Intracardiac and Cerebral Thrombosis Complicated With Mycoplasma Pneumonia.

A seven-year-old girl developed multiposition thrombosis after fever and respiratory symptoms. Chest computed tomography (CT) scan demonstrated bilateral infiltrates, consolidation of the right lower lobe, and pleural effusion in the right lung field. Brain magnetic resonance imaging (MRI) showed multiple abnormal signals in the brain with limited diffusion, and cerebral infarction could not be excluded. Echocardiography revealed hypoechoic mitral valve tips, which are likely to be suspected as vegetation. Mycoplasma pneumoniae infection was clarified by a four-fold increase in IgG antibodies to M. pneumoniae sera. D-dimer levels were elevated increasingly. We found and reported this rare pediatric case of an M. pneumoniae-induced severe pneumonia complicated with intracardiac and cerebral thrombosis. We investigate the clinical characteristics, diagnosis, and treatment of refractory mycoplasma pneumonia complicated with intracardiac and cerebral thrombosis in children.

The combination of tumor mutational burden and T-cell receptor repertoire predicts the response to immunotherapy in patients with advanced non-small cell lung cancer.

Tumor mutational burden (TMB) and T-cell receptor (TCR) might predict the response to immunotherapy in patients with non-small cell lung cancer (NSCLC). However, the predictive value of the combination of TMB and TCR was not clear. Targeted DNA and TCR sequencing were performed on tumor biopsy specimens. We combined TMB and TCR diversity into a TMB-and-TCR (TMR) score using logistic regression. In total, 38 patients with advanced NSCLC were divided into a discovery set (n = 17) and validation set (n = 21). A higher TMR score was associated with better response and longer progression-free survival to immunotherapy in both the discovery set and validation set. The performance of TMR score was confirmed in the two external validation cohorts of 225 NSCLC patients and 306 NSCLC patients. Tumors with higher TMR scores were more likely to combine with LRP1B gene mutation (p = 0.027) and top 1% CDR3 sequences (p = 0.001). Furthermore, LRP1B allele frequency was negatively correlated with the top 1% CDR3 sequences (r = -0.55, p = 0.033) and positively correlated with tumor shrinkage (r = 0.68, p = 0.007). The TMR score could serve as a potential predictive biomarker for the response to immunotherapy in advanced NSCLC.

Advances in Integrated Multi-omics Analysis for Drug-Target Identification.

As an essential component of modern drug discovery, the role of drug-target identification is growing increasingly prominent. Additionally, single-omics technologies have been widely utilized in the process of discovering drug targets. However, it is difficult for any single-omics level to clearly expound the causal connection between drugs and how they give rise to the emergence of complex phenotypes. With the progress of large-scale sequencing and the development of high-throughput technologies, the tendency in drug-target identification has shifted towards integrated multi-omics techniques, gradually replacing traditional single-omics techniques. Herein, this review centers on the recent advancements in the domain of integrated multi-omics techniques for target identification, highlights the common multi-omics analysis strategies, briefly summarizes the selection of multi-omics analysis tools, and explores the challenges of existing multi-omics analyses, as well as the applications of multi-omics technology in drug-target identification.

Targeted mitigation of neointimal hyperplasia via magnetic field-directed localization of superparamagnetic iron oxide nanoparticle-labeled endothelial progenitor cells following carotid balloon catheter injury in rats.

BACKGROUND: The transplantation of endothelial progenitor cells (EPCs) has been shown to reduce neointimal hyperplasia following arterial injury. However, the efficacy of this approach is hampered by limited homing of EPCs to the injury site. Additionally, the in vivo recruitment and metabolic activity of transplanted EPCs have not been continuously monitored. METHODS: EPCs were labeled with indocyanine green (ICG)-conjugated superparamagnetic iron oxide nanoparticles (SPIONs) and subjected to external magnetic field targeting to enhance their delivery to a carotid balloon injury (BI) model in Sprague-Dawley rats. Magnetic particle imaging (MPI)/ fluorescence imaging (FLI) multimodal in vivo imaging, 3D MPI/CT imaging and MPI/FLI ex vivo imaging was performed after injury. Carotid arteries were collected and analyzed for pathology and immunofluorescence staining. The paracrine effects were analyzed by enzyme-linked immunosorbent assay. RESULTS: The application of a magnetic field significantly enhanced the localization and retention of SPIONs@PEG-ICG-EPCs at the site of arterial injury, as evidenced by both in vivo continuous monitoring and ex vivo by observation. This targeted delivery approach effectively inhibited neointimal hyperplasia and increased the presence of CD31-positive cells at the injury site. Moreover, serum levels of SDF-1α, VEGF, IGF-1, and TGF-ß1 were significantly elevated, indicating enhanced paracrine activity. CONCLUSIONS: Our findings demonstrate that external magnetic field-directed delivery of SPIONs@PEG-ICG-EPCs to areas of arterial injury can significantly enhance their therapeutic efficacy. This enhancement is likely mediated through increased paracrine signaling. These results underscore the potential of magnetically guided SPIONs@PEG-ICG-EPCs delivery as a promising strategy for treating arterial injuries.

