Characteristics of Abdominal Fat Based on CT Measurements to Predict Early Recurrence After Initial Surgery of NMIBC in Stage Ta/T1.

INTRODUCTION: This study aimed to assess the predictive value of abdominal fat characteristics measured by computed tomography (CT) in identifying early recurrence within one year post-initial transurethral resection of bladder tumor (TURBT) in patients with nonmuscle-invasive bladder cancer (NMIBC). A predictive model integrating fat features and clinical factors was developed to guide individualized treatment. MATERIALS AND METHODS: A retrospective analysis of 203 NMIBC patients from two medical centers was conducted. Abdominal CT images were analyzed using 3D Slicer software. Spearman correlation, logistic regression, and the Lasso algorithm were employed for data analysis. Predictive efficacy was assessed using the area under the curve (AUC) of receiver operating characteristic (ROC) and decision curve analysis (DCA). Calibration was evaluated using the Hosmer-Lemeshow test. RESULTS: Significant differences in abdominal fat characteristics were found between the recurrence and nonrecurrence groups. All fat features positively correlated with body mass index (BMI), with bilateral perirenal fat thickness (PrFT) showing superior predictive performance. Multivariate logistic regression identified independent predictors of early recurrence, including tumor number, early perfusion chemotherapy, left and right PrFT, and visceral fat area (VFA) at umbilical and renal hilum levels. The Lasso-based model achieved an AUC of 0.904, outperforming existing models. CONCLUSION: Abdominal fat characteristics, especially bilateral PrFT, strongly correlate with early recurrence in NMIBC. The Lasso-based model, integrating fat and clinical factors, offers superior predictive efficacy and could improve individualized treatment strategies.

Construction and validation of a nomogram for predicting the prognosis of breast cancer patients who received adjuvant therapy: an analysis based on the SEER database.

Background: Breast cancer is the most common malignant tumor in women globally. Despite advances in primary treatment, the role of adjuvant therapy in reducing recurrence and improving survival is critical; however, there is a notable lack of tailored prognostic models for patients receiving adjuvant therapy. This study used the Surveillance, Epidemiology, and End Results (SEER) database to develop a prognostic nomogram for breast cancer patients receiving adjuvant therapy. Methods: The data of breast cancer patients who received adjuvant therapy after surgery in 2014-2015 were extracted from the SEER database. Univariate Cox regression identified significant prognostic variables that were further refined by least absolute shrinkage and selection operator (LASSO) regression and cross-validation analyses. These variables were incorporated into a multivariate Cox regression analysis to establish the predictive model. This model was visualized and validated using various statistical measures. Results: A total of 54,960 patients were included in the study, with 38,472 in the training set and 16,488 in the validation set. Age, sex, race, marital status, grade, tumor (T) stage, lymph node (N) stage, subtype, and radiotherapy were found to be significant independent risk factors of 1-, 3-, and 5-year overall survival (OS). The receiver operating characteristic curve area for 1-, 3-, and 5-year OS was >0.76 in both sets. The consistency index values were 0.768 and 0.763 for the training and validation sets, respectively. The calibration curves showed good fit, and the nomogram exhibited substantial clinical utility. Conclusions: Incorporating various significant factors, the constructed nomogram was able to effectively predict the prognosis of breast cancer patients who received adjuvant therapy. This nomogram extends understandings of complex prognosis scenarios. In addition, it could enhance personalized treatment plans and assist in patient counseling.

Development and validation of a nomogram for major adverse cardiovascular events after chronic total occlusion percutaneous coronary intervention for ischemic heart failure.

