Prognostic value of mild asymptomatic intracranial atherosclerosis stenosis in patients with hypertension.

BACKGROUND AND AIMS: Mild asymptomatic intracranial atherosclerotic stenosis (aICAS) is common in Chinese patients with hypertension. However, there are no data on its prognostic value in this population. The aim of the present study was to clarify the prevalence and associated cardiovascular risk factors of mild aICAS and determine its prognostic value for overall and cardiovascular mortality in patients with hypertension. METHODS: In total, 1813 participants were evaluated for aICAS using computed tomographic angiography. The predictive effect of mild to severe aICAS on all-cause and cardiovascular mortality was evaluated using Kaplan-Meier survival curves and Cox regression analyses. RESULTS: The prevalence rate of mild aICAS was 35.7%. Poorly controlled hypertension, in combination with diabetes and dyslipidemia, was associated with aICAS. Patients with aICAS had an independently significant increase in the risk of all-cause and cardiovascular death, with adjusted hazard ratios (HRs) for mild to severe stenosis ranging from 1.52 to 3.03 for all-cause death and from 2.48 to 6.38 for cardiovascular death. Among the patients with mild aICAS, only those with more than two stenoses had increased mortality after adjustment, with an HR of 2.35 (95% CI: 1.36-4.04) for total death and 4.41 (95% CI: 1.78-10.93) for cardiovascular death. CONCLUSIONS: A significant association between mild aICAS and mortality in stroke-free patients with hypertension was revealed. The results indicate that mild aICAS might be an imaging marker for cerebrovascular lesions in patients with hypertension and poor control of blood pressure and lipids in this population requires further research.

Neuroprotective effects of CysLT2R antagonist on Angiostrongylus cantonensis-induced edema and meningoencephalitis.

Cysteinyl leukotrienes (CysLTs) can induce a disruption of the blood-brain barrier (BBB), and this reaction is mediated by cysteinyl-leukotriene receptors. In this study, we used A. cantonensis-induced eosinophilic meningoencephalitis as a model to investigate whether the CysLT2 receptor involved in the pathogenesis of angiostrongyliasis meningoencephalitis. The present study provides evidence that the CysLT2 receptor antagonist HAMI3379 reduced the number of infiltrated eosinophils and brain edema in eosinophilic meningoencephalitis. Additionally, we found that HAMI3379 significantly decreased the protein levels of M1 polarisation markers (CD80, iNOS, IL-5 and TNF-α), increased the expression of M2 polarisation markers (CD206, IL-10 and TGF-ß) both in vivo and in vitro. Matrix metalloproteinase-9, S100B, GFAP, fibronectin, and claudin-5 were markedly lower after HAMI3379 treatment. Therefore, HAMI3379 reduced the BBB dysfunction in angiostrongyliasis meningoencephalitis. We have identified microRNA-155 as a BBB dysfunction marker in eosinophilic meningoencephalitis. The results showed that microRNA-155 was 15-fold upregulated in eosinophilic meningoencephalitis and 20-fold upregulated after HAMI3379 treatment. Our results suggest that CysLT2R may be involved in A. cantonensis-induced brain edema and eosinophilic meningoencephalitis and that down-regulation of CysLT2R could be a novel and potential therapeutic strategy for the treatment of angiostrongyliasis meningoencephalitis.

Curative effects and mechanisms of AG1296 and LY294002 co-therapy in Angiostrongylus cantonensis-induced neurovascular unit dysfunction and eosinophilic meningoencephalitis.

