SHARPIN contributes to sevoflurane-induced neonatal neurotoxicity through up-regulating HMGB1 to repress M2 like-macrophage polarization.

Sevoflurane exposure can result in neurotoxicity especially among children, which remains an important complication after surgery. However, its related mechanisms remain unclear. Here, we investigated the biological roles of SHARPIN in sevoflurane-induced neurotoxicity. As detected by qPCR, Western blotting and immunohistochemical staining, SHARPIN and HMGB1 expression was elevated in sevoflurane-stimulated mice as compared with the control mice. SHARPIN depletion attenuated hippocampus injury, repressed the expression of HMGB1 and M1-like macrophage markers (iNOS, TNF-α, IL-1ß, IL-6), but enhanced the expression of M2-like macrophage markers (ARG-1, IL-10). GST pull-down and Co-IP assays demonstrated that SHARPIN directly interacted with HMGB1 to enhance HMGB1 expression in SH-SY5Y cells. The inhibitory effects of SHARPIN silencing on inflammatory reaction and M1-like macrophages were counteracted by HMGB1 overexpression. Finally, SHARPIN-HMGB1 pathway affected neuroinflammation triggered by sevoflurane via modulating macrophage polarization. Collectively, our data suggested that SHARPIN stimulated sevoflurane-induced neurotoxicity via converting M2-like macrophages to M1-like macrophages by enhancing HMGB1 expression. SHARPIN intervention may be a promising therapeutic method to relieve sevoflurane-induced neurotoxicity.

Validity, feasibility, and effectiveness of a voice-recognition based digital cognitive screener for dementia and mild cognitive impairment in community-dwelling older Chinese adults: A large-scale implementation study.

INTRODUCTION: We investigated the validity, feasibility, and effectiveness of a voice recognition-based digital cognitive screener (DCS), for detecting dementia and mild cognitive impairment (MCI) in a large-scale community of elderly participants. METHODS: Eligible participants completed demographic, cognitive, functional assessments and the DCS. Neuropsychological tests were used to assess domain-specific and global cognition, while the diagnosis of MCI and dementia relied on the Clinical Dementia Rating Scale. RESULTS: Among the 11,186 participants, the DCS showed high completion rates (97.5%) and a short administration time (5.9 min) across gender, age, and education groups. The DCS demonstrated areas under the receiver operating characteristics curve (AUCs) of 0.95 and 0.83 for dementia and MCI detection, respectively, among 328 participants in the validation phase. Furthermore, the DCS resulted in time savings of 16.2% to 36.0% compared to the Mini-Mental State Examination (MMSE) and Montral Cognitive Assessment (MoCA). DISCUSSION: This study suggests that the DCS is an effective and efficient tool for dementia and MCI case-finding in large-scale cognitive screening. HIGHLIGHTS: To our best knowledge, this is the first cognitive screening tool based on voice recognition and utilizing conversational AI that has been assessed in a large population of Chinese community-dwelling elderly. With the upgrading of a new multimodal understanding model, the DCS can accurately assess participants' responses, including different Chinese dialects, and provide automatic scores. The DCS not only exhibited good discriminant ability in detecting dementia and MCI cases, it also demonstrated a high completion rate and efficient administration regardless of gender, age, and education differences. The DCS is economically efficient, scalable, and had a better screening efficacy compared to the MMSE or MoCA, for wider implementation.

N-Heterocyclic Olefin Type Ionic Liquid with Innate Soft Lewis-Base Character as an Effective Additive for Hybrid Quasi-2D and 3D Perovskite Solar Cells.

