Neutrophil extracellular traps mediate cardiomyocyte ferroptosis via the Hippo-Yap pathway to exacerbate doxorubicin-induced cardiotoxicity.

Doxorubicin-induced cardiotoxicity (DIC), which is a cardiovascular complication, has become the foremost determinant of decreased quality of life and mortality among survivors of malignant tumors, in addition to recurrence and metastasis. The limited ability to accurately predict the occurrence and severity of doxorubicin-induced injury has greatly hindered the prevention of DIC, but reducing the dose to mitigate side effects may compromise the effective treatment of primary malignancies. This has posed a longstanding clinical challenge for oncologists and cardiologists. Ferroptosis in cardiomyocytes has been shown to be a pivotal mechanism underlying cardiac dysfunction in DIC. Ferroptosis is influenced by multiple factors. The innate immune response, as exemplified by neutrophil extracellular traps (NETs), may play a significant role in the regulation of ferroptosis. Therefore, the objective of this study was to investigate the involvement of NETs in doxorubicin-induced cardiomyocyte ferroptosis and elucidate their regulatory role. This study confirmed the presence of NETs in DIC in vivo. Furthermore, we demonstrated that depleting neutrophils effectively reduced the occurrence of doxorubicin-induced ferroptosis and myocardial injury in DIC. Additionally, our findings showed the pivotal role of high mobility group box 1 (HMGB1) as a critical molecule implicated in DIC and emphasized its involvement in the modulation of ferroptosis subsequent to NETs inhibition. Mechanistically, we obtained preliminary evidence suggesting that doxorubicin-induced NETs could modulate yes-associated protein (YAP) activity by releasing HMGB1, which subsequently bound to toll like receptor 4 (TLR4) on the cardiomyocyte membrane, thereby influencing cardiomyocyte ferroptosis in vitro. Our findings suggest that doxorubicin-induced NETs modulate cardiomyocyte ferroptosis via the HMGB1/TLR4/YAP axis, thereby contributing to myocardial injury. This study offers a novel approach for preventing and alleviating DIC by targeting alterations in the immune microenvironment.

Nicotine exacerbates endothelial dysfunction and drives atherosclerosis via extracellular vesicle-miRNA.

AIMS: Nicotine, a major component of tobacco, is an important factor contributing to atherosclerosis. However, the molecular mechanisms underlying the link between nicotine and atherosclerosis are unclear. As extracellular vesicles (EVs) are involved in intercellular communication in atherosclerosis, we investigated whether their influence on arterial pathophysiology under nicotine stimulation. METHODS AND RESULTS: EVs from the serum of smokers (smoker-EVs) were significantly increased and exacerbated endothelial inflammation, as well as apoptosis according to functional studies. Meanwhile, inhibition of EVs blunted the nicotine-induced atherosclerosis progression, and injection of nicotine-induced EVs promoted atherosclerosis progression in ApoE-/- mice. Furthermore, quantitative reverse transcription-polymerase chain reaction analysis revealed a remarkable increase in miR-155 levels in smoker-EVs, which was correlated with carotid plaque formation in patients measured by ultrasound imaging. Moreover, CD14 levels were significantly increased in EVs from smokers (representing EVs derived from monocytes), indicating that monocytes are an important source of smoker-EVs. DNA methylation and the transcription factor HIF1α may contribute to increased miR-155 levels in monocytes, as assessed with bisulfite conversion sequencing and chromatin immunoprecipitation. Mechanistically, EVs encapsulated miR-155 induced endothelial cell dysfunction by directedly targeting BCL2, MCL1, TIMP3, BCL6, and activating NF-κB pathway, as verified in a series of molecular and biological experiments. Injecting EVs from nicotine-stimulated monocytes promoted plaque formation and triggered vascular endothelial injury in ApoE-/- mice, whereas inhibition of miR-155 weakened this effect. CONCLUSION: Our findings revealed an EV-dependent mechanism of nicotine-aggravated atherosclerosis. Accordingly, we propose an EV-based intervention strategy for atherosclerosis management.