Hypomethylation-associated LINC00987 downregulation induced lung adenocarcinoma progression by inhibiting the phosphorylation-mediated degradation of SND1.

DNA methylation, an epigenetic regulatory mechanism dictating gene transcription, plays a critical role in the occurrence and development of cancer. However, the molecular underpinnings of LINC00987 methylation in the regulation of lung adenocarcinoma (LUAD) remain elusive. This study investigated LINC00987 expression in LUAD patients through analysis of The Cancer Genome Atlas data sets. Quantitative real-time polymerase chain reaction (RT-qPCR) and fluorescence in situ hybridization assays were used to assess LINC00987 expression in LUAD. The bisulfite genomic sequence PCR (BSP) assay was used to determine the methylation levels of the LINC00987 promoter. The interaction between LINC00987 and SND1 was elucidated via immunoprecipitation and RNA pull-down assays. The functional significance of LINC00987 and SND1 in Calu-3 and NCI-H1688 cells was evaluated in vitro through CCK-8, EdU, Transwell, flow cytometry, and vasculogenic mimicry (VM) tube formation assays. LINC00987 expression decreased in LUAD concomitant with hypermethylation of the promoter region, while hypomethylation of the LINC00987 promoter in LUAD tissues correlated with tumor progression. Treatment with 5-Aza-CdR augmented LINC00987 expression and inhibited tumor growth. Mechanistically, LINC00987 overexpression impeded LUAD progression and VM through direct binding with SND1, thereby facilitating its phosphorylation and subsequent degradation. Additionally, overexpression of SND1 counteracted the adverse effects of LINC00987 downregulation on cell proliferation, apoptosis, cell migration, invasion, and VM in LUAD in vitro. In conclusion, this pioneering study focuses on the expression and function of LINC00987 and reveals that hypermethylation of the LINC00987 gene may contribute to LUAD progression. LINC00987 has emerged as a potential tumor suppressor gene in tumorigenesis through its binding with SND1 to facilitate its phosphorylation and subsequent degradation.

The diagnostic value of bronchial provocation testing combined with fractional exhaled nitric oxide (FeNO) in children with chest tightness-variant asthma (CTVA).

BACKGROUND: Chest tightness-variant asthma (CTVA) is a novel atypical asthma characterized by chest tightness as the sole or primary symptom. OBJECTIVES: To investigate the value of bronchial provocation testing combined with fractional exhaled nitric oxide (FeNO) in the diagnosis of CTVA in children. METHODS: This study included 95 children aged 6-14 years with chest tightness as the sole symptom, with a duration of symptoms exceeding 4 weeks. All subjects underwent FeNO measurement, pulmonary function testing, and bronchial provocation testing using the Astograph method. Subjects with positive bronchial provocation testing were classified as the CTVA group, while those with negative results served as the non-CTVA control group. RESULTS: The lung function of children in both groups was normal. The FeNO level in the CTVA group was (22.35 ± 9.91) ppb, significantly higher than the control group (14.85 ± 5.63) ppb, with a statistically significant difference (P < 0.05). The value of FeNO in diagnosing CTVA was analyzed using an ROC curve, with an area under the curve of 0.073 (P < 0.05). The optimal cutoff point for diagnosing CTVA using FeNO was determined to be 18.5 ppb, with a sensitivity of 60.3 % and specificity of 77.8 %. There was a negative correlation between FeNO and Dmin as well as PD15 (P = 0.006). CONCLUSION: FeNO can serve as an adjunctive diagnostic tool for CTVA, with the optimal cutoff point for diagnosing CTVA being 18.5 ppb. However, FeNO is not a specific diagnostic marker for CTVA and should be used in conjunction with bronchial provocation testing to enhance its diagnostic value.

