Deep Cerebellar Nuclei Functional Connectivity with Cerebral Cortex in Temporal Lobe Epilepsy With and Without Focal to Bilateral Tonic-Clonic Seizures: a Resting-State fMRI Study.

We aimed to explore the altered functional connectivity patterns within cerebello-cerebral circuits in temporal lobe epilepsy (TLE) patients with and without focal to bilateral tonic-clonic seizures (FBTCS). Forty-two patients with unilateral TLE (21 with and 21 without FBTCS) and 22 healthy controls were recruited. We chose deep cerebellar nuclei as seed regions, calculated static and dynamic functional connectivity (sFC and dFC) in the patients with and without FBTCS and healthy controls, and compared sFC and dFC among the three groups. Correlation analyses were used to assess relationships between the significantly altered imaging features and patient clinical parameters. Compared to the group without FBTCS, the FBTCS group showed decreased sFC between the right dentate nuclei and left hemisphere regions including the middle frontal gyrus, superior temporal gyrus, superior medial frontal gyrus and posterior cingulate gyrus, and significantly increased dFC between the right interposed nuclei and contralateral precuneus. Relative to HCs, the FBTCS group demonstrated prominently decreased sFC between the right dentate nuclei and left middle frontal gyrus. No significant correlations between the altered imaging features and patient clinical parameters were observed. Our results suggest that the disrupted cerebello-cerebral FC might be related to cognitive impairment, epileptogenesis, and propagation of epileptic activities in patients with FBTCS.

Correlation analysis between regional homogeneity and executive dysfunction in anti-N-methyl-D-aspartate receptor encephalitis patients.

BACKGROUND AND PURPOSE: Anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis is characterized by a range of cognitive impairments, especially in executive function. Our study aims to identify the abnormal regional homogeneity (ReHo) in anti-NMDAR encephalitis patients and its relationship with the executive function. METHODS: Forty patients and 42 healthy volunteers undertook an Attention Network Test and a resting-state functional magnetic resonance imaging scan. ReHo analysis was performed to investigate the neuronal activity synchronization in all subjects. Based on ReHo analysis, a multivariate pattern analysis (MVPA) was carried out to identify the brain regions that differed the most between the two groups. RESULTS: Compared to controls, the patients had higher executive control scores (p < 0.05). The patients presented reduced ReHo values in the bilateral posterior cerebellar lobe, anterior cerebellar lobe, midbrain, bilateral caudate nucleus, right superior frontal gyrus, right middle temporal gyrus, bilateral inferior parietal lobule and the left middle frontal gyrus. The ReHo values of the bilateral inferior parietal lobule in patients were found to be negatively associated with executive control scores. The classification of patients and controls using MVPA had an accuracy of 76.83%, a sensitivity of 82.50%, a specificity of 71.43% and the area under the curve was 0.83. CONCLUSIONS: Our study provides evidence of abnormal cerebral function in anti-NMDAR encephalitis patients, which may contribute to unveiling the neuropathological mechanisms of anti-NMDAR encephalitis and their influences on executive dysfunction. The MVPA classifier, based on ReHo, is helpful in identifying anti-NMDAR encephalitis patients from healthy controls.

A study of brain functional network and alertness changes in temporal lobe epilepsy with and without focal to bilateral tonic-clonic seizures.

BACKGROUND: Temporal lobe epilepsy (TLE) is commonly refractory. Epilepsy surgery is an effective treatment strategy for refractory epilepsy, but patients with a history of focal to bilateral tonic-clonic seizures (FBTCS) have poor outcomes. Previous network studies on epilepsy have found that TLE and idiopathic generalized epilepsy with generalized tonic-clonic seizures (IGE-GTCS) showed altered global and nodal topological properties. Alertness deficits also were found in TLE. However, FBTCS is a common type of seizure in TLE, and the implications for alertness as well as the topological rearrangements associated with this seizure type are not well understood. METHODS: We obtained rs-fMRI data and collected the neuropsychological assessment data from 21 TLE patients with FBTCS (TLE- FBTCS), 18 TLE patients without FBTCS (TLE-non- FBTCS) and 22 controls, and constructed their respective functional brain networks. The topological properties were analyzed using the graph theoretical approach and correlations between altered topological properties and alertness were analyzed. RESULTS: We found that TLE-FBTCS patients showed more serious impairment in alertness effect, intrinsic alertness and phasic alertness than the patients with TLE-non-FBTCS. They also showed significantly higher small-worldness, normalized clustering coefficient (γ) and a trend of higher global network efficiency (gE) compared to TLE-non-FBTCS patients. The gE showed a significant negative correlation with intrinsic alertness for TLE-non-FBTCS patients. CONCLUSION: Our findings show different impairments in brain network information integration, segregation and alertness between the patients with TLE-FBTCS and TLE-non-FBTCS, demonstrating that impairments of the brain network may underlie the disruptions in alertness functions.

