BACKGROUND:Pulmonary arterial hypertension (PAH) is a lethal vascular disorder characterized by irreversible remodeling of the pulmonary arteries, but the systematic role of the integrated stress response (ISR)-related genes (ISR-RGs) in its pathogenesis remains unexplored. OBJECTIVE:This study aimed to identify and validate ISR-associated potential biomarkers for PAH using integrative bioinformatics, single-cell transcriptomics, and experimental approaches. METHODS:We analyzed bulk RNA-seq datasets (GSE38267, GSE131793) and a single-cell RNA sequencing (scRNA-seq) dataset (GSE210248) from PAH patients and controls. A total of 529 ISR-RGs were integrated. Differential expression analysis, machine learning, and functional enrichment analyses were employed to identify potential biomarkers. A diagnostic nomogram was constructed and validated. Immune infiltration, regulatory networks, drug-gene interactions, and molecular docking were further investigated. Key cellular mechanisms were elucidated via scRNA-seq, and biomarker expression was validated using Reverse Transcription Quantitative Polymerase Chain Reaction (RT-qPCR) and Enzyme-linked immunosorbent assay (ELISA) in clinical whole blood samples. RESULTS:We identified four ISR-related diagnostic biomarkers: ABCC4, ATM, SERPINH1, and ZBTB40. These genes showed consistent dysregulation in PAH across multiple datasets and were integrated into a nomogram with good predictive performance (hosmer-lemeshow (HL) test P = 0.432). Gene set enrichment analysis (GSEA) revealed their involvement in translation, neutrophil degranulation, and glucocorticoid pathways. The scRNA-seq highlighted their cell-type-specific expression in T cells and monocytes. Molecular docking identified CAMONSERTIB as a potent ATM-targeting drug (binding energy: -10.2 kcal/mol), and its therapeutic effects on pulmonary arterial hypertension were validated through both animal and cellular models. RT-qPCR and Elisa confirmed upregulation of ABCC4 and downregulation of ATM, SERPINH1 and ZBTB40 in PAH patients. CONCLUSIONS:This study identified four novel ISR-related biomarkers for PAH and elucidated their roles in immune infiltration and cellular remodeling. The findings provided new insights into PAH pathogenesis and offered potential tools for diagnosis and targeted therapy.

As an RNA-binding protein, DEAD-box RNA helicase 17 (DDX17) plays a critical role in influencing gene expression and participates in the proliferation and migration of several cell lines. The current study aims to investigate the role of DDX17 in vascular smooth muscle cell (VSMC) proliferation and migration and vascular intimal hyperplasia. DDX17 expression was upregulated in injured mouse arteries and platelet derived growth factor (PDGF)-BB-treated VSMCs. An adeno-associated virus serotype 9 vector carrying Ddx17 short hairpin RNA (shDdx17) was used to silence DDX17 expression in vivo. DDX17 silencing significantly ameliorated injury-induced mouse vascular intimal hyperplasia. In vitro, the recombinant lentivirus carrying Ddx17 shRNA (Len-Ddx17i) was used to inhibition DDX17 expression in VSMCs. DDX17 deficiency inhibited PDGF-BB-induced phenotypic switching of VSMCs. Bioinformatics analysis revealed that DDX17 expression is closely related to glucose metabolism- and oxidative stress-associated pathways. Next, we found that glycolysis and oxidative stress were both attenuated by DDX17 ablation in VSMCs. Mechanically, reduced ras homolog enriched in brain (RHEB) expression and decreased mammalian target of rapamycin complex 1 (mTORC1) activity were observed after silencing of DDX17 in PDGF-BB-challenged VSMCs. Upregulating RHEB expression or elevating mTORC1 activity abolished the inhibitory effects of DDX17 silencing on PDGF-BB-induced glycolysis, oxidative stress, proliferation, and migration in VSMCs. Furthermore, the decreased mTORC1 activity induced by DDX17 deficiency was also reversed by RHEB overexpression. In conclusion, DDX17 silencing attenuates VSMC proliferation and migration by inhibiting RHEB/mTORC1-mediated glycolysis and oxidative stress, thus suppressing vascular intimal hyperplasia.