BACKGROUND: Co-therapy with albendazole and steroid is commonly used in patients with eosinophilic meningoencephalitis caused by Angiostrongylus cantonensis infections. However, anthelminthics often worsen symptoms, possibly due to the inflammatory reaction to antigens released by dying worms. Therefore, the present study was to investigate the curative effects and probable mechanisms of the platelet-derived growth factor receptor-beta (PDGFR-ß) inhibitor AG1296 (AG) and the phosphoinositide 3-kinase inhibitor (PI3K) LY294002 (LY) in A. cantonensis-induced neurovascular unit dysfunction and eosinophilic meningoencephalitis. METHODS: Western blots were used to detect matrix protein degradation and the expressions of PDGFR-ß/PI3K signaling pathway. The co-localization of PDGFR-ß and vascular smooth muscle cells (VSMCs), and metalloproteinase-9 (MMP-9) and VSMCs on the blood vessels were measured by confocal laser scanning immunofluorescence microscopy. Sandwich enzyme-linked immunosorbent assays were used to test S100B, interleukin (IL)-6, and transforming growth factor beta in the cerebrospinal fluid to determine their possible roles in mouse resistance to A. cantonensis. RESULTS: The results showed that AG and LY cotherapy decreased the MMP-9 activity and inflammatory reaction. Furthermore, S100B, IL-6 and eosinophil counts were reduced by inhibitor treatment. The localization of PDGFR-ß and MMP-9 was observed in VSMCs. Furthermore, we showed that the degradation of the neurovascular matrix and blood-brain barrier permeability were reduced in the mouse brain. CONCLUSIONS: These findings demonstrate the potential of PDGFR-ß inhibitor AG and PI3K inhibitor LY co-therapy as anti-A. cantonensis drug candidates through improved neurovascular unit dysfunction and reduced inflammatory response.

Exploration of the Molecular Mechanism by Which Caveolin-1 Regulates Changes in Blood-Brain Barrier Permeability Leading to Eosinophilic Meningoencephalitis.

Angiostrongylus cantonensis, a zoonotic parasite, can invade the human central nervous system (CNS) and cause acute eosinophilic meningitis or eosinophilic meningoencephalitis. Mice infected with A. cantonensis show elevated levels of pro-inflammatory cytokines, plasminogen activators, and matrix metalloproteinase-9, resulting in disruption of the blood-brain barrier (BBB) and immune cell infiltration into the CNS. Caveolin-1 (Cav-1) regulates the permeability of the BBB, which affects immune cells and cerebrospinal fluid. This intricate interaction ultimately fuels the progression of brain damage and edema. This study aims to investigate the regulatory role of Cav-1 in the pathogenesis of meningoencephalitis induced by A. cantonensis infection. We investigated pathological alterations by triphenyl-tetrazolium chloride, brain water content, BBB permeability, Western blot analysis, and gelatin zymography in BALB/c mice after A. cantonensis. The study evaluates the critical role of Cav-1 regulation through the TLR4/MyD88 signaling pathway, modulates tight junction proteins, influences BBB permeability, and contributes to brain damage in A. cantonensis-induced meningoencephalitis.

Amygdala-Targeted Relief of Neuropathic Pain: Efficacy of Repetitive Transcranial Magnetic Stimulation in NLRP3 Pathway Suppression.

This study investigates the effectiveness of repetitive transcranial magnetic stimulation (rTMS) as a nonpharmacological approach to treating neuropathic pain (NP), a major challenge in clinical research. Conducted on male Sprague-Dawley rats with NP induced through chronic constriction injury of the sciatic nerve, the research assessed pain behaviors and the impact of rTMS on molecular interactions within the amygdala. Through a comprehensive analysis involving Mechanical Withdrawal Threshold (MWT), Thermal Withdrawal Latency (TWL), RNA transcriptome sequencing, RT-qPCR, Western blotting, immunofluorescence staining, and Co-Immunoprecipitation (Co-IP), the study focused on the expression and interaction of integrin αvß3 and its receptor P2X7R. Findings reveal that rTMS significantly influences the expression of integrin αvß3 in NP models, suggesting an inhibition of the NP-associated NLRP3 inflammatory pathway through the disruption of integrin αvß3-P2X7R interactions. These outcomes highlight the potential of rTMS in alleviating NP by targeting molecular interactions within the amygdala, offering a promising therapeutic avenue for managing NP.

Important nutrient sources and carbohydrate metabolism patterns in the growth and development of spargana.