In optimizing perovskites with ionic liquid (IL), the comparative study on Lewis acid-base (LAB) and hydrogen-bonding (HB) interactions between IL and perovskite is lacking. Herein, methyl is substituted for hydrogen on 2-position of imidazolium ring of N-heterocyclic carbene (NHC) type IL IdH to weaken HB interactions, and the resulting N-heterocyclic olefin (NHO) type IL IdMe with softer Lewis base character is studied in both hybrid quasi-2D (Q-2D) and 3D perovskites. It is revealed that IdMe participates in constructing high-quality Q-2D perovskite (n = 4) and provides stronger passivation for 3D perovskite compared with IdH. Power conversion efficiency (PCE) of Q-2D PEA2 MA3 Pb4 I13 perovskite solar cells (PVSCs) is boosted to 17.68% from 14.03%. PCE and device stability of 3D PVSCs enhances simultaneously. Both theoretical simulations and experimental results show that LAB interactions between NHO and Pb2+ take the primary optimization effects on perovskite. The success of engineering LAB interactions also offers inspiration to develop novel ILs for high-performance PVSCs.

LncRNA ROR modulates myocardial ischemia-reperfusion injury mediated by the miR-185-5p/CDK6 axis.

LncRNAs and miRNAs are correlated with the pathogenesis of myocardial ischemia-reperfusion injury (MIRI). Whether lncRNA ROR or miR-185-5p plays a crucial role in MIRI is still unclear. In in-vitro, human cardiac myocytes (HCMs) were treated with hypoxia/reoxygenation (H/R). Wistar rats were used to set up an in-vitro I/R model by means of recanalization after ligation. Evaluation of the myocardial injury marker lactate dehydrogenase (LDH) in HCMs cells was performed. The expression of miR-185-5p and ROR, IL-1ß, and IL-18 were detected by qRT-PCR. ELISA was also performed to evaluate the secretion of IL-1ß and IL-18. Western blotting was carried out to determine CDK6, NLRP3, GSDMD-N, ASC, and cleaved-caspase1 protein expression. The relationship between miR-185-5p and CDK6 or ROR was confirmed by a dual-luciferase reporter assay. Our findings revealed that H/R treated HCMs showed a significantly decreased miR-185-5p expression and increased expression of CDK6 and ROR. ROR knockdown reduced H/R induced pyroptosis and inflammation, while knockdown of miR-185-5p accelerated the effect. Furthermore, miR-185-5p was negatively regulated and absorbed by ROR in HCMs. Overexpression of miR-185-5p reversed the H/R-induced cell pyroptosis and upregulation of LDH, IL-1ß, and IL-18. In HCMs, miR-185-5p was also negatively regulated and related to CDK6 expression. Moreover, overexpression of CDK6 significantly inhibited the effects of miR-185-5p mimics on the inflammatory response and pyroptosis of HCMs. Knockdown of ROR alleviated H/R-induced myocardial injury by elevating miR-185-5p and inhibiting CDK6 expression. Taken together, our results show that the ROR/miR-185-5p/CDK6 axis modulates cell pyroptosis induced by H/R and the inflammatory response of HCMs.

Surgical treatment of a patient with live intracranial sparganosis for 17 years.

BACKGROUND: The incidence of sparganosis, especially intracranial live sparganosis is very low in China. Due to the lack of typical clinical manifestations, it is difficult to make a clear preoperative diagnosis of the disease, which often leads to delays the disease and serious consequences. CASE PRESENTATION: A 23-year-old man presented with a 17-year history of intermittent seizures and right extremity numbness and weakness. Magnetic resonance imaging (MRI) showed patchy, nodular and line-like enhancement. Enzyme-linked immunosorbent assay (ELISA) detected positive antibodies to Spirometra mansoni in peripheral blood and cerebrospinal fluid (CSF). In addition, during the operation, an ivory-colored live sparganosis was removed under the precise positioning of neuronavigation, and the patient was diagnosed with cerebral sparganosis. The patient began praziquantel and sodium valproate treatment after the operation, and was followed up for 3 months. There was no recurrence of epilepsy, and the weakness and numbness of the right limb improved. CONCLUSION: Nonspecific clinical manifestations often make the diagnosis of cerebral sparganosis difficult, and a comprehensive diagnosis should be made based on epidemiological history, clinical manifestations, ELISA results and imaging findings. Surgery is the preferred method for the treatment of cerebral sparganosis, and more satisfactory results can be achieved under the precise positioning of neuronavigation.