Physical exercise is a non-pharmacological intervention that helps prevent pathological cardiac hypertrophy. However, the underlying molecular mechanisms remain unclear. Telomerase reverse transcriptase (TERT) has non-telomeric functions such as protection against mitochondrial dysfunction and oxidative stress, and its myocardial expression is upregulated by physical exercise. Here, we found that physical exercise caused myocardial upregulation of mitochondrial TERT and sustenance during transverse aortic constriction (TAC)-induced cardiac hypertrophy. Overexpression of mitochondrial-targeted TERT (mito-TERT) via adeno-associated virus serotype 9 carrying the TERT-coding sequence fused with N-terminal mitochondrial-targeting sequence improved cardiac function and attenuated cardiac hypertrophy. Mechanistically, mito-TERT ameliorated mitochondrial dysfunction and oxidative stress, which were associated with improving the activity and subunit composition of complex I. Remarkably, the telomerase activator TA-65 also exhibited an antihypertrophic effect. Collectively, our results reveal a significant role for mito-TERT in mediating the antihypertrophic effect of physical exercise and demonstrate that TERT is a potential drug target for treating cardiac hypertrophy.

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.

Purpose:Pulmonary arterial hypertension (PAH) is a devastating disease with little effective treatment. The proliferation of pulmonary artery smooth muscle cells (PASMCs) induced by the nuclear factor-κB (NF-κB) signaling activation plays a pivotal role in the pathogenesis of PAH. Forsythoside B (FTS•B) possesses inhibitory effect on NF-κB signaling pathway. The present study aims to explore the effects and mechanisms of FTS•B in PAH.Methods:Sprague-Dawley rats received monocrotaline (MCT) intraperitoneal injection to establish PAH model, and FTS•B was co-treated after MCT injection. Right ventricular hypertrophy and pulmonary artery pressure were measured by echocardiography and right heart catheterization, respectively. Histological alterations were detected by H&E staining and immunohistochemistry. FTS•B's role in PASMC proliferation and migration were evaluated by CCK-8 and wound healing assay. To investigate the underlying mechanisms, Western blotting, immunofluorescence staining and ELISA were conducted. The NF-κB activator PMA was used to investigate the role of NF-κB in FTS•B's protective effects against PAH.Results:FTS•B markedly alleviated MCT-induced vascular remodeling and pulmonary artery pressure, and improved right ventricular hypertrophy and survival. FTS•B also reversed PDGF-BB-induced PASMC proliferation and migration, decreased PCNA and CyclinD1 expression in vitro. The elevated levels of IL-1β and IL-6 caused by MCT were decreased by FTS•B. Mechanistically, MCT-triggered phosphorylation of p65, IκBα, IKKα and IKKβ was blunted by FTS•B. FTS•B also reversed MCT-induced nuclear translocation of p65. However, all these protective effects were blocked by PMA-mediated NF-κB activation.Conclusion:FTS•B effectively attenuates PAH by suppressing the NF-κB signaling pathway to attenuate vascular remodeling. FTS•B might be a promising drug candidate with clinical translational potential for the treatment of PAH.

Sepsis is a life-threatening condition involving dysfunctional organ responses stemming from dysregulated host immune reactions to various infections. The lungs are most prone to failure during sepsis, resulting in acute lung injury (ALI). ALI is associated with oxidative stress and inflammation, and current therapeutic strategies are limited. To develop a more specific treatment, this study aimed to synthesise Prussian blue nanozyme (PBzyme), which can reduce oxidative stress and inflammation, to alleviate ALI. PBzyme with good biosafety was synthesised using a modified hydrothermal method. PBzyme was revealed to be an activator of haem oxygenase-1 (HO-1), improving survival rate and ameliorating lung injury in mice. Zinc protoporphyrin, an inhibitor of HO-1, inhibited the prophylactic therapeutic efficacy of PBzyme on ALI, and affected the nuclear factor-κB signaling pathway and activity of HO-1. This study demonstrates that PBzyme can alleviate oxidative stress and inflammation through HO-1 and has a prophylactic therapeutic effect on ALI. This provides a new strategy and direction for the clinical treatment of sepsis-induced ALI.