BACKGROUND: Sparganosis is a worldwide food-borne parasitic disease caused by spargana infection, which infects the muscle of frogs and snakes as well as many tissues and organs in humans. There are currently no viable treatments for sparganosis. Understanding spargana's nutrition source and carbohydrate metabolism may be crucial for identifying its energy supply and establishing methods of treatment for sparganosis. METHODS: Using an amino acid analyzer and nutrient concentration detection kits, we assessed nutrient concentrations in the muscles of Fejervarya limnocharis and Pelophylax plancyi infected or not infected with spargana. Quantitative polymerase chain reaction (PCR) was used to quantify the major enzymes involved in five glucose metabolism pathways of spargana developing in vivo. We also used quantitative PCR to assess key enzymes and transcriptome sequencing to explore the regulation of carbohydrate metabolic pathways in vitro in response to different 24-h food treatments. RESULTS: Infected muscle tissues had considerably higher concentrations of glucogenic and/or ketogenic amino acids, glucose, and glycogen than non-infected muscle tissues. We discovered that the number of differentially expressed genes in Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis was larger in low-glucose than in other dietary groups. We examined differences in the expression of genes producing amino acid transporters, glucose transporters, and cathepsins in spargana grown in various nutritional environments. In the normal saline group, only the major enzymes in the tricarboxylic acid cycle (TCA), glycogenesis, and glycogenolysis pathways were expressed. The L-glutamine group had the greatest transcriptional levels of critical rate-limiting enzymes of gluconeogenesis and glycogenesis. Furthermore, the low-glucose group had the highest transcriptional levels of critical rate-limiting enzymes involved in the TCA, glycolytic, and glycogenolysis pathways. Surprisingly, when compared to the in vitro culturing groups, spargana developing in vivo exhibited higher expression of these critical rate-limiting enzymes in these pathways, with the exception of the pentose phosphate pathway. CONCLUSIONS: Spargana have a variety of nutritional sources, and there is a close relationship between nutrients and the carbohydrate metabolism pathways. It takes a multi-site approach to block nutrient absorption and carbohydrate metabolism pathways to provide energy to kill them.

hUC-MSC-EV-miR-24 enhances the protective effect of dexmedetomidine preconditioning against myocardial ischemia-reperfusion injury through the KEAP1/Nrf2/HO-1 signaling.

The cardioprotective effect of microRNAs (miRNAs) on myocardial ischemic-reperfusion (I/R) injury has been documented. Here, we aim to decipher the mechanism of miR-24 delivered by human umbilical cord mesenchymal stem cell-derived extracellular vesicles (hUC-MSC-EVs) in myocardial I/R injury after dexmedetomidine (DEX) preconditioning. We collected and identified hUC-MSCs and extracted EVs, which were co-cultured with DEX-preconditioned hypoxia/reoxygenation (H/R) cardiomyocyte models or injected into I/R mouse models. The cardiomyocytes and myocardial injury were evaluated by molecular biology experiments. miR-24 was highly expressed in hUC-MSC-EVs. hUC-MSC-EVs could transfer miR-24 into cardiomyocytes where miR-24 augmented cell viability and inhibited cell apoptosis after DEX preconditioning. In the co-culture system of RAW264.7 macrophages with hUC-MSC-EVs, miR-24 promoted M2-type polarization of macrophages and reduced M1-type macrophage polarization. Mechanistically, miR-24 targeted KEAP1 and inhibited its expression, resulting in disruption of the Nrf2/HO-1 signaling. In vivo data confirmed that miR-24 delivered by hUC-MSC-EVs enhanced the suppressing effect of DEX preconditioning on inflammation and apoptosis in rats following myocardial I/R injury. Overall, miR-24 delivered by hUC-MSC-EVs can promote M2 polarization of macrophages and enhance the protective effect of DEX preconditioning on myocardial I/R injury by down-regulating the KEAP1/Nrf2/HO-1 signaling axis.

Image quality of coronary CT angiography at ultra low tube voltage reconstructed with a deep-learning image reconstruction algorithm in patients of different weight.