Milk fat globule membrane promotes brain development in piglets by enhancing the connection of white matter fiber trace.

Introduction: Brain development during infancy is crucial for later health and development. Although Milk Fat Globule Membrane (MFGM) has been demonstrated to enhance brain development, further investigation is needed to determine the optimal dose. Methods: In this study, 80 piglets aged 2 days were randomly assigned to four groups: Control group, MFGM-L (1.74 g MFGM per 100 g diet), MFGM-M (4.64 g MFGM per 100 g diet), and MFGM-H (6.09 g MFGM per 100 g diet). Daily body weight and milk intake of the piglets were recorded until 31 days postnatal. Learning and memory abilities were evaluated using the spatial T-maze test on day 15. MRI analysis was conducted to assess functional and structural changes in brain tissues. Additionally, mRNA and protein expression of brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NTF-3) in the hippocampus and prefrontal cortex were evaluated. Results: The results indicated that the MFGM supplemented diet significantly improved the accuracy of the piglets in the T-maze test, with the MFGM-L group exhibiting the best performance. MRI showed no volumetric differences in the gray and white matter between the groups. However, the fractional anisotropy in the left and right hippocampus of piglets in the MFGM-L group was significantly higher than in the other three groups. Furthermore, there was a strong correlation between the accuracy of the T-maze test and hippocampal fractional anisotropy. Discussion: The MFGM supplemented diet also increased the expression of BDNF in the cerebral cortex. However, the changes in BDNF were not consistent with the results of the T-maze test. In conclusion, adding 1.74 g MFGM per 100 g diet can significantly improve neonatal piglets' learning and memory abilities, potentially by enhancing the connection of white matter fiber bundles in the brain.

Predictive Value of the Lipoprotein(a) to Prealbumin Ratio and of the NT-proBNP to LVEF Ratio for Major Adverse Cardiovascular Events Following Percutaneous Coronary Intervention in Patients with Acute Coronary Syndrome.

OBJECTIVE: To investigate the lipoprotein(a) [Lp(a)] to prealbumin (PA) ratio and the N-terminal pro-brain natriuretic peptide (NT-proBNP) to left ventricular ejection fraction (LVEF) ratio for the prediction of major adverse cardiovascular events (MACE) in patients with acute coronary syndrome (ACS) after percutaneous coronary intervention (PCI). METHODS: A 1:1 matched case-control study was performed to retrospectively analyze ACS patients who underwent PCI from January 2022 to June 2022. Patients with MACE were selected as the case group (n = 55), and age- and gender-matched patients without MACE were selected as the control group (n = 55). Clinical data for the two groups was compared by univariate and multivariate logistic regression analysis. Risk factors and the odds ratio (OR) for MACE in ACS patients were evaluated, and receiver operating characteristic curve (ROC) were used to evaluate the Lp(a)/PA ratio, the NT-proBNP/LVEF ratio, and their combination for the prediction of MACE in ACS patients. RESULTS: The MACE and non-MACE groups showed statistically significant differences for time from onset to PCI, LVEF, NT-proBNP, white blood cell (WBC), Lp(a), PA, Lp(a)/PA, NT-proBNP/LVEF, number of catheterizations, number of implanted stents >2, and support diameter >3 (p < 0.05). Multivariate logistic regression analysis showed that LVEF, Lp(a)/PA and NT-proBNP/LVEF were independent risk factors for MACE. ROC curve analysis for Lp(a)/PA showed that the area under the curve (AUC) for the prediction of MACE was 0.779 (0.693-0.864), the cut-off point was 1.36, the sensitivity was 69.1%, and the specificity was 74.5%. The AUC for NT-proBNP/LVEF in predicting MACE was 0.827 (0.75-0.904), the cut-off point was 61.04, the sensitivity was 65.5%, and the specificity was 92.7%. For the combination of Lp(a)/PA and NT-proBNP/LVEF, the AUC for the prediction of MACE was 0.889 (0.830-0.947), the cut-off point was 0.37, the sensitivity was 81.8%, and the specificity was 81.8%. CONCLUSION: The combination of Lp(a)/PA and NT-proBNP/LVEF at admission showed good predictive value for the occurrence of MACE in ACS patients after PCI.

