Nucleophosmin1 (NPM1) proteins, initially recognized as central guardians of nucleolar architecture and function, have recently been redefined as pivotal hubs that integrate diverse forms of chronic cellular stress signaling. Although the roles of NPM1 have been extensively elucidated in tumor biology, its broad involvement in non-communicable chronic inflammatory diseases (NCDs) remains insufficiently and unsystematically summarized. Here, we highlight NPM1 as a key sensor of stress-induced nucleolar disassembly, nucleocytoplasmic translocation, and p53 stabilization. In pathological conditions such as myocardial ischemia, endothelial dysfunction, atherosclerosis, and chemotherapy-associated cardiotoxicity, NPM1 exhibits pronounced context dependence functioning either to initiate cytoprotective responses or to promote inflammation and apoptosis. In parallel, NPM1 plays a central role in maintaining genomic stability by sequestering, mobilizing, and regulating essential enzymes across multiple DNA damage repair pathways, including base excision repair (BER) and translesion synthesis (TLS). Dysregulation of these functions is closely linked to chronic pathological processes driven by metabolic stress, oxidative stress, and proteotoxicity. Collectively, available evidence suggests that NPM1, as a core node of the nucleolus–nucleoplasm signaling axis, may constitute a common molecular pathological basis underlying multiple chronic inflammatory diseases, including cancer, cardiovascular diseases, diabetes, and neurodegenerative disorders. A deeper dissection of its post-translational modifications, stress-dependent subcellular re-localization, and interactions with partner proteins is expected to provide a novel conceptual framework and therapeutic avenues for the development of NPM1-based targeted interventions. Accordingly, this review synthesizes the core molecular mechanisms of the NPM1 in the maintenance of cellular homeostasis, including regulating nucleolar stress, DNA damage repair, and inflammation, We place a particular emphasis on how these baseline pathways translate into distinct functional phenotypes within the pathological processes of chronic diseases, including cardiovascular, metabolic, and neurodegenerative disorders.

Background:Elevated red cell distribution width (RDW) has been implicated in chronic mountain sickness; however, its relationship with acute mountain sickness (AMS) remains uncertain. We aimed to evaluate the association between elevated RDW and AMS among Chinese young men undergoing high-altitude air ascent. Methods:157 participants (median age, 22 years) were enrolled and passively ascended primarily by air from 500 m to 3,650 m, spending approximately 3.5 hours. Participants were classified as AMS+ and AMS- based on their Lake Louise AMS score (LLS) after 24 hours at 3,650 m. Measurements included heart rate (HR), blood pressure, pulse oximeter saturation (SpO2), and complete blood count (CBC). Statistical analyses included correlation analysis, logistic regression, and receiver operating characteristic (ROC) curve analysis. Results:The prevalence of AMS at 3,650 m was 45%. AMS+ participants had higher HR and RDW and lower SpO2 than AMS- participants. LLS was positively correlated with age, BMI, HR, and RDW, and negatively correlated with SpO2. Adjusted logistic regression revealed independent risk factors for AMS, including lower SpO2 (odds ratio [OR] = 0.809, P < 0.01), higher RDW coefficient of variation (RDW-CV) (OR = 2.790, P < 0.01), and a higher neutrophil-to-monocyte ratio (OR = 1.114, P < 0.05). ROC curve analysis demonstrated that elevated RDW-CV is a significant diagnostic indicator for AMS, with an optimal cutoff of 13.7, yielding a sensitivity of 94.37%, specificity of 45.35%, and an area under the curve (AUC) of 0.703. Conclusion:The findings suggest that elevated RDW-CV is linked to an increased risk of AMS among Chinese young men primarily undergoing air ascent to 3,650 m.