LncRNA 4344 promotes NLRP3-related neuroinflammation and cognitive impairment by targeting miR-138-5p.

OBJECTIVE: Cognitive impairment is a common neurological disease of which NLRP3-related neuroinflammation has been demonstrated to be an essential mediator. Previous studies have indicated that long non-coding RNAs (lncRNAs) are critical for the development of neurological disorders. However, the roles and functions of lncRNA 4344 in neuroinflammation during cognitive impairment are unknown and need to be further elucidated. METHODS: Lipopolysaccharide (LPS)-induced rat cognitive impairment and rat microglia (RM) cell inflammation models were established in vitro and in vivo. The Morris water maze test was used to evaluate the cognitive behavior of the rats. Gene expression was assessed using real-time quantitative polymerase chain reaction, and protein levels using enzyme-linked immunosorbent assay, or western blot analysis. The targeting relationship between lncRNA 4344, miR-138-5p, and NLRP3 was identified using bioinformatics analysis and a dual-luciferase reporter gene assay. Hematoxylin-Eosin and Nissl stainings, terminal deoxynucleotidyl transferase dUTP nick end labeling, or immunofluorescence staining assays were performed to detect pathological changes, neuronal apoptosis, or positive cells in hippocampal tissues, respectively. RESULTS: The expression levels of lncRNA 4344 and NLRP3 were upregulated in the hippocampal tissues of LPS-treated rats and RM cells, and showed a strong positive correlation between each other. LncRNA 4344 overexpression further enhanced the expression of NLRP3 and its downstream genes (caspase-1, IL-1ß, and IL-18), as well as neuronal apoptosis in LPS-stimulated RM cells, whereas lncRNA 4344 silencing attenuated the inflammatory injuries. Moreover, miR-138-5p was the direct target of lncRNA 4344 and was downregulated in the RM cell inflammation model. We also found that miR-138-5p directly reduced the expression of NLRP3 and its downstream genes. Subsequently, the results of the animal experiments showed that the lncRNA 4344/miR-138-5p/NLRP3 axis plays an essential role in regulating the cognitive behavior, pathological changes and apoptosis of hippocampal neurons, expression of inflammation-related factors (NLRP3, caspase-1, IL-1ß, and IL-18), and microglial activation in LPS-induced cognitive impairment rats. CONCLUSION: Our results demonstrated for the first time that lncRNA 4344 regulates NLRP3-related neuroinflammation and cognitive impairment by targeting miR-138-5p, providing a possible target for the treatment of diseases characterized by a cognitive deficit.

Identification, characterization, and comparison of n-alkanols and anesthetics binding to the C1b subdomain of protein kinase cα: similar function with different binding sites.

Protein kinase C (PKC) is a family of lipid-activated enzymes involved in anesthetic preconditioning signaling pathways. Previously, n-alkanols and general anesthetics have been found to activate PKC by binding to the kinase C1B subdomain. In the present study, we attempt to ascertain the molecular mechanism and interaction mode of human PKCα C1B subdomain with a variety of exogenous n-alkanols and volatile general anesthetics as well as endogenous activator phorbol ester (PE) and co-activator diacylglycerol (DG). Systematic bioinformatics analysis identifies three spatially vicinal sites on the subdomain surface to potentially accommodate small-molecule ligands, where the site 1 is a narrow, amphipathic pocket, the site 2 is a wide, flat and hydrophobic pocket, and the site 3 is a rugged, polar pocket. Further interaction modeling reveals that site 1 is the cognate binding region of natural PE activator, which can moderately simulate the kinase activity in an independent manner. The short-chain n-alkanols are speculated to also bind at the site to competitively inhibit PE-induced kinase activation. The long-chain n-alkanols and co-activator DG are found to target site 2 in a nonspecific manner, while the volatile anesthetics prefer to interact with site 3 in a specific manner. Since the site 1 is composed of two protein loops that are also shared by sites 2 and 3, binding of n-alkanols, DG and anesthetics to sites 2 and 3 can trigger a conformational displacement on the two loops, which enlarges the pocket size and changes the pocket configuration of site 1 through an allosteric mechanism, consequently enhancing kinase activation by improving PE affinity to the site.

