The association of systemic inflammatory response index and neutrophil-to-high-density lipoprotein ratio mediated by fasting blood glucose with 90-day prognosis in acute ischemic stroke patients.

BACKGROUND AND PURPOSE: The contribution of individual and combined inflammatory markers for the prognosis of acute ischemic stroke (AIS) remains elusive. This study investigated the effect of systemic inflammatory response index (SIRI), and neutrophil to high-density lipoprotein ratio (NHR), which is mediated by fasting blood glucose (FBG), on 90-day prognosis of patients with AIS. METHODS: In this pre-specified substudy of an observational cohort study, 2828 patients with AIS were enrolled from the Nanjing Stroke Registry between January 2017 to July 2021. Peripheral venous blood was collected from patients fasting for at least 8 hours within 24 hours of admission to gather information on the following parameters: neutrophil count, lymphocyte count, monocyte count, HDL level, and fasting blood glucose level. Then, the SIRI and NHR values were calculated. Following this, the correlation among SIRI, NHR, and modified Rankin Scale (mRS) scores 90d after onset was examined via univariate and multivariate logistic analyses. Lastly, mediation analysis was performed to examine the relationship between systematic inflammatory response and study outcomes mediated by FBG. RESULTS: SIRI and NHR were both negatively correlated with clinical outcomes (p < 0.05). Logistic regression analysis revealed that SIRI and NHR were independently associated with poor outcomes after adjusting for potential confounders. Subgroup analyses further validated these correlations. Meanwhile, mediation analysis corroborated that FBG partially mediated the associations between SIRI and a poor prognosis at 90d (indirect effect estimate = 0.0038, bootstrap 95% CI 0.001 to 0.008; direct effect estimate = 0.1719, bootstrap 95% CI 0.1258 to 0.2179). Besides, FBG also played a mediating role between NHR and poor outcomes (indirect effect estimate = 0.0066, bootstrap 95% CI 0.002 to 0.120; direct effect estimate = 0.1308, bootstrap 95% CI 0.0934 to 0.1681). CONCLUSIONS: Our study demonstrated that SIRI and NHR are positively associated with poor clinical and mortality outcomes at 90d in AIS patients, which was partially mediated by FBG.

Correlation between blood inflammatory indices and carotid intima-media thickness in the middle-aged and elderly adults.

OBJECTIVES: This study aimed to investigate the correlations between carotid intima-media thickness (IMT) and systemic immune inflammation index (SII), platelet-to-lymphocyte ratio (PLR), and neutrophil-to-lymphocyte (NLR) ratio. MATERIALS AND METHODS: This was a cross-sectional study enrolling a total of 582 middle-aged and elderly patients. The correlations between SII, PLR, and NLR with IMT were assessed using logistic regression models, which were subsequently incorporated into the underlying models with traditional risk factors and their predictive values for IMT. RESULTS: NLR exhibited a significant correlation with IMT in the simple regression analysis (ß = 0.01, 95 %CI= 0.00-0.02, p < 0.05). After controlling for potential confounding variables in the multivariate analysis, the association between NLR and both Maximum IMT [ß = 0.04, 95 %CI = 0.02-0.07, p = 0.0006] and Mean IMT [ß = 0.05, 95 %CI = 0.02-0.07, p = 0.0001] remained statistically significant. Additionally, PLR was found to be a significant independent predictor of Maximum IMT [ß = 0.04, 95 % CI =0.00-0.07, p = 0.0242] and Mean IMT [ß = 0.04, 95 % CI = 0.01-0.07, p = 0.0061]. Similarly, SII was identified as an independent predictor of Maximum IMT [ß = 1.87, 95 % CI =1.24, p = 0.0003]. The study found a significant positive correlation between Maximum IMT and the levels NLR, PLR, and SII. Specifically, in the Maximum IMT group, higher quartiles of NLR, PLR, and SII were associated with increased odds ratios (OR) for elevated IMT levels, with statistically significant results for NLR (Q4vsQ1: OR 3.87, 95 % CI 1.81-8.29), PLR (Q4vsQ1: OR 2.84, 95 % CI 1.36-5.95), and SII (Q4vsQ1: OR 2.64, 95 % CI 1.30-5.37). Finally, the inclusion of NLR, PLR, and NLR+PLR+SII in the initial model with traditional risk factors resulted in a marginal improvement in the predictive ability for Maximum IMT, as evidenced by the net reclassification index (p < 0.05). CONCLUSIONS: This study discovered a positive correlation between SII, PLR, NLR, and IMT, which are likely to emerge as new predictors for IMT thickening. These findings lay a theoretical reference for future predictive research and pathophysiological research on carotid intima-media thickening.