BACKGROUND:Perivascular macrophages play a significant role in the pathogenesis of hypoxia-induced pulmonary hypertension via crosstalk to pulmonary artery smooth muscle cells (PASMCs) to stimulate their proliferation and pulmonary vascular remodeling. However, whether hypoxia exposure of macrophages affects cellular crosstalk remains entirely unclear. This study aimed to decipher the effects of hypoxia on macrophages' crosstalk to PASMCs and elucidate the underlying molecular mechanisms. METHODS:Conditioned medium obtained from bone marrow-derived macrophages under normoxia or hypoxia was transferred for hypoxic culture of primary mouse PASMCs, followed by RNA sequencing analysis. Myeloid-specific SerpinB1-overexpressing mice were generated to explore SerpinB1's role in macrophage inflammatory phenotype, PASMC proliferation, and pulmonary vascular remodeling. RESULTS:Hypoxia-exposure of macrophages produced a conspicuous augmentation to the pro-proliferative effect of the conditioned medium on PASMCs. Hypoxia exposure aggravated macrophage inflammatory phenotype, as indicated by marked enrichment of multiple inflammatory pathways and elevated levels of inflammatory cytokines. SerpinB1 (serpin family B member 1) was identified as the key downstream mediator of hypoxia to regulate macrophage inflammatory phenotype because hypoxia induced its drastic downregulation and subsequent NLRP3 (NOD [nucleotide oligomerization domain]-, LRR [leucine-rich repeat]-, and PYD [pyrin domain]-containing protein 3)-independent inflammatory caspase-1 activation. Myeloid-specific overexpression of SerpinB1 largely blunted hypoxia-induced macrophage inflammatory phenotype and amplified the pro-proliferative effect on PASMCs. Myeloid SerpinB1-overexpressing mice exhibited lower right ventricular systolic pressure, milder right ventricular hypertrophy, and pulmonary vascular remodeling after chronic hypoxia exposure. CONCLUSIONS:Hypoxia exposure directly amplifies the pro-proliferative crosstalk of macrophages to PASMCs via downregulating SerpinB1 to induce caspase-1 activation and inflammatory phenotype. Targeting macrophage SerpinB1 may hold promise for treating pulmonary hypertension.

Tang, Xu-gang, Xiu-chuan Li, Bao-mei Song, Shuang Li, Qiang Wang, and Yong-jian Yang. Association between decreased pulse oximetry and acute mountain sickness upon rapid ascent to 4,086 m among young Chinese men. High Alt Med Biol. 27:49-46, 2026. BACKGROUND:Research on predicting acute mountain sickness (AMS) based on the decreased pulse oximeter saturation (SpO2) during rapid train travel to high altitudes is limited and inconsistent. We aimed to assess whether lower SpO2 levels are associated with AMS in a young Chinese male population following a rapid ascent to high altitude by train. METHODS:The study involved 375 young Chinese men with a median age of 21. The participants spent 43 hours ascending from an altitude of 400 m to 4,086 m, including 41 hours by train and 2 hours by car. They were divided into AMS+ and AMS- groups based on the Lake Louise AMS score (LLS) after being exposed to 4,086 m for 24 hours. Participants' SpO2 and heart rate (HR) were measured. AMS was assessed using the LLS. Data were analyzed using Spearman's correlation, logistic regression, and receiver operating characteristic (ROC) analysis. RESULTS:At 4,086 m, the overall AMS prevalence was 31%. The HR was significantly higher in the AMS+ group compared to the AMS- group. Conversely, SpO2 was lower in the AMS+ group. Correlation analysis showed that LLS was positively correlated with HR and negatively correlated with SpO2. Adjusted logistic regression identified lower SpO2 (OR = 0.909, 95% CI: 0.867-0.953, p < 0.001) and HR (OR = 1.031, 95% CI: 1.010-1.052, p < 0.01) as independent risk factors for AMS. ROC analysis indicated that lower SpO2 is a significant marker for diagnosing moderate to severe AMS. The optimal cut-off value for SpO2 was 81.5%, with a sensitivity of 66.7%, a specificity of 75.7%, and an AUC of 0.724, with lower and upper confidence limits of 0.555 and 0.893, respectively. CONCLUSION:This study suggests that lower SpO2 levels are associated with AMS in young Chinese men who rapidly ascend to 4,086 m, primarily by train.