Altered static and dynamic functional network connectivity in temporal lobe epilepsy with different disease duration and their relationships with attention.

The brain network alterations associated with temporal lobe epilepsy (TLE) progression are still unclear. The purpose of this study was to investigate altered patterns of static and dynamic functional network connectivity (sFNC and dFNC) in TLE with different durations of disease. In this study, 19 TLE patients with a disease duration of ≤5 years (TLE-SD), 24 TLE patients with a disease duration of >5 years (TLE-LD), and 21 healthy controls (HCs) underwent resting-state functional magnetic resonance imaging and attention network test. We used group independent component analysis to determine the target resting-state networks. Sliding window correlation and k-means clustering analysis methods were used to obtain different dFNC states, temporal properties, and temporal variability. We then compared sFNC and dFNC between groups and found that compared with HCs, TLE-SD patients had increased sFNC between the dorsal attention network and sensorimotor network/visual network (VN), but decreased sFNC between the inferior-posterior default mode network and VN. In the strongly connected dFNC state, TLE-SD patients spent more time, had greater mean dwell time, and showed greater inconsistent abnormal network connectivity. There was a significant negative correlation between the temporal variability of auditory network- left fronto-parietal network connectivity and orienting effect. No significant differences in sFNC and dFNC were detected between TLE-LD and HC groups. These findings suggest that the damage and functional brain network abnormalities gradually occur in TLE patients after the onset of epilepsy, which might lead to functional network reorganization and compensatory remodeling as the disease progresses.

Overexpression of cortistatin alleviates oxygen/glucose-deprivation-induced ER stress and prompts neural stem cell proliferation via SSTR2.

Cerebral infarction (CI), a blood circulatory disorder, causes a high mortality and disability rate worldwide. Intriguingly, a newly discovered neuropeptide, Cortistatin (CST), has been indicated to inhibit the cortical activity. In our research, we aimed to explore the functional relevance of CST in neural stem cells (NSCs) in CI rats. The expression of CST was determined in NSCs induced by oxygen-glucose deprivation (OGD). NSCs isolated from the embryonic rat brain were treated with OGD to establish an in vitro CI model while dithiothreitol (DTT) was introduced to induce endoplasmic reticulum stress (ERS), which were evaluated by assessment of GRP94, caspase-12 and CHOP expression. Then CST expression was restored by transfection of oe-CST, followed by assessment of NSC proliferation ability and cytotoxicity. Finally, the expression of CST and its receptor Somatostatin receptor subtype 2 (SSTR2) was quantified for mechanism exploration. CST was downregulated in CI, which was further confirmed in NSCs under OGD treatment. Overexpressed CST was found to promote cell activity and attenuate OGD-induced cytotoxicity of NSCs. Meanwhile, it was observed that the injured proliferation ability of NSCs was restored by CST overexpression. Besides, lower expression of GRP94, caspase-12 and CHOP was indicative of suppressed occurrence of ERS by CST. Mechanically, CST inhibited ERS through SSTR2. CST could facilitate the proliferation of NSCs in CI induced by OGD, ultimately highlighting a novel therapeutic target for CI treatment.

Disrupted alertness and related functional connectivity in patients with focal impaired awareness seizures in temporal lobe epilepsy.

