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Objective To explore the metabolic differences for the occurrence and development of cardiovascular and cerebrovascular diseases, the study performed the plasma metabolic analysis by nano-enhanced laser desorption ionization-mass spectrometry (NELDI-MS) on a large cohort. Methods * People were enrolled from general population establishment and follow-up cohort in Pudong New Area, Shanghai. Plasma samples were prospectively collected from 14 419 cohort people who met the criteria from February to August 2019. All the cohort people were divided into coronary heart disease (CHD) group (n=1 608), stroke group (n=461), cardiovascular and cerebrovascular diseases (CHD+stroke) group (n=145) and the control group (n=12 205). The plasma metabolic fingerprints (PMFs) of the enrolled samples were collected by NELDI-MS and then analyzed by statistical analysis for identifying the typical metabolic biomakers in patients with stroke, patients with CHD, and patients with both CHD and stroke. Results * Three hundred and forty-five metabolic signal peaks were extracted as PMFs. Six metabolic biomarkers with differential regulations were identified as the potential risk factor for cardiovascular and cerebrovascular diseases respectively by mass spectrometry data analysis. Further, the six metabolic biomarkers were mapped into the altered ketone body and fatty acid metabolism clusters. In the cluster of ketone body metabolism, the intensities of amidosulfonic acid, acetoacetic acid and methylmalonic acid were significantly increased in patients with CHD, but significantly decreased in patients with stroke and cardiovascular cerebrovascular diseases. In the cluster of fatty acid metabolism, the intensities of glucose, galacturonic acid and α-linolenic acid were significantly decreased in patients with cardiovascular and cerebrovascular diseases, but significantly increased in patients with stroke. According to the above six metabolic biomakers, three related metabolic pathways were identified in the cluster of ketone body metabolism, and two related metabolic pathways were identified in the cluster of fatty acid metabolism. Conclusion * The novel solid-phase MS approach used in this study has realized the high-efficiency collection of PMFs in a large cohort of people. Six plasma metabolic biomarkers with differential regulation are identified in cohort people with cardiovascular and cerebrovascular diseases, shedding light on the molecular pathological mechanisms of cardiovascular and cerebrovascular diseases from metabolic perspectives. It is expected to provide metabolic clues for the pathogenesis of cardiovascular and cerebrovascular diseases. [ABSTRACT FROM AUTHOR]

Objective * To explore the epidemiology and risk factors of single and co-morbidity of cardio-cerebrovascular diseases based on a large-scale prospective cohort of elderly people in the community. Methods * The subjects of the study came from Shanghai Community Elderly Cohort. The baseline survey of this cohort began in February 2019 and ended in August 2019, collecting information including demographic information, diseases and family history, lifestyle and psychological status of cohort members. According to self-reported coronary heart disease and/or stroke, all cohort members were divided into four groups, which were single coronary heart disease group, single stroke group, cardio-cerebrovascular disease group (with both coronary heart disease and stroke), and control group (without coronary heart disease and stroke). Baseline information, disease history, lifestyle factors, psychological and sleep status among the four groups were analysed. Results * A total of 17 948 eligible subjects participated in the cohort study, including 2 050 cohort members with single coronary heart disease, 724 cohort members with single stroke, 269 cohort members with cardio-cerebrovascular disease, and 14 905 cohort members without coronary heart disease and stroke. The average age of these four groups were (70.4±6.2) years, (71.8±7.1) years, (73.2±7.0) years and (68.3±5.9) years, respectively. The proportions of hypertension (76.6%), hyperlipidemia (38.3%) and diabetes (26.0%) were the highest in the cardiocerebrovascular disease group, followed by the single stroke group (74.2%, 26.8% and 25.8%, respectively), and the single coronary heart disease group (72.9%, 21.1% and 21.7%, respectively), and the control group had the lowest proportion (54.6%, 8.7% and 15.4%, respectively). The proportions of depression symptoms (16.0%), anxiety symptoms (13.1%), sedentary habit (2.2%), and poor or fairly poor sleep (38.6%) in the cardio-cerebrovascular disease group were the highest, followed by the single stroke group (10.1%, 6.6%, 2.2% and 27.2%, respectively) and the single coronary heart disease group (7.9%, 4.8%, 0.5% and 27.0%, respectively). The proportion of regular exercise was the lowest in the cardio-cerebrovascular disease group (29.5%), while the proportion was the highest in the control group (39.2%). Conclusion * Patients with coronary heart disease or stroke, especially those with both coronary heart disease and stroke, have a high proportion of co-morbidity with primary diseases, unhealthy lifestyles and psychological disorders. [ABSTRACT FROM AUTHOR]