The correlation of intraoperative hypotension and postoperative cognitive impairment: a meta-analysis of randomized controlled trials.

BACKGROUND: There is no consensus on whether intraoperative hypotension is associated with postoperative cognitive impairment. Hence, we performed a meta-analysis to evaluate the correlation of intraoperative hypotension and the incidence of postoperative delirium (POD) or postoperative cognitive dysfunction (POCD). METHODS: We searched PubMed, Embase, and Cochrane Library databases to find randomized controlled trials (RCTs) in which reported the relationship between intraoperative hypotension and POD or POCD. The retrieval time is up to January 2020, without language restrictions. Quality assessment of the eligible studies was conducted by two researchers independently with the Cochrane evaluation system. RESULTS: We analyzed five eligible RCTs. Based on the relative mean arterial pressure (MAP), participants were divided into low-target and high-target groups. For the incidence of POD, there were two studies with 99 participants in the low-target group and 94 participants in the high-target pressure group. For the incidence of POCD, there were four studies involved 360 participants in the low-target group and 341 participants in the high-target group, with a study assessed both POD and POCD. No significant difference between the low-target and the high-target group was observed in the incidence of POD (RR = 3.30, 95% CI 0.80 to 13.54, P = 0.10), or POCD (RR = 1.26, 95% CI 0.76 to 2.08, P = 0.37). Furthermore, it also demonstrates that intraoperative hypotension prolonged the length of ICU stay, but did not increased the mortality, the length of hospital stay, and mechanical ventilation (MV) time. CONCLUSIONS: There is no significant correlation between intraoperative hypotension and the incidence of POD or POCD.

Label-free detection of microRNA: two-stage signal enhancement with hairpin assisted cascade isothermal amplification and light-up DNA-silver nanoclusters.

A method is described for the determination of microRNAs via two-stage signal enhancement. This is attained by combining hairpin (HP) assisted cascade isothermal amplification with light-up DNA-Ag nanoclusters. A rationally designed dual-functional HP is used, and microRNA-21 is chosen as a model analyte. At the first stage, upon the hybridization of the microRNA-21 with HP, microRNA recycling via polymerase-displacement reaction and a circulative nicking-replication process are achieved. This generates numerous G-abundant overhang DNA sequences. In the second stage, the above-released G-abundant overhang DNA sequences hybridize with the dark green Ag NCs, and this results in the appearance of bright red fluorescence. Thanks to the two signal enhancement processes, a linear dependence between the fluorescence intensity at 616 nm and the concentration of microRNA-21 is obtained in the range from 1 pM to 20 pM with a detection limit of 0.7 pM. The strategy clearly discriminates between perfectly-matched and mismatched targets. The method was applied to the determination of microRNA-21 in a spiked serum sample. Graphical abstractSchematic representation of microRNA detection by integrating hairpin assisted cascade isothermal amplification with light-up DNA Ag nanoclusters. With microRNA, G-abundant overhang DNA sequences from amplification reaction hybridize with dark green Ag nanoclusters to produce a concentration-dependent bright red fluorescence.

The lncRNA ROR/miR-124-3p/TRAF6 axis regulated the ischaemia reperfusion injury-induced inflammatory response in human cardiac myocytes.