BACKGROUND: Chronic total occlusion percutaneous coronary intervention (CTO-PCI) is an available means of revascularization in patients with ischemic heart failure (IHF). However, the prognosis of IHF patients undergoing CTO-PCI remains unclear due to the lack of reliable clinical predictive tools. AIM: This study aimed to establish a nomogram for major adverse cardiovascular events (MACE) after CTO-PCI in IHF patients. METHODS: Sixty-seven potential predictive variables for MACE in 560 IHF patients undergoing CTO-PCI were screened using least absolute shrinkage and selection operator regression. A nomogram was constructed based on multivariable Cox regression to visualize the risk of MACE, and then evaluation was carried out using the concordance index (C-index), time-independent receiver operating characteristic (timeROC) curves, calibration curves, and decision curve analysis (DCA). RESULTS: During a median follow-up of 32.0 months, there were 208 MACE occurrences. Seven variables were selected for nomogram construction: age, left ventricular ejection fraction, left ventricular end-diastolic diameter, N-terminal precursor B-type diuretic peptide, bending, and use of intravascular ultrasound and beta-blockers. The C-index was 0.715 (0.680-0.750) and the internal validation result was 0.715 (0.676-0.748). The timeROC area under the curve at 6 months, 1 year, and 2 years was 0.750 (0.653-0.846), 0.747 (0.690-0.804), and 0.753 (0.708-0.798), respectively. The calibration curves and DCA showed the nomogram had acceptable calibration and clinical applicability. CONCLUSIONS: We developed a simple and efficient nomogram for MACE after CTO-PCI in IHF patients, which helps in early risk stratification and postoperative management optimization.

The association between dietary selenium intake and telomere length in hypertension.

Telomere length is closely linked to biological aging, oxidative stress, and the development of cardiovascular diseases. This study aimed to assess the association between dietary selenium intake and telomere length in individuals with hypertension. Data on dietary selenium intake were captured through the National Health and Nutrition Examination Survey (NHANES) computer-assisted dietary interview system (CADI). Telomere length determination entailed selecting blood samples from all participants in the NHANES database. The analysis was performed using Analysis System software, with Empower stats utilized for data analysis. Results showed that there was a significant association between dietary selenium intake and telomere length in hypertension, particularly within the female group. In female hypertension cases, a 1 mcg increase in dietary selenium intake corresponded to a telomere length increase of 1.19 bp, even after adjusting for age, race, BMI, marital status, physical activity, energy intake, and stroke history. The relationship between dietary selenium intake and telomere length exhibited a linear pattern in female hypertension patients. This study identified a positive association between dietary selenium intake and telomere length in hypertension, particularly within the female group.

Co-delivery Nano System of MS-275 and V-9302 Induces Pyroptosis and Enhances Anti-Tumor Immunity Against Uveal Melanoma.

In the treatment of uveal melanoma (UVM), histone deacetylase inhibitors (HDACi) have emerged as a promising epigenetic therapy. However, their clinical efficacy is hindered by the suboptimal pharmacokinetics and the strong self-rescue of tumor cells. To overcome these limitations, reactive oxygen species (ROS)-responsive nanoparticles (NPs) are designed that encapsulate HDACi MS-275 and the glutamine metabolism inhibitor V-9302. Upon reaching the tumor microenvironment, these NPs can disintegrate, thereby releasing MS-275 to increase the level of ROS and V-9302 to reduce the production of glutathione (GSH) related to self-rescue. These synergistic effects lead to a lethal ROS storm and induce cell pyroptosis. When combined with programmed cell death protein 1 monoclonal antibodies (α-PD-1), these NPs facilitate immune cell infiltration, improving anti-tumor immunity, converting "immune-cold" tumors into "immune-hot" tumors, and enhancing immune memory in mice. The findings present a nano-delivery strategy for the co-delivery of epigenetic therapeutics and metabolic inhibitors, which induces pyroptosis in tumors cells and improves the effectiveness of chemotherapy and immunotherapy.

Arbuscular mycorrhizal fungi reduce soil N2O emissions by altering root traits and soil denitrifier community composition.

