PIEZO1 as a new target for hyperglycemic stress-induced neuropathic injury: The potential therapeutic role of bezafibrate.

Hyperglycemic stress can directly lead to neuronal damage. The mechanosensitive ion channel PIEZO1 can be activated in response to hyperglycemia, but its role in hyperglycemic neurotoxicity is unclear. The role of PIEZO1 in hyperglycemic neurotoxicity was explored by constructing a hyperglycemic mouse model and a high-glucose HT22 cell model. The results showed that PIEZO1 was significantly upregulated in response to high glucose stress. In vitro experiments have shown that high glucose stress induces changes in neuronal cell morphology and membrane tension, a key mechanism for PIEZO1 activation. In addition, high glucose stress upregulates serum/glucocorticoid-regulated kinase-1 (SGK1) and activates PIEZO1 through the Ca2+ pool and store-operated calcium entry (SOCE). PIEZO1-mediated Ca2+ influx further enhances SGK1 and SOCE, inducing intracellular Ca2+ peaks in neurons. PIEZO1 mediated intracellular Ca2+ elevation leads to calcium/calmodulin-dependent protein kinase 2α (CaMK2α) overactivation, which promotes oxidative stress and apoptosis signalling through p-CaMK2α/ERK/CREB and ox-CaMK2α/MAPK p38/NFκB p65 pathways, subsequently inducing synaptic damage and cognitive impairment in mice. The intron miR-107 of pantothenic kinase 1 (PANK1) is highly expressed in the brain and has been found to target PIEZO1 and SGK1. The PANK1 receptor is activated by peroxisome proliferator-activated receptor α (PPARα), an activator known to upregulate miR-107 levels in the brain. The clinically used lipid-lowering drug bezafibrate, a known PPARα activator, may upregulate miR-107 through the PPARɑ/PANK1 pathway, thereby inhibiting PIEZO1 and improving hyperglycemia-induced neuronal cell damage. This study provides a new idea for the pathogenesis and drug treatment of hyperglycemic neurotoxicity and diabetes-related cognitive dysfunction.

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.

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.

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.

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.

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.

NLRP3 inflammasome in cognitive impairment and pharmacological properties of its inhibitors.

Cognitive impairment is a multifactorial and multi-step pathological process that places a heavy burden on patients and the society. Neuroinflammation is one of the main factors leading to cognitive impairment. The inflammasomes are multi-protein complexes that respond to various microorganisms and endogenous danger signals, helping to initiate innate protective responses in inflammatory diseases. NLRP3 inflammasomes produce proinflammatory cytokines (interleukin IL-1ß and IL-18) by activating caspase-1. In this review, we comprehensively describe the structure and functions of the NLRP3 inflammasome. We also explore the intrinsic relationship between the NLRP3 inflammasome and cognitive impairment, which involves immune cell activation, cell apoptosis, oxidative stress, mitochondrial autophagy, and neuroinflammation. Finally, we describe NLRP3 inflammasome antagonists as targeted therapies to improve cognitive impairment.

Hsp22 pretreatment protects against LPS-induced hippocampal injury by alleviating neuroinflammation and apoptosis by regulating the NLRP3/Caspase1/IL-1ß signaling pathway in mice.

Neuroinflammation is an important reason for the occurrence and development of cognitive impairment. The Lentiviral vector Hsp22 was constructed for intracerebroventricular injection pretreatment, LPS was used to induce the cognitive impairment model in mice, and the Morris water maze was used to examine the changes in cognitive behavior in mice. LPS was used to induce BV-2 microglial cells, and plasmid pretreatment was used to overexpress Hsp22. HE staining, Nissl staining, immunohistochemistry, immunofluorescence, ELISA and protein blotting were used to examine microglial activation, changes in inflammatory factors, changes in pathway proteins and apoptosis. The results showed that LPS induced microglial expression of NLRP3/Caspase-1/IL-1ß signaling pathway protein Iba1, and the inflammatory protein and inflammatory factors IL-1ß, IL-6 and TNF-α, the expression of Bax increased significantly, Bcl2 expression decreased, and the learning and memory abilities of mice decreased significantly. Preconditioning with the Hsp22-overexpressing lentivirus attenuated LPS-induced activation of hippocampal microglia, the expression of inflammatory factors and pathway proteins, and apoptosis, and improved cognitive impairment in mice. In addition, plasmid-mediated Hsp22 overexpression reversed LPS-induced inflammation. These findings suggest that Hsp22 overexpression is a promising method for the treatment of cognitive impairment.

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.

Small extracellular vesicles secreted by induced pluripotent stem cell-derived mesenchymal stem cells improve postoperative cognitive dysfunction in mice with diabetes.