OBJECTIVE: Focal impaired awareness seizures are common in temporal lobe epilepsy (TLE). The cognitive impairment associated with this type of seizure is unclear. Alertness is a fundamental aspect of cognition. The locus coeruleus (LC) is closely related to alertness. We aimed to assess the impairment in alertness and LC-related alertness network in patients with focal impaired awareness seizures. METHODS: Patients with unilateral TLE were grouped into the only focal impaired awareness seizure group (focal group, n = 19) and the focal impaired awareness seizure with focal to bilateral tonic-clonic seizure (FBTCS) group (FBTCS group, n = 19) and compared with matched healthy controls (HC, n = 19). Alertness was assessed with the attention network test. Functional magnetic resonance imaging (fMRI) was used to construct an alertness-related LC-based functional connectivity (FC) network. RESULTS: The focal group exhibited impaired tonic and phasic alertness and exhibited a decreased trend of LC-based FC to the left superior frontal gyrus (SFG). The FBTCS group exhibited impaired tonic alertness, phasic alertness, and alertness efficiency. No significant difference or trend in LC-based FC was found in the FBTCS group. SIGNIFICANCE: This study reveals disrupted alertness and alertness-related LC-based FC in patients with focal impaired awareness seizures. Our results further demonstrate that the patterns of impaired alertness and of changed LC-based FC were not significantly different between focal impaired awareness seizures and FBTCS.

Alterations in intra- and internetwork functional connectivity associated with levetiracetam treatment in temporal lobe epilepsy.

OBJECTIVE: Levetiracetam (LEV) is an antiepileptic drug with a novel pharmacological mechanism. Advances in functional magnetic resonance imaging (fMRI) enable researchers to explore the cognitive effects of antiepileptic drugs on the living brain. This study aimed to explore how the functional connectivity patterns of the cognitive networks changed in association with LEV treatment. METHODS: Patients with temporal lobe epilepsy (TLE), including both users and nonusers of LEV, were included in this study along with healthy controls. Core cognitive networks were extracted using an independent component analysis approach. Functional connectivity patterns within and between networks were investigated. The relationships between functional connectivity patterns and clinical characteristics were also examined. RESULTS: The patterns of intranetwork connectivity in the default mode network (DMN), left executive control network (lECN), and dorsal attention network (DAN) differed among the three groups. The internetwork interactions did not show intergroup differences once corrected for multiple comparisons. No correlation between functional connectivity and clinical characteristics was found in patients with TLE. CONCLUSIONS: Changes in intranetwork connectivity are a key effect of LEV administration. SIGNIFICANCE: Alterations in intranetwork connectivity patterns may underlie the cognitive effects of LEV administration; this finding improves our understanding of the neural mechanisms of LEV therapy.

ILK promotes survival and self-renewal of hypoxic MSCs via the activation of lncTCF7-Wnt pathway induced by IL-6/STAT3 signaling.

Mesenchymal stem cells (MSCs) have been applied in treating various diseases including myocardial infarction (MI) and achieved a bit of success; however, the decreased survival rate of MSCs after transplantation greatly limited the efficacy for cell therapy. How to improve the MSC survival rate in stem cell transplantation has undoubtedly become urgent and genetic engineering may be an ideal and feasible way. In this study, we explored the effects on MSCs survival and self-renewal by overexpression of integrin-linked kinase (ILK) in MSCs under hypoxic stimulation and aimed to reveal the molecular mechanisms from the point of paracrine function of MSCs. We first found that overexpression of ILK induced the expression and secretion of IL-6 increased significantly in MSCs under hypoxic stimulation, and the survival and self-renewal of MSCs exposed to hypoxia were enhanced after ILK overexpression. Then the activation of JAK2/STAT3 signaling was detected because of the increased IL-6, and an lncRNA, named lncTCF7, was upregulated remarkably, promoting the activation of Wnt pathway that was required for keeping cell viability and stemness of MSCs. Moreover, we further verified that inhibition of STAT3 signaling by WP1066 and silencing lncTCF7 expression eliminated the protective effects of ILK overexpression on cell survival and self-renewal of MSCs under hypoxic sitmulation. In conclusion, our results uncovered a novel function of ILK to promote MSC survival and self-renewal, suggesting more application potentials of MSC cell therapy on MI.

Aloperine Activates the PI3K/Akt Pathway and Protects Against Coronary Microembolisation-Induced Myocardial Injury in Rats.