Arbuscular mycorrhizal fungi (AMF) increase the ability of plants to obtain nitrogen (N) from the soil, and thus can affect emissions of nitrous oxide (N2O), a long-lived potent greenhouse gas. However, the mechanisms underlying the effects of AMF on N2O emissions are still poorly understood, particularly in agroecosystems with different forms of N fertilizer inputs. Utilizing a mesocosm experiment in field, we examined the effects of AMF on N2O emissions via their influence on maize root traits and denitrifying microorganisms under ammonia and nitrate fertilizer input using 15N isotope tracer. Here we show that the presence of AMF alone or both maize roots and AMF increased maize biomass and their 15N uptake, root length, root surface area, and root volume, but led to a reduction in N2O emissions under both N input forms. Random forest model showed that root length and surface area were the most important predictors of N2O emissions. Additionally, the presence of AMF reduced the (nirK + nirS)/nosZ ratio by increasing the relative abundance of nirS-Bradyrhizobium and Rubrivivax with ammonia input, but reducing nosZ-Azospirillum, Cupriavidus and Rhodopseudomonas under both fertilizer input. Further, N2O emissions were significantly and positively correlated with the nosZ-type Azospirillum, Cupriavidus and Rhodopseudomonas, but negatively correlated with the nirS-type Bradyrhizobium and Rubrivivax. These results indicate that AMF reduce N2O emissions by increasing root length to explore N nutrients and altering the community composition of denitrifiers, suggesting that effective management of N fertilizer forms interacting with the rhizosphere microbiome may help mitigate N2O emissions under future N input scenarios.

Function of NEK2 in clear cell renal cell carcinoma and its effect on the tumor microenvironment.

BACKGROUND: Previous studies have revealed the critical functions of NEK2 in controlling the cell cycle which is linked to poor prognosis in multiple tumor types, but less research has been devoted to clear cell renal cell carcinoma (ccRCC). METHODS: We downloaded clinical data from the gene expression omnibus (GEO) and TCGA databases together with transcriptional and mutational datasets. Strongly coexpressed genes with NEK2 were extracted from TCGA-KIRC cohort, and were submitted to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) for functional analyses. According to NEK2 levels, the survival status, mutational characteristics, response to immunotherapy and sensitivity to drugs of the patients were studied. The potential correlations between NEK2 levels and immune cell state as well as immune cell infiltration were examined using the GEPIA, TIMER and TISIDB databases. Double immunofluorescence (IF) was performed to identify the NEK2 overexpression and relationship with CD8 in ccRCC. RESULTS: The NEK2 gene was overexpressed and would enhance the nuclear division and cell cycle activities in ccRCC. ccRCC patients with high NEK2 expression had worse clinical outcomes, higher mutation burden and better therapeutic response. Moreover, NEK2 gene overexpression was positively related to various immune cell marker sets, which was also proved by validation cohort, and more infiltration of various immune cells. CONCLUSION: ccRCC patients with NEK2 high expression have a poorer prognosis than those with NEK2 low expression, resulting from its function of promoting proliferation, accompanied by increased infiltration of CD8 + T cells and Tregs and T-cell exhaustion and will respond better to proper treatments.

Melanoma differentiation-associated protein 5 prevents cardiac hypertrophy via apoptosis signal-regulating kinase 1-c-Jun N-terminal kinase/p38 signaling.