Two-dimensional speckle tracking echocardiography help identify breast cancer therapeutics-related cardiac dysfunction.

BACKGROUND: Cancer therapeutics-related cardiac dysfunction (CTRCD) from different chemotherapy strategies are underdetermined by echocardiography. As an imaging marker of subclinical cardiac dysfunction, two-dimensional speckle tracking echocardiography (2D-STE) may assist in identifying the impact patterns of different CTRCD. METHODS: A total of 67 consecutive patients with invasive ductal breast carcinoma who will undertake neoadjuvant chemotherapy were enrolled and grouped according to their different chemotherapy regimens based on their biopsy results. Group A included 34 patients who received anthracycline without trastuzumab, whereas Group B had 33 patients who received trastuzumab without anthracycline. Echocardiography was performed at three time-points, i.e., baseline (T0), cycle-2 (T2), and cycle-4 (T4) of chemotherapy. Conventional echocardiographic measurements and 2D-STE strain values, and myocardial work (MW) parameters, were compared between different groups at different time-points. RESULTS: The mean age had no statistical difference between the two groups. E/e' was the only conventional echocardiographic parameter that had variation in group A (P < 0.05). Compared with baseline, GLS in group A decreased at T2, and GCS decreased at T4 (P < 0.05). GLS and GCS in group B both decreased at T4 (P < 0.05). More patients in group A had a more than 15% fall of baseline GLS rather than GCS at T2 (P < 0.05), however, there was no difference of either GLS or GCS decline rate at T4 between the two groups. All the MW parameters in group A had variations overtime, whereas only GCW in group B (P < 0.05). CONCLUSION: Early subclinical myocardial dysfunction can be identified by 2D-STE in breast cancer patients with chemotherapy, and GLS provides profound value in demonstrating the temporal changes in early myocardial damage induced by anthracycline. LV contractility injury in patients with trastuzumab may be mild at first but increases in severity with exposure time as early as cycle-4. Awareness of these differences may help to stratify the prevention of late cardiovascular events caused by different CTRCDs. In addition, GCW may be the most sensitive myocardial work parameter of CTRCD.

Melatonin alleviates arginine vasopressin-induced cardiomyocyte apoptosis via increasing Mst1-Nrf2 pathway activity to reduce oxidative stress.

Heart failure patients have elevated arginine vasopressin (AVP) levels, which are involved in inducing peripheral vasoconstriction and cardiac hypertrophy. This hypertrophy, along with cardiomyocyte apoptosis, results from oxidative stress. Therefore, the antioxidant drug, melatonin (Mel), is commonly used to treat cardiac hypertrophy and apoptosis; however, whether it could alleviate AVP-induced myocardialinjury remains to be addressed. In this study, high AVP doses were found to induce H9c2 cardiomyoblast apoptosis, demonstrated by increased terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive cells, pro-apoptotic B-cell lymphoma-2 (Bcl-2)-associated X protein (Bax) up-regulation, and anti-apoptotic Bcl-2 downregulation. This AVP-induced apoptotic increase, along with lowered cell viability, was also associated with higher reactive oxygen species (ROS) levels and lowered mitochondrial membrane potentials (MMP), which were all reversed upon Mel administration. Further investigations found that apoptosis, ROS, and MMP outcomes under high AVP were associated with Mst1-nuclear factor erythroid 2-related factor 2 (Nrf2) pathway suppression, yielding mitochondrial dysfunction, and Mel reversed them via promoting Mst1 phosphorylation, which then activated Nrf2 to increase anti-oxidative enzyme production. These findings were supported by siRNA gene suppression, where knocking down either Nrf2 or Mst1 abrogated the anti-apoptotic effects of Mel in cardiomyoblasts. Therefore, Mel could reduce cardiomyoblast apoptosis under high AVP levels, via Mst1-Nrf2 pathway re-activation, to enhance anti-oxidative responses.