Background: GE Healthcare's new generation of deep-learning image reconstruction (DLIR), the Revolution Apex CT is the first CT image reconstruction engine based on a deep neural network to be approved by the US Food and Drug Administration (FDA). It can generate high-quality CT images that restore the true texture with a low radiation dose. The aim of the present study was to assess the image quality of coronary CT angiography (CCTA) at 70 kVp with the DLIR algorithm as compared to the adaptive statistical iterative reconstruction-Veo (ASiR-V) algorithm in patients of different weight. Methods: The study group comprised 96 patients who underwent CCTA examination at 70 kVp and were subdivided by body mass index (BMI) into normal-weight patients [48] and overweight patients [48]. ASiR-V40%, ASiR-V80%, DLIR-low, DLIR-medium, and DLIR-high images were obtained. The objective image quality, radiation dose, and subjective score of the two groups of images with different reconstruction algorithms were compared and statistically analyzed. Results: In the overweight group, the noise of the DLIR image was lower than that of the routinely used ASiR-40%, and the contrast-to-noise ratio (CNR) of DLIR (H: 19.15±4.31; M: 12.68±2.91; L: 10.59±2.32) was higher than that of the ASiR-40% reconstructed image (8.39±1.46), with statistically significant differences (all P values <0.05). The subjective image quality evaluation of DLIR was significantly higher than that of ASiR-V reconstructed images (all P values <0.05), with the DLIR-H being the best. In a comparison of the normal-weight and overweight groups, the objective score of the ASiR-V-reconstructed image increased with increasing strength, but the subjective image evaluation decreased, and both differences (i.e., objective and subjective) were statistically significant (P<0.05). In general, the objective score of the DLIR reconstruction image between the two groups increased with increased noise reduction, and the DLIR-L image was the best. The difference between the two groups was statistically significant (P<0.05), but there was no significant difference in subjective image evaluation between the two groups. The effective dose (ED) of the normal-weight group and the overweight group was 1.36±0.42 and 1.59±0.46 mSv, respectively, and was significantly higher in the overweight group (P<0.05). Conclusions: As the strength of the ASiR-V reconstruction algorithm increased, the objective image quality increased accordingly, but the high-strength ASiR-V changed the noise texture of the image, resulting in a decrease in the subjective score, which affected disease diagnosis. Compared with the ASiR-V reconstruction algorithm, the DLIR reconstruction algorithm improved the image quality and diagnostic reliability for CCTA in patients with different weights, especially in heavier patients.

Cardioprotective effects of circ_0002612 in myocardial ischemia/reperfusion injury correlate with disruption of miR-30a-5p-dependent Ppargc1a inhibition.

INTRODUCTION: Novel mechanistic insights into the effects of circular RNAs (circRNAs) on the physiology and pathology of cardiovascular diseases are under increasingly active investigation. This study defined the cardioprotective role and mechanistic actions of circ_0002612 in myocardial ischemia/reperfusion injury (MI/RI). METHODS: MI/RI was induced in mice by ligation of the left anterior descending (LAD) artery followed by reperfusion, and the in vitro model was established in cultured cardiomyocytes under hypoxia/reoxygenation (H/R) conditions. Interaction among circ_0002612, miR-30a-5p, Ppargc1a, and NLRP3 was predicted by bioinformatics analysis and further experimentally identified. Gain- and loss-of-function experiments were performed to evaluate the effect of the circ_0002612/miR-30a-5p/Ppargc1a/NLRP3 axis on the cardiac function and myocardial infarction of I/R-injured mice, as well as viability and apoptosis of H/R-challenged cardiomyocytes. RESULTS: In the myocardial tissues of MI/RI mice, miR-30a-5p was negatively correlated with circ_0002612 or Ppargc1a, but circ_0002612 was positively correlated with the expression of Ppargc1a. circ_0002612 competitively bound to miR-30a-5p to release expression of its target gene Ppargc1a. circ_0002612 promoted cardiomyocyte viability while suppressing the apoptosis by impairing the miR-30a-5p-mediated inhibition of Ppargc1a. Additionally, Ppargc1a inhibited the expression of NLRP3 and consequently facilitated cardiomyocyte proliferation while suppressing cell apoptosis. By inhibiting the expression of NLRP3, circ_0002612 protected mice from MI/RI. CONCLUSION: Overall, this study demonstrates the cardioprotective role of circ_0002612 against MI/RI, which may be a viable target for MI/RI.

Cognitive protection of sinomenine in type 2 diabetes mellitus through regulating the EGF/Nrf2/HO-1 signaling, the microbiota-gut-brain axis, and hippocampal neuron ferroptosis.