BACKGROUND: Coronary microembolisation (CME)-induced myocardial apoptosis is a key factor in progressive cardiac dysfunction. Aloperine (ALO) plays a protective role in the cardiovascular system, but its role and the mechanism -underlying its protection against CME are unclear. Therefore, we aimed to verify whether ALO has a protective effect against CME-induced myocardial injury, as well as whether this effect has a relationship with regulation of the PI3K/Akt pathway for rats. METHODS: Forty Sprague-Dawley rats were randomised into 4 equal groups: CME, CME + ALO, CME + ALO + LY294002 (LY) and a Sham group. Twelve hours after surgery, the rats' cardiac function, apoptosis index, microinfarct and serum cardiac-troponin I (cTnI) level were measured. Levels of p-Akt, total Akt, Bcl-2, Bax and cleaved caspase-3 were detected. RESULTS: ALO improved cardiac dysfunction induced by CME, while also decreasing serum levels of cTnI and microinfarct areas. In addition, ALO inhibited myocardial apoptosis, which may have been partially as a result of downregulated cleaved caspase-3 and Bax, upregulated Bcl-2 and increased protein levels in phosphorylated Akt. However, these ALO effects were blocked if ALO was administered along with LY. CONCLUSIONS: ALO can inhibit cardiomyocyte apoptosis and consequently attenuate CME-induced myocardial injury. These functions are realised by activating PI3K/Akt signalling pathway.

Naringenin prevents ischaemic stroke damage via anti-apoptotic and anti-oxidant effects.

Apoptosis and oxidative stress are considered to be the major factors associated with the development and progression of many ischaemic cerebrovascular diseases. Naringenin (NAR) is an abundant flavanone in citrus plants and has been found to exhibit anti-oxidant, anti-carcinogenic and anti-apoptotic effects. This study aimed to investigate the anti-apoptotic and anti-oxidant effects of naringenin on ischaemic stroke. In vitro, cortical neuron cells isolated from the brains of neonatal Sprague-Dawley rats were randomly divided into control, oxygen and glucose deprivation/reperfusion (OGD/Rep), NAR-L, NAR-M and NAR-H groups. MTT and RT-PCR were used for cell proliferation and apoptosis-related proteins analyses. The effects of NAR on the Nrf2 signalling pathway were investigated using transfection approaches. Differences in mitochondrial dysfunction were analyzed by flow cytometry. In vivo, middle cerebral artery occlusion (MCAO) model was prepared and neurological defects and the brain wet/dry (W/D) ratio were assessed and recorded; apoptosis was measured based on the TUNEL assay. Additionally, biochemical indices were detected both in vitro and in vivo. NAR promoted cortical neuron cell proliferation, inhibited apoptosis and oxidative stress, and regulated the localization of Nrf2 protein (P<.05). Furthermore, silencing and overexpression of Nrf2 affected cortical neuron cell proliferation and apoptosis (P<.05). In vivo, NAR could alleviate cerebral oedema, improve neurological defects, and reduce apoptosis and oxidative stress (P<.05). These findings demonstrated that NAR could reduce apoptosis and oxidative stress and that Nrf2 signalling pathway is involved in this regulatory process. NAR has health-promoting properties because of its anti-apoptotic and anti-oxidant effects in cases of ischaemic stroke.

Mesenchymal stem cells overexpressing integrin-linked kinase attenuate left ventricular remodeling and improve cardiac function after myocardial infarction.

In the present study, we investigated whether mesenchymal stem cells (MSCs) overexpressing integrin-linked kinase (ILK) might regulate ventricular remodeling and cardiac function in a porcine myocardial infarction model. ILK-modified MSCs (ILK-MSCs) (n = 8), MSCs (n = 8) or placebo (n = 8) were injected into peri-infarct myocardium 7 days after ligation of the left anterior descending coronary artery. ILK expression was confirmed by immunofluorescence, real-time PCR, Western blot analysis, and flow cytometry. In vitro assays indicated increased proliferation and reduced apoptosis of MSCs due to overexpression of ILK. Echocardiographic, single-photon emission computed tomography and positron emission tomography analyses demonstrated preserved cardiac function and myocardial perfusion. Reduced fibrosis, increased cardiomyocyte proliferation, and enhanced angiogenesis were observed in the ILK-MSC group. Reduced apoptosis, as demonstrated by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling analysis, was also noted. In conclusion, ILK promotes MSC proliferation and suppresses apoptosis. ILK-MSC transplantation improves ventricular remodeling and cardiac function in pigs after MI. It is associated with increased angiogenesis, reduced apoptosis, and increased cardiomyocyte proliferation. This may represent a new approach to the treatment of post-infarct remodeling and subsequent heart failure.