Background:The sleep quality of Han Chinese and Tibetan firefighters at high altitude remains poorly understood. This study investigates the prevalence of sleep disturbances in these groups and whether ethnicity affects sleep quality in these two populations. Methods:Male firefighters were recruited from China Fire and Rescue stations at high altitude of 500 m, 2570 m, and 4509 m in Southwest China. The Pittsburgh Sleep Quality Index (PSQI) assessed sleep quality, considering scores >5 as poor sleep quality. Symptoms of anxiety and depression were evaluated using the 7-item Generalized Anxiety Disorder Questionnaire (GAD-7) and the 9-item Patient Health Questionnaire (PHQ-9). Results:As altitude increased, the total PSQI scores of Han Chinese firefighters showed a non-statistically significant rise: 4 (2-5) at 500 m, 4 (3-6.75) at 2570 m, and 5 (2.75-6) at 4509 m. Poor sleep quality prevalence also rose: 23%, 31%, and 44%, respectively. In contrast, the sleep quality of Tibetan firefighters remained relatively stable and was better than that of their Han Chinese counterparts. Furthermore, the GAD-7 and PHQ-9 scores were higher in Han Chinese firefighters compared to Tibetan firefighters. The PSQI score was positively correlated with GAD-7 scores (ρ = 0.454, p < 0.001) and PHQ-9 scores (ρ = 0.380, p < 0.001) but negatively correlated with Tibetan ethnicity (ρ = -0.228, p < 0.001). Logistic regression analysis indicated that, compared to Tibetans, being Han Chinese (odds ratio [OR] = 3.050, 95% confidence interval [CI]: 1.214-7.665) and having higher GAD-7 scores (OR = 1.816, 95% CI: 1.332-2.477) were independently associated factors for poor sleep quality. Conclusion:This study suggests that Han Chinese firefighters in this field sample across these stations are at greater risk of poor sleep quality than Tibetan firefighters, with elevated GAD-7 scores being a potential contributing factor for poor sleep quality.

Epilepsy is a chronic central nervous system disorder characterized by abnormal synchronous neuronal discharges, posing a serious threat to global public health. The classic Chinese medicine formula Chaihu Longgu Muli Decoction has demonstrated significant anti-epileptic efficacy in clinical practice. Guided by the TCM theory that “The Heart and Gallbladder Have a Separate Connection,” and incorporating the principles of meridian interconnectivity and Qi transformation, this study analyzes the core pathogenesis of epilepsy as “dysfunction of the Gallbladder Pivot leading to Qi stagnation, phlegm, and fire, which ascend to disturb the Heart Spirit.” Modern medical research supports this theory, confirming that bile acid metabolism disorders and neuroinflammatory responses are common in epilepsy patients. Through a systematic analysis of the composition and compatibility of Chaihu Longgu Muli Decoction, this article reveals its triple mechanism of action: “unblocking and facilitating the Gallbladder Pivot,” “clearing and transforming phlegm-fire,” and “restoring the ascending and descending movement of Qi.” This multi-target, multi-level approach enables systematic intervention in the complex pathological network of epilepsy. This study not only offers innovative insights into TCM treatment of epilepsy from the unique perspective of “The Heart and Gallbladder Have a Separate Connection,” but also highlights the systemic advantages of TCM formulas in holistic regulation and multi-target intervention. Furthermore, it provides important theoretical foundations and new research directions for clinical application, integrative medicine approaches, and TCM treatment of complex neurological disorders.

DEAD-box RNA helicase 17 (DDX17), a key member of the DEAD-box family, is vital in cellular physiological processes. This review summarizes its structural properties, distribution, functions, disease associations, and research trends. Structurally, DDX17 has a conserved DEAD-box domain with RNA-dependent ATPase and helicase activities, producing p72 and p82 isoforms. It distributes in the nucleus and cytoplasm, highly expressed in cardiomyocytes and neuronal tissues. Functionally, DDX17 regulates RNA metabolism, DNA repair, and protein interactions. It is linked to chronic non-infectious diseases: promoting tumor progression via pathways like Wnt/β-catenin; protecting myocardial function in cardiovascular diseases; and involving in neurological disorders.This review provides insights for exploring its biological functions and clinical applications.