Case report: Novel NUS1 variant in a Chinese patient with tremors and intellectual disability.

Introduction: Nuclear undecaprenyl pyrophosphate synthase 1 (NUS1) gene variants are associated with a range of phenotypes, including epilepsy, intellectual disability, cerebellar ataxia, Parkinson's disease, dystonia, and congenital disorders of glycosylation. Additionally, cases describing genotypes and clinical features are rare. Case Presentation: Herein, we report the case of a 23-year-old Chinese female patient who presented with tremors, intellectual disability, and epilepsy. A history of carbon monoxide exposure, brain trauma, or encephalitis was not present in this case. Trio whole-exome sequencing analysis revealed a de novo pathogenic variant of c.750del in exon 4, leading to p.Leu251* amino acid substitution. Genetic analysis failed to identify the identical mutations in the remaining family members who underwent screening. The patient was diagnosed with a rare congenital disease, "congenital glycosylation disorder, type 1aa, autosomal dominant, type 55, with seizures (MRD-55)." Conclusion: We provide further evidence for the role of variants in NUS1 in the development of tremors, epilepsy, and intellectual disabilities. These findings expand our understanding of the clinical phenotypes of NUS1 variants.

Adrenomyeloneuropathy manifesting as adrenal insufficiency and bilateral lower extremity spastic paraplegia: A case report and literature review.

RATIONALE: Adrenomyeloneuropathy (AMN) is a variant type of X-linked adrenoleukodystrophy, and it is a genetic metabolic disease with strong clinical heterogeneity so that it is easily misdiagnosed and underdiagnosed. Moreover, most patients with AMN have an insidious clinical onset and slow progression. Familiarity with the pathogenesis, clinical features, diagnosis, and treatment of AMN can help identify the disease at an early stage. PATIENT CONCERNS: We present a case of 35-year-old male, who was admitted to our hospital due to "immobility of the lower limbs for 2 years and worsening for half a year," accompanied by skin darkening and hyperpigmentation of lips, oral mucosa, and areola since puberty. DIAGNOSIS: The level of very long-chain fatty acids was high and genetic testing depicted that exon 1 of the ABCD1 gene had a missense mutation of C.761c>T, which was diagnosed as AMN. INTERVENTIONS: Baclofen was administered to improve muscle tension combined with glucocorticoid replacement therapy. OUTCOMES: The condition was relieved after half a year. LESSONS: The clinical manifestations of AMN are diverse. When patients with adrenocortical dysfunction complicated with progressive spastic paraplegia of lower limbs are involved, AMN should be highly suspected, and the determination of very long-chain fatty acids and genetic testing should be performed as soon as possible to confirm the diagnosis because early treatment can help prevent or delay the progression of the disease.

The Role of Remnant Cholesterol Beyond Low-Density Lipoprotein Cholesterol in Arterial Stiffness: A Cross-Sectional Study.

Background: Previous evidence has demonstrated that elevated low-density lipoprotein cholesterol (LDL-C) was associated with atherosclerosis. However, there is scarce population-based evidence for the role of remnant cholesterol (remnant-C) in arterial stiffness, an imaging marker for subclinical atherosclerosis. Herein, we aimed to evaluate the correlation of remnant-C with arterial stiffness beyond LDL-C in a check-up population. Methods: The study included consecutive subjects who visited the Murakami Memorial Hospital for health check-ups between 2004 and 2012. The calculation of remnant-C occurred as total cholesterol minus high-density lipoprotein cholesterol (HDL-C) minus LDL-C. The brachial-ankle pulse wave velocity (baPWV) >1400 cm/sec was defined as arterial stiffness or baPWV abnormality. The independent correlation of remnant-C level to arterial stiffness was evaluated using adjusted regression models. Results: A total of 909 participants were included (mean age 51.1 ± 9.6 years, male sex 64.9%). In multivariate linear regression analyses, remnant-C remained an independent predictor of the baPWV predictor [ß: 94.76, 95% confidence interval (CI) 42.19-147.33, P < 0.001] after adjusting for confounders. After multivariable adjustment, including LDL-C, the highest remnant-C quartile odd ratio (OR) (95% CI) was 2.79 (1.27-6.09) for baPWV abnormality compared to the lowest quartile. Furthermore, each 10-mg/dL increase in remnant-C correlated with a 28% increased risk for baPWV abnormality (OR: 1.28, 95% CI: 1.04-1.57). Moreover, the correlation between remnant-C and baPWV abnormality was still significant in the participant subgroup with optimal levels of LDL-C. Conclusions: Our findings demonstrated that remnant-C levels correlated to arterial stiffness with the dependence of LDL-C and other cardiovascular risk factors in a check-up population.