Background and Purpose: Atherosclerosis is a chronic inflammatory disease, and retinoid X receptor-α (RXRα) is an intriguing anti-atherosclerosis target. This study investigated whether and how an RXRα modulator, K-80003, derived from a non-steroidal anti-inflammatory drug attenuates atherosclerotic plaque progression and destabilization.Experimental Approach: Our previously established ApoE-/- mouse model of carotid vulnerable plaque progression was treated with K-80003 or vehicle for 4 or 8 weeks. Samples of carotid arteries and serum were collected to determine atherosclerotic lesion size, histological features, expression of related proteins, and lipid profiles. In vitro studies were carried out in 7-ketocholesterol (7-KC)-stimulated macrophages treated with or without K-80003.Key Results: K-80003 significantly reduced lesion size, plaque rupture, macrophage infiltration, and inflammatory cytokine levels. Plaque macrophages positive for nuclear p65 (RelA) NF-κB subunit were markedly reduced after K-80003 treatment. Also, K-80003 treatment inhibited 7-KC-induced p65 nuclear translocation, IκBα degradation, and transcription of NF-κB target genes. In addition, K-80003 inhibited NF-κB pathway mainly through the reduction of p62/sequestosome 1 (SQSTM1), probably due to promotion of autophagic flux by K-80003. Mechanistically, cytoplasmic localization of RXRα was associated with decreased autophagic flux. Increasing cytoplasmic RXRα expression by overexpression of RXRα/385 mutant decreased autophagic flux in RAW264.7 cells. Finally, K-80003 strongly inhibited 7-KC-induced RXRα cytoplasmic translocation.Conclusions and Implications: K-80003 suppressed atherosclerotic plaque progression and destabilization by promoting macrophage autophagic flux and consequently inhibited the p62/SQSTM1-mediated NF-κB proinflammatory pathway. Thus, targeting RXRα-mediated autophagy-inflammation axis by its noncanonical modulator may represent a promising strategy to treat atherosclerosis. [ABSTRACT FROM AUTHOR]

Angiotensin II (Ang II) is the predominant effector peptide of the renin-angiotensin system. Ang II contributes to vascular remodeling in many cardiovascular diseases (eg, hypertension, atherosclerosis, restenosis, and aneurysm). Orphan nuclear receptor Nur77 has a crucial role in the functional regulation of vascular cells. The objective of this study was to define the specific role of Nur77 in Ang II-induced vascular remodeling. Nur77 expression was initially found to be elevated in medial vascular smooth muscle cells (VSMCs) of thoracic aortas from mice continuously infused with Ang II for 2 weeks using a subcutaneous osmotic minipump. Cellular studies revealed that Nur77 expression was upregulated by Ang II via the MAPK/PKA-CREB signaling pathway. Ang II-induced proliferation, migration, and phenotypic switching were significantly enhanced in VSMCs isolated from Nur77(-/-) mice compared with wild-type VSMCs. Consistent with the role in VSMCs, we found that compared with wild-type mice, Nur77(-/-) mice had elevated aortic medial areas and luminal diameters, more severe elastin disruption and collagen deposition, increased VSMC proliferation and matrix metalloproteinase production, and decreased VSMC-specific genes SM-22α and α-actin expression, after 2 weeks of exogenous Ang II administration. The results of additional experiments suggested that Nur77 suppressed Ang II-induced β-catenin signaling pathway activation by promoting β-catenin degradation and inhibiting its transcriptional activity. Our findings indicated that Nur77 is a critical negative regulator of Ang II-induced VSMC proliferation, migration, and phenotypic switching via the downregulation of β-catenin activity. Nur77 may reduce Ang II-induced vascular remodeling involved in many cardiovascular diseases. [ABSTRACT FROM AUTHOR]

Background: Retinoblastoma protein-interacting zinc-finger gene 1 (RIZ1) displays strong tumor suppressive activities, and its expression is often silenced in many types of human tumors. However, the relationship between RIZ1 expression and glioma prognosis remains unclear.Methods: The dysregulation of RIZ1 was evaluated using real-time polymerase chain reaction, western blot, and immunohistochemical analysis of gliomas from 51 patients. Correlation analysis was performed to examine relationships between RIZ1 immunoreactivity, clinicopathological features, and patient prognosis. Also, human malignant glioma U87 and U251 cell lines were stably transduced with ectogenic RIZ1 using a lentiviral vector to investigate the effects of induced expression of RIZ1 on cell proliferation, cell cycle, and apoptosis.Results: Real-time polymerase chain reaction and western blot analysis showed that RIZ1 was downregulated in high-grade gliomas compared with low-grade gliomas and normal brain tissue. Immunohistochemistry showed less RIZ1 labeling in high-grade gliomas than in low-grade gliomas. There was a negative correlation between RIZ1 and Ki-67 immunoreactivity. Clinicopathological evaluation revealed that RIZ1 expression was negatively correlated with tumor grade and patient age. Kaplan-Meier survival analysis showed a positive correlation between RIZ1 immunoreactivity level and progression-free and overall survival times. Multivariate analysis showed that high RIZ1 expression was an independent prognostic factor for patients with gliomas. Induced expression of RIZ1 in U87 and U251 cells reduced cell proliferation and increased apoptosis, and cell cycle analysis revealed that a majority of cells were arrested at G2-M. Moreover, transfection with a RIZ1 expression vector increased p53 and caspase-3 expression and decreased p-IKBα and p-AKT protein levels, suggesting that RIZ1 may stimulate p53-mediated apoptosis and inhibit p-IKBα and p-AKT signaling pathways.Conclusions: Our results suggest that high RIZ1 labeling is indicative of lower grades of gliomas and is associated with better progression-free and overall survival rates. Therefore, RIZ1 may be a promising therapeutic target for patients with gliomas. [ABSTRACT FROM AUTHOR]