The role of the thalamus in modular functional networks in temporal lobe epilepsy with cognitive impairment.

OBJECTIVE: Cognitive deficit is common in patients with temporal lobe epilepsy (TLE). Here, we aimed to investigate the modular architecture of functional networks associated with distinct cognitive states in TLE patients together with the role of the thalamus in modular networks. METHODS: Resting-state functional magnetic resonance imaging scans were acquired from 53 TLE patients and 37 matched healthy controls. All patients received the Montreal Cognitive Assessment test and accordingly were divided into TLE patients with normal cognition (TLE-CN, n = 35) and TLE patients with cognitive impairment (TLE-CI, n = 18) groups. The modular properties of functional networks were calculated and compared including global modularity Q, modular segregation index, intramodular connections, and intermodular connections. Thalamic subdivisions corresponding to the modular networks were generated by applying a 'winner-take-all' strategy before analyzing the modular properties (participation coefficient and within-module degree z-score) of each thalamic subdivision to assess the contribution of the thalamus to modular functional networks. Relationships between network properties and cognitive performance were then further explored. RESULTS: Both TLE-CN and TLE-CI patients showed lower global modularity, as well as lower modular segregation index values for the ventral attention network and the default mode network. However, different patterns of intramodular and intermodular connections existed for different cognitive states. In addition, both TLE-CN and TLE-CI patients exhibited anomalous modular properties of functional thalamic subdivisions, with TLE-CI patients presenting a broader range of abnormalities. Cognitive performance in TLE-CI patients was not related to the modular properties of functional network but rather to the modular properties of functional thalamic subdivisions. CONCLUSIONS: The thalamus plays a prominent role in modular networks and potentially represents a key neural mechanism underlying cognitive impairment in TLE.

Preparation and Characterization of Modified Kaolin by a Mechanochemical Method.

A mechanochemical approach was utilized to prepare modified kaolin, and the hydrophobic modification of kaolin was realized. The study aims to investigate the changes in particle size, specific surface area, dispersion ability, and adsorption performance of kaolin. The structure of kaolin was analyzed using infrared spectroscopy, scanning electron microscopy, and X-ray diffraction, and the alterations to the kaolin microstructure were thoroughly researched and discussed. The results demonstrated that this modification method can effectively improve the dispersion and adsorption capacities of kaolin. Mechanochemical modification can increase the specific surface area of kaolin particles, reduce their particle size, and improve their agglomeration behavior. The layered structure of the kaolin was partially destroyed, the degree of order was debased, and the activity of its particles was enhanced. Furthermore, organic compounds were adsorbed on the surface of the particles. The appearance of new infrared peaks in the modified kaolin's infrared spectrum suggested that the kaolin has undergone a chemical modification process, introducing new functional groups.

Targeting the MicroRNA-490-3p-ATG4B-Autophagy Axis Relieves Myocardial Injury in Ischemia Reperfusion.

We investigated the potential role of miR-490-3p in ischemia reperfusion (IR) injury. We first determined the expression of miR-490-3p and autophagy-related 4B cysteine (ATG4B) in IR. Then, to explore whether miR-490-3p would affect autophagy, apoptosis, and IR injury, we evaluated apoptosis, autophagy, and infarct size via gain- and loss-of-function experiments. Furthermore, we used adenovirus to enhance or inhibit the expression of ATG4B, and then measured autophagy, apoptosis, and IR injury. miR-490-3p was downregulated in the hearts during the process of IR, while ATG4B was upregulated. The inhibition of miR-490-3p or overexpression of ATG4B could promote the expression of LC3II, increase the autolysosomes, inhibit the expression of p62, and reduce infarct size. On all accounts, the inhibition of miR-490-3p could promote autophagy to reduce myocardial IR injury by upregulating ATG4B, a finding that provides new insights for the protective mechanism of autophagy in IR. Graphical Abstract.

Abnormal Static and Dynamic Functional Connectivity in Left and Right Temporal Lobe Epilepsy.