The relationship between systemic inflammation index, systemic immune-inflammatory index, and inflammatory prognostic index and 90-day outcomes in acute ischemic stroke patients treated with intravenous thrombolysis.

BACKGROUND AND PURPOSE: To explore the association of systemic inflammatory index (SIRI), systemic immune-inflammatory index (SII) and inflammatory prognosis index (IPI) with 90d outcomes in patients with acute ischemic stroke (AIS) after intravenous thrombolysis. METHODS: The patients who underwent intravenous thrombolysis were enrolled in the present study from September 2019 to December 2022. According to the relevant blood indexes obtained in 24 h after admission, the corresponding values of SIRI, SII and IPI were calculated. The correlation among SIRI, SII, IPI, and admission NIHSS scores was examined by Spearman correlation analysis. ROC curve analysis was conducted to determine the optimal cut-off value of SIRI, SII, IPI, and their corresponding sensitivity and specificity to evaluate their predictive value on admission for poor prognosis. To investigate whether high SIRI, SII, and IPI were independent predictors of poor outcomes within 90 days, variables with P-value < 0.05 during univariate analysis were included in multivariate analysis. RESULTS: Compared with the good outcome group, the poor outcome group had higher SIRI, IPI, and SII. Spearman correlation analysis showed that the SIRI, IPI, and SII levels significantly correlated with the admission NIHSS score (r = 0.338, 0.356, 0.427, respectively; Ps < 0.001). Univariate analysis and Multivariate logistic regression analysis revealed high SIRI, SII, and IPI values as independent risk factors for poor 90-day prognosis (OR = 1.09, 1.003 and 7.109, respectively). CONCLUSIONS: High SIRI, IPI, and SII values are correlated with poor 90d outcomes in AIS patients undergoing intravenous thrombolysis.

Association of remnant cholesterol with intracranial atherosclerosis in community-based population: The ARIC study.

OBJECTIVE: To evaluate the association between remnant cholesterol (remnant-C) and intracranial atherosclerotic disease (ICAD) in the Atherosclerosis Risk in Communities Neurocognitive Study (ARIC-NCS). METHODS: We studied 1,564 participants with data on lipid profiles and high-resolution vessel wall MRI (VWMRI) from the ARIC-NCS. Remnant-C was computed as total cholesterol minus high-density lipoprotein cholesterol minus low-density lipoprotein cholesterol (LDL-C). The primary outcomes were the presence of intracranial plaques and luminal stenosis. Contributors were separated into four different groups based on remnant-C (22 mg/dL) and LDL-C (100 mg/dL) levels to investigate the function of remnant-C vs. LDL-C on ICAD. Multivariable logistic regression models were utilized to estimate the correlation among the discordant/concordant remnant-C and LDL-C, and ICAD. RESULTS: A total of 1,564 participants were included (age 76.2 ± 5.3). After multivariable adjustment, log remnant-C was correlated with greater ICAD risk [odds ratio (OR) 1.36, 95% confidence interval (CI) 1.01 to 1.83]. The lower remnant-C/higher LDL-C group and the higher remnant-C/lower LDL-C group manifested a 1.53-fold (95% CI 1.06 to 2.20) and 1.52-fold (95% CI 1.08 to 2.14) greater risk of ICAD, relative to those having lower remnant-C/low LDL-C. Additionally, remnant-C ≥ 22 mg/dL distinguished participants at a greater risk of the presence of any stenosis compared to those at lower levels, even in participants with optimal levels of LDL-C. CONCLUSIONS: Elevated levels of remnant-C were connected to ICAD independent of LDL-C and traditional risk factors. The mechanisms of remnant-C association with ICAD probably offer insight into preventive risk-factor of ischemic stroke.