Postoperative cognitive dysfunction (POCD) is a common surgical complication. Diabetes mellitus (DM) increases risk of developing POCD after surgery. DM patients with POCD seriously threaten the quality of patients' life, however, the intrinsic mechanism is unclear, and the effective treatment is deficiency. Previous studies have demonstrated neuronal loss and reduced neurogenesis in the hippocampus in mouse models of POCD. In this study, we constructed a mouse model of DM by intraperitoneal injection of streptozotocin, and then induced postoperative cognitive dysfunction by transient bilateral common carotid artery occlusion. We found that mouse models of DM-POCD exhibited the most serious cognitive impairment, as well as the most hippocampal neural stem cells (H-NSCs) loss and neurogenesis decline. Subsequently, we hypothesized that small extracellular vesicles secreted by induced pluripotent stem cell-derived mesenchymal stem cells (iMSC-sEVs) might promote neurogenesis and restore cognitive function in patients with DM-POCD. iMSC-sEVs were administered via the tail vein beginning on day 2 after surgery, and then once every 3 days for 1 month thereafter. Our results showed that iMSC-sEVs treatment significantly recovered compromised proliferation and neuronal-differentiation capacity in H-NSCs, and reversed cognitive impairment in mouse models of DM-POCD. Furthermore, miRNA sequencing and qPCR showed miR-21-5p and miR-486-5p were the highest expression in iMSC-sEVs. We found iMSC-sEVs mainly transferred miR-21-5p and miR-486-5p to promote H-NSCs proliferation and neurogenesis. As miR-21-5p was demonstrated to directly targete Epha4 and CDKN2C, while miR-486-5p can inhibit FoxO1 in NSCs. We then demonstrated iMSC-sEVs can transfer miR-21-5p and miR-486-5p to inhibit EphA4, CDKN2C, and FoxO1 expression in H-NSCs. Collectively, these results indicate significant H-NSC loss and neurogenesis reduction lead to DM-POCD, the application of iMSC-sEVs may represent a novel cell-free therapeutic tool for diabetic patients with postoperative cognitive dysfunction.

A Multicenter, Randomized, Double-Blind, Positive-Controlled, Non-Inferiority, Phase III Clinical Trial Evaluating the Efficacy and Safety of Emulsified Isoflurane for Anesthesia Induction in Patients.

BACKGROUND: Emulsified isoflurane was designed to circumvent the deficiencies of inhalation anesthetics, which have a longer time to onset, result in a higher drug consumption, and for which a specific anesthesia machine is required for clinical use. The aim of this study was to compare the efficacy and safety of emulsified isoflurane with propofol for anesthesia induction in adults patients. METHODS: This multicenter, randomized, double-blind, positive-controlled, non-inferiority, phase III clinical trial compared the efficacy and safety of emulsified isoflurane with propofol for anesthesia induction. Each patient in the emulsified isoflurane group received a single bolus injection of 12% emulsified isoflurane at a dose of 30 mg/kg, and each patient in the propofol group received a single bolus injection of 0.8% propofol at a dose of 2 mg/kg. The primary outcome of the efficacy evaluation was the proportion of participants with successful anesthesia induction, which was regarded as a Modified Observer's Assessment of Alertness/Sedation (MOAA/S) score of < 1 and lack of use of other sedative drugs. A number of secondary efficacy outcomes were also assessed. Safety was monitored based on (1) adverse events, (2) repeated measurement of vital signs; (3) physical examination, (4) routine laboratory examinations of hematology, biochemistry, urine, coagulation function, and (5) 12-lead electrocardiogram. RESULTS: A total of 416 patients were enrolled (n = 208 in each group) and 398 patients were administered study drug. The proportion of participants with successful anesthesia induction was 100% with a 95% confidence interval of - 1.9% to + 1.9% for the emulsified isoflurane and propofol groups, which met the predesigned non-inferiority criteria of 5%. The study demonstrated the non-inferiority of sedation produced by emulsified isoflurane compared to propofol. Among the secondary efficacy outcomes, emulsified isoflurane showed a better cardiovascular stability than propofol. The number of patients from the emulsified isoflurane group who experienced drug-related adverse events was significantly higher than that of patients from the propofol group. However, there was no significant difference between the two groups in terms of adverse events or drug-related adverse events of grades 3-5. CONCLUSIONS: Emulsified isoflurane exhibited non-inferiority of anesthesia/sedation compared to propofol in patients undergoing anesthesia induction. CLINICAL TRIAL REGISTRATION: ChiCTR2000038185, registered on 12 December, 2020 ( www.chictr.org.cn ).