Magnetic and near-infrared-II fluorescence Au-Gd nanoclusters for imaging-guided sensitization of tumor radiotherapy.

The significant role of multifunctional nanoprobes with complementary advantages in magnetic and near-infrared-II (NIR-II, 1000-1700 nm) fluorescence properties has been documented in precision cancer theranostics. However, certain limitations, including the large size (>10 nm), low NIR-II fluorescence quantum yield (QY < 1.0%), and inefficient magnetic performance (relaxation rate < 5.0 s-1 mM-1) of nanoprobes, restrict their biomedical applications and clinical translation. Albumin-based biomineralization was adopted to prepare bright NIR-II Au NCs, which were further conjugated with DTPA and Gd ions to produce magnetic and NIR-II Au-Gd NCs. Albumin-based biomineralization helped to develop ultrasmall Au-Gd nanoclusters with ultrasmall size (∼2 nm), high NIR-II fluorescence QY (∼3.0%), and effective magnetic resonance imaging (MRI) performance (relaxation rate (r1) = 22.6 s-1 mM-1). On the one hand, Au-Gd NCs achieved NIR-II fluorescence and MRI dual-modal imaging of tumors with a high signal-to-background ratio (SBR = 8.2) in mice. On the other hand, their effective metabolism simultaneously through the kidney and liver minimized their toxicity in vivo. Moreover, compared to the control group, the survival time of tumor-bearing mice was extended by three times when Au-Gd NCs with high-Z elements were used to perform dual-modal imaging-guided sensitization of tumor radiotherapy. Thus, ultrasmall nanoprobes with complementary imaging modalities and therapeutic functions manifest great potential in cancer precision diagnosis and therapy.

Melatonin alleviates doxorubicin-induced mitochondrial oxidative damage and ferroptosis in cardiomyocytes by regulating YAP expression.

Doxorubicin (Dox) is a high-efficiency agent for cancer therapy. However, it causes cardiotoxicity which limits its clinical application. Despite more efforts has been made to seek protective decisions, unfortunately, the poor prognosis suggests the need for new treatments. As a powerful mitochondrial antioxidant, melatonin (Mel) has been found to confer cardioprotection against various cardiovascular diseases. Currently, the mechanism through which Mel confers protection is not well understood. In this study, we established a Dox-induced cardiotoxicity model in H9c2 cardiomyocytes, zebrafish, and SD rats to explore the mechanism by which Mel alleviates Dox-induced cardiotoxicity. In vivo and in vitro experiments showed that Dox significantly decreased the viability of H9c2 cells, induced apoptosis, myocardial injury, and effectively up-regulated the expression of p-YAP but down-regulated the expression of YAP. Furthermore, we found that Dox significantly up-regulated the expression of ferroptosis-associated protein ACSL4 and down-regulated expression of GPX4. Interestingly, these effects of Dox were reversed following treatment with Mel, indicating that ferroptosis mediated the protective effects of Mel against Dox-induced cardiomyocyte injury. Furthermore, we used YAP-siRNA in vitro and verteporfin (Ver) in vivo to down-regulate the expression level of YAP. The results showed that YAP down-regulation abolished the protective effects of Mel including apoptosis, mitochondrial lipid peroxidation, and ferroptosis. Collectively, these results show that Mel regulates ferroptosis by modulating YAP expression to counteract Dox-induced cardiotoxicity.

Right atrial papillary fibroelastoma arising from the Chiari network detected by echocardiography: a case report and literature review.

PURPOSE: To improve our understanding of cardiac papillary fibroelastomaand provide evidence for its treatment and prognosis. MATERIALS AND METHODS: We report a 54-year-old Chinese male who was hospitalized for a 14-day headache with a previous vertebral aneurysm history. A right atrial mass arising from the Chiari network was detected by echocardiography and complete tumor resection was performed finally. Pathologic findings confirmed the diagnosis of cardiac papillary fibroelastoma. The recovery of the patient was uneventful and follow-up echocardiographic examination revealed no recurrence of the tumor. RESULTS: Transthoracic echocardiography revealed a mobile, sessile mass in the right atrium without obstructing the orifice of the tricuspid valve. The subsequent transesophageal echocardiography confirmed the presence of a 1.56cm × 1.24cm mobile, sessile, irregular mass arising from the Chiari network (Fig. 1) and showed no evidence of patent foramen ovale. CONCLUSIONS: Early recognition and surgical excision is essential for patients with cardiac papillary fibroelastoma.