Recent years have witnessed a growing research interest in traditional Chinese medicine as a neuroprotective nutrient in the management of diabetic cognitive dysfunction. However, the underlying molecular mechanisms of sinomenine in mediating ferroptosis of hippocampal neurons have been poorly understood. This study sought to decipher the potential effect and molecular mechanism of sinomenine in the cognitive dysfunction following type 2 diabetes mellitus (T2DM). Multi-omics analysis was conducted to identify the microbiota-gut-brain axis in T2DM patient samples obtained from the publicly available database. In HT-22 cells, erastin was utilized to create a ferroptosis model, and streptozotocin was injected intraperitoneally to create a rat model of DM. It was noted that intestinal flora imbalance occurred in patients with T2DM-associated cognitive dysfunction. Sinomenine could reduce Erastin-induced hippocampus neuronal ferroptosis by increasing EGF expression. EGF protected hippocampal neurons against ferroptosis by activating the Nrf2/HO-1 signaling pathway. Furthermore, in vivo results confirmed that sinomenine blocked ferroptosis of hippocampal neurons and alleviated cognitive dysfunction in T2DM rats. Collectively, these results suggest that sinomenine confers neuroprotective effects by curtailing hippocampal neuron ferroptosis via the EGF/Nrf2/HO-1 signaling and microbiota-gut-brain axis. It may be a candidate for the treatment of diabetic cognitive dysfunction.

Phase Retrieval-Based Phase-Contrast Imaging and CT of Living Zebrafish.

Zebrafish are widely used as experimental animal models. They are small and move fast in the water. Real-time imaging of fast-moving zebrafish is a challenge, and it requires that the imaging technique has higher spatiotemporal resolution and penetration ability. The purpose of this study was to evaluate the feasibility of dynamic phase retrieval (PR)-based phase-contrast imaging (PCI) for real-time displaying of the breathing and swimming process in unanesthetized free-moving zebrafish, and to evaluate the feasibility of PR-based phase-contrast CT (PCCT) for visualizing the soft tissues in anesthetized living zebrafish. PR was performed using the phase-attenuation duality (PAD) method with the δ/ß values (PAD property) of 100 and 1000 for dynamic PR-based PCI and PR-based PCCT, respectively. The contrast-to-noise ratio (CNR) was used for quantitatively assessing the visibility of the adipose tissue and muscle tissue. The skeleton and swim bladder chambers in fast-moving zebrafish were clearly shown. The dynamic processes of breathing and swimming were visibly recorded. The respiratory intensity and frequency and the movement flexibility of the zebrafish could be dynamically evaluated. By producing more obvious image contrast, PR-based PCCT clearly showed the adipose tissue and muscle tissue. The CNRs from PR-based PCCT were significantly higher than those from PR-free PCCT for both adipose tissue (9.256 ± 2.037 vs. 0.429 ± 0.426, p < 0.0001) and muscle tissue (7.095 ± 1.443 vs. 0.324 ± 0.267, p < 0.0001). Dynamic PR-based PCI holds the potential for investigating both morphological abnormalities and motor disorders. PR-based PCCT offers clear visualization and the potential for quantification of soft tissues in living zebrafish.

The value of 18F-fluorodeoxyglucose positron emission tomography/magnetic resonance whole-body scans and local enhancement scans in the preoperative staging and resectability assessment of pancreatic adenocarcinoma.

Background: In addition to contrast-enhanced multiphase computed tomography (CT) and magnetic resonance imaging (MRI), integrated positron emission tomography (PET)/magnetic resonance (MR) is increasingly being used for the preoperative evaluation of pancreatic cancer. The purpose of this study was to explore the value of hybrid 18F-fluorodeoxyglucose (18F-FDG) PET/MR imaging in preoperative assessment and treatment decision-making. Methods: A retrospective data collection (of imaging, clinical, and pathological information) was conducted on patients who underwent 18F-FDG PET/MR with clinically diagnosed or suspected pancreatic cancer from March 2018 to March 2022 in Ruijin Hospital. The data of 76 patients were initially included, with 1 of the 76 patients eventually being excluded due to a misdiagnosis of inflammatory disease. Of the 75 patients, 38 underwent pancreatic tumor resection and 10 underwent laparoscopic exploration. The accuracy of 18F-FDG PET/MR for pancreatic cancer staging and the assessment of pancreatic resectability was evaluated based on pathological results, intraoperative findings, and documented final clinical stages of illness. The adjustments to patient treatment plans were also analyzed before and after 18F-FDG PET/MR examination. Results: The accuracy of clinical tumor node metastasis (TNM) staging of pancreatic cancer by 18F-FDG PET/MR was 73.3% (55/75). The area under the curve (AUC) of 18F-FDG PET/MR for diagnosing the advanced stage (III-IV) versus the nonadvanced stage (I-II) of disease was 0.922 [95% confidence interval (CI): 0.852-0.993]. The treatment regimen of 20.0% (15/75) of patients was impacted. The accuracy of the evaluation of the resectability of pancreatic cancer with 18F-FDG PET/MR was 91.9% (34/37). With the surgical and pathological results being used as a reference, the overall accuracy of preoperative 18F-FDG PET/MR for T staging was 62.2%, and the AUC for diagnosing T4 versus T1-3 was 0.872 (95% CI: 0.660-1.000). Conclusions: 18F-FDG PET/MR performs well in diagnosing advanced pancreatic cancer and thus may impact the treatment decisions for a considerable number of patients. 18F-FDG PET/MR has a high level of accuracy in evaluating the resectability of pancreatic cancer before surgery.