Efficacy and safety of remimazolam besylate in bronchoscopy for adults: A multicenter, randomized, double-blind, positive-controlled clinical study.

Background: With the development of fiberoptic bronchoscopy in the diagnosis and treatment of various pulmonary diseases, the anesthesia/sedation requirements are becoming more demanding, posing great challenges for patient safety while ensuring a smooth examination/surgery process. Remimazolam, a brand-new ultra-short-acting anesthetic, may compensate for the shortcomings of current anesthetic/sedation strategies in bronchoscopy. Methods: This study was a prospective, multicenter, randomized, double-blind, parallel positive controlled phase 3 clinical trial. Subjects were randomized to receive 0.2 mg/kg remimazolam besylate or 2 mg/kg propofol during bronchoscopy to evaluate the efficacy and safety of remimazolam. Results: A total of 154 subjects were successfully sedated in both the remimazolam group and the propofol group, with a success rate of 99.4% (95%CI of the adjusted difference -6.7 × 10%-6% to -5.1 × 10%-6%). The sedative effect of remimazolam was noninferior to that of propofol based on the prespecified noninferiority margin of -5%. Compared with the propofol group, the time of loss of consciousness in the remimazolam group (median 61 vs. 48s, p < 0.001), the time from the end of study drug administration to complete awakening (median 17.60 vs. 12.80 min, p < 0.001), the time from the end of bronchoscopy to complete awakening (median 11.00 vs. 7.00 min, p < 0.001), the time from the end of study drug administration to removal of monitoring (median 19.50 vs. 14.50 min, p < 0.001), and the time from the end of bronchoscopy to removal of monitoring (median 12.70 vs. 8.60 min, p < 0.001) were slightly longer. The incidence of Adverse Events in the remimazolam group and the propofol group (74.8% vs. 77.4%, p = 0.59) was not statistically significant, and none of them had Serious Adverse Events. The incidence of hypotension (13.5% vs. 29.7%, p < 0.001), hypotension requiring treatment (1.9% vs. 7.7%, p = 0.017), and injection pain (0.6% vs. 16.8%, p < 0.001) were significantly lower in the remimazolam group than in the propofol group. Conclusion: Moderate sedation with 0.2 mg/kg remimazolam besylate is effective and safe during bronchoscopy. The incidence of hypotension and injection pain was less than with propofol, but the time to loss of consciousness and recovery were slightly longer. Clinical Trial Registration: clinicaltrials.gov, ChiCTR2000039753.

A voice recognition-based digital cognitive screener for dementia detection in the community: Development and validation study.

Introduction: To facilitate community-based dementia screening, we developed a voice recognition-based digital cognitive screener (digital cognitive screener, DCS). This proof-of-concept study aimed to investigate the reliability, validity as well as the feasibility of the DCS among community-dwelling older adults in China. Methods: Eligible participants completed demographic, clinical, and the DCS. Diagnosis of mild cognitive impairment (MCI) and dementia was made based on the Montreal Cognitive Assessment (MoCA) (MCI: MoCA < 23, dementia: MoCA < 14). Time and venue for test administration were recorded and reported. Internal consistency, test-retest reliability and inter-rater reliability were examined. Receiver operating characteristic (ROC) analyses were conducted to examine the discriminate validity of the DCS in detecting MCI and dementia. Results: A total of 103 participants completed all investigations and were included in the analysis. Administration time of the DCS was between 5.1-7.3 min. No significant difference (p > 0.05) in test scores or administration time was found between 2 assessment settings (polyclinic or community center). The DCS showed good internal consistency (Cronbach's alpha = 0.73), test-retest reliability (Pearson r = 0.69, p < 0.001) and inter-rater reliability (ICC = 0.84). Area under the curves (AUCs) of the DCS were 0.95 (0.90, 0.99) and 0.77 (0.67, 086) for dementia and MCI detection, respectively. At the optimal cut-off (7/8), the DCS showed excellent sensitivity (100%) and good specificity (80%) for dementia detection. Conclusion: The DCS is a feasible, reliable and valid digital dementia screening tool for older adults. The applicability of the DCS in a larger-scale community-based screening stratified by age and education levels warrants further investigation.

Knockout of circRNA single stranded interacting protein 1 (circRBMS1) played a protective role in myocardial ischemia-reperfusion injury though inhibition of miR-2355-3p/Mammalian Sterile20-like kinase 1 (MST1) axis.