Quantitative shear wave elastography in primary invasive breast cancers, based on collagen-S100A4 pathology, indicates axillary lymph node metastasis.

BACKGROUND: The purpose of this study was to evaluate the value of quantitative shear wave elastography (SWE) in indicating the axillary lymph node metastasis (LNM) of invasive breast cancers (IBCs) and to investigate if S100A4 plays a key role in promoting metastasis and increasing stiffness in IBC. METHODS: The differences in SWE of 223 IBC patients were compared between the LNM+ and LNM- groups and the optimal cutoff values of SWE for diagnosing LNM were calculated. We searched the gene expression omnibus (GEO) to determine whether S100A4 was more highly expressed in IBCs that were LNM+ than in those that were LNM-. Sirius red and immunohistochemical staining were used to examine the collagen deposition and S100A4 expression of included tissue samples, and correlations of SWE and S100A4 expression with collagen deposition were analyzed. RESULTS: The optimal cutoff values for Emax (the maximum stiff value), Emean (the mean stiff value), and EmeanR (the ratio of Emean between mass and parenchyma) for diagnosing axillary LNM were 111.05 kPa, 79.80 kPa, and 6.89, respectively. GSE9893 exhibited more increased S100A4 expression in IBCs that were LNM+ than in those that were LNM-. Collagen volume fraction (CVF) and the average optical density of S100A4 (AODS100A4) in the LNM+ group were significantly higher than those in the LNM- group. Emax, Emean, EmeanR, and AODS100A4 were all positively correlated with CVF. CONCLUSIONS: SWE in primary IBC could be useful for indicating axillary LNM. S100A4 may be a factor that regulates cancer-associated collagen deposition and metastasis; however, prospective molecular biological studies are needed.

The early alteration of left ventricular strain and dys-synchrony index in breast cancer patients undergoing anthracycline therapy using layer-specific strain analysis.

PURPOSE: The primary aim of this study was to evaluate early changes in cardiac function after anthracycline therapy with layer-specific speckle-tracking echocardiography (STE) and mechanical dys-synchrony. METHODS: A total of 78 breast cancer patients (ranging 31~72 years) exposed to anthracycline treatment were recruited in this study. All patients received both conventional two-dimensional speckle-tracking echocardiographs at baseline, as well as after the completion of 2 and 4 cycles of the regimen. Layer-specific longitudinal strain (LS) and circumferential strain (CS) of the 3 myocardial layers (endocardium, mid-myocardium, and epicardium) were automatically measured. Peak systolic dispersion (PSD) was defined as the standard deviation of the time to peak strain of the 18 segments, divided by the RR interval. RESULTS: There were no significant differences in conventional echocardiographic parameters during treatment (all P > .05). Peak endocardium CS at basal level decreased significantly after 2 and 4 cycles compared with baseline (both P = .001), while PSD significantly increased in that same period versus baseline (both P = .000). Endocardium and mid-myocardium LS, peak mid-myocardium and epicardium CS at the basal level, peak CS of all three layers at the papillary level, and peak endocardium and mid-myocardium CS at the apical level all significantly decreased after 4 cycles, compared with baseline and 2 cycles (all P = .000). CONCLUSION: This study showed that myocardial deformation impairment occurred as early as 2 cycles after anthracycline chemotherapy. Endocardium CS at the basal level and left ventricular dys-synchrony index PSD were the initial cardiac abnormalities in anthracycline-treated breast cancer patients.