Pathological cardiac hypertrophy (CH) is driven by maladaptive changes in myocardial cells in response to pressure overload or other stimuli. CH has been identified as a significant risk factor for the development of various cardiovascular diseases, ultimately resulting in heart failure. Melanoma differentiation-associated protein 5 (MDA5), encoded by interferon-induced with helicase C domain 1 (IFIH1), is a cytoplasmic sensor that primarily functions as a detector of double-stranded ribonucleic acid (dsRNA) viruses in innate immune responses; however, its role in CH pathogenesis remains unclear. Thus, the aim of this study was to examine the relationship between MDA5 and CH using cellular and animal models generated by stimulating neonatal rat cardiomyocytes with phenylephrine and by performing transverse aortic constriction on mice, respectively. MDA5 expression was upregulated in all models. MDA5 deficiency exacerbated myocardial pachynsis, fibrosis, and inflammation in vivo, whereas its overexpression hindered CH development in vitro. In terms of the underlying molecular mechanism, MDA5 inhibited CH development by promoting apoptosis signal-regulating kinase 1 (ASK1) phosphorylation, thereby suppressing c-Jun N-terminal kinase/p38 signaling pathway activation. Rescue experiments using an ASK1 activation inhibitor confirmed that ASK1 phosphorylation was essential for MDA5-mediated cell death. Thus, MDA5 protects against CH and is a potential therapeutic target.

Construction of Multifunctional Covalent Organic Frameworks for Photocatalysis.

Covalent organic frameworks (COFs) have recently drawn intense attention due to their potential applications in photocatalysis. Herein, we report a multifunctional COF which consists of triphenylamine (TPA) and 2,2'-bipyridine (2, 2'-bipy) entities. The obtained TAPA-BPy-COF is a heterogeneous photocatalyst and can efficiently catalyze the oxidative coupling of thiols to disulfides. In addition, TAPA-BPy-COF can be further metalated by Pd(II) via 2,2'-bipy-metal coordination. The generated Pd@TAPA-BPy-COF can highly promote photocatalytic synthesis of 3-cyanopyridines via cascade addition/cyclization of arylboronic acids with γ-ketodinitriles in heterogeneous way. This work has demonstrated the way for the rational design and preparation of more efficient photoactive COFs for photocatalysis.

Phenanthroline-Decorated Covalent Organic Framework for Catalytic Synthesis of 2-Aminobenzothiazoles in Water.

2-Aminobenzothiazoles are widely used in the fields of pharmaceuticals and pesticides. Herein, we report a metal-free protocol for the preparation of 2-aminobenzothiazoles by a covalent organic framework (COF) catalyzed tandem reaction. In the presence of catalytic amount of phenanthroline-decorated COF (Phen-COF), a variety of 2-aminobenzothiazoles are obtained in excellent yields by the cross-coupling of 2-iodoanilines with isothiocyanates at room temperature in water. In addition, the COF-catalyst is very stable and can be reused at least seven times without loss of its catalytic activity.

cGAS-STING Pathway Activation and Systemic Anti-Tumor Immunity Induction via Photodynamic Nanoparticles with Potent Toxic Platinum DNA Intercalator Against Uveal Melanoma.

The cGAS-STING pathway, as a vital innate immune signaling pathway, has attracted considerable attention in tumor immunotherapy research. However, STING agonists are generally incapable of targeting tumors, thus limiting their clinical applications. Here, a photodynamic polymer (P1) is designed to electrostatically couple with 56MESS-a cationic platinum (II) agent-to form NPPDT -56MESS. The accumulation of NPPDT -56MESS in the tumors increases the efficacy and decreases the systemic toxicity of the drugs. Moreover, NPPDT -56MESS generates reactive oxygen species (ROS) under the excitation with an 808 nm laser, which then results in the disintegration of NPPDT -56MESS. Indeed, the ROS and 56MESS act synergistically to damage DNA and mitochondria, leading to a surge of cytoplasmic double-stranded DNA (dsDNA). This way, the cGAS-STING pathway is activated to induce anti-tumor immune responses and ultimately enhance anti-cancer activity. Additionally, the administration of NPPDT -56MESS to mice induces an immune memory effect, thus improving the survival rate of mice. Collectively, these findings indicate that NPPDT -56MESS functions as a chemotherapeutic agent and cGAS-STING pathway agonist, representing a combination chemotherapy and immunotherapy strategy that provides novel modalities for the treatment of uveal melanoma.

A Case of Primary Lymphoepithelioma-Like Carcinoma of the Bladder With Review.

