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The risk for suffering immune checkpoint inhibitors (ICIs)‐associated myocarditis increases in patients with pre‐existing conditions and the mechanisms remain to be clarified. Spatial transcriptomics, single‐cell RNA sequencing, and flow cytometry are used to decipher how anti‐cytotoxic T lymphocyte antigen‐4 m2a antibody (anti‐CTLA‐4 m2a antibody) aggravated cardiac injury in experimental autoimmune myocarditis (EAM) mice. It is found that anti‐CTLA‐4 m2a antibody increases cardiac fibroblast‐derived C‐X‐C motif chemokine ligand 1 (Cxcl1), which promots neutrophil infiltration to the myocarditic zones (MZs) of EAM mice via enhanced Cxcl1‐Cxcr2 chemotaxis. It is identified that the C–C motif chemokine ligand 5 (Ccl5)‐neutrophil subpopulation is responsible for high activity of cytokine production, adaptive immune response, NF‐κB signaling, and cellular response to interferon‐gamma and that the Ccl5‐neutrophil subpopulation and its‐associated proinflammatory cytokines/chemokines promoted macrophage (Mφ) polarization to M1 Mφ. These altered infiltrating landscape and phenotypic switch of immune cells, and proinflammatory factors synergistically aggravated anti‐CTLA‐4 m2a antibody‐induced cardiac injury in EAM mice. Neutralizing neutrophils, Cxcl1, and applying Cxcr2 antagonist dramatically alleviates anti‐CTLA‐4 m2a antibody‐induced leukocyte infiltration, cardiac fibrosis, and dysfunction. It is suggested that Ccl5‐neutrophil subpopulation plays a critical role in aggravating anti‐CTLA‐4 m2a antibody‐induced cardiac injury in EAM mice. This data may provide a strategic rational for preventing/curing ICIs‐associated myocarditis. [ABSTRACT FROM AUTHOR]

Targeting cytotoxic T‐lymphocyte‐associated antigen‐4 (CTLA‐4) with specific antibody offers long‐term benefits for cancer immunotherapy but can cause severe adverse effects in the heart. This study aimed to investigate the role of anti‐CTLA‐4 antibody in pressure overload‐induced cardiac remodeling and dysfunction. Transverse aortic constriction (TAC) was used to induce cardiac hypertrophy and heart failure in mice. Two weeks after the TAC treatment, mice received anti‐CTLA‐4 antibody injection twice a week at a dose of 10 mg/kg body weight. The administration of anti‐CTLA‐4 antibody exacerbated TAC‐induced decline in cardiac function, intensifying myocardial hypertrophy and fibrosis. Further investigation revealed that anti‐CTLA‐4 antibody significantly elevated systemic inflammatory factors levels and facilitated the differentiation of T helper 17 (Th17) cells in the peripheral blood of TAC‐treated mice. Importantly, anti‐CTLA‐4 mediated differentiation of Th17 cells and hypertrophic phenotype in TAC mice were dramatically alleviated by the inhibition of interleukin‐17A (IL‐17A) by an anti‐IL‐17A antibody. Furthermore, the C‐X‐C motif chemokine receptor 4 (CXCR4) antagonist AMD3100, also reversed anti‐CTLA‐4‐mediated cardiotoxicity in TAC mice. Overall, these results suggest that the administration of anti‐CTLA‐4 antibody exacerbates pressure overload‐induced heart failure by activating and promoting the differentiation of Th17 cells. Targeting the CXCR4/Th17/IL‐17A axis could be a potential therapeutic strategy for mitigating immune checkpoint inhibitors‐induced cardiotoxicity. [ABSTRACT FROM AUTHOR]