Delivery of miR-130a-3p Through Adipose-Derived Stem Cell-Secreted EVs Protects Against Diabetic Peripheral Neuropathy via DNMT1/NRF2/HIF1α/ACTA1 Axis.

Peripheral neuropathy is common in diabetic patients and can lead to amputations or foot ulcers. microRNAs (miRNAs) possess crucial roles in diabetic peripheral neuropathy (DPN). This study aims to investigate the role miR-130a-3p played in DPN and its underlying molecular mechanisms. miR-130a-3p expression in clinical tissue samples, established DPN rat models, and extracellular vesicles (EVs) derived from adipose-derived stem cells (ADSCs) were determined. Schwann cells (SCs) were co-cultured with ADSC-derived EVs and treated with high glucose. The direct relationship and functional significance of miR-130a-3p, DNMT1, nuclear factor E2-related factor 2 (NRF2), hypoxia-inducible factor-1α (HIF1α), and skeletal muscle actin alpha 1 (ACTA1) was identified. The in vitro and in vivo implication of ADSC-derived EVs carrying miR-130a-3p was assessed. miR-130a-3p was poorly expressed in DPN patients and rats but highly expressed in ADSC-derived EVs. miR-130a-3p could be delivered to SCs through ADSC-derived EVs to inhibit SC apoptosis and promote proliferation under a high-glucose environment. miR-130a-3p activated NRF2/HIF1α/ACTA1 axis through down-regulating DNMT1. In vivo injection of ADSC-derived EVs activated NRF2/HIF1α/ACTA11 axis to promote angiogenesis in DPN rat model. These data together supported that ADSC-derived EVs carrying miR-130a-3p could alleviate DPN by accelerating SC proliferation and inhibiting apoptosis, providing a potential treatment against DPN.

Dunaliella salina Alga Protects against Myocardial Ischemia/Reperfusion Injury by Attenuating TLR4 Signaling.

Myocardial ischemia/reperfusion (I/R) injury is marked by rapid increase in inflammation and not only results in myocardial apoptosis but also compromises the myocardial function. Dunaliella salina (D. salina), a halophilic unicellular microalga, has been used as a provitamin A carotenoid supplement and color additive. Several studies have reported that D. salina extract could attenuate lipopolysaccharides-induced inflammatory effects and regulate the virus-induced inflammatory response in macrophages. However, the effects of D. salina on myocardial I/R injury remain unknown. Therefore, we aimed to investigate the cardioprotection of D. salina extract in rats subjected to myocardial I/R injury that was induced by occlusion of the left anterior descending coronary artery for 1 h followed by 3 h of reperfusion. Compared with the vehicle group, the myocardial infarct size significantly decreased in rats that were pre-treated with D. salina. D. salina significantly attenuated the expressions of TLR4, COX-2 and the activity of STAT1, JAK2, IκB, NF-κB. Furthermore, D. salina significantly inhibited the activation of caspase-3 and the levels of Beclin-1, p62, LC3-I/II. This study is the first to report that the cardioprotective effects of D. salina may mediate anti-inflammatory and anti-apoptotic activities and decrease autophagy through the TLR4-mediated signaling pathway to antagonize myocardial I/R injury.

Dexmedetomidine alleviates myocardial ischemia-reperfusion injury by down-regulating miR-34b-3p to activate the Jagged1/Notch signaling pathway.