Evidence suggests circRBMS1 regulates mRNA to mediate cell apoptosis, inflammation, and oxidative stress in different diseases. MST1 is reported to be the target and activator of apoptosis-related molecules and signaling pathways. Hence, the present study aims to investigate the role of circ-RBMS1/miR-2355-3p/MST1 in the development of I/R injury. In vitro experiments showed increased circ-RBMS1 and decreased miR-2355-3p in H/R-induced HCMs. CircRBMS1 served as a sponge for miR-2355-3p and miR-2355-3p targeted MST1. Furthermore, knockout of circRBMS1 attenuated cell apoptosis, oxidized stress, and inflammation in H/R-induced HCMs. In vivo experiments indicated circRBMS1 knockdown attenuated cardiac function damage, cell apoptosis, oxidative stress injury and inflammatory response through miR-2355-3p/MST1 axis in mice. In summary, these results demonstrated circRBMS1 played a protective role in myocardial I/R injury though inhibition of miR-2355-3p/MST1 axis. It might provide a new therapeutic target for cardiac I/R injury.

CB2R Activation Regulates TFEB-Mediated Autophagy and Affects Lipid Metabolism and Inflammation of Astrocytes in POCD.

Evidence suggests that the accumulation of lipid drots (LDs) accelerates damage to mitochondria and increases the release of inflammatory factors. These have been implicated as a mechanism underlying neurodegenerative diseases or tumors and aging-related diseases such as postoperative cognitive dysfunction (POCD), nevertheless, accumulation of lipid droplets has not been extensively studied in the central nervous system (CNS). Here, we found that after surgery, there was activation of astrocytes and lipid accumulation in the hippocampus. However, cannabinoid receptor type II (CB2R) activation significantly reduced lipid accumulation in astrocytes and change the expression of genes related to lipid metabolism. CB2R reduces the release of the inflammatory factors interleukin-1 beta (IL-1ß) and interleukin 6 (IL-6) in peripheral serum and simultaneously improves cognitive ability in mice with POCD. Further research on mechanisms indicates that CB2R activation promotes the nuclear entry of the bHLH-leucine zipper transcription factor, the transcription factor EB (TFEB), and which is a master transcription factor of the autophagy-lysosomal pathway, also reduces TFEB-S211 phosphorylation. When CB2R promotes TFEB into the nucleus, TFEB binds at two sites within promoter region of PGC1α, promoting PGC1α transcription and accelerating downstream lipid metabolism. The aforementioned process leads to autophagy activation and decreases cellular lipid content. This study uncovers a new mechanism allowing CB2R to regulate lipid metabolism and inflammation in POCD.

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.

Carbohydrate-substituted N-heterocyclic carbenes Palladium complexes: High efficiency catalysts for aqueous Suzuki-Miyaura reaction.

Metal complexes that contain carbohydrate-substituent (Carb-) N-heterocyclic carbenes (NHCs) ligand have demonstrated great success as catalysts for organic synthesis reactions. In this study, four new Carb-NHC-Pd complexes 2a-d were prepared and their catalytic activities for Suzuki-Miyaura reaction were evaluated. The Carb-NHC-Pd complex behaved as a general surfactant which leads to the formation of a temporary oil-in-water contact interface, thereby promoting the Suzuki-Miyaura reaction. A long hydrophobic alkyl chain (-nC16H33) was remotely linked to complex 2d, in which Carb-NHCs showed high electron-donating properties, and steric bulk with 1JCH constant of 1H NMR. Complex 2d exhibited a higher catalytic activity as compared with 2a (-nC2H5), 2b (-nC4H9), and 2c (-nC8H17). A series of fluorene-cored materials with different aryl groups were synthesized with high yields (34 examples, 91-99%) under the optimized reaction conditions.

Piezo1 Channels as Force Sensors in Mechanical Force-Related Chronic Inflammation.

Mechanical damage is one of the predisposing factors of inflammation, and it runs through the entire inflammatory pathological process. Repeated or persistent damaging mechanical irritation leads to chronic inflammatory diseases. The mechanism of how mechanical forces induce inflammation is not fully understood. Piezo1 is a newly discovered mechanically sensitive ion channel. The Piezo1 channel opens in response to mechanical stimuli, transducing mechanical signals into an inflammatory cascade in the cell leading to tissue inflammation. A large amount of evidence shows that Piezo1 plays a vital role in the occurrence and progression of chronic inflammatory diseases. This mini-review briefly presents new evidence that Piezo1 responds to different mechanical stresses to trigger inflammation in various tissues. The discovery of Piezo1 provides new insights for the treatment of chronic inflammatory diseases related to mechanical stress. Inhibiting the transduction of damaging mechanical signals into inflammatory signals can inhibit inflammation and improve the outcome of inflammation at an early stage. The pharmacology of Piezo1 has shown bright prospects. The development of tissue-specific Piezo1 drugs for clinical use may be a new target for treating chronic inflammation.

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.