptosis, migration, invasion and cell cycle were explored. METHODS: CCK-8 assay, trypan blue dye exclusion test, imagings photographed by HoloMonitorTM M4, transwell assay and flow cytometry assay were performed for functional analyses on cell proliferation, morphology, migration, invasion, apoptosis, necrosis and cell cycle. The expressions of genes on protein levels were tested by western blot. Tumor-bearing mice were used to evaluate the effects of intermittent fasting combined with 20(S)-PPD. RESULTS: We firstly confirmed that fasting-mimicking increased the anti-proliferation effect of 20(S)-PPD in human HepG2 cells in vitro. In fasting-mimicking culturing medium, the apoptosis and necrosis induced by 20(S)-PPD increased and more cells were arrested at G0-G1 phase. Meanwhile, invasion and migration of cells were decreased by down-regulating the expressions of matrix metalloproteinase (MMP)-2 and MMP-9 in fasting-mimicking medium. Furthermore, the in vivo study confirmed that intermittent fasting enhanced the tumor growth inhibition of 20(S)-PPD in H22 tumor-bearing mice without obvious side effects. CONCLUSION: Fasting significantly sensitized HCC cells to 20(S)-PPD in vivo and in vitro. These data indicated that dietary restriction can be one of the potential strategies of chinese medicine or its active metabolites against hepatocellular carcinoma.

Neuroprotective Effects of Exogenous Irisin in Kainic Acid-Induced Status Epilepticus.

Elevated reactive oxygen species (ROS) level is considered a crucial causative factor for neuronal damage in epilepsy. Irisin has been reported to ameliorate mitochondrial dysfunction and to reduce ROS levels; therefore, in this study, the effect of exogenous irisin on neuronal injury was evaluated in rats with kainic acid (KA)-induced status epilepticus (SE). Our results showed that exogenous irisin treatment significantly increased the expression of brain-derived neurotrophic factor (BDNF) and uncoupling protein 2 (UCP2), and reduced the levels of neuronal injury and mitochondrial oxidative stress. Additionally, an inhibitor of UCP2 (genipin) was administered to investigate the underlying mechanism of irisin-induced neuroprotection; in rats treated with genipin, the neuroprotective effects of irisin on KA-induced SE were found to be partially reversed. Our findings confirmed the neuroprotective effects of exogenous irisin and provide evidence that these effects may be mediated via the BDNF/UCP2 pathway, thus providing valuable insights that may aid the development of exogenous irisin treatment as a potential therapeutic strategy against neuronal injury in epilepsy.

The neuroprotective effect and possible therapeutic application of xenon in neurological diseases.

Xenon is an inert gas with stable chemical properties which is used as an anesthetic. Recent in vitro and in vivo findings indicate that xenon also elicits an excellent neuroprotective effect in subanesthetic concentrations. The mechanisms underlying this primarily involve the attenuation of excitotoxicity and the inhibition of N-methyl-d-aspartic acid (NMDA) receptors and NMDA receptor-related effects, such as antioxidative effects, reduced activation of microglia, and Ca2+ -dependent mechanisms, as well as the interaction with certain ion channels and glial cells. Based on this strong neuroprotective role, a large number of experimental and clinical studies have confirmed the significant therapeutic effect of xenon in the treatment of neurological diseases. This review summarizes the reported neuroprotective mechanisms of xenon and discusses its possible therapeutic application in the treatment of various neurological diseases.

Succinate accumulation contributes to oxidative stress and iron accumulation in pentylenetetrazol-induced epileptogenesis and kainic acid-induced seizure.

This study explored the role of succinate accumulation in the oxidative stress and iron accumulation in both pentylenetetrazol (PTZ)-induced epileptogenesis and kainic acid (KA)-induced status epilepticus (SE). The levels of succinate, oxidative stress, iron content, iron-related protein expression, and the severity of neuronal injury and seizures were measured in both models. We found that increased concentrations of succinate were associated with increased levels of oxidative stress, iron content, iron regulator protein, and iron importer divalent metal transporter 1, as well as decreased levels of iron exporter ferropotin 1. Aggravated neuronal injury was observed in the hippocampi and cortices of both models. The cell-permeable molecule dimethyl malonate (DM), a competitive inhibitor of succinate dehydrogenase (SDH), significantly attenuated succinate accumulation, reduced the oxidative stress and iron levels, and mitigated the severity of the seizures and neuronal injury. Our results thus indicate that the accumulation of succinate due to the reverse catalysis of SDH may exacerbate oxidative stress and thus induce iron accumulation and neuronal injury in both models. Targeting succinate accumulation may achieve neuroprotective and anti-seizure effects.