Objective: To study the mechanism of Shengsui Jiangu Capsule promoting vitamin D3 regulating bone turnover in rats with alcoholic osteoporosis. Methods: 120 SD rats were randomly divided into four groups: model group (alcoholic osteoporosis model group), blank control group, western medicine control group (calcium carbonate tablet and affa D3 control group), Chinese medicine experimental group (Shengsui Jiangu capsule experimental group), 30 rats in each group. After 8, 12 and 16 weeks, the serum levels of 25 hydroxyvitamin D3 (25(OH)D3),1,25dihydroxyvitamin D3 (1,25(OH)2D3), cross-linked carboxy-terminal peptide of type 1 collagen (ß-CTX) and N-terminal propeptide of type 1 collagen (P1NP) in rats and the density of the femur of rats were detected and compared. The correlation between vitamin D3 markers (25(OH)D3 and 1,25(OH)2D3) and bone turnover indices (P1NP and ß-CTX) and bone mineral density was analyzed. Results: In the experimental group, bone mineral density (BMD) was significantly increased (P<0.01), bone repair and mineral stability and balance were maintained during bone turnover, the level of bone formation marker P1NP was significantly increased (P<0.01), and the level of bone resorption marker ß-CTX was significantly decreased (P<0.01). Serum levels of 25(OH)D3 and 1,25(OH)2D3 were increased (P<0.01), and significantly higher than those in western medicine control group (P<0.05). Conclusion: Shengsui Jiangu capsule can effectively improve bone density in alcoholic osteoporosis (AOP) rats, and its mechanism may be related to promoting bone calcium absorption and regulating bone conversion. [ABSTRACT FROM AUTHOR]

Regenerative medicine techniques to recover cardiac and vascular function are being increasingly investigated as management strategies for cardiovascular diseases. Circulating endothelial progenitor cells (EPCs) derived from bone marrow are immature cells capable of differentiating into mature endothelial cells and play a role in vascular reparative processes and neoangiogenesis. The potency of EPCs for cardiovascular regeneration has been demonstrated in many preclinical studies and therapeutic utility of EPCs has been evaluated in early-phase clinical trials. However, the regenerative activity and efficiency of the differentiation of EPCs are still limited, and a directed differentiation method for EPCs cells has not been fully demonstrated. In this review, we introduce the role of circulating EPCs as biomarkers of cardiovascular diseases and medical applications of EPCs for cardiovascular regeneration.

Background and Purpose: The epithelial sodium channel (ENaC) is expressed in endothelial cells and acts as a negative modulator of vasodilatation. Oxidized LDL (ox-LDL) is a key pathological factor in endothelial dysfunction. In the present study we examined the role of ENaC in ox-LDL-induced endothelial dysfunction and its associated signal transduction pathway.Experimental Approach: Patch clamp techniques combined with pharmacological approaches were used to examine ENaC activity in the endothelial cells of a split-open mouse thoracic aorta. Western blot analysis was used to determine ENaC expression in the aorta. The aorta relaxation was measured using a wire myograph assay.Key Results: Ox-LDL, but not LDL, significantly increased ENaC activity in the endothelial cells attached to split-open thoracic aortas, and the increase was inhibited by a lectin-like ox-LDL receptor-1 (LOX-1) antagonist (κ-carrageenan), an NADPH oxidase inhibitor (apocynin), and a scavenger of ROS (TEMPOL). Sodium nitroprusside, an NO donor, diminished the ox-LDL-mediated activation of ENaC, and this effect was abolished by inhibiting soluble guanylate cyclase (sGC) and PKG. Ox-LDL reduced the endothelium-dependent vasodilatation of the aorta pectoralis induced by ACh, and this reduction was partially restored by blocking ENaC.Conclusion and Implications: Ox-LDL stimulates ENaC in endothelial cells through LOX-1 receptor-mediated activation of NADPH oxidase and accumulation of intracellular ROS. Since the stimulation of ENaC can be reversed by elevating NO, we suggest that both inhibition of ENaC and an elevation of NO may protect the endothelium from ox-LDL-induced dysfunction.Linked Articles: This article is part of a themed section on Spotlight on Small Molecules in Cardiovascular Diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.8/issuetoc. [ABSTRACT FROM AUTHOR]

Background and Purpose: Our recent studies show that the reduced activity of epithelial sodium channels (ENaC) in endothelial cells accounts for the adaptation of vasculature to salt in Sprague-Dawley rats. The present study examines a hypothesis that enhanced ENaC activity mediates the loss of vasorelaxation in Dahl salt-sensitive (SS) rats.Experimental Approach: We used the cell-attached patch-clamp technique to record ENaC activity in split-open mesenteric arteries. Western blot and immunofluorescence staining were used to evaluate the levels of aldosterone, ENaC, eNOS and NO. Blood pressure was measured with the tail-cuff method and the artery relaxation was measured with the wire myograph assay.Key Results: High-salt (HS) diet significantly increased plasma aldosterone and ENaC activity in the endothelial cells of Dahl SS rats. The endothelium-dependent artery relaxation was blunted by HS challenge in these rats. Amiloride, a potent blocker of ENaC, increased both phosphorylated eNOS and NO and therefore prevented the HS-induced loss of vasorelaxation. As, in SS rats, endogenous aldosterone was already elevated by HS challenge, exogenous aldosterone did not further elevate ENaC activity in the rats fed with HS. Eplerenone, a mineralocorticoid receptor antagonist, attenuated the effects of HS on both ENaC activity and artery relaxation.Conclusions and Implications: These data suggest that HS diet blunts artery relaxation and causes hypertension via a pathway associated with aldosterone-dependent activation of ENaC in endothelial cells. This pathway provides one of the mechanisms by which HS causes hypertension in Dahl SS rats.Linked Articles: This article is part of a themed section on Spotlight on Small Molecules in Cardiovascular Diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.8/issuetoc. [ABSTRACT FROM AUTHOR]