BACKGROUND:Doxorubicin (DOX) is a potent anticancer chemotherapeutic agent whose clinical application is substantially constrained by its cardiotoxicity. The pathophysiology of DOX-induced cardiotoxicity manifests as cardiomyocyte pyroptosis and inflammation. Amentoflavone (AMF) is a naturally occurring biflavone possessing anti-pyroptotic and anti-inflammatory properties. However, the mechanism through which AMF alleviates DOX-induced cardiotoxicity remains undetermined. PURPOSE:This study aimed at investigating the role of AMF in alleviating DOX-induced cardiotoxicity. STUDY DESIGN AND METHODS:To assess the in vivo effect of AMF, DOX was intraperitoneally administered into a mouse model to induce cardiotoxicity. To elucidate the underlying mechanisms, the activities of STING/NLRP3 were quantified using the NLRP3 agonist nigericin and the STING agonist amidobenzimidazole (ABZI). Primary cardiomyocytes isolated from neonatal Sprague-Dawley rats were treated with saline (vehicle) or DOX with or without AMF and/or ABZI. The echocardiogram, haemodynamics, cardiac injury markers, heart/body weight ratio, and pathological alterations were monitored; the STING/NLRP3 pathway-associated proteins were detected by western blot and cardiomyocyte pyroptosis was analysed by immunofluorescence staining of cleaved N-terminal GSDMD and scanning electron microscopy. Furthermore, we evaluated the potential of AMF in compromising the anticancer effects of DOX in human breast cancer cell lines. RESULTS:AMF substantially alleviated cardiac dysfunction and reduced heart/body weight ratio and myocardial damage in mice models of DOX-induced cardiotoxicity. AMF effectively suppressed DOX-mediated upregulation of IL-1β, IL-18, TNF-α, and pyroptosis-related proteins, including NLRP3, cleaved caspase-1, and cleaved N-terminal GSDMD. The levels of apoptosis-related proteins, namely Bax, cleaved caspase-3, and BCL-2 were not affected. In addition, AMF inhibited STING phosphorylation in DOX-affected hearts. Intriguingly, the administration of nigericin or ABZI dampened the cardioprotective effects of AMF. The in vitro anti-pyroptotic effect of AMF was demonstrated in attenuating the DOX-induced reduction in cardiomyocyte cell viability, upregulation of cleaved N-terminal GSDMD, and pyroptotic morphology alteration at the microstructural level. AMF exhibited a synergistic effect with DOX to reduce the viability of human breast cancer cells. CONCLUSION:AMF alleviates DOX-induced cardiotoxicity by suppressing cardiomyocyte pyroptosis and inflammation via inhibition of the STING/NLRP3 signalling pathway, thereby validating its efficacy as a cardioprotective agent.

Objective: Excessive proliferation and migration of pulmonary arterial smooth muscle cell (PASMC) is a core event of pulmonary hypertension (PH). Regulators of G protein signaling 10 (RGS10) can regulate cellular proliferation and cardiopulmonary diseases. We demonstrate whether RGS10 also serves as a regulator of PH.Methods: PASMC was challenged by hypoxia to induce proliferation and migration. Adenovirus carrying Rgs10 gene (Ad-Rgs10) was used for external expression of Rgs10. Hypoxia/SU5416 or MCT was used to induce PH. Right ventricular systolic pressure (RVSP) and right ventricular hypertrophy index (RVHI) were used to validate the establishment of PH model.Results: RGS10 was downregulated in hypoxia-challenged PASMC. Ad-Rgs10 significantly suppressed proliferation and migration of PASMC after hypoxia stimulus, while silencing RGS10 showed contrary effect. Mechanistically, we observed that phosphorylation of S6 and 4E-Binding Protein 1 (4EBP1), the main downstream effectors of mammalian target of rapamycin complex 1 (mTORC1) as well as phosphorylation of AKT, the canonical upstream of mTORC1 in hypoxia-induced PASMC were negatively modulated by RGS10. Both recovering mTORC1 activity and restoring AKT activity abolished these effects of RGS10 on PASMC. More importantly, AKT activation also abolished the inhibitory role of RGS10 in mTORC1 activity in hypoxia-challenged PASMC. Finally, we also observed that overexpression of RGS10 in vivo ameliorated pulmonary vascular wall thickening and reducing RVSP and RVHI in mouse PH model.Conclusion: Our findings reveal the modulatory role of RGS10 in PASMC and PH via AKT/mTORC1 axis. Therefore, targeting RGS10 may serve as a novel potent method for the prevention against PH."