Cushing disease has a very high mortality rate and glucocorticoid resistance caused by GR down-regulation is one major reason of mortality. Although HIF1α signaling and GR signaling are involved in the pathogenesis of pituitary adenomas, it's unclear whether and how these two essential pathways could cross-talk with each other. Here, we performed a comprehensive study to investigate the reciprocal effects of HIF1α and GR on each other in AtT20 cell lines and explored the potential therapeutic effect of HIF1α inhibitor in in-vivo mouse model. We find that hypoxia up-regulated the promoter activity, mRNA and protein levels of GR and the induced GR protein was localized in cytosol. On the other hand, GR activation by its agonist DEX increased HIF1α protein through post-transcriptional mechanism. However, hypoxia and DEX show differential synergistic effects on HIF1α and GR. In hypoxia-DEX condition, HIF1α protein was further up-regulated but mainly localized in cytosol while GR was trapped and degraded in cytosol via UPS pathway. Further Co-IP experiments demonstrate that DNA binding domain of GR can interact with PASb domain of HIF1α. In a in-vivo mouse model of Cushing's disease, HIF1α inhibitor reduced HIF1α and GR protein levels, reduced tumor size and lowered the plasma concentrations of ACTH and corticosterone. In summary, we find that a novel HIF1α-GR crosstalk contributes to the pathogenesis of pituitary adenomas and HIF1α inhibitor shows potential therapeutic effects for Cushing's disease., Competing Interests: None., (AJTR Copyright © 2021.)

Background and Purpose: Atherosclerosis is a chronic inflammatory disease, and retinoid X receptor-α (RXRα) is an intriguing anti-atherosclerosis target. This study investigated whether and how an RXRα modulator, K-80003, derived from a non-steroidal anti-inflammatory drug attenuates atherosclerotic plaque progression and destabilization., Experimental Approach: Our previously established ApoE -/- mouse model of carotid vulnerable plaque progression was treated with K-80003 or vehicle for 4 or 8 weeks. Samples of carotid arteries and serum were collected to determine atherosclerotic lesion size, histological features, expression of related proteins, and lipid profiles. In vitro studies were carried out in 7-ketocholesterol (7-KC)-stimulated macrophages treated with or without K-80003., Key Results: K-80003 significantly reduced lesion size, plaque rupture, macrophage infiltration, and inflammatory cytokine levels. Plaque macrophages positive for nuclear p65 (RelA) NF-κB subunit were markedly reduced after K-80003 treatment. Also, K-80003 treatment inhibited 7-KC-induced p65 nuclear translocation, IκBα degradation, and transcription of NF-κB target genes. In addition, K-80003 inhibited NF-κB pathway mainly through the reduction of p62/sequestosome 1 (SQSTM1), probably due to promotion of autophagic flux by K-80003. Mechanistically, cytoplasmic localization of RXRα was associated with decreased autophagic flux. Increasing cytoplasmic RXRα expression by overexpression of RXRα/385 mutant decreased autophagic flux in RAW264.7 cells. Finally, K-80003 strongly inhibited 7-KC-induced RXRα cytoplasmic translocation., Conclusions and Implications: K-80003 suppressed atherosclerotic plaque progression and destabilization by promoting macrophage autophagic flux and consequently inhibited the p62/SQSTM1-mediated NF-κB proinflammatory pathway. Thus, targeting RXRα-mediated autophagy-inflammation axis by its noncanonical modulator may represent a promising strategy to treat atherosclerosis., (© 2019 The British Pharmacological Society.)

Aim: Sulfadiazine (SD) is a classic antibiotic for intracranial infection. Due to the medical market policy, SD has not been chosen as an essential drug in all the hospitals in China. However, its therapeutic effect is definite and cannot be substituted. The aim of this study was to evaluate the therapeutic and economic value of SD compared to other popular antibiotics in patients with refractory intracranial infection., Material and Methods: A retrospective single-center study was performed from January 2011 until December 2012. Thirteen patients diagnosed with refractory intracranial infection were treated with SD. The clinical effects were reviewed., Results: Treatment was successful for 12 of the patients (cure rate=92.3%). One patient died of secondary epilepsy, respiratory complications, and multiple organ failure. Only one patient was allergic to SD, and there were no drug-related liver or kidney side effects., Conclusion: SD is a safe, effective, and economical antibiotic, and is used by our neurosurgical department. It should be offered as an option for the patients with refractory intracranial infection, especially for patients with lower ability to pay.