Boronyl as a terminal ligand in boron oxide clusters: hexagonal ring C(2v) B6O4 and ethylene-like D(2h) B6O4(-/2-).

Considerable recent research effort has been devoted to the development of boronyl (BO) chemistry. Here we predict three perfectly planar boron boronyl clusters: C2v B6O4 (1, (1)A1), D2h B6O4(−) (2, (2)B3u), and D2h B6O4(2−) (3, (1)Ag). These are established as the global-minimum structures on the basis of the coalescence kick and basin hopping structural searches and electronic structure calculations at the B3LYP/aug-cc-pVTZ level, with complementary CCSD/6-311+G* and single-point CCSD(T)/6-311+G*//B3LYP/aug-cc-pVTZ calculations for 2. The C2v B6O4 neutral cluster features a hexagonal B4O2 ring with two terminal BO groups. The D2h B6O4(−/2−) clusters have ethylene-like structures and are readily formulated as B2(BO)4(−/2−), in which a B2 core with double bond character is bonded to four terminal BO groups. Chemical bonding analyses show that B6O4 (1) possesses an aromatic π bonding system with three delocalized, six-centered π bonds over the hexagonal ring, rendering it an inorganic analogue of benzene, whereas the B6O4(−/2−) (2 and 3) species closely resemble ethylene in terms of structures and bonding. This work provides new examples for the analogy between boron oxides and hydrocarbons.

Evaluation of Left Ventricular Regional Systolic Function Using Tissue Doppler Echocardiography After Mesenchymal Stem Cell Transplantation in Rabbits With Myocardial Infarction.

OBJECTIVES: The aim of this work was to assess left ventricular (LV) regional systolic function in rabbits with myocardial infarction after allogeneic mesenchymal stem cell (MSC) transplantation using quantitative tissue velocity imaging. METHODS: Thirty New Zealand White rabbits were assigned into 3 groups randomly: a sham-operated group (n = 10), a myocardial infarction (MI) group (n = 10), and a MSC transplantation group (n = 10). Mesenchymal stem cells (1 × 10(7) in total) were delivered into 5 spots around the left anterior descending artery (LAD) blood supply area via direct intramyocardial injections 1 hour after LAD ligation in the MSC group, whereas the MI group received the same amount of phosphate-buffered saline injections. Echocardiography was performed before LAD ligation and 1 day and 2 weeks after MSC transplantation, respectively. The peak systolic velocity (Vs) of each LV wall segment was measured. The myocardial slices were harvested for histologic staining after the last echocardiographic examination. RESULTS: The velocity curves for the LV myocardium before LAD ligation had a trend showing that the Vs value decreased gradually from basal to apical segments. The Vs values for the LV segments around the infarcted area in the MSC group decreased significantly compared with the sham group (P < .05) 1 day after MSC transplantation, whereas they increased significantly 2 weeks after MSC transplantation compared with 1 day after LAD ligation (P < .05). CONCLUSIONS: This study demonstrates that quantitative tissue velocity imaging may provide a promising approach to quantitatively assessing LV regional systolic function before and after MSC transplantation.

[Clinical analysis of surgical treatment of 568 cleft palate patients].

PURPOSE: To summarize the outcomes of surgical treatment of 568 cleft palate patients. METHODS: 568 cleft palate patients of different age, gender were operated with the help of high-frequency electric knife. Iodoform gauze packing or absorbable hemostatic gauze was used on both sides of the relaxation incision. After surgery, the diet, temperature changes, wound healing and bleeding, postoperative cleft or perforation were observed and analyzed. RESULTS: Postoperative infection was not found in all cases. 24 patients had fever, most of them used iodoform gauze packing on both sides of the relaxation incision, returned to normal diet in longer time. 8 patients developed bleeding and 13 had postoperative cleft or perforation. CONCLUSIONS: It is suggested that intraoperative high-frequency electric knife can be used for cleft palate surgery to reduce the amount of bleeding,the use of absorbable hemostatic gauze is more helpful for wound healing and postoperative recovery.