Pulmonary arterial hypertension (PAH) is characterized by progressive vascular remodeling caused by the excessive proliferation and survival of pulmonary artery smooth muscle cells (PASMCs). Dual-specificity tyrosine regulated kinase 1A (DYRK1A) is a pleiotropic kinase involved in the regulation of multiple biological functions, including cell proliferation and survival. However, the role and underlying mechanisms of DYRK1A in PAH pathogenesis remain unclear. We found that DYRK1A was upregulated in PASMCs in response to hypoxia, both in vivo and in vitro. Inhibition of DYRK1A by harmine significantly attenuated hypoxia-induced pulmonary hypertension and pulmonary artery remodeling. Mechanistically, we found that DYRK1A promoted pulmonary arterial remodeling by enhancing the proliferation and survival of PASMCs through activating the STAT3/Pim-1/NFAT pathway, because STAT3 gain-of-function via adeno-associated virus serotype 2 (AAV2) carrying the constitutively active form of STAT3 (STAT3C) nearly abolished the protective effect of harmine on PAH. Collectively, our results reveal a significant role for DYRK1A in pulmonary arterial remodeling and suggest it as a drug target with translational potential for the treatment of PAH.

Abstract: Excessive proliferation and migration of vascular smooth muscle cells (VSMCs) cause neointimal hyperplasia after percutaneous vascular interventions. Nuclear receptor subfamily 1 group D member 1 (NR1D1), a crucial member of circadian clock, is involved in the regulation of atherosclerosis and cellular proliferation. However, whether NR1D1 affects vascular neointimal hyperplasia remains unclear. In this study, we found that activating NR1D1 reduced injury-induced vascular neointimal hyperplasia. Overexpression of NR1D1 reduced the number of Ki-67-positive VSMCs and migrated VSMCs after platelet-derived growth factor (PDGF)-BB treatment. Mechanistically, NR1D1 suppressed the phosphorylation of AKT and 2 main effectors of the mammalian target of rapamycin complex 1 (mTORC1), S6, and 4EBP1 in PDGF-BB-challenged VSMCs. Re-activation of mTORC1 by Tuberous sclerosis 1 siRNA (siTsc1) and re-activation of AKT by SC-79 abolished NR1D1-mediated inhibitory effects on proliferation and migration of VSMCs. Moreover, decreased mTORC1 activity induced by NR1D1 was also reversed by SC-79. Simultaneously, Tsc1 knockdown abolished the vascular protective effects of NR1D1 in vivo. In conclusion, NR1D1 reduces vascular neointimal hyperplasia by suppressing proliferation and migration of VSMCs in an AKT/mTORC1-dependent manner.

Doxorubicin (DOX) has aroused contradiction between its potent anti-tumor capacity and severe cardiotoxicity. Galangin (Gal) possesses antioxidant, anti-inflammatory, and antiapoptotic activities. We aimed to explore the role and underlying mechanisms of Gal on DOX-induced cardiotoxicity. Mice were intraperitoneally injected with DOX (3 mg/kg, every 2 days for 2 weeks) to generate cardiotoxicity model and Gal (15 mg/kg, 2 weeks) was co-administered via gavage daily. Nuclear factor erythroid 2-related factor 2 (Nrf2) specific inhibitor, ML385, was employed to explore the underlying mechanisms. Compared to DOX-insulted mice, Gal effectively improved cardiac dysfunction and ameliorated myocardial damage. DOX-induced increase of reactive oxygen species, malondialdehyde, and NADPH oxidase activity and downregulation of superoxide dismutase (SOD) activity were blunted by Gal. Gal also markedly blocked increase of IL-1 & beta;, IL-6, and TNF-& alpha; in DOX-insulted heart. Mechanistically, Gal reversed DOX-induced downregulation of Nrf2, HO-1, and promoted nuclear translocation of Nrf2. ML385 markedly blunted the cardioprotective effects of Gal, as well as inhibitive effects on oxidative stress and inflammation. Gal ameliorates DOX-induced cardiotoxicity by suppressing oxidative stress and inflammation via activating Nrf2/HO-1 signaling pathway. Gal may serve as a promising cardioprotective agent for DOX-induced cardiotoxicity. Galangin activates nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase 1 (HO-1) signaling pathway to suppress oxidative stress and inflammation, subsequently exerts cardio-protectivity against doxorubicin (DOX)-induced cardiotoxicity.image