Xenon Exerts Neuroprotective Effects on Kainic Acid-Induced Acute Generalized Seizures in Rats via Increased Autophagy.

Xenon has been shown to have neuroprotective effects and is clinically used as a favorable safe inhalation anesthetic. We previously confirmed the neuroprotective effects of xenon treatment in epileptic animals. However, the mechanism underlying these protective effects remains unclear. We aimed to assess the effects of xenon inhalation on autophagy in neuronal injury induced by acute generalized seizures. Kainic acid (KA) was injected into the lateral ventricle of male Sprague-Dawley rats to induce acute generalized seizures. Next, the rats were treated via inhalation of a 70% xenon/21% oxygen/9% nitrogen mixture for 60 min immediately after KA administration. The control group was treated via inhalation of a 79% nitrogen/21% oxygen mixture. Subsequently, two inhibitors (3-methyladenine or bafilomycin A1) or an autophagy inducer (rapamycin) were administered, respectively, before KA and xenon administration to determine the role of autophagy in the protective effects of xenon. The levels of apoptosis, neuronal injury, and autophagy were determined in all the rats. Xenon inhalation significantly attenuated the severity of the seizure-induced neuronal injury. Increased autophagy accompanied this inhibitive effect. Autophagy inhibition eliminated these xenon neuroprotective effects. A simulation of autophagy using rapamycin recapitulated xenon's protective effects on KA-induced acute generalized seizures in the rats. These findings confirmed that xenon exerts strong neuroprotective effects in KA-induced acute generalized seizures. Further, they indicate that increased autophagy may underlie the protective effects of xenon. Therefore, xenon and autophagy inducers may be useful clinical options for their neuroprotective effects in epileptic seizures.

Attenuation of the mutual elevation of iron accumulation and oxidative stress may contribute to the neuroprotective and anti-seizure effects of xenon in neonatal hypoxia-induced seizures.

Previous studies have suggested that xenon inhalation has neuroprotective and antiepileptic effects; however, the underlying mechanisms involved remain unclear. This study aimed to investigate the possible xenon inhalation mechanisms involved in the neuroprotection and antiepileptic effects. A neonatal hypoxic C57BL/6J mouse model was used for the experiments. Immediately after hypoxia treatment, the treatment group inhaled a xenon mixture (70% xenon/21% oxygen/9% nitrogen) for 60 min, while the hypoxia group inhaled a non-xenon mixture (21% oxygen/79% nitrogen) for 60 min. Seizure activity was recorded at designated time points using electroencephalography. Oxidative stress levels, iron levels, neuronal injury, and learning and memory functions were also studied. The results showed that hypoxia increased the levels of iron, oxidative stress, mitophagy, and neurodegeneration, which were accompanied by seizures and learning and memory disorders. In addition, our results confirmed that xenon treatment significantly attenuated the hypoxia-induced seizures and cognitive defects in neonatal C57 mice. Moreover, the increased levels of iron, oxidative stress, mitophagy, and neuronal injury were reduced in xenon-treated mice. This study confirms the significant protective effects of a xenon mixture on hypoxia-induced damage in neonatal mice. Furthermore, our results suggest that reducing oxidative stress levels and iron accumulation may be the underlying mechanisms of xenon activity. Studying the protective mechanisms of xenon will advance its applications in potential therapeutic strategies.

IL-10 provides cardioprotection in diabetic myocardial infarction via upregulation of Heme clearance pathways.