The excessive migration and proliferation of vascular smooth muscle cells (VSMCs) plays a vital role in vascular intimal hyperplasia. CIRBP is involved in the proliferation of various cancer cells. This study was aimed to explore the role of CIRBP in the proliferation and migration of VSMCs. Adenovirus was used to interfere with cold-inducible RNA-binding protein (CIRBP) expression, while lentivirus was used to overexpress Ras homolog enriched in brain (Rheb). Western blotting and qRT-PCR were used to evaluate the expression of CIRBP, Rheb, and mechanistic target of rapamycin complex 1 (mTORC1) activity. The cell proliferation was determined by Ki67 immunofluorescence staining and CCK-8 assay. The wound healing assay was performed to assess cell migration. Additionally, immunohistochemistry was conducted to explore the role of CIRBP in intimal hyperplasia after vascular injury. We found that silencing CIRBP inhibited the proliferation and migration of VSMCs, decreased the expression of Rheb and mTORC1 activity. Restoration of mTORC1 activity via insulin or overexpression of Rheb via lentiviral transfection both attenuated the inhibitory effects of silencing CIRBP on the proliferation and migration of VSMCs. Moreover, Rheb overexpression abolished the inhibitory effect of silencing CIRBP on mTORC1 activity in VSMCs. CIRBP was upregulated in the injured carotid artery. Silencing CIRBP ameliorated intimal hyperplasia after vascular injury. In the summary, silencing CIRBP attenuates mTORC1 activity via reducing Rheb expression, thereby supressing the proliferation and migration of VSMCs and intimal hyperplasia after vascular injury.

Sepsis-induced acute lung injury (ALI) is one of the serious life-threatening complications of sepsis and is pathologically associated with mitochondrial dysfunction. Ginsenoside Rg1 has good therapeutic effects on ALI. Herein, the pharmacological effects of Rg1 in sepsis-induced ALI were investigated. Sepsis-induced ALI models were established by CLP operation and LPS treatment. HE staining was adopted to analyze lung pathological changes. The expression and secretion of cytokines were measured by RT-qPCR and ELISA. Cell viability and apoptosis were assessed by MTT assay, flow cytometry and TUNEL staining. ROS level and mitochondrial membrane potential (MMP) were analyzed using DHE probe and JC-1 staining, respectively. FBXO3 m6A level was assessed using MeRIP assay. The interactions between FBXO3, YTHDF1, and PGC-1α were analyzed by Co-IP or RIP. Rg1 administration ameliorated LPS-induced epithelial cell inflammation, apoptosis, and mitochondrial dysfunction in a dose-dependent manner. Mechanically, Rg1 reduced PGC-1α ubiquitination modification level by inhibiting FBXO3 expression m6A-YTHDF1 dependently. As expected, Rg1’s mitigative effect on LPS-induced inflammation, apoptosis and mitochondrial dysfunction in lung epithelial cells was abolished by FBXO3 overexpression. Moreover, FBXO3 upregulation eliminated the restoring effect of Rg1 on CLP-induced lung injury in rats. Rg1 activated PGC-1α/Nrf2 signaling pathway by reducing FBXO3 stability in an m6A-YTHDF1-dependent manner to improve mitochondrial function in lung epithelial cells during sepsis-induced ALI progression.

Objective: To explore the effect of a stratified dose of norepinephrine (NE) on cellular immune response in patients with septic shock, and to construct a prognostic model of septic shock. Methods: A total of 160 patients with septic shock (B group) and 58 patients with sepsis (A group) were given standard cluster therapy. Patients with septic shock were divided into four groups (B1-B4 groups: 0.01-0.2, 0.2-0.5, 0.5-1.0, and >1 mu g/kg/min) according to the quartile method of the early (72 h) time-weighted average dose of NE and clinical application. The cellular immune indexes at 24 h (T0) and 4-7 days (T1) after admission were collected. The difference method was used to explore the effect of NE stratified dose on cellular immune effect in patients with septic shock. A multivariate COX proportional risk regression model was used to analyze the independent prognostic risk factors, and a prognostic risk model was constructed. Results: The differences of Delta IL-1 beta, Delta IL-6, Delta IL-10, absolute value difference of T lymphocyte (Delta CD3+/CD45+#) and Th helper T cell (Delta CD3+ CD4+/CD45+#), CD64 infection index difference, Delta mHLA-DR, regulatory T lymphocyte ratio difference (Delta Tregs%) between group A, B1, B2, B3, and B4 were statistically significant (P < 0.05). There was a nonlinear relation between the stratified dose of NE and Delta IL-6, Delta IL-10, Delta CD3+/CD45+#, Delta mHLA-DR%. The threshold periods of NE-induced proinflammatory and anti-inflammatory immune changes were 0.3-0.5 mu g/kg/min. Multivariate COX model regression analysis showed that age, nutritional patterns, weighted average dose of norepinephrine, IL-6, absolute value of T lymphocytes, and mHLA-DR were independent risk factors affecting the prognosis of patients with septic shock (P < 0.05). The prognostic risk model was constructed (AUC value = 0.813, 95% CI: 0.752-0.901). Conclusion: NE has a certain inhibitory effect on cellular immune function in patients with septic shock. A prognostic risk model was constructed with stronger prediction efficiency for the prognosis of patients with septic shock.