Lymphoepithelioma-like carcinoma (LELC) was characterized by epithelial neoplastic cells developing in solid or incohesive sheets mixed with a noticeable lymphoid infiltration. Lymphoepithelioma-like carcinoma of the bladder (LELCB), which was first described by Zukerberg, is a rare variant of LELC. Here we reported a new case of LELCB occurring in a 70-year-old woman presenting with hematuria. Computed tomography (CT) and cystoscopy revealed a tumor on the left upper wall of the bladder. A partial cystectomy was finally performed. Pathological and immunohistochemical analysis revealed LELCB. After receiving systemic adjuvant chemotherapy, the patient conducted a 25-month follow-up without experiencing a recurrence.

Tunable Pt-Ni Interaction Induced Construction of Disparate Atomically Dispersed Pt Sites for Acidic Hydrogen Evolution.

Developing cost-effective Pt-based electrocatalysts for the hydrogen evolution reaction (HER) is highly urgent. Herein, we report novel electrocatalysts with individually dispersed Pt active sites and tunable Pt-Ni interaction decorated on carbon-wrapped nanotube frameworks (Pt/Ni-DA). Pt/Ni-DA exhibits superior HER performance at low Pt concentrations with an ultralow overpotential of 18 mV at 10 mA cm-2 and an ultrahigh mass activity of 2.13 A mgPt-1 at an overpotential of 50 mV, which is about four times higher than that of commercial Pt/C. X-ray absorption fine structure (XAFS) confirms the extension of Pt from the Ni surface to the Ni bulk phase. Mechanistic research and density functional theory (DFT) calculations collectively reveal that the dispersibility and distribution of Pt atoms in Ni regulate the electronic configuration of Pt sites, optimizing the binding energy of reaction intermediates and facilitating electron transfer during the HER process. This work highlights the importance of the electronic structure alternation through the accommodation effect toward enhanced catalytic performance in HER.

Giant Adrenal Cyst: A Case Report.

Giant adrenal cysts are rare lesions, most often discovered incidentally. In this case report, a patient presenting with nonspecific abdominal distension is described. Imaging studies revealed a vast cystic mass closely attached to the left adrenal gland. Neither routine laboratory tests nor endocrine function tests revealed abnormalities. By performing open surgery, the cystic mass was completely removed. According to the pathological results, the wall of the cystic mass has an endothelial structure and some vascular components. Comprehensive analysis indicated that this case was an angiomatous adrenal endothelial cyst which was an extremely uncommon form of an adrenal cyst. Over a one-year follow-up, no evidence of recurrence was observed in the patient postoperatively. Through this case, we wish to raise awareness of this disease.

Arbuscular Mycorrhizal Fungi Shift Soil Bacterial Community Composition and Reduce Soil Ammonia Volatilization and Nitrous Oxide Emissions.

Arbuscular mycorrhizal fungi (AMF) establish mutualistic relationships with the majority of terrestrial plants, increasing plant uptake of soil nitrogen (N) in exchange for photosynthates. And may influence soil ammonia (NH3) volatilization and nitrous oxide (N2O) emissions directly by improving plant N uptake, and/or indirectly by modifying soil bacterial community composition for the soil C availability increasing. However, the effects of AMF on soil NH3 volatilization and N2O emissions and their underlying mechanisms remain unclear. We carried out two independent experiments using contrasting methods, one with a compartmental box device (in 2016) and the other with growth pot experiment (in 2020) to examine functional relationships between AMF and soil NH3 volatilization and N2O emissions under varying N input. The presence of AMF significantly reduced soil NH3 volatilization and N2O emissions while enhancing plant biomass and plant N acquisition, and reducing soil NH4+ and NO3-, even with high N input. The presence of AMF also significantly reduced the relative abundance within the bacterial orders Sphingomonadales and Rhizobiales. Sphingomonadales correlated significantly and positively with soil NH3 volatilization in 2016 and N2O emissions, whereas Rhizobiales correlated positively with soil N2O emissions. High N input significantly increased soil NH3 volatilization and N2O emissions with increasing relative abundance of Sphingomonadales and Rhizobiales. These findings demonstrate the contribution of AMF in regulating NH3 and N2O emission by improving plant N uptake and altering soil bacterial communities. They also suggest that altering the rhizosphere microbiome might offer additional potential for restoration of N-enriched agroecosystems.

n-Octyl substituted quinoxaline-based polymer donor enabling all-polymer solar cell with efficiency over 17.