Myocardial ischaemia reperfusion injury (MIRI) is considered the primary cause of death in patients with cardiovascular diseases. Recently, long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) have been found to be involved in the pathogenesis of MIRI. However, whether lncRNA ROR and miR-124-3p play roles in MIRI and the underlying mechanism remain undetermined. HCMs were exposed to hypoxic conditions for 2 h followed by re-oxygenation (H/R) treatment. Expression of miR-124-3p and lncRNA ROR in HCMs was measured by qRT-PCR. TRAF6 expression was evaluated by qRT-PCR and western blotting. ELISA and qRT-PCR were conducted to assess the production of TNF-α, IL-6, and IL-1ß. The interaction between miR-124-3p and TRAF6, as well as between miR-124-3p and lncRNA ROR, was verified by dual-luciferase reporter assay. Cell apoptosis was detected by flow cytometry analysis. Our data revealed that miR-124-3p was significantly downregulated, while TRAF6 and lncRNA ROR were upregulated in both MIRI rat model and H/R treated HCMs. Overexpression of miR-124-3p reversed the H/R-induced cell apoptosis and upregulation of TNF-α, IL-6, and IL-1ß. Mechanistically, miR-124-3p bound and negatively regulated TRAF6 expression in HCMs. Moreover, TRAF6 overexpression significantly blocked the effects of miR-124-3p mimics on cell apoptosis and inflammatory response of HCMs, which involved the NF-κB pathway. Further analysis showed that lncRNA ROR sponged and negatively regulated miR-124-3p in HCMs. Overexpression of IL-1ß was demonstrated to promote H/R induced cell apoptosis in HCMs. In addition, overexpression of ROR further enhanced the H/R-induced inflammation and cell apoptosis through its action on miR-124-3p. The lncRNA ROR/miR-124-3p/TRAF6 axis regulated the H/R-induced cell apoptosis and inflammatory response of HCMs.

Catalyst-Free Annulation of 2-Pyridylacetates and Ynals with Molecular Oxygen: An Access to 3-Acylated Indolizines.

A catalyst and additive-free annulation of 2-pyridylacetates and ynals under molecular oxygen was the first developed, affording 3-acylated indolizines in good to excellent yields. Molecular oxygen was used as the source of the carbonyl oxygen atom in indolizines. This approach was compatible with a wide range of functional groups, and especially it has been successfully extended to unsaturated double bonds and triple bonds, which were difficult to prepare by previous methods in a single step.

Graphene oxide-based fluorometric determination of microRNA-141 using rolling circle amplification and exonuclease III-aided recycling amplification.

A graphene oxide-based method has been developed for ultrasensitive and selective determination of microRNA-141 by means of rolling circle amplification (RCA) and exonuclease III (Exo III)-assisted recycling amplification. The method uses (a) a padlock probe with a hybrid sequence that is complementary to the target microRNA-141 at both the 5'- and the 3'-end, and (b) a long binding region of a signalling reporter strand. On addition of microRNA-141, it acts as the primer for triggering the RCA reaction following ligation. This results in the formation of a repeatedly concatenated sequence of the padlock probe. Subsequently, the RCA product hybridizes with the fluorescein-labelled signal strand to form the duplex DNA containing the blunt 3'-termini of signal strand. Addition of Exo III causes signal strand digestion and leads to RCA product recycling and liberation of fluorescein. Added graphene oxide does not absorb the fluorescein liberated because of the poor mutual interaction. Therefore, microRNA-141 can be quantified by measurement of the green fluorescence under excitation/emission wavelengths of 470/520 nm. The method has a 100 aM detection limit towards microRNA-141 and works in the wide range from 1 fM to 1 nM. It can discriminate even single-mismatched microRNA and shows good selectivity and sensitivity when applied to spiked human serum. Graphical abstract Schematic representation of a graphene oxide (GO)-based method for fluorometric determination of microRNA by using rolling circle amplification and exonuclease III (Exo III)-aided recycling amplification. With microRNA, the fluorescein-labelled signal strand becomes digested, and this genererates a fluorescent signal.

[Effect of triptolide on cognitive dysfunction in vascular dementia rats through SIRT1/NF-κB signaling pathway].