Exercise ameliorates pulmonary hypertension (PH) progression. However, the underlying mechanisms are largely unclear. Musclin is an exercise-responsive myokine that exerts protective effects on cardiovascular diseases. The current study aims to explore the role of musclin in the development of PH. A monocrotaline (MCT)-induced mouse PH model is established. Adeno-associated virus serotype 6 (AAV6)-mediated gene transfer is used to induce musclin overexpression in skeletal muscle. Ultrasound and morphological analyses are utilized to assess the severity of PH. Cell viability assay, Ki-67 immunofluorescence staining, wound healing assay, and transwell assay are used to evaluate the proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs). We find that the musclin levels in both plasma and skeletal muscle are decreased in MCT-treated mice. The external expression of musclin in skeletal muscle ameliorates pulmonary arterial remodeling and right ventricular dysfunction. In vitro, musclin treatment suppresses hypoxia-induced glycolysis, oxidative stress, proliferation, and migration. Further experiments reveal that musclin inhibits mechanistic target of rapamycin complex 1 (mTORC1) activity in hypoxia-stimulated PASMCs and pulmonary arteries of MCT-treated mice. Reactivating mTORC1 abolishes the protective role of musclin against PH. Additionally, musclin enhances its interaction with natriuretic peptide receptor 3 (NPR3) in PASMCs. Silencing of NPR3 reverses the inhibitory effects of musclin on AKT phosphorylation, mTORC1 activity, glycolysis, oxidative stress, proliferation, and migration in hypoxia-challenged PASMCs. In conclusion, our study highlights the inhibitory role of musclin in the proliferation and migration of PASMCs and PH progression, thereby providing a novel potent therapeutic strategy for treating PH and partly clarifying the mechanism of exercise-mediated protection against PH.

Belonging to a lipid phosphatase family containing 16 members, myotubularin-related proteins (MTMRs) are widely expressed in a variety of tissues and organs. MTMRs preferentially hydrolyzes phosphatidylinositol 3-monophosphate and phosphatidylinositol (3,5) bis-phosphate to generate phosphatidylinositol and phosphatidylinositol 5-monophosphate, respectively. These phosphoinositides (PIPs) promote membrane degradation during autophagosome-lysosomal fusion and are also involved in various regulatory signal transduction. Based on the ability of modulating the levels of these PIPs, MTMRs exert physiological functions such as vesicle trafficking, cell proliferation, differentiation, necrosis, cytoskeleton, and cell migration. It has recently been found that MTMRs are also involved in the occurrence and development of several cardiovascular diseases, including cardiomyocyte hypertrophy, proliferation of vascular smooth muscle cell, LQT1, aortic aneurysm, etc. This review summarizes the functions of MTMRs and highlights their pathophysiological roles in cardiovascular diseases.