[Phenotype and genotype characteristics of children with cardiomyopathy associated with MYH7 gene mutation: a retrospective analysis]. / MYH7åŸºå› å˜å¼‚ç›¸å ³å„¿ç«¥å¿ƒè‚Œç— è¡¨åž‹ä¸ŽåŸºå› åž‹ç‰¹ç‚¹çš„å›žé¡¾æ€§åˆ†æž.

OBJECTIVES: To investigate the clinical phenotype and genotype characteristics of children withcardiomyopathy (CM) associated with MYH7 gene mutation. METHODS: A retrospective analysis was conducted on the medical data of five children with CM caused by MYH7 gene mutation who were diagnosed and treated in the Department of Cardiology, Hebei Children's Hospital. RESULTS: Among the five children with CM, there were three girls and two boys, all of whom carried MYH7 gene mutation. Seven mutation sites were identified, among which five were not reported before. Among the five children, there were three children with hypertrophic cardiomyopathy, one child with dilated cardiomyopathy, and one child with noncompaction cardiomyopathy. The age ranged from 6 to 156 months at the initial diagnosis. At the initial diagnosis, two children had the manifestations of heart failure such as cough, shortness of breath, poor feeding, and cyanosis of lips, as well as delayed development; one child had palpitation, blackness, and syncope; one child had fever, runny nose, and abnormal liver function; all five children had a reduction in activity endurance. All five children received pharmacotherapy for improving cardiac function and survived after follow-up for 7-24 months. CONCLUSIONS: The age of onset varies in children with CM caused by MYH7 gene mutation, and most children lack specific clinical manifestations at the initial diagnosis and may have the phenotype of hypertrophic cardiomyopathy, dilated cardiomyopathy or noncompaction cardiomyopathy. The children receiving early genetic diagnosis and pharmacological intervention result in a favorable short-term prognosis.

Spatial heterogeneity of T cell repertoire across NSCLC tumors, tumor edges, adjacent and distant lung tissues.

Background: A better understanding of T cells in lung cancer and their distribution across tumor-adjacent lungs and peripheral blood is needed to improve efficacy and minimize toxicity from immunotherapy to lung cancer patients. Methods: Here, we performed CDR3ß TCR sequencing of 136 samples from 20 patients with early-stage NSCLC including peripheral blood mononuclear cells, tumors, tumor edges (<1 cm from tumor), as well as adjacent lungs 1 cm, 2 cm, 5 cm, and 10 cm away from the tumor to gain insight into the spatial heterogeneity of T cells across the lungs in patients with NSCLC. PD-L1, CD4, and CD8 expression was assessed using immunohistochemical staining, and genomic features were derived by targeted sequencing of 1,021 cancer-related genes. Multiplex immunohistochemistry against PD-1, CTLA4, LAG3, and TIM3 was performed on four patients to assess T cell exhaustion. Results: Our study reveals a decreasing gradient in TIL Tumor Infiltrating Lymphocytes homology with tumor edge, adjacent lungs, and peripheral blood but no discernible distance-associated patterns of T cell trafficking within the adjacent lung itself. Furthermore, we show a decrease in pathogen-specific TCRs in regions with high T cell clonality and PD-L1 expression. Conclusions: Exclusion in T exhaustion cells at play across the lungs of patients with NSCLC may potentially be the mechanism for lung cancer occurrence.

Combination of Walnut Peptide and Casein Peptide alleviates anxiety and improves memory in anxiety mices.