Pathological cardiac hypertrophy is a key risk factor for heart failure. We found that the protein expression levels of the ZNF307 (zinc finger protein 307) were significantly increased in heart samples from both human patients with dilated cardiomyopathy and mice subjected to aortic banding. Therefore, we aimed to elucidate the role of ZNF307 in the development of cardiac hypertrophy and to explore the signal transduction events that mediate the effect of ZNF307 on cardiac hypertrophy, using cardiac-specific ZNF307 transgenic (ZNF307-TG) mice and ZNF307 global knockout (ZNF307-KO) mice. The results showed that the deletion of ZNF307 potentiated aortic banding-induced pathological cardiac hypertrophy, fibrosis, and cardiac dysfunction; however, the aortic banding-induced cardiac hypertrophic phenotype was dramatically diminished by ZNF307 overexpression in mouse heart. Mechanistically, the antihypertrophic effects mediated by ZNF307 in response to pathological stimuli were associated with the direct inactivation of NF-κB (nuclear factor-κB) signaling and blockade of the nuclear translocation of NF-κB subunit p65. Furthermore, the overexpression of a degradation-resistant mutant of IκBα (IκBαS32A/S36A) reversed the exacerbation of cardiac hypertrophy, fibrosis, and dysfunction shown in aortic banding-treated ZNF307-KO mice. In conclusion, our findings demonstrate that ZNF307 ameliorates pressure overload-induced cardiac hypertrophy by inhibiting the activity of NF-κB-signaling pathway. [ABSTRACT FROM AUTHOR]

Anoctamin1 (ANO1) encodes a Ca2+-activated chloride (Cl−) channel (CaCC) in variety tissues of many species. Whether ANO1 expresses and functions as a CaCC in cardiomyocytes remain unknown. The objective of this study is to characterize the molecular and functional expression of ANO1 in cardiac myocytes and the role of ANO1-encoded CaCCs in ischemia-induced arrhythmias in the heart. Quantitative real-time RT-PCR, immunofluorescence staining assays, and immunohistochemistry identified the molecular expression, location, and distribution of ANO1 in mouse ventricular myocytes (mVMs). Patch-clamp recordings combined with pharmacological analyses found that ANO1 was responsible for a Ca2+-activated Cl− current ( ICl.Ca) in cardiomyocytes. Myocardial ischemia led to a significant increase in the current density of ICl.Ca, which was inhibited by a specific ANO1 inhibitor, T16Ainh-A01, and an antibody targeting at the pore area of ANO1. Moreover, cardiomyocytes isolated from mice with ischemia-induced arrhythmias had an accelerated early phase 1 repolarization of action potentials (APs) and a deeper 'spike and dome' compared to control cardiomyocytes from non-ischemia mice. Application of the antibody targeting at ANO1 pore prevented the ischemia-induced early phase 1 repolarization acceleration and caused a much shallower 'spike and dome'. We conclude that ANO1 encodes CaCC and plays a significant role in the phase 1 repolarization of APs in mVMs. The ischemia-induced increase in ANO1 expression may be responsible for the increased density of ICl.Ca in the ischemic heart and may contribute, at least in part, to ischemia-induced arrhythmias. J. Cell. Physiol. 230: 337-346, 2015. © 2014 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