OBJECTIVE: Temporal lobe epilepsy (TLE) can be conceptualized as a network disease. However, the network characteristics in lateralization remain controversial. METHODS: In this study, resting-state functional MRI scans were acquired from 53 TLE patients [22 with left-side TLE (LTLE) and 31 with right-side TLE (RTLE)] and 37 matched healthy controls. We focused on the characteristics of static and dynamic functional connectivity, including static connectivity patterns and topological properties, as well as temporal properties of the dynamic connectivity state and the variability of the dynamic connectivity and network topological organization. Correlation analyses were conducted between abnormal static and dynamic properties and cognitive performances. RESULTS: The static functional connectivity analysis presented a significantly decreased cortical-cortical connectivity pattern and increased subcortical-cortical connectivity pattern in RTLE. The global-level network in RTLE showed a significant decrease in global efficiency. The dynamic functional connectivity analysis revealed that RTLE patients exhibited aberrant connectivity states, as well as increased variability in the subcortical-cortical connectivity. The global-level network in RTLE revealed increased variance in global efficiency and local efficiency. The static or dynamic functional connectivity in LTLE did not show any significant abnormalities. The altered dynamic properties were associated with worsening cognitive performance in language and conceptual thinking by the TLE patients. CONCLUSION: Our findings demonstrated the presence of abnormalities in the static and dynamic functional connectivity of TLE patients. RTLE patients exhibited more pronounced aberrant connectivity patterns and topological properties, which might represent a mechanism for reconfiguration of brain networks in RTLE patients. These observations extended our understanding of the pathophysiological network mechanisms of TLE.

Comparison of topological properties of functional brain networks with graph theory in temporal lobe epilepsy with different duration of disease.

BACKGROUND: Our study was performed to measure the alterations in topological properties of the functional brain network of temporal lobe epilepsy (TLE) at different durations, exploring the potential progression and neuropathophysiological mechanisms of TLE. METHODS: Fifty-eight subjects, including 17 TLE patients with a disease duration of ≤5 years (TLE-SD), 20 TLE patients with a disease duration of >5 years (TLE-LD), and 21 healthy controls firstly underwent the Attention Network Test (ANT) to assess the alertness function and received the resting-state functional magnetic resonance imaging (rs-fMRI). Next, a functional brain network was set up, and then the related graph of theoretical network analysis was conducted. Finally, the correlation between network property and the neuropsychological score was analyzed. RESULTS: The global and local efficiencies of functional brain networks in TLE-SD patients significantly decreased and tended toward random alterations. Also, the degree centrality (DC) and nodal efficiency (Ne) in right medial pre-frontal thalamus (mPFtha) and right rostral temporal thalamus (rTtha) of TLE-SD patients significantly reduced. Further analysis showed that alertness was positively associated with the characteristic path length but negatively related to the global and local efficiencies in TLE-SD patients; alertness was negatively related to the Ne of mPFtha in TLE-LD patients. CONCLUSIONS: Our study showed that the functional brain network of TLE patients might undergo compensatory reorganization as the disease progresses, which provides useful insights into the progression and mechanism of TLE.

Nobiletin protects against myocardial injury and myocardial apoptosis following coronary microembolization via activating PI3K/Akt pathway in rats.

It has been found that use of drugs which upregulate the PI3K/Akt pathway can effectively reduce cardiomyocyte apoptosis which has been induced by coronary microembolization (CME). However, whether this functional protein is able to be modified through pretreatment via nobiletin (NOB) in models of CME has not yet been investigated. Therefore, this study set out to explore the cardioprotective effect of NOB on rats with myocardial injuries induced by CME and also explored the potential mechanism which underlies this cardioprotective effect. The study used 40 Sprague-Dawley (SD) rats, which were randomized into four groups: the sham, CME, CME+NOB, and CME+NOB+LY294002 (LY) groups. Twelve hours after surgery, levels of microinfarct, serum c-troponin I (cTnI), cardiac function, apoptotic index, and oxidative stress [superoxide dismutase (SOD) and malondialdehyde (MDA)] were measured for rats in each group. Western blot analysis was performed to detect any protein involved in the PI3K/Akt pathway. Nobiletin improved cardiac dysfunction which had been induced by CME, decreased serum level of cTnI and MDA, and increased serum SOD activities. In addition, nobiletin inhibited myocardial apoptosis, which may be connected to downregulated apoptotic index, upregulated Bcl-2, and cleaved caspase-3 and Bax, while it increased protein levels in phosphorylated Akt. However, when nobiletin was co-administered with LY294002, a PI3K (phosphatidylinositol 3-kinase)/Akt inhibitor, all of the previously mentioned effects were blocked. Nobiletin is able to inhibit cardiomyocyte apoptosis and can consequently attenuate CME-induced myocardial injuries. These functions are realized through the activation of the PI3K/Akt signaling pathway as well as by reducing oxidative stress.