Introduction: Anxiety disorders continue to prevail as the most prevalent cluster of mental disorders following the COVID-19 pandemic, exhibiting substantial detrimental effects on individuals' overall well-being and functioning. Even after a search spanning over a decade for novel anxiolytic compounds, none have been approved, resulting in the current anxiolytic medications being effective only for a specific subset of patients. Consequently, researchers are investigating everyday nutrients as potential alternatives to conventional medicines. Our prior study analyzed the antianxiety and memory-enhancing properties of the combination of Walnut Peptide (WP) and Casein Peptide (CP) in zebrafish. Methods and Results: Based on this work, our current research further validates their effects in mice models exhibiting elevated anxiety levels through a combination of gavage oral administration. Our results demonstrated that at 170 + 300 mg human dose, the WP + CP combination significantly improved performances in relevant behavioral assessments related to anxiety and memory. Furthermore, our analysis revealed that the combination restores neurotransmitter dysfunction observed while monitoring Serotonin, gamma-aminobutyric acid (GABA), dopamine (DA), and acetylcholine (ACh) levels. This supplementation also elevated the expression of brain-derived neurotrophic factor mRNA, indicating protective effects against the neurological stresses of anxiety. Additionally, there were strong correlations among behavioral indicators, BDNF (brain-derived neurotrophic factor), and numerous neurotransmitters. Conclusion: Hence, our findings propose that the WP + CP combination holds promise as a treatment for anxiety disorder. Besides, supplementary applications are feasible when produced as powdered dietary supplements or added to common foods like powder, yogurt, or milk.

SGLT2 Inhibitor-pretreated Macrophage Transplantation Improves Adverse Ventricular Remodeling After Acute Myocardial Infarction.

ABSTRACT: Macrophages play an important role in the progression of acute myocardial infarction (AMI). Studies have shown that sodium-dependent glucose transporter 2 inhibitor (SGLT2i) after AMI could increase the proportion of M2 type/M1 macrophages and reduces adverse ventricular remodeling (AVR) post-AMI. This study aimed to investigate whether SGLT2i-pretreated macrophage transplantation could reduce AVR after AMI and the underlying mechanisms. C57BL/6 mice were used to establish an AMI model by ligating the coronary arteries. Dynamic observation of transplanted bone marrow-derived macrophages (BMDMs) was performed using an in vivo imaging system. Cardiac function was assessed using echocardiography. The fibrosis ratio was measured using Masson's trichrome staining. Cardiomyocyte (CM) apoptosis was measured using the TUNEL assay. Macrophage subtypes were measured using flow cytometry. We detected the expression of inflammatory factors in the myocardium and serum using enzyme-linked immunosorbent assay and reverse transcription-polymerase chain reaction. The in vivo imaging system revealed that transplanted SGLT2i-pretreated BMDMs were present in the infarcted myocardium for 7 days. Flow cytometry revealed that SGLT2i-pretreated BMDMs promoted the conversion of native-derived macrophages to the M2 type. SGLT2i-pretreated BMDMs also reduced inflammatory factors (IL-6, TNFα, and IL-1ß) in the infarcted myocardium and serum. At 28 days post-AMI, SGLT2i-pretreated BMDMs increased cardiac function and vascular density, but reduced CM hypertrophy. SGLT2i-pretreated BMDMs could reduce CM apoptosis and fibrotic area ratio. In conclusion, transplanted SGLT2i-pretreated BMDMs were present in the infarcted myocardium for 7 days and improved AVR by reducing inflammation and modulating the conversion of native mice-derived macrophages to M2-type macrophages.

Recent Advances in the Development of Pyrazole Derivatives as Anticancer Agents.

Pyrazole derivatives, as a class of heterocyclic compounds, possess unique chemical structures that confer them with a broad spectrum of pharmacological activities. They have been extensively explored for designing potent and selective anticancer agents. In recent years, numerous pyrazole derivatives have been synthesized and evaluated for their anticancer potential against various cancer cell lines. Structure-activity relationship studies have shown that appropriate substitution on different positions of the pyrazole ring can significantly enhance anticancer efficacy and tumor selectivity. It is noteworthy that many pyrazole derivatives have demonstrated multiple mechanisms of anticancer action by interacting with various targets including tubulin, EGFR, CDK, BTK, and DNA. Therefore, this review summarizes the current understanding on the structural features of pyrazole derivatives and their structure-activity relationships with different targets, aiming to facilitate the development of potential pyrazole-based anticancer drugs. We focus on the latest research advances in anticancer activities of pyrazole compounds reported from 2018 to present.

Study on Microstructure Evolution Mechanism of Gradient Structure Surface of AA7075 Aluminum Alloy by Ultrasonic Surface Rolling Treatment.