Copper stress-induced phytotoxicity associated with photosynthetic characteristics and lignin metabolism in wheat seedlings.

Copper (Cu) pollution is one of environmental problems that adversely affects the growth and development of plants. However, knowledge of lignin metabolism associated with Cu-induced phytotoxicity mechanism is insufficient. The objective of this study was to reveal the mechanisms underlying Cu-induced phytotoxicity by evaluating changes in the photosynthetic characteristics and lignin metabolism in the seedlings of wheat cultivar 'Longchun 30'. Treatment with varying concentrations of Cu clearly retarded seedling growth, as demonstrated by a reduction in the growth parameters. Cu exposure reduced the photosynthetic pigment content, gas exchange parameters, and chlorophyll fluorescence parameters, including the maximum photosynthetic efficiency, potential efficiency of photosystem II (PS II), photochemical efficiency of PS II in light, photochemical quenching, actual photochemical efficiency, quantum yield of PS II electron transport, and electron transport rate, but notably increased the nonphotochemical quenching and quantum yield of regulatory energy dissipation. Additionally, a significant increase was observed in the amount of cell wall lignin in wheat leaves and roots under Cu exposure. This increase was positively associated with the up-regulation of enzymes related to lignin synthesis, such as phenylalanine ammonia-lyase, 4-coumarate:CoA ligase, cinnamyl alcohol dehydrogenase, laccase, cell wall bound (CW-bound) guaiacol peroxidase, and CW-bound conifer alcohol peroxidase, and TaPAL, Ta4CL, TaCAD, and TaLAC expression. Correlation analysis revealed that lignin levels in the cell wall were negatively correlated with the growth of wheat leaves and roots. Taken together, Cu exposure inhibited photosynthesis in wheat seedlings, resulting from a reduction in photosynthetic pigment content, light energy conversion, and photosynthetic electron transport in the leaves of Cu-stressed seedlings, and the Cu-inhibitory effect on seedling growth was related to the inhibition of photosynthesis and an increase in cell wall lignification.

Profiling microRNA from peripheral blood mononuclear cells in early-onset familial Alzheimer's disease.

MicroRNAs (miRNAs) refer to short in-length, noncoding RNAs that regulate numerous cellular functions by targeting mRNA, and numerous types of research have shown that miRNA is vitalin Alzheimer's disease. For identifying differentially expressed miRNAs in the peripheral blood mononuclear cell (PBMC) of early-onset familial Alzheimer's disease (EOFAD), we conducted this study which might give a reference for potential therapeutic targets or biomarkers for this disease. On the basis of high-throughput sequencing, we screened the miRNAs expression profiles in PBMC regarding both EOFAD patients and healthy controls, and the biological information was analyzed. Compared with the PBMC of healthy controls, 142 miRNAs were differentially expressed in EOFAD patients ( P < 0.05), including 48 significantly differentially expressed miRNAs, 37 of which were significantly upregulated, including miR-3614-5p, miR-193A-5p, miR-2115-5p, miR-143-3p, etc. and 11 were significantly downregulated, including miR-484, miR-708-5p, miR-205-5p, miR-31-5p, etc. According to biological information analysis, 768 miRNA target genes were differentially expressed, which may be involved in multiple gene functions and cell cycle, cell senescence, and several signaling pathways, including FoxO, MAPK, Ras, mTOR, neurotrophin, etc. There are differential expressions of miRNAs in PBMC of EOFAD patients and controls, revealing their importance in Alzheimer's disease as indicated by co-expression network analysis; this may support basic information for new biomarkers or treatment exploring.

Piezo-Activated Atomic-Thin Molybdenum Disulfide/MXene Nanoenzyme for Integrated and Efficient Tumor Therapy via Ultrasound-Triggered Schottky Electric Field.