This study demonstrated the preparation of Co0.85Se bundle-like nanostructures (BNs) by a template-directed approach under solvothermal conditions. The Co0.85Se BNs were utilized as catalysts in the reduction of 4-nitrophenol in the presence of NaBH4. The kinetics of the reduction of 4-nitrophenol at three different reaction temperatures were investigated to evaluate the catalytic activity of the Co0.85Se BNs. The activation energy (Ea), activation enthalpy (ΔH‡), and activation entropy (ΔS‡) of the Co0.85Se BNs and Co0.85Se nanoparticles (NPs) are 14.66 kJ mol−1, 12.15 kJ mol−1, 42.51 J mol−1 K−1, and 17.78 kJ mol−1, 16.55 kJ mol−1, 50.66 J mol−1 K−1, respectively. The above results revealed that the Co0.85Se BNs exhibited a higher catalytic performance for the hydrogenation of 4-nitrophenol by NaBH4 than that of the Co0.85Se NPs at room temperature. It is believed that the prepared Co0.85Se BNs have potential applications in catalysis. [ABSTRACT FROM AUTHOR]

A microsphere (CA/BC) was prepared using biochar (BC) encapsulated with calcium alginate (CA) as a green adsorbent for Pb(Ⅱ) removal from aqueous solution. The effects of the initial Pb(Ⅱ) concentration, initial pH value of the Pb(Ⅱ) solution, and equilibrium contact time were investigated. The isothermal thermodynamic data of the BC and CA/BC conformed to the Langmuir model. The maximum adsorption capacities of the BC and CA/BC from the Langmuir equation were 93.20 mg·g -1 and 155.04 mg·g -1 respectively, at pH=5. The adsorption of Pb(Ⅱ) by the BC was in good agreement with the pseudo-second-order equation, indicating that chemisorption was the rate-controlling step. The adsorption of Pb(Ⅱ) by the CA/BC was in good agreement with the pseudo-first-order model, which suggested that the rate-limiting step was governed by diffusion. Mechanism studies for Pb(Ⅱ) removal by the CA/BC showed that the nature of Pb(Ⅱ) abstraction took place through ion exchange between Ca(Ⅱ) and Pb(Ⅱ) as well as via the formation of a coordination complex.

Objective: To explore the diagnosis and treatment of pregnancy-associated acute Stanford type A aortic dissection to improve the maternal and fetal outcomes., Methods: We analyzed the perioperative data of 5 pregnant women with acute Stanford type A aortic dissection treated between June, 2009 and February, 2017., Results: The median age of the women was 30 years (range, 22-34 years) with gestational weeks of 23-38 weeks upon diagnosis. All the 5 patients received surgical interventions. Three patients underwent caesarean delivery and hysterectomy, and the fetuses survived after the surgery; 2 patients chose to continue pregnancy following the surgery, among whom one died due to postoperative complications and the other underwent termination of pregnancy. During follow-up, the surviving patients showed no endoleak in the descending aorta stent and the distal dissection remained stable., Conclusion: The maternal and fetal outcomes of pregnancy-associated acute Stanford type A aortic dissection can be improved by multidisciplinary cooperation and optimization of the surgical approaches according to the time of pregnancy, fetal development and conditions of the aortic lesions.

Anoctamin1 (ANO1) encodes a Ca(2+)-activated chloride (Cl(-)) channel (CaCC) in variety tissues of many species. Whether ANO1 expresses and functions as a CaCC in cardiomyocytes remain unknown. The objective of this study is to characterize the molecular and functional expression of ANO1 in cardiac myocytes and the role of ANO1-encoded CaCCs in ischemia-induced arrhythmias in the heart. Quantitative real-time RT-PCR, immunofluorescence staining assays, and immunohistochemistry identified the molecular expression, location, and distribution of ANO1 in mouse ventricular myocytes (mVMs). Patch-clamp recordings combined with pharmacological analyses found that ANO1 was responsible for a Ca(2+)-activated Cl(-) current (I(Cl.Ca)) in cardiomyocytes. Myocardial ischemia led to a significant increase in the current density of I(Cl.Ca), which was inhibited by a specific ANO1 inhibitor, T16A(inh)-A01, and an antibody targeting at the pore area of ANO1. Moreover, cardiomyocytes isolated from mice with ischemia-induced arrhythmias had an accelerated early phase 1 repolarization of action potentials (APs) and a deeper "spike and dome" compared to control cardiomyocytes from non-ischemia mice. Application of the antibody targeting at ANO1 pore prevented the ischemia-induced early phase 1 repolarization acceleration and caused a much shallower "spike and dome". We conclude that ANO1 encodes CaCC and plays a significant role in the phase 1 repolarization of APs in mVMs. The ischemia-induced increase in ANO1 expression may be responsible for the increased density of I(Cl.Ca) in the ischemic heart and may contribute, at least in part, to ischemia-induced arrhythmias., (© 2014 Wiley Periodicals, Inc.)