The materials with grain size gradient variation on the surface, which were prepared with mechanical-induced severe plastic deformation, always show high resistance to high and low cycle fatigue and frictional wear because of their good strength-ductility synergy. The ultrasonic surface rolling treatment (USRT) has the advantages of high processing efficiency, good surface quality, and large residual compressive stress introduced to the surface after treatment. The USRT was used to prepare aluminum alloy (AA7075) samples with a surface gradient structure; meanwhile, the microstructural evolution mechanism of the deformation layers on the gradient structure was studied with XRD, SEM, and TEM. The microstructure with gradient distribution of grain size and dislocation density formed on the surface of AA7075 aluminum alloy after USRT. The surface layer consists of nanocrystals with random orientation distribution, and high-density dislocation cells and subgrains formed in some grains in the subsurface layer, while the center of the material is an undeformed coarse-grained matrix. The results show that the dislocation slip dominates the grain refinement process, following the continuous cutting and refinement of dislocation cells, subgrains, and fragmentation of the second precipitates. This study systematically clarified the mechanism of grain refinement and nanocrystallization on the surface of high-strength aluminum alloys and laid a theoretical foundation for further research on mechanical behavior and surface friction and wear properties of high-strength non-ferrous materials with gradient structure.

[Clinical and genetic characteristics of children with primary dilated cardiomyopathy]. / å„¿ç«¥åŽŸå‘æ€§æ‰©å¼ åž‹å¿ƒè‚Œç— çš„ä¸´åºŠç‰¹å¾åŠé—ä¼ å­¦åˆ†æž.

OBJECTIVES: To study the genetic characteristics, clinical characteristics, and prognosis of children with primary dilated cardiomyopathy (DCM). METHODS: A retrospective analysis was performed on the medical data of 44 children who were diagnosed with DCM in Hebei Children's Hospital from July 2018 to February 2023. According to the genetic testing results, they were divided into two groups: gene mutation-positive group (n=17) and gene mutation-negative group (n=27). The two groups were compared in terms of clinical data at initial diagnosis and follow-up data. RESULTS: Among the 44 children with DCM, there were 21 boys (48%) and 23 girls (52%). Respiratory symptoms including cough and shortness of breath were the most common symptom at initial diagnosis (34%, 15/44). The detection rate of gene mutations was 39% (17/44). There were no significant differences between the two groups in clinical characteristics, proportion of children with cardiac function grade Ⅲ or Ⅳ, brain natriuretic peptide levels, left ventricular ejection fraction, and left ventricular fractional shortening at initial diagnosis (P>0.05). The median follow-up time was 23 months, and 9 children (20%) died, including 8 children from the gene mutation-positive group, among whom 3 had TTN gene mutation, 2 had LMNA gene mutation, 2 had TAZ gene mutation, and 1 had ATAD3A gene mutation. The gene mutation-positive group had a significantly higher mortality rate than the gene mutation-negative group (P<0.05). CONCLUSIONS: There is no correlation between the severity of DCM at initial diagnosis and gene mutations in children. However, children with gene mutations may have a poorer prognosis.

Mechanochemically synthesized silicotungsten acidified ZVI composite for persulfate activation: Enhancement of the electron transfer and Fe slowly release mechanism.

Zero-valent iron (ZVI) is a promising technology for groundwater treatment, and its efficiency primarily depends on the electron transfer. However, there are still some problems such as low electron efficiency of ZVI particles and high yield of iron sludge that limits the performance, which warrant further investigation. In our study, a silicotungsten acidified ZVI composite (m-WZVI) was synthesized by ball milling to activate PS to degrade phenol. m-WZVI has a better performance on phenol degradation (with a removal rate of 91.82%) than ball mill ZVI(m-ZVI) with persulfate (PS) (with a removal rate of 59.37%). Compared with m-ZVI, the first-order kinetic constant (kobs) of m-WZVI/PS is 2-3 times higher than that of the others. Iron ion was gradually leached in m-WZVI/PS system, being only 2.11 mg/L after 30 min, having to avoid excessive consumption of active substances. The underlying mechanisms of m-WZVI for PS activation mainly include: 1) were elucidated through different characterizations analyses that accounted for silictungstic acid (STA) can be combined with ZVI, and a new electron donor (SiW124-) was obtained, which improved the transfer rate performance of electrons for activating PS; 2) singlet oxygen (1O2) is the main active substance for phenol degradation, but other radicals also played an important role. Therefore, m-WZVI has good prospects for improving the electron utilization of ZVI.