Monolayer molybdenum disulfide (MoS2 ) nanoenzymes exhibit a piezoelectric polarization, which generates reactive oxygen species to inactivate tumors under ultrasonic strain. However, its therapeutic efficiency is far away from satisfactory, due to stackable MoS2 , quenching of piezo-generated charges, and monotherapy. Herein, chitosan-exfoliated monolayer MoS2 (Ch-MS) is composited with atomic-thin MXene, Ti3 C2 (TC), to self-assemble a multimodal nanoplatform, Ti3 C2 -Chitosan-MoS2 (TC@Ch-MS), for tumor inactivation. TC@Ch-MS not only inherits piezoelectricity from monolayer MoS2 , but also maintains remarkable stability. Intrinsic metallic MXene combines with MoS2 to construct an interfacial Schottky heterojunction, facilitating the separation of electron-hole pairs and endowing TC@Ch-MS increase-sensitivity magnetic resonance imaging responding. Schottky interface also leads to peroxidase mimetics with excellent catalytic performance toward H2 O2 in the tumor microenvironment under mechanical vibration. TC@Ch-MS possesses the superior photothermal conversion efficiency than pristine TC under near-infrared ray illumination, attributed to its enhanced interlaminar conductivity. Meanwhile, TC@Ch-MS realizes optimized efficiency on tumor apoptosis with immunotherapy. Therefore, TC@Ch-MS achieves an integrated diagnosis and multimodal treatment nanoplatform, whereas the toxicity to normal tissue cells is negligible. This work may shed fresh light on optimizing the piezoelectric materials in biological applications, and also give prominence to the significance of intrinsic metallicity in MXene.

Association between Serum Amyloid A Level and White Matter Hyperintensity Burden: a Cross-Sectional Analysis in Patients with Acute Ischemic Stroke.

INTRODUCTION: This work aimed to determine the potential link between white matter hyperintensity (WMH) burden and serum amyloid A (SAA) level in patients with acute ischemic stroke. METHODS: Consecutive patients with acute large artery atherosclerosis (LAA) stroke between April 2021 and May 2022 were included. WMH volumes (periventricular, deep, and total) were measured using the Fazekas score and a semiautomated volumetric analysis on fluid-attenuated inversion recovery-magnetic resonance imaging. The burdens of WMH were scored to assess the dose-dependent association between SAA and WMH volume. Multivariate regression and a two-piecewise linear regression model were used to evaluate whether SAA levels are an independent predictor of WMH, and to discover the threshold effect or saturation effect of SAA levels with respect to WMH volume. RESULTS: The mean age of patients was 63.2 ± 11.5 years, with 65.9% men. The median SAA level was 3.93 mg/L and the total WMH volume of 6.86 cm3. In the multivariable analysis, SAA remained an independent predictor of total WMH volume [ß = 0.82, 95% confidence interval (CI) = 0.49-1.07, p < 0.001], periventricular WMH volume (adjusted ß = 0.76, 95% CI = 0.46-1.07, p < 0.001), and deep WMH volume (adjusted ß = 0.26, 95% CI = 0.06-0.45, p = 0.011) after controlling for confounders. Furthermore, SAA levels were associated with periventricular Fazekas score, deep Fazekas score, and Fazekas grades. Threshold effect and saturation effect analyses demonstrated a nonlinear relationship between SAA levels and periventricular white matter hyperintensity (PVWMH) volumes, with SAA levels (2.12-19.89 mg/L) having significant dose-dependent relationships with periventricular WMH volumes (adjusted ß = 1.98, 95% CI = 1.12-2.84, p < 0.001). CONCLUSION: SAA level ranging from 2.12 to 19.89 mg/L is dose-dependently associated with periventricular WMH development. These findings point the way forward for future research into the pathophysiology of WMH.

Preliminary study of sound touch elastography in diffuse thyroid disease in children.

Objective: The purpose of this study was to evaluate the use of sound touch elastography (STE) in conjunction with conventional ultrasound in the differential diagnosis of diffuse thyroid disease (DTD) and normal thyroid in children. Methods: Studies performed on 62 children with DTD and 30 normal volunteers were reviewed. Standard gray scale ultrasound, Doppler ultrasound and STE of the examinees, and the serum test results of children with DTD were collected, analyzed and compared. Results: The STE-Mean values in the Graves' disease (GD) group, Hashimoto's thyroiditis (HT) group, and normal control group, respectively, were 19.35 ± 5.00 kPa, 19.43 ± 6.06 kPa, and 11.24 ± 1.99 kPa. With an area under the ROC curve (AUC) of 0.945, STE-Mean values differentiated DTD from normal children. The peak systolic velocity (PSV) of the superior thyroid artery separated DTD from normal children and AUC from children with GD and HT, respectively, and was 0.992 and 0.864. The PSV of superior thyroid artery revealed a somewhat favorable connection with FT3 and FT4. Conclusion: The STE results revealed that thyroid stiffness was higher in children with DTD than in normal children, but further differentiation into GD and HT subgroups lacked specificity, and the superior thyroid artery flow velocity might be a good supplement to distinguish both.