BACKGROUND:In-stent restenosis hardly limits the therapeutic effect of the percutaneous vascular intervention. Although the restenosis is significantly ameliorated after the application of new drug-eluting stents, the incidence of restenosis remains at a high level.OBJECTIVE:Vascular adventitial fibroblasts (AFs) play an important role in intimal hyperplasia and subsequent restenosis. The current study was aimed to investigate the role of nuclear receptor subfamily 1, group D, member 1 (NR1D1) in the vascular intimal hyperplasia.METHODS AND RESULTS:We observed increased expression of NR1D1 after the transduction of adenovirus carrying Nr1d1 gene (Ad-Nr1d1) in AFs. Ad-Nr1d1 transduction significantly reduced the numbers of total AFs, Ki-67-positive AFs, and the migration rate of AFs. NR1D1 overexpression decreased the expression level of β-catenin and attenuated the phosphorylation of the effectors of mammalian target of rapamycin complex 1 (mTORC1), including mammalian target of rapamycin (mTOR) and 4E binding protein 1 (4EBP1). Restoration of β-catenin by SKL2001 abolished the inhibitory effects of NR1D1 overexpression on the proliferation and migration of AFs. Surprisingly, the restoration of mTORC1 activity by insulin could also reverse the decreased expression of β-catenin, attenuated proliferation, and migration in AFs induced by NR1D1 overexpression. In vivo, we found that SR9009 (an agonist of NR1D1) ameliorated the intimal hyperplasia at days 28 after injury of carotid artery. We further observed that SR9009 attenuated the increased Ki-67-positive AFs, an essential part of vascular restenosis at days 7 after injury to the carotid artery.CONCLUSION:These data suggest that NR1D1 inhibits intimal hyperplasia by suppressing the proliferation and migration of AFs in a mTORC1/β-catenin-dependent manner.

目的:探讨冷诱导RNA结合蛋白(CIRBP)对小鼠血管平滑肌细胞(VSMCs)增殖及迁移过程的调控及机制.方法:将雄性C57BL/6J小鼠分为假手术对照组、假手术干扰组、颈总动脉损伤对照组和颈总动脉损伤干扰组,每组5只.造模后按照组别分别用阴性对照腺病毒(AD-NC)和沉默CIRBP腺病毒(AD-CIRBPI)转染,28 d后观察CIRBP表达及血管内膜的增生情况.将小鼠VSMCs分为对照组和腺病毒沉默组,分别用AD-NC和AD-CIRBPI转染细胞48 h,然后加入激活雷帕霉素靶蛋白复合物1(mTORC1)活性的胰岛素.通过RT-qPCR检测CIRBP的mRNA表达,Western blot检测CIRBP、磷酸化核糖体蛋白S6(p-S6Ser235/236)和磷酸化4E结合蛋白1(p-4EBP1Thr37/46)蛋白水平变化,Ki67免疫荧光染色和CCK-8实验检测细胞增殖,划痕实验检测细胞迁移,HE染色检测颈动脉内膜增生程度.结果:沉默CIRBP后,VSMCs的活力下降,Ki67阳性细胞比率降低,细胞迁移速度减慢,同时mTORC1活性下降.加入胰岛素恢复mTORC1活性后,细胞活力、Ki67阳性细胞率和细胞迁移速度下降幅度减弱.损伤小鼠颈总动脉内皮后CIRBP表达增加,体内干扰小鼠CIRBP表达后,小鼠血管内皮损伤后内膜增生程度减轻.结论:CIRBP通过mTORC1途径加强小鼠VSMCs增殖及迁移,促进小鼠血管损伤后血管内膜增生.

Purpose: We aimed to explore whether anxiety is a risk factor for acute mountain sickness [AMS] in a young Chinese male population. Patients and Methods: A total of 143 young Chinese men with a median age of 23 years (IQR, 21-25) were employed in the present study, and they were divided into the AMS+ and AMS- groups according to the Lake Louise AMS score [AMS-S] after exposure at 3800 m for two days. Participants' pulse oximeter saturation [SpO(2)] and heart rate [HR] were measured. AMS was evaluated using the AMS-S. The anxiety and sleep quality of the subjects were assessed using the Zung Self-Rating Anxiety Scale [SAS] and the Athens Insomnia Scale [AIS], respectively. Outcomes were analysed using Spearman's partial correlation and logistic regression analysis. Results: After two days of exposure at 3800 m, the overall prevalence of AMS was 54% in the whole group. The HR was significantly higher in the AMS+ group than in the AMS- group, as well as the SAS score and AIS score. A converse pattern was observed for SpO(2). A significant difference was observed for the change in SAS and AIS score between the AMS+ and AMS- groups. Correlation analysis showed that AMS-S was positively correlated with SAS score, AIS score, HR, Delta SAS score, Delta AIS score, and Delta HR but negatively correlated with SpO(2). AIS score was positively correlated with SAS score. After logistic regression analysis was adjusted for HR, SpO(2), Delta AIS and Delta HR, SAS score (OR=1.446, 95% CI 1.200-1.744, p<0.001), AIS score (OR=1.216, 95% CI 1.033-1.432) and Delta SAS score (OR=1.158, 95% CI 1.012-1.327) were identified as independent risk factors for AMS. Conclusion: The present study suggests that anxiety is a risk factor for AMS among young Chinese men, and poor sleep quality may partially mediate the association.