RAS protein activator like 2 (Rasal2) exerts pro-proliferative effect in several types of cells. However, whether Rasal2 is involved in the regulation of pulmonary artery smooth muscle cell (PASMC) remains unclear. In the current study, we explored the role of Rasal2 in proliferation and migration of PASMC during the development of pulmonary arterial hypertension (PAH). We found that the protein level of Rasal2 was increased in both pulmonary arteries of chronic hypoxia-induced pulmonary hypertension (CH-PH) mice and hypoxia-challenged PASMC. Overexpression of Rasal2 caused enhanced proliferation and migration of PASMC after hypoxia exposure. Mechanistically, we found elevated phosphorylation of AKT and two downstream effectors of mammalian target of Rapamycin complex 1 (mTORC1), S6 and 4E-Binding Protein 1 (4EBP1) after Rasal2 overexpression in hypoxia-challenged PASMC. Inactivation of mTORC1 abolished Rasal2-mediated enhancement of proliferation and migration of PASMC. Furthermore, we also demonstrated that AKT might act downstream of Rasal2 to enhance the activity of mTORC1. Once AKT was inactivated by MK-2206 application, overexpression of Rasal2 failed to further increase the phosphorylation level of S6 and 4EBP1. Finally, inhibition of AKT also blocked Rasal2-induced proliferation and migration in hypoxia-challenged PASMC. In conclusion, Rasal2 promotes the proliferation and migration of PASMC during the development of PAH via AKT/mTORC1 pathway.

Sepsis-induced cardiomyopathy is a decisive factor that plays a critical role in the high mortality of septic patients in the critically ill. Mitochondrial dysfunction occurring during sepsis is a vital contributor to the pathogenesis of myocardial damage. Rosmarinic acid (RA), a natural poly-phenolic compound, has showed cardio-protective and mitochondrial protective effect. The present study was aimed to investigate the effect of RA on sepsis-induced cardiomyopathy. Adult mice were subjected to intraperitoneal injection of saline (control) or lipopolysaccharide (LPS, 5 mg/kg) to mimic sepsis-induced cardiomyopathy. Immediately after LPS challenge, vehicle or RA (100 mg/kg/day) was administrated via gavage. Cardiac function was examined with echocardiographic analyses 12 hours after LPS challenge and cumulative survival of mice was recorded for 8 days. Heart tissues were harvested 12 hours after LPS challenge to perform histological analyses and determine mitochondrial function. We found RA significantly improved cardiac function and survival of LPS-injected mice. Histologically, RA attenuated LPS-mediated cardiomyocyte damage, indicated by decreased cardiomyocyte apoptosis and improved myocardial swollen and disarrangement. Moreover, RA attenuated LPS-mediated myocardial mitochondrial dysfunction, indicated by improved mitochondrial ultrastructure, increased mitochondrial membrane potential (MMP), synthesis of adenosine triphosphate (ATP), markedly decreased reactive oxygen species (ROS) level and alleviated oxidative stress in heart tissues. RA treatment downregulated protein expression of Sirt1 and peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α), and Sirt1 inhibition blocked protective effect of RA on LPS-induced myocardial damage and mitochondrial dysfunction. Collectively, RA attenuates LPS-induced cardiac dysfunction via activating Sirt1/PGC-1α pathway to alleviate mitochondrial impairment. It may be a promising cardio-protective drug to be used for septic patients.