To investigate the effect of triptolide on cognitive dysfunction in vascular dementia rats and its effect on SIRT1/NF-κB pathway,fifty healthy male Sprague-Dawley rats were randomly divided into 5 groups: Sham operation group( Sham group),vascular dementia model group( 2 VO group),triptolide intraperitoneal injection group( TR group),triptolide intraperitoneal injection + EX527 intracerebroventricular administration group( T+E group),EX527 intracerebroventricular administration group( EX527 group). After 4 weeks of modeling,Morris water maze test and object recognition test were used to evaluate the learning and memory ability of rats. The morphological changes of hippocampus in each group were observed in brain tissue. The chemical colorimetry was used to detect the activities of SOD and MDA in hippocampus. IL-6 and TNF-α levels were detected by ELISA. Western blot was used to detect the expression of SIRT1,NF-κB,IκBα and caspase 3 in hippocampus. The results showed that compared with the Sham group,the learning and memory ability of the vascular dementia model rats was reduced,the SOD activity in the hippocampus was decreased,the MDA activity and IL-6 level were increased,the neuronal degeneration changed significantly,the expression of SIRT1 and IκBα was decreased and the expression of caspase 3 and NF-κB was significantly increased. After intervention by triptolide,the level of oxidative stress and the degenerative changes in hippocampus were significantly slowed down. The expression of SIRT1 and IκBα protein was increased and the expression of caspase 3 and NF-κB was significantly decreased. While,after intervention by triptolide and EX527,the expression of SIRT1 was decreased,the levels of oxidative stress and neuronal degeneration in the hippocampus were aggravated,and the learning and memory ability was reduced. The results showed that triptolide could improve cognitive impairment in vascular dementia rats and its mechanism may be related to SIRT1/NF-κB signaling pathway.

Versatile Assembly of Metal-Coordinated Calix[4]resorcinarene Cavitands and Cages through Ancillary Linker Tuning.

We propose a design strategy for assembly of metal-coordinated calix[4]resorcinarene cavitands and cages by tuning of the ancillary linkers. Assembly of newly functionalized cavitand with angular isophthalic acid analogs affords three intriguing metal-coordinated cavitands with deep cavities, 1a-1c. Further, by mediating appropriate spacers between two isophthalic acids, two bowl-shaped cavitands are successfully joined together to produce three elegant coordination cages with tunable sizes and shapes, 2a-2c. The cavitand and cage crystals possess considerable amount of accessible porosities, as clearly established by gas adsorption measurements. Remarkably, 1a-1c also exhibit high structural flexibilities, reversibly transforming between the open-pore and the narrow-pore structures, upon removal and sorption of guest molecules, as evidenced by diffraction and gas adsorption measurements. By combining experimental studies with density functional theory (DFT) calculations, we thoroughly elucidated the mechanism of the structural transformations in response to external stimuli in this new class of flexible porous solids.

NAF-1 antagonizes starvation-induced autophagy through AMPK signaling pathway in cardiomyocytes.

NAF-1 (nutrient-deprivation autophagy factor-1), an autophagy-related gene-related (ATG) protein, has been implicated in the autophagic pro-survival response. However, its role in autophagy has not been examined in the cardiomyocytes. In this study, we found that nutritional stress (NS) induced by glucose deprivation strongly induced autophagy in cultured neonatal rat cardiomyocytes, which was associated with NAF-1 down-regulation in cardiomyocytes under NS conditions. Furthermore, we demonstrate that ectopic expression of NAF-1 was sufficient to inhibit autophagy in cardiomyocytes under glucose deprivation conditions. Moreover, results of the co-immunoprecipitation assay indicate that NAF-1 antagonized autophagy by promoting the interaction between Beclin1 and Bcl-2 in NS-induced cardiomyocytes. Importantly, our results indicate that overexpression of NAF-1 significantly inhibited AMPK activity and protected cardiomyocytes from NS-induced cell death. Taken together, these data show that ectopic expression of NAF-1 antagonizes the degree of autophagy in cardiomyocytes and enhances cell survival during starvation conditions.