Diabetes is a risk factor for myocardial infarction, and outcomes after myocardial infarction are worse among diabetics compared with nondiabetics. Diabetes is associated with impaired Heme clearance. Here, we determined whether heme toxicity and impaired heme clearance contribute to diabetic myocardial infarction injury and assessed IL-10 as a therapeutic agent for diabetic myocardial infarction. Plasma-free hemoglobin was significantly elevated in diabetic mice compared with nondiabetic mice after myocardial infarction. Infarct size had strong correlation to the level of plasma-free hemoglobin. Hemoglobin and reactive iron deposition within the infarct zone were also demonstrated in diabetic MI. IL-10 significantly reduced infarct size and improved cardiac function in diabetic mice. Moreover, IL-10 improved capillary density, reduced apoptosis, and decreased inflammation in the border zone of the infarcted hearts, findings that were partially inhibited by Tin protoporphyrin (a heme oxygenase-1 inhibitor). IL-10 upregulated CD163, the hemoglobin:haptoglobin scavenger receptor, and heme oxygenase-1 in THP-1-derived and primary human CD14+ macrophages. IL-10 significantly protected against ischemic injury when HL-1 cardiomyocytes were cotreated with hemoglobin. Together, our findings indicate that IL-10 is cardioprotective in diabetic myocardial infarction via upregulation of heme clearance pathways. These findings implicate heme clearance as a potentially novel therapeutic direction for diabetic myocardial infarction.

Safflor Yellow B Attenuates Ischemic Brain Injury via Downregulation of Long Noncoding AK046177 and Inhibition of MicroRNA-134 Expression in Rats.

Stroke breaks the oxidative balance in the body and causes extra reactive oxygen species (ROS) generation, leading to oxidative stress damage. Long noncoding RNAs (lncRNAs) and microRNAs play pivotal roles in oxidative stress-mediated brain injury. Safflor yellow B (SYB) was able to effectively reduce ischemia-mediated brain damage by increasing antioxidant capacity and inhibiting cell apoptosis. In this study, we investigated the putative involvement of lncRNA AK046177 and microRNA-134 (miR-134) regulation in SYB against ischemia/reperfusion- (I/R-) induced neuronal injury. I/R and oxygen-glucose deprivation/reoxygenation (OGD/R) were established in vivo and in vitro. Cerebral infarct volume, neuronal apoptosis, and protein expression were detected. The effects of SYB on cell activity, cell respiration, nuclear factor erythroid 2-related factor 2 (Nrf2), antioxidant enzymes, and ROS were evaluated. I/R or OGD/R upregulated the expression of AK046177 and miR-134 and subsequently inhibited the activation and expression of CREB, which caused ROS generation and brain/cell injury. SYB attenuated the effects of AK046177, inhibited miR-134 expression, and promoted CREB activation, which in turn promoted Nrf2 expression, and then increased antioxidant capacities, improved cell respiration, and reduced apoptosis. We suggested that the antioxidant effects of SYB were driven by an AK046177/miR-134/CREB-dependent mechanism that inhibited this pathway, and that SYB has potential use in reducing or possibly preventing I/R-induced neuronal injury.

Role of Elevated Thrombospondin-1 in Kainic Acid-Induced Status Epilepticus.

Previous studies have suggested that thrombospondin-1 (TSP-1) regulates the transforming growth factor beta 1 (TGF-ß1)/phosphorylated Smad2/3 (pSmad2/3) pathway. Moreover, TSP-1 is closely associated with epilepsy. However, the role of the TSP-1-regulated TGF-ß1/pSmad2/3 pathway in seizures remains unclear. In this study, changes in this pathway were assessed following kainic acid (KA)-induced status epilepticus (SE) in rats. The results showed that increases in the TSP-1/TGF-ß1/pSmad2/3 levels spatially and temporally matched the increases in glial fibrillary acidic protein (GFAP)/chondroitin sulfate (CS56) levels following KA administration. Inhibition of TSP-1 expression by small interfering RNA or inhibition of TGF-ß1 activation with a Leu-Ser-Lys-Leu peptide significantly reduced the severity of KA-induced acute seizures. These anti-seizure effects were accompanied by decreased GFAP/CS56 expression and Smad2/3 phosphorylation. Moreover, inhibiting Smad2/3 phosphorylation with ponatinib or SIS3 also significantly reduced seizure severity, alongside reducing GFAP/CS56 immunoreactivity. These results suggest that the TSP-1-regulated TGF-ß1/pSmad2/3 pathway plays a key role in KA-induced SE and astrogliosis, and that inhibiting this pathway may be a potential anti-seizure strategy.