Exosomal miR-221-3p Derived from Bone Marrow Mesenchymal Stem Cells Alleviates Asthma Progression by Targeting FGF2 and Inhibiting the ERK1/2 Signaling Pathway.

Exosomes derived from human bone marrow mesenchymal stem cells (BMSCs) play potential protective roles in asthma. However, the underlying mechanisms remain not fully elucidated. Herein, exosomes were isolated from BMSCs, and the morphology, particle size, and exosome marker proteins were identified by transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), and Western blot, respectively. Then airway smooth muscle cells (ASMCs) were treated with transforming growth factor-ß1 (TGF-ß1) to construct a proliferation model and then incubated with BMSCs-derived exosomes. We found that exosome incubation increased miR-221-3p expression and inhibited proliferation, migration, and the levels of extracellular matrix (ECM) proteins including fibronectin and collagen III. Moreover, FGF2 was identified as a target gene of miR-221-3p. FGF2 overexpression reversed the inhibitory effects of exosomal miR-221-3p on ASMC progression. Besides, the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) is inhibited by exosomal miR-221-3p, which was reversed by FGF2 overexpression. And ERK1/2 signaling activator reversed the effects of exosomal miR-221-3p on ASMC progression. Additionally, an ovalbumin (OVA)-induced asthmatic mice model was established, and exosome treatment alleviated airway hyper-responsiveness (AHR), histopathological damage, and ECM deposition in asthmatic mice. Taken together, our findings indicated that exosomal miR-221-3p derived from BMSCs inhibited FGF2 expression and the ERK1/2 signaling, thus attenuating proliferation, migration, and ECM deposition in ASMCs and alleviating asthma progression in OVA-induced asthmatic mice. Our findings may provide a novel therapeutic strategy for asthma.

Non-invasive prediction of histologic chorioamnionitis using maternal serum markers in women with preterm prelabour rupture of membranes.

PROBLEM: This study aimed to evaluate and compare the predictive accuracy of serum markers for histological chorioamnionitis (HCA) among women with preterm prelabour rupture of membranes (PPROM), and to develop a nomogram prediction model to minimize the damage of the disease. METHOD OF STUDY: This case-control study included 153 pregnant women with PPROM with a gestational age of 20+0 ∼36+6 weeks. The subjects were assigned into two groups: PPROM with and without HCA. According to the results of logistic regression analysis, the predictive equation and nomogram were generated using key parameters, and the discrimination and consistency of the model were evaluated by receiver operating characteristic (ROC) curves and calibration curves. RESULTS: From 153 subjects with PPROM, 77 developed HCA. Compared with the PPROM without HCA group, the CRP, PCT and NLR were significantly higher in HCA group (P < 0.001), and the CRP had the highest predictive value. The area under the curve (AUC) of the prediction model was 0.873, and the sensitivity and specificity of predicting HCA were 68.8% and 92.1%, respectively. And the calibration curves fitted well with the realistic situation. CONCLUSION: Maternal serum CRP and NLR could be used as predictive biomarkers for HCA in women with PPROM, while PCT needs to be further explored due to its slightly lower predictive value. Our serum markers and gestational age at PPROM could be used as a non-invasive and convenient method to predict HCA in women with PPROM.

Inhibition of KIR2.1 decreases pulmonary artery smooth muscle cell proliferation and migration.