Type 2 diabetes mellitus (T2DM)-associated mitochondrial impairment may a key factor leading to liver injury. Transient receptor potential receptor vanilloid 1 (TRPV1) regulates the energy expenditure and cholesterol metabolism in hepatocytes and protects against oxidative toxicity. Optic atrophy 1 (OPA1) is involved in the protection of TRPV1 on cardiac microvascular and lung injury. The aim of this study is to identify the role of TRPV1 in redox signals and liver protection via OPA1. TRPV1 knockout (TRPV1-/-) mice were used. And T2DM associated liver injury was induced by high glucose and high fatty acid (HG/HF) treatment. Mechanisms were studied by TUNEL staining, transmission electron microscope (TEM) analysis, reverse transcription polymerase chain reaction (RT-PCR) and Western blotting in vivo and in vitro. We determined that HG/HF treatment increased TRPV1 expression in liver tissues and AML12 cells. The knockout of TRPV1 increased the apoptotic hepatocytes rate. The inhibition of TRPV1 by 5'-iRTX in HG/HF group elevated the reactive oxygen species (ROS) levels, whereas TRPV1 agonist capsaicin reduced ROS. Our studies also showed that the OPA1 expression was lower in livers from HG/HF treated mice than the control, and genetic ablation of TRPV1 decreased OPA1 expression to a greater extent than the HG/HF mice. The protective effects of TRPV1 on mitochondrial were blocked by OPA1 siRNA. In conclusion, our study showed that the identified regulation of TRPV1 to OPA1 has important implication to the pathogenesis of T2DM-associated liver injury. Targeting the action of TRPV1 and OPA1 presents a potential therapeutic intervention.

Myocardial injury is a serious complication of sepsis. The present study aimed to identify potential biomarkers of sepsis-induced myocardial injury. Differentially expressed genes (DEGs) in patients and mice with sepsis-induced myocardial injury were identified via bioinformatic analysis. The identified DEG was tested in elderly patients with sepsis-induced myocardial injury. We identified 19 co-expressed DEGs. The most significant DEG was eotaxin-1/CCL11. We enrolled 25 controls without infections and 28 patients with sepsis-induced myocardial injury. Six of patients died within 30 days. Circulating eotaxin-1/CCL11 levels were significantly higher in patients with sepsis-induced myocardial injury than controls and were higher in non-survivors than survivors (both P < 0.01). Eotaxin-1/CCL11 was positively correlated with troponin I (r=0.48, P=0.01), B-type natriuretic peptide (BNP, r=0.44, P=0.02), and white blood cell (WBC) count (r=0.41, P=0.03). For the prediction of 30-day mortality, eotaxin-1/CCL11 had the greatest discriminatory ability (AUC 0.97) compared with troponin I (AUC 0.89), BNP (AUC 0.80), and WBC count (AUC 0.86). Taken together, eotaxin-1/CCL11 was upregulated in sepsis-injured myocardium and circulating eotaxin-1/CCL11 was a biomarker for predicting severity and mortality of elderly patients with sepsis-induced myocardial injury. These results suggest that eotaxin-1/CCL11 may become a useful biomarkers and potential therapeutic target for sepsis-induced myocardial injury.

Ischemia and anoxia-induced mitochondrial impairment may be a key factor leading to heart injury during myocardial infarction (MI). Calpain 1 and 2 are involved in the MI-induced mitochondria injury. G protein-coupled receptor 35 (GPR35) could be triggered by hypoxia. Whether or not GPR35 regulates calpain 1/2 in the pathogenesis of MI is still unclear. In this study, we determined that MI increases GPR35 expression in myocardial tissue. Suppression of GPR35 protects heart from MI injury in mice through reduction of reactive oxygen species activity and mitochondria-dependent apoptosis. Further studies show that GPR35 regulates calpain 1/2. Suppression of GPR35 reduces the expression and activity of calpain 1/2, and alleviates calpain 1/2-associated mitochondrial injury to preserve cardiac function. Based on these data, we conclude that a functional inhibition of GPR35 downregulates calpain 1/2 and contributes to maintenance of cardiac function under pathologic conditions with mitochondrial disorder. In conclusion, our study showed that the identified regulation by GPR35 of calpain 1/2 has important implications for the pathogenesis of MI. Targeting the action of GPR35 and calpain 1/2 in mitochondria presents a potential therapeutic intervention for MI.

目的 探讨心电图教学改革在护理专业大学生中的应用效果.方法 将某校护理本科2014级学生作为观察组,以2013级护理本科生作为历史对照.观察组采用新教改后的教学模式,对照组采用传统的方案实施教学.教学结束后对学生进行卷面测试和学习态度的问卷调查.结果 实验组在心电图总分和判图得分两方面均明显高于对照组(P＜0.05);2014级学生对新教改的满意率达到97.73％,86.36％的学生喜欢读图分析教学法,对心电图教学资源的利用率为100％.结论 心电图教学新模式有助于提升学生的学习兴趣,培养和训练护理专业学生基本的心电图技能,值得在护理专业学生的心电图教学中推广.