Resveratrol Attenuates Cardiomyocyte Apoptosis in Rats Induced by Coronary Microembolization Through SIRT1-Mediated Deacetylation of p53.

OBJECTIVE: Coronary microembolization (CME)-induced cardiomyocyte apoptosis is the primary factor in causing cardiac dysfunction. Resveratrol (RES) is known to play a protective role in a variety of cardiovascular diseases, yet it is not known whether RES has a protective role in CME. Therefore, the effect of RES on cardiomyocyte apoptosis and cardiac function damage which are induced by CME in rats was investigated in this study. METHODS: Fifty Sprague-Dawley rats were separated into 5 groups randomly (10 rats were included in each): sham group, CME group, RES+CME group, RES+CME+Sirtuin-1 (SIRT-1) inhibitor EX527 (RES+CME+EX) group, and CME+EX group. Cardiac function, serum c-troponin I (cTnI) level, apoptotic index, and microinfarct were measured by cardiac ultrasound, myocardial enzyme assessment, TdT-mediated dUTP Nick-end labeling and hematoxylin-basic fuchsin-picric acid staining. The levels of p53, p53 acetylation, SIRT-1, Bax, Bcl-2, and cleaved caspase-3 were detected by Western blot. RESULTS: Myocardial dysfunction, enhanced apoptotic index as well as cTnI were caused after the operation of CME. Coronary microembolization induced increased expression of p53 acetylation and cleaved caspase-3, while the SIRT-1 and Bcl-2/Bax ratio was reduced. The CME effect was reversed by RES while EX527 attenuated this protective effect. CONCLUSIONS: Resveratrol can improve cardiac function, in the sense that it attenuates CME-induced cardiomyocyte apoptosis, which is perhaps associated with its inhibition pro-apoptotic pathway of p53 which is transcription-independent.

LncRNA KLF3-AS1 in human mesenchymal stem cell-derived exosomes ameliorates pyroptosis of cardiomyocytes and myocardial infarction through miR-138-5p/Sirt1 axis.

AIM: Myocardial infarction (MI) is a severe disease with increased mortality and disability rates, posing heavy economic burden for society. Exosomes were uncovered to mediate intercellular communication after MI. This study aims to explore the effect and mechanism of lncRNA KLF3-AS1 in exosomes secreted by human mesenchymal stem cells (hMSCs) on pyroptosis of cardiomyocytes and MI. METHODS: Exosomes from hMSCs were isolated and identified. Exosomes from hMSCs with transfection of KLF3-AS1 for overexpression were injected into MI rat model or incubated with hypoxia cardiomyocytes. Effect of KLF3-AS1 on MI area, cell viability, apoptosis, and pyroptosis was determined. The relationship among miR-138-5p, KLF3-AS1, and Sirt1 was verified by dual-luciferase reporter assay. Normal cardiomyocytes were transfected with miR-138-5p inhibitor or sh-Sirt1 to clarify whether alteration of miR-138-5p or sh-Sirt1 can regulate the effect of KLF3-AS1 on cardiomyocytes. RESULTS: Exosomes from hMSCs were successfully extracted. Transfection of KLF3-AS1 exosome in rats and incubation with KLF3-AS1 exosome in hypoxia cardiomyocytes both verified that overexpression of KLF3-AS1 in exosomes leads to reduced MI area, decreased cell apoptosis and pyroptosis, and attenuated MI progression. KLF3-AS1 can sponge miR-138-5p to regulate Sirt1 expression. miR-138-5p inhibitor transfection and KLF3-AS1 exosome incubation contribute to attenuated pyroptosis and MI both in vivo and in vitro, while transfection of sh-Sirt1 could reverse the protective effect of exosomal KLF3-AS1 on hypoxia cardiomyocytes. CONCLUSION: LncRNA KLF3-AS1 in exosomes secreted from hMSCs by acting as a ceRNA to sponge miR-138-5p can regulate Sirt1 so as to inhibit cell pyroptosis and attenuate MI progression.