The investigation of effective therapeutic drugs for pulmonary hypertension (PH) is critical. KIR2.1 plays crucial roles in regulating cell proliferation and migration, and vascular remodeling. However, researchers have not yet clearly determined whether KIR2.1 participates in the proliferation and migration of pulmonary artery smooth muscle cells (PASMCs) and its role in pulmonary vascular remodeling (PVR) also remains elusive. The present study aimed to examine whether KIR2.1 alters PASMC proliferation and migration, and participates in PVR, as well as to explore its mechanisms of action. For the in vivo experiment, a PH model was established by intraperitoneally injecting Sprague­Dawley rats monocrotaline (MCT). Hematoxylin and eosin staining revealed evidence of PVR in the rats with PH. Immunofluorescence staining and western blot analysis revealed increased levels of the KIR2.1, osteopontin (OPN) and proliferating cell nuclear antigen (PCNA) proteins in pulmonary blood vessels and lung tissues following exposure to MCT, and the TGF­ß1/SMAD2/3 signaling pathway was activated. For the in vitro experiments, the KIR2.1 inhibitor, ML133, or the TGF­ß1/SMAD2/3 signaling pathway blocker, SB431542, were used to pre­treat human PASMCs (HPASMCs) for 24 h, and the cells were then treated with platelet­derived growth factor (PDGF)­BB for 24 h. Scratch and Transwell assays revealed that PDGF­BB promoted cell proliferation and migration. Immunofluorescence staining and western blot analysis demonstrated that PDGF­BB upregulated OPN and PCNA expression, and activated the TGF­ß1/SMAD2/3 signaling pathway. ML133 reversed the proliferation and migration induced by PDGF­BB, inhibited the expression of OPN and PCNA, inhibited the TGF­ß1/SMAD2/3 signaling pathway, and reduced the proliferation and migration of HPASMCs. SB431542 pre­treatment also reduced cell proliferation and migration; however, it did not affect KIR2.1 expression. On the whole, the results of the present study demonstrate that KIR2.1 regulates the TGF­ß1/SMAD2/3 signaling pathway and the expression of OPN and PCNA proteins, thereby regulating the proliferation and migration of PASMCs and participating in PVR.

Differential Expression and Correlation Analysis of Global Transcriptome for Hemorrhagic Transformation After Acute Ischemic Stroke.

In order to explore the epigenetic characteristics of hemorrhagic transformation (HT) after acute ischemic stroke, we used transcriptome sequencing technology to analyze the global transcriptome expression profile of patients with and without HT after acute ischemic stroke and to study the differential expression of messenger RNA (mRNA), long noncoding RNA (lncRNA), circular RNA (circRNA) and mircoRNA (miRNA) between the two groups. To further explore the role of differentially expressed genes in HT, we annotated the function of differentially expressed genes by using gene ontology (GO) and pathway analysis on the results and showed that there were 1,051 differential expressions of lncRNAs, 2,575 differential expressions of mRNAs, 447 differential expressions of circRNAs and 47 miRNAs in patients with HT compared with non-HT patients. Pathway analysis showed that ubiquitin-mediated proteolysis, MAPK signal pathway, axon guidance, HIF-1 signal pathway, NOD-like receptor signal pathway, beta-alanine metabolism, Wnt signal pathway, sphingolipid signal pathway, neuroactive ligand-receptor interaction, and intestinal immune network used in IgA production play an important role in HT. Terms such as iron homeostasis, defense response, immune system process, DNA conformational change, production of transforming growth factor beta-2, and oxidoreductase activity were enriched in the gene list, suggesting a potential correlation with HT. A total of 261 lncRNA-miRNA relationship pairs and 21 circRNA-miRNA relationship pairs were obtained; additionally, 5 circRNAs and 13 lncRNAs were screened, which can be used as competing endogenous RNA (ceRNA) to compete with miRNA in the co-expression network. Co-expression network analysis shows that these differentially expressed circRNA and lncRNA may play a vital role in HT and provide valuable information for new biomarkers or therapeutic targets.

[Connexin 43 (Cx43) inhibits autophagy of rat thoracic aortic smooth muscle cells induced by ox-LDL].

Objective To investigate the role of connexin 43 (Cx43) in the autophagy of rat thoracic aortic vascular smooth muscle cells (VSMCs) induced by oxidized low-density lipoprotein (ox-LDL). Methods The primary VSMCs were identified by immunofluorescence cytochemical staining of α-smooth muscle actin (α-SMA). After ox-LDL treatment, the foam cells were identified by oil red O staining; the expression of microtubule associated protein 1 light chain 3 (LC3) protein in VSMCs treated with 0, 40, 80, 160 µg/mL ox-LDL for 0, 6, 12, 24 hours and the expression of Cx43 protein treated with 80 µg/mL ox-LDL for 24 hours were detected by Western blotting. VSMCs were randomly divided into control group, ox-LDL group, and ox-LDL combined with Cx43 specific antagonist Gap26 group to detect the expressions of LC3 and beclin 1 by Western blotting. Results The positive rate of α-SMA in the isolated cells was more than 95%. The oil red O positive cells in ox-LDL treated cells significantly increased, ox-LDL decreased the ratio of LC3II/LC3I and the expression of beclin 1 protein in a concentration- and time-dependent manner, and the expression of Cx43 protein was significantly increased. After administration of Gap26, the ratio of LC3II/LC3I and the expression of beclin 1 protein were up-regulated. Conclusion Cx43 inhibits autophagy of VSMCs induced by ox-LDL. Cx43 inhibits ox-LDL induced autophagy.