BACKGROUND: Myocardial ischemia/reperfusion (I/R) injury is a fatal event that usually occurs after reperfusion therapy for myocardial infarction. Dexmedetomidine (Dex) has been shown to be beneficial in the treatment of myocardial infarction, however, its underlying mechanism for regulating I/R injury is unclear. METHODS: H9c2 cell and rat models of I/R injury were established via oxygen-glucose deprivation reoxygenation (OGD/R) and occlusion of the left anterior descending branch of coronary artery, respectively. Flow cytometry, MTT, or DHE assay detected cell activity, ROS, or apoptosis, respectively. The expression levels of miR-34b-3p and related mRNAs were determined using qRT-PCR. Related protein expression levels were detected by Western blotting and ELISA test. The interaction between miR-34b-3p and Jagged1 was assessed by dual luciferase reporter and RIP assays. The morphology of cardiac tissue was examined by TTC, HE, and TUNEL labeling. RESULTS: Dex markedly inhibited the inflammatory damage and apoptosis caused by OGD/R in H9c2 cells. MiR-34b-3p and Jagged1 levels were increased and decreased in myocardial I/R injury model, respectively, while Dex reversed this effect. Moreover, miR-34b-3p was firstly reported to directly bind and decrease Jagged1 expression, thereby inhibiting Notch signaling pathway. Transfection of agomiR-34b-3p or Jagged1 silencing eliminated Dex's defensive impact on OGD/R-induced cardiomyocytes damage. Dex relieved the myocardial I/R injury of rats via inhibiting miR-34b-3p and further activating Notch signaling pathway. CONCLUSION: Dex protected myocardium from I/R injury via suppressing miR-34b-3p to activate Jagged1-mediated Notch signaling pathway. Our findings revealed a novel mechanism underlying of Dex on myocardial I/R injury.

Sinomenine alleviates diabetic peripheral neuropathic pain through inhibition of the inositol-requiring enzyme 1 alpha-X-box binding protein 1 pathway by downregulating prostaglandin-endoperoxide synthase 2.

INTRODUCTION: We tried to show the effect of sinomenine (SIN) in diabetic peripheral neuropathic pain (DPNP) and the related underlying mechanism. METHODS: Network pharmacological analysis and bioinformatics analysis were carried out for identification of the active ingredients of Sinomenium acutum and the related genes. The DPNP rat model was constructed and primary rat spinal cord microglial cells were isolated for in vitro cell experiments. The therapeutic role of SIN in DPNP was determined in vivo and in vitro through analysis of microglial cell activation and inflammatory response. RESULTS: Therapeutic role of S. acutum in DPNP was mainly achieved by regulating 14 key genes, among which the target gene prostaglandin-endoperoxide synthase 2 (PTGS2) of SIN might be the key gene. An in vivo experiment showed that SIN inactivated the inositol-requiring enzyme 1 alpha-X-box binding protein 1 pathway by downregulating PTGS2, which relieved pain symptoms in DPNP rats. It was confirmed in vivo that SIN inhibited the pathway through PTGS2 to alleviate the activation of spinal cord microglial cells and inflammatory response. CONCLUSION: SIN decreases the expression of PTGS2 to inactivate the inositol-requiring enzyme 1 alpha-X-box binding protein 1 signaling pathway, which inhibits microglial activation, as well as the release of inflammatory factors, thus alleviating DPNP.

Effect of gadopentetate dimeglumine on bone growth in zebrafish caudal fins.

Compared with MR plain scanning, gadolinium (Gd)-enhanced MR scanning can provide more diagnostic information. Gadopentetate dimeglumine is generally used as an MR enhancement contrast agent in some countries. It is a member of linear Gd-based contrast agents (GBCAs) which are considered more likely to release free Gd ions (Gd3+) than macrocyclic GBCAs. Gd3+ is one of the most effective known calcium antagonists, and can compete with calcium ions (Ca2+) in Ca2+-related biological reactions. In this study, animal models of tissue regeneration were established by cutting the caudal fins of zebrafish, and the models were exposed with gadopentetate dimeglumine solution for different immersion times of 1, 3, and 5 min. Three GBCA exposures per week were performed in the first 3 weeks of the follow-up time. Morphological parameters such as regenerative area (RA), bone density, bone thickness and regenerative bone volume (RBV) were quantified using a camera and synchrotron radiation micro CT. RA decreased as total Gd intake increased in both the female group (ρ = -0.784, P < 0.0001) and the male group (ρ = -0.471, P = 0.011). The bone density of the regenerated bone increased after Gd exposure in the treated groups. The morphology of the regenerated bone from the treated groups became shorter and thicker. Our results showed that gadopentetate dimeglumine had osteogenic toxicity in zebrafish.