目的 探讨综合护理干预在动态心电图检查中的应用效果.方法 收集我院2016年3月 ～2017年8月动态心电图检查的100例患者,随机分成观察组和对照组各50例,对照组进行叮嘱患者检查注意事项、检查仪器佩戴以及一定的活动指导等常规护理,观察组进行综合护理干预.结果 观察组干扰发生例数、导线或者电极脱落明显低于对照组,总检测时间完整例数、生活日志记录合格例数明显高于对照组,两组比较有统计学意义(P<0.05),观察组未发生不良事件,护理满意度为100.0％,对照组发生不良事件3例,护理满意度为82.0％,两组比较有统计学意义(P<0.05).结论 综合护理干预可以明显降低干扰、导线或者电极脱落发生率和不良事件发生率,提高总检测时间完整率和生活日志记录合格率,提高护理满意度.

目的 应用基于奥马哈系统的延续性护理方法,处理老年髋臼骨折患者出院后康复过程中的护理问题并归纳整理干预措施,为促进老年髋臼骨折患者出院后的护理和科学康复方法提供依据.方法 选取2012年1月 ～2016年12月西部战区总医院骨科收治的老年髋臼骨折复位内固定患者122例,针对出院后的护理模式分为干预组58例和对照组64例进行前瞻性对照研究.对照组采用髋臼骨折术后常规护理方法;干预组应用以奥马哈系统为基础的延续性护理方法,对患者在生理领域、健康相关行为领域、社会心理领域及环境领域进行个性化的干预.两组患者均在手术后1、3和6个月门诊随访.对护理问题的改善成效评价采用Likert 5分法,从认知、行为、状况3方面来评价;采用Modified Merle D′Aubigne Postel Score量表对髋关节功能进行评分;并统计两组并发症情况.结果 与对照组相比较,干预组患者的疼痛、神经肌肉功能、身体活动、自我照顾4个护理问题均明显改善(P<0.05);干预组术后髋关节功能评分明显好于对照组(P<0.05);干预组术后关节僵硬、创伤性关节炎、坐骨神经损伤等并发症的发生率明显低于对照组(P<0.05).结论 运用以奥马哈系统为基础的延续性护理方法,可以在老年髋臼骨折术后院外康复的关键时期改善患者护理问题、加快恢复关节功能,实现以患者为中心的整体护理要求,明显提高老年髋臼骨折患者术后康复效果.

Cardiac fibroblasts (CFs) are a critical cell population responsible for myocardial extracellular matrix homeostasis. After stimulation by myocardial infarction (MI), CFs transdifferentiate into cardiac myofibroblasts (CMFs) and play a fundamental role in the fibrotic healing response. Transient receptor potential ankyrin 1 (TRPA1) channels are cationic ion channels with a high fractional Ca 2+ current, and they are known to influence cardiac function after MI injury; however, the molecular mechanisms regulating CMF transdifferentiation remain poorly understood. TRPA1 knockout mice, their wild-type littermates, and mice pretreated with the TRPA1 agonist cinnamaldehyde (CA) were subjected to MI injury and monitored for survival, cardiac function, and fibrotic remodeling. TRPA1 can drive myofibroblast transdifferentiation initiated 1 week after MI injury. In addition, we explored the underlying mechanisms via in vitro experiments through gene transfection alone or in combination with inhibitor treatment. TRPA1 overexpression fully activated CMF transformation, while CFs lacking TRPA1 were refractory to transforming growth factor β - (TGF- β -) induced transdifferentiation. TGF- β enhanced TRPA1 expression, which promoted the Ca 2+ -responsive activation of calcineurin (CaN). Moreover, dual-specificity tyrosine-regulated kinase-1a (DYRK1A) regulated CaN-mediated NFAT nuclear translocation and TRPA1-dependent transdifferentiation. These findings suggest a potential therapeutic role for TRPA1 in the regulation of CMF transdifferentiation in response to MI injury and indicate a comprehensive pathway driving CMF formation in conjunction with TGF- β , Ca 2+ influx, CaN, NFATc3, and DYRK1A.