Minocycline alleviates LPS-induced cognitive dysfunction in mice by inhibiting the NLRP3/caspase-1 pathway.

BACKGROUND: Growing experimental evidence indicates that cognitive impairment is linked to neuroinflammation. Minocycline (MINO), an antibiotic known for its anti-inflammatory, has shown promise in alleviating cognitive impairment. Nonetheless, the exact mechanism through which MINO improves cognitive impairment is not yet understood. METHODS: A neuroinflammatory model was establish by utilizing lipopolysaccharide. The assessment of mice's cognitive and learning abilities was conducted through the MWM and Y-maze tests. The evaluation of hippocampal neuronal injury and microglial activation were achieved by performing HE staining and IHC, respectively. To evaluate BV2 cell viability and apoptosis, the CCK-8 and Hoechst 33342/PI staining assays were employed. In order to assess the protein and RNA expression levels of NLRP3, caspase-1, IL-1ß, IL-18, Iba-1, and Bcl2/Bax, WB and RT-qPCR were utilized. Additionally, the inhibitory effect of MINO on apoptosis by targeting the NLRP3/caspase-1 pathway was investigated using Nigericin. RESULTS: MINO was effective in reducing the time it took for mice to escape from the test, increasing the number of platforms they crossed, and mitigating damage to the hippocampus while also suppressing microglial activation and the expression of Iba-1 in a neuroinflammatory model caused by LPS. Furthermore, MINO improved the viability of BV2 cell and reduced apoptosis. It also had the effect of reducing the expression levels of NLRP3/Caspase-1, IL-1ß, IL-18, and BAX, while upregulating the expression of Bcl2. Additionally, MINO was found to downregulate the NLRP3 expression, which is specifically activated by nigericin. CONCLUSION: The protective effect of MINO relies on the crucial involvement of the NLRP3/caspase-1 pathway.

CircHDAC9 regulates myocardial ischemia-reperfusion injury via miR-671-5p/SOX4 signaling axis.

BACKGROUND: Myocardial ischemia-reperfusion (I/R), a harmful process in the treatment of cardiovascular diseases, can cause secondary damage to the cardiac tissues. Circular RNAs (circRNAs) are important regulators in a number of cardiac disorders. However, the role of circHDAC9 in myocardial I/R injury has not been clarified. METHODS: Human cardiac myocytes (HCMs) were treated with hypoxia/reoxygenation (H/R) and mice were subjected to I/R. Quantitative reverse transcriptase-polymerase chain reaction (RT-qPCR) was used to analyze the expression of circHDAC9, miR-671-5p, and SOX4, and western blot was used to detect SOX4 protein. The binding relationship among circHDAC9, miR-671-5p, and SOX4 was confirmed by RNA pull-down, luciferase, and RNA immunoprecipitation (RIP) assays. The effects of circHDAC9/miR-671-5p/SOX4 axis on the apoptosis, oxidative stress and inflammation were evaluated in both myocardial I/R injury models. RESULTS: The expression of circHDAC9 and SOX4 was noticeably elevated, whereas miR-671-5p expression was downregulated in both myocardial I/R injury models. circHDAC9 knockdown significantly reduced the apoptosis, activities of caspase-3 and caspase-9, ROS intensity, MDA activity, and concentrations of TNF-α, IL-1ß, and IL-6, but increased the viability and SOD activity in H/R-treated HCMs. Suppression of circHDAC9 dramatically reduced the levels of circHDAC9 and SOX4, while enhanced miR-671-5p expression in H/R-treated HCMs. CircHDAC9 functioned via sponging miR-671-5p to regulate SOX4 expression in vitro. Additionally, silencing of circHDAC9 improved the pathological abnormalities and cardiac dysfunction, and reduced the apoptosis, oxidative stress and inflammation in mice with myocardial I/R injury. CONCLUSIONS: Inhibition of circHDAC9 significantly improved myocardial I/R injury by regulating miR-671-5p/SOX4 signaling pathway.