BcGRP23: A novel gene involved in the chlorophyll metabolic pathway that is activated by BES1 in flowering Chinese cabbage.

Glycine-rich proteins (GRPs) are a large family of proteins that play vital roles in cell wall remodeling, metabolism and development, and abiotic stress response. Although the functions of GRPs in cell wall remodeling have been extensively characterized, only a few studies have explored their effects on chlorophyll metabolism and hormone response. Accordingly, we aimed to determine the molecular mechanism of BcGRP23 and its role in chlorophyll metabolism and the BRI1-EMS-SUPPRESSOR 1 (BES1) signaling pathway in flowering Chinese cabbage. The expression levels of BcGRP23 in the leaves and stems gradually decreased with increasing growth and development of flowering Chinese cabbage, while BcGRP23 was barely expressed after flowering. As plant growth continued, the GUS (ß-glucuronidase) stain gradually became lighter in hypocotyls and was largely free of growth points. The petioles and stems of BcGRP23-silenced plants lost their green color, and the contents of chlorophyll a (Chl a) and Chl b were significantly reduced. Further research revealed that the expression levels of chlorophyll degradation-related genes were significantly increased in silenced plants compared with the control; however, the opposite was noted for the BcGRP23-overexpressing lines. The BcGRP23 promoter sequence contains numerous hormone-responsive elements. In fact, the expression of BcGRP23 was upregulated in flowering Chinese cabbage following treatment with the hormones indole-3-acetic acid (IAA), gibberellin (GA), 6-benzylaminopurine (6-BA), methyl jasmonate (MeJA), and brassinosteroid (BR). Treatment with BR led to the most significant upregulation. BES1, in response to BRs, directly activated the BcGRP23 promoter. Overall, BcGRP23 regulated the expression of chlorophyll degradation-related genes, thereby affecting the chlorophyll content. Furthermore, the expression of BcGRP23 was significantly regulated by exogenous BR application and was directly activated by BES1. These findings preliminarily suggest the molecular mechanism and regulatory pathway of BcGRP23 in the growth and development of flowering Chinese cabbage plants and their response to environmental stress.

Calycosin attenuates Angiostrongylus cantonensis-induced parasitic meningitis through modulation of HO-1 and NF-κB activation.

Angiostrongylus cantonensis causes a form of parasitic meningitis in humans. Albendazole (ABZ) kills nematode larvae in the brain. However, dead larvae can trigger a severe inflammatory response, resulting in brain damage. Accumulating evidence suggests that calycosin represents a potential anti-inflammatory therapeutic candidate. In this study, we investigated the combined effects of ABZ and calycosin in angiostrongyliasis caused by A. cantonensis in BALB/c mice. Inflammatory mediators (such as phospho-nuclear factor-κB, cyclooxygenase-2, matrix metalloproteinase-9, tumour necrosis factor-α and interleukin-1ß) are associated with the development of meningitis and immune inflammatory reactions. We found that A. cantonensis significantly induces inflammatory mediator production and increases the blood­brain barrier (BBB) permeability. However, co-administration of both ABZ and calycosin markedly suppressed meningitis and inflammatory mediator production and decreased the BBB permeability compared to treatment with a single drug. Furthermore, calycosin and ABZ plus calycosin treatment facilitated production of the antioxidant haem oxygenase-1 (HO-1). Moreover, co-therapy with ABZ and calycosin failed to mitigate angiostrongyliasis in the presence of tin-protoporphyrin IX, an HO-1-specific inhibitor. This finding suggests that the beneficial effects of ABZ plus calycosin treatment on the regulation of inflammation are mediated by the modulation of HO-1 activation. The present results provide new insights into the treatment of human angiostrongyliasis using co-therapy with ABZ and calycosin.