Plexin D1 mediates disturbed flow-induced M1 macrophage polarization in atherosclerosis.

Atherosclerosis preferentially develops at bifurcations exposed to disturbed flow. Plexin D1 (PLXND1) responds to mechanical forces and drives macrophage accumulation in atherosclerosis. Here, multiple strategies were used to identify the role of PLXND1 in site-specific atherosclerosis. Using computational fluid dynamics and three-dimensional light-sheet fluorescence-microscopy, the elevated PLXND1 in M1 macrophages was mainly distributed in disturbed flow area of ApoE-/- carotid bifurcation lesions, and visualization of atherosclerosis in vivo was achieved by targeting PLXND1. Subsequently, to simulate the microenvironment of bifurcation lesions in vitro, we co-cultured oxidized low-density lipoprotein (oxLDL)-treated THP-1-derived macrophages with shear-treated human umbilical vein endothelial cells (HUVECs). We found that oscillatory shear induced the increase of PLXND1 in M1 macrophages, and knocking down PLXND1 inhibited M1 polarization. Semaphorin 3E, the ligand of PLXND1 which was highly expressed in plaques, strongly enhanced M1 macrophage polarization via PLXND1 in vitro. Our findings provide insights into pathogenesis in site-specific atherosclerosis that PLXND1 mediates disturbed flow-induced M1 macrophage polarization.

SGLT2 inhibitor dapagliflozin alleviates intramyocardial hemorrhage and adverse ventricular remodeling via suppressing hepcidin in myocardial ischemia-reperfusion injury.

Intramyocardial hemorrhage (IMH), a reperfusion therapy-associated complication, is the extravasation of red blood cells caused by severe microvascular injury. IMH is an independent predictor of adverse ventricular remodeling (AVR) after acute myocardial infarction (AMI). Hepcidin, a major regulator of iron uptake and systemic distribution, is a key factor affecting AVR. However, the role of cardiac hepcidin in the development of IMH has not been completely elucidated. This study aimed to explore if sodium-dependent glucose co-transporter 2 inhibitor (SGLT2i) exerts therapeutic effects on IMH and AVR by suppressing hepcidin and to elucidate the underlying mechanisms. SGLT2i alleviated IMH and AVR in the ischemia-reperfusion injury (IRI) mouse model. Additionally, SGLT2i downregulated the cardiac levels of hepcidin in IRI mice, suppressed M1-type macrophage polarization, and promoted M2-type macrophage polarization. The effects of hepcidin knockdown on macrophage polarization were similar to those of SGLT2i in RAW264.7 cells. SGLT2i treatment or hepcidin knockdown inhibited the expression of MMP9, an inducer of IMH and AVR, in RAW264.7 cells. Regulation of macrophage polarization and reduction of MMP9 expression by SGLT2i and hepcidin knockdown is achieved through activation of pSTAT3. In conclusion, this study demonstrated that SGLT2i alleviated IMH and AVR by regulating macrophage polarization. The potential mechanism through which SGLT2i exerted its therapeutic effect seems to involve the downregulation of MMP9 via the hepcidin-STAT3 pathway.

[Recent research on childhood hypertrophic cardiomyopathy caused by MYH7 gene mutations]. / MYH7åŸºå› çªå˜è‡´å„¿ç«¥è‚¥åŽšåž‹å¿ƒè‚Œç— çš„ç ”ç©¶è¿›å±•.

Hypertrophic cardiomyopathy (HCM) is the most common monogenic inherited myocardial disease in children, and mutations in sarcomere genes (such as MYH7 and MYBPC3) are the most common genetic etiology of HCM, among which mutations in the MYH7 gene are the most common and account for 30%-50%. MYH7 gene mutations have the characteristics of being affected by environmental factors, coexisting with multiple genetic variations, and age-dependent penetrance, which leads to different or overlapping clinical phenotypes in children, including various cardiomyopathies and skeletal myopathies. At present, the pathogenesis, course, and prognosis of HCM caused by MYH7 gene mutations in children remain unclear. This article summarizes the possible pathogenesis, clinical phenotype, and treatment of HCM caused by MYH7 gene mutations, in order to facilitate the accurate prognostic evaluation and individualized management and treatment of the children with this disorder.