α1 -Adrenoceptors activate the NLRP3 inflammasome through downregulation of Kir2.1 in cardiac inflammation.

NEW FINDINGS: What is the central question of this study? What is the mechanism of cardiac inflammation induced by α1 -adrenoceptor stimulation by NLRP3 inflammasome activation? What is the main finding and its importance? In the mechanism of cardiac inflammation induced by α1 -adrenoceptor overactivation, Kir2.1 exerts cardioprotective and anti-inflammatory effects by inhibiting the activation of the NLRP3 inflammasome. ABSTRACT: Overstimulation of sympathetic nerves in cardiovascular diseases can lead to impaired cardiomyocyte function and potential heart failure, which activates not only the ß-adrenoceptors but also the α1 -adrenoceptors (α1 -AR). A previous report indicated that NLRP3 inflammasome activation is involved in cardiac inflammation induced by the α1 -AR agonist phenylephrine (PE), but the mechanism is still unknown. Here, we aimed to study whether Kir2.1 is involved in cardiac inflammation caused by PE. The results from in vitro experiments showed that PE upregulated the expression levels of NLRP3, caspase-1, interleukin (IL)-18 and IL-1ß and downregulated the expression level of Kir2.1 in H9C2 cells. The Kir2.1 agonist zacopride downregulated the expression of NLRP3, caspase-1, IL-1ß and IL-18, and the Kir2.1 inhibitor ML133 upregulated their expression. To further explore the mechanism, we found that zacopride downregulated the protein expression level of p-p65 and that ML133 upregulated it. Moreover, the nuclear factor-κB (NF-κB) signalling pathway inhibitor curcumenol reversed the expression of NLRP3 inflammasomes caused by PE in H9C2 cells. In in vivo experiments, the protein expression level of Kir2.1 in the PE group was significantly decreased, and the activation of Kir2.1 by zacopride reduced cardiac inflammation. In short, Kir2.1 is involved in α1 -AR overactivation, which induces cardiac inflammation, through the NF-κB signalling pathway, and activating Kir2.1 can downregulate NLRP3 inflammation and exert cardioprotective effects induced by zacopride.

Proteomics analysis reveals the correlation of programmed ROS-autophagy loop and dysregulated G1/S checkpoint with imatinib resistance in chronic myeloid leukemia cells.

Although tyrosine kinase inhibitors (TKIs), including imatinib, have greatly improved clinical treatment of patients with chronic myeloid leukemia (CML), drug resistance remains a major obstacle. Studies on the mechanisms underlying imatinib resistance and other alternative drugs are urgently needed. Liquid chromatography tandem mass spectrometry was applied to investigate the differences in proteomics and phosphoproteomics between K562 and K562/G (imatinib resistant K562). Multiple bioinformatics analyses were performed to unveil the differential signal pathways. CCK-8 was used to detect cell proliferation. Flow cytometry was performed to analyze reactive oxygen species (ROS), cell cycle, and cell apoptosis. Western blotting and quantitative real-time reverse transcription-polymerase chain reaction (qRT-PCR) were used to observe the changes of ROS and autophagy associated with imatinib resistance in CML. Our results indicated that ROS-autophagy formed one negative feedback loop and was associated with imatinib resistance. Additionally, the limited-rate enzymes of serine synthesis pathway were escalated in K562/G, which could contribute to the increased cyclin-dependent kinases and cell proliferation index. According to phosphoproteomics data, K562/G cells exhibited abnormal phosphorylation of splicing signals. These results revealed that it could be one useful strategy to correct metabolism shift and oxidative stress, or moderately regulate autophagy. Future research should focus on the discovery of potential targets in ROS-autophagy loop.