Aim To explore the role and mechanism of nuclear receptor subfamily 1,group D,member 1（NR1D1） in the proliferation and migration of mouse adventitial fibroblasts（AFs）. Methods Primary AFs isolated from C57BL/6J mice were cultured. Adenovirus carrying Nr1d1 gene was used to overexpress NR1D1 in AFs. The expression of β-catenin was restored by SKL2001. Proliferating cell nuclear antigen（Ki-67） immunofluorescence staining and CCK-8 staining were used to determine cell proliferation, and scratch test was used to determine cell migration. qPCR was used to determine the mRNA level of Nr1d1. Western blot was used to determine the protein levels of NR1D1 and β-catenin. To investigate the role of NR1D1 in intimal hyperplasia, 20 male wild type C57BL/6J mice were randomly divided into sham group,carotid artery endothelial injury,sham + SR9009（ NR1D1 agonist） group and carotid artery endothelial injury + SR9009（ n = 5 in each group）. They were treated with DMSO or SR9009（ 100 mg·kg-1·d-1）via intraperitoneal injection for 14 days after operation,respectively. The degree of carotid intimal hyperplasia was measured by HE staining 28 days after operation.Results NR1D1 overexpression significantly reduced the percentage of Ki-67-positive cells（ P ＜ 0. 01）,total cell number（ P ＜ 0. 01） and slowed down the rate of wound-healing（ P ＜ 0. 01）. NR1D1 overexpression significantly inhibited the expression of β-catenin（ P＜ 0. 05）. After the expression of β-catenin was restored by SKL2001,the inhibitory effects of NR1D1overexpression on the proliferation and migration of AFs were abolished（ P ＜ 0. 01）. Enhanced activity of NR1D1 significantly ameliorated intimal hyperplasia after carotid endothelial injury（ P ＜ 0. 01）. Conclusion NR1D1 may inhibit the proliferation and migration of AFs via suppressing the expression of β-catenin.

Myocardial infarction (MI) is regarded as a serious ischemic heart disease on a global level. The current study set out to explore the mechanism of the Notch signaling pathway in the regulation of fibrosis remodeling after the occurrence of MI. First, experimental mice were infected with recombination signal binding protein J (RBP-J) shRNA and empty adenovirus vector, followed by the establishment of MI mouse models and detection of cardiac function. After 4 weeks of MI, mice in the sh-RBP-J group were found to exhibit significantly improved cardiac function relative to the sh-NC group. Moreover, knockdown of RBP-J brought about decreased infarct area, promoted cardiac macrophages M2 polarization, reduced cardiac fibrosis, and further decreased transcription and protein expressions of inflammatory factors and fibrosis-related factors. Furthermore, downregulation of cylindromatosis (CYLD) using si-CYLD reversed the results that knockdown of RBP-J inhibited fibrogenesis and the release of inflammatory factors. Altogether, our findings indicated that the blockade of Notch signaling promotes M2 polarization of cardiac macrophages and improves cardiac function by inhibiting the imbalance of fibrotic remodeling after MI.