Dexamethasone upregulates macrophage PIEZO1 via SGK1, suppressing inflammation and increasing ROS and apoptosis.

The side effects of high-dose dexamethasone in anti-infection include increased ROS production and immune cell apoptosis. Dexamethasone effectively activates serum/glucocorticoid-regulated kinase 1 (SGK1), which upregulates various ion channels by activating store-operated calcium entry (SOCE), leading to Ca2+ oscillations. PIEZO1 plays a crucial role in macrophages' immune activity and function, but whether dexamethasone can regulate PIEZO1 by enhancing SOCE via SGK1 activation remains unclear. The effects of dexamethasone were assessed in a mouse model of sepsis, and primary BMDMs and the RAW264.7 were treated with overexpression plasmids, siRNAs, or specific activators or inhibitors to examine the relationships between SGK1, SOCE, and PIEZO1. The functional and phenotypic changes of mouse and macrophage models were detected. The results indicate that high-dose dexamethasone upregulated SGK1 by activating the macrophage glucocorticoid receptor, which enhanced SOCE and subsequently activated PIEZO1. Activation of PIEZO1 resulted in Ca2+ influx and cytoskeletal remodelling. The increase in intracellular Ca2+ mediated by PIEZO1 further increased the activation of SGK1 and ORAI1/STIM1, leading to intracellular Ca2+ peaks. In the context of inflammation, activation of PIEZO1 suppressed the activation of TLR4/NFκB p65 in macrophages. In RAW264.7 cells, PIEZO1 continuous activation inhibited the change in mitochondrial membrane potential, accelerated ROS accumulation, and induced autophagic damage and cell apoptosis in the late stage. CaMK2α was identified as a downstream mediator of TLR4 and PIEZO1, facilitating high-dose dexamethasone-induced macrophage immunosuppression and apoptosis. PIEZO1 is a new glucocorticoid target to regulate macrophage function and activity. This study provides a theoretical basis for the rational use of dexamethasone.

ω3-PUFA alleviates neuroinflammation by upregulating miR-107 targeting PIEZO1/NFκB p65.

BACKGROUND: MiR-107 is reduced in sepsis and associated with inflammation regulation. Dietary supplementation with polyunsaturated fatty acids (ω3-PUFA) can increase the expression of miR-107; this study investigated whether the ω3-PUFA can effectively inhibit neuroinflammation and improve cognitive function by regulating miR-107 in the brain. METHODS: The LPS-induced mouse model of neuroinflammation and the BV2 cell inflammatory model were used to evaluate the effects of ω3-PUFA on miR-107 expression and inflammation. Intraventricular injection of Agomir and Antagomir was used to modulate miR-107 expression. HE and Nissl staining for analyzing hippocampal neuronal damage, immunofluorescence analysis for glial activation, RT-qPCR, and Western blot were conducted to examine miR-107 expression and inflammation signalling. RESULTS: The result shows that LPS successfully induced the mouse neuroinflammation model and BV2 cell inflammation model. Supplementation of ω3-PUFA effectively reduced the secretion of pro-inflammatory factors TNFα, IL1ß, and IL6 induced by LPS, improved cognitive function impairment, and increased miR-107 expression in the brain. Overexpression of miR-107 in the brain inhibited the nuclear factor κB (NFκB) pro-inflammatory signalling pathway by targeting PIEZO1, thus suppressing microglial and astrocyte activation and reducing the release of inflammatory mediators, which alleviated neuroinflammatory damage and improved cognitive function in mice. miR-107, as an intron of PANK1, PANK1 is subject to PPAR α Adjust. ω3-PUFA can activate PPARα, but ω3-PUFA upregulates brain miR-107, and PPARα/PANK1-related pathways may not be synchronized, and further research is needed to confirm the specific mechanism by which ω3-PUFA upregulates miR-107. CONCLUSION: The miR-107/PIEZO1/NFκB p65 pathway represents a novel mechanism underlying the improvement of neuroinflammation by ω3-PUFA.