Apolipoprotein E (ApoE) isoforms affect the risk of developing Alzheimer's disease (AD). ApoE-associated risk may be related to its binding to and clearance by cell surface receptors, such as the members of the low-density lipoprotein (LDL) receptor family. Previous studies had shown association of LDL receptor-related protein (LRP) and AD, therefore we speculated that another member of this LDL receptor family, LRP8 (also called apolipoprotein E receptor 2 or ApoER2), which is predominantly expressed in brain, might be associated with Alzheimer's disease. To explore this hypothesis, we screened exons 2–19 of the LRP8 gene in a total of 204 AD and 184 elderly control subjects for polymorphisms using the conformation-sensitive gel electrophoresis method. Our results revealed four sequence alterations: two predicted to result in amino acid changes (E46D and R952Q), one in an intron (IVS9+7G>A), and one synonymous polymorphism (2622T>C). The latter was found in four AD patients (2.0%) and 11 controls (6.0%), a significant difference (P=0.042). Further study is needed to confirm this possible association of LRP8 with AD.

Characterized by abnormal proliferation and migration of vascular smooth muscle cells (VSMCs), neointima hyperplasia is a hallmark of vascular restenosis after percutaneous vascular interventions. Vaccinia-related kinase 1 (VRK1) is a stress adaption-associated ser/thr protein kinase that can induce the proliferation of various types of cells. However, the role of VRK1 in the proliferation and migration of VSMCs and neointima hyperplasia after vascular injury remains unknown. We observed increased expression of VRK1 in VSMCs subjected to platelet-derived growth factor (PDGF)-BB by western blotting. Silencing VRK1 by shVrk1 reduced the number of Ki-67-positive VSMCs and attenuated the migration of VSMCs. Mechanistically, we found that relative expression levels of β-catenin and effectors of mTOR complex 1 (mTORC1) such as phospho (p)-mammalian target of rapamycin (mTOR), p-S6, and p-4EBP1 were decreased after silencing VRK1. Restoration of β-catenin expression by SKL2001 and re-activation of mTORC1 by Tuberous sclerosis 1 siRNA (siTsc1) both abolished shVrk1-mediated inhibitory effect on VSMC proliferation and migration. siTsc1 also rescued the reduced expression of β-catenin caused by VRK1 inhibition. Furthermore, mTORC1 re-activation failed to recover the attenuated proliferation and migration of VSMC resulting from shVrk1 after silencing β-catenin. We also found that the vascular expression of VRK1 was increased after injury. VRK1 inactivation in vivo inhibited vascular injury-induced neointima hyperplasia in a β-catenindependent manner. These results demonstrate that inhibition of VRK1 can suppress the proliferation and migration of VSMC and neointima hyperplasia after vascular injury via mTORC1/β-catenin pathway.

ABSTRACT:The incidence of myocardial dysfunction caused by sepsis is high, and the mortality of patients with sepsis can be significantly increased. During sepsis, oxidative stress and inflammation can lead to severe organ dysfunction. Flavone chrysin is one of the indispensable biological active ingredients for different fruits and vegetables and has antioxidant and anti-inflammatory properties. However, it is not clear whether chrysin is an effective treatment for heart dysfunction caused by sepsis. We found that it had protective effects against the harmful effects caused by LPS, manifested in improved survival, normalized cardiac function, improved partial pathological scores of myocardial tissue, and remission of apoptosis, as well as reduced oxidative stress and inflammation. Mechanism studies have found that chrysin is an important antioxidant protein, a key regulator of heme oxygenase 1 (HO-1). We found that HO-1 levels were increased after LPS intervention, and chrysin further increased HO-1 levels, along with the addition of Nrf2, a regulator of antioxidant proteins. Pretreatment with PD98059, an extracellular signal-regulated kinase-specific inhibitor, blocked chrysin-mediated phosphorylation of Nrf2 and the nuclear translocation of Nrf2. The protective effect of chrysin on sepsis-induced cardiac dysfunction was blocked by ZnPP, which is a HO-1 blocker. Chrysin increased antioxidant activity and reduced markers of oxidative stress (SOD and MDA) and inflammation (MPO and IL-1β), all of which were blocked by ZnPP. This indicates that HO-1 is the upstream molecule regulating the protective effect of chrysin. Thus, by upregulation of HO-1, chrysin protects against LPS-induced cardiac dysfunction and inflammation by inhibiting oxidative stress.