Recently, the power conversion efficiencies (PCEs) of all-polymer solar cells (all-PSCs) have increased rapidly. To further increase the PCE of all-PSCs, it is necessary to create new donor polymers matching the polymer acceptors. In this paper, we synthesize a new quinoxaline-based polymer donor PBQ8 with n-octyl side chain on the quinoxaline unit, which possesses the same skeleton structure to the previously reported PBQ5 (with isooctyl side chain). The effects of alkyl side chains on the physicochemical properties of the polymer donor were investigated. In comparison with PBQ5, PBQ8 exhibits stronger intermolecular interactions and better molecular packing. When blending with polymer acceptor PY-IT, the PBQ8:PY-IT based devices demonstrated a higher PCE value of 17.04%, which is one of the highest PCEs occurred in the all-PSCs. And the PBQ5:PY-IT (PCE 15.56%, Voc 0.907 V, FF 69.72%, and Jsc 24.60 mA cm-2) is much lower. The PBQ8:PY-IT blend displayed more efficient exciton dissociation, better molecular stacking properties, preferable phase separation and higher mobility. These indicate that as an effective method, side chain engineering can improve the efficiency of the all-PSCs.

Dual-specificity phosphatase 12 attenuates oxidative stress injury and apoptosis in diabetic cardiomyopathy via the ASK1-JNK/p38 signaling pathway.

Diabetic cardiomyopathy (DCM) is ventricular dysfunction that occurs in patients with diabetes mellitus (DM), independent of recognized risk factors, such as coronary artery disease, hypertension, and valvular heart disease. Dual-specificity phosphatase 12 (DUSP12) is a dual-specificity phosphatase expressed in all tissues. Genome-wide linkage studies have found an association between DUSP12 and type 2 diabetes (T2D). However, the role of DUSP12 in DCM remains largely unknown. Ubiquitously expressed DUSP12 is involved in nonalcoholic fatty liver disease, bacterial infection, and myocardial hypertrophy and plays a critical role in tumorigenesis. Herein, we observed an increased expression of DUSP12 in a hyperglycemia cell model and a high-fat diet (HFD) mouse model. Heart-specific DUSP12-deficient mice showed severe cardiac dysfunction and remodeling induced by an HFD. DUSP12 deficiency exacerbated oxidative stress injury and apoptosis, whereas DUSP12 overexpression had the opposite effect. At the molecular level, DUSP12 physically bound to apoptotic signal-regulated kinase 1 (ASK1), promoted its dephosphorylation, and inhibited its action on c-Jun N-terminal kinase and p38 mitogen-activated protein kinase. Rescue experiments have shown that oxidative stress injury and apoptosis, exacerbated by DUSP12 deficiency, are alleviated by ASK1 inhibition. Therefore, we consider DUSP12 an important signaling pathway in DCM.

Xiaotansanjiefang inhibits the viability of colorectal cancer cells via Jagged 1/Notch 3/Snail signaling pathway.

The purpose of this study is to explore the anti-colorectal cancer of Xiaotansanjiefang, a famous traditional Chinese medicine, and its potential anti-cancer mechanism. In this study, the HCT116 cell spheres were prepared as in vitro study model. We found the Xiaotansanjiefang medication was able to inhibit the proliferation of HCT116 cell spheres in a dose-dependent manner, especially in 3 and 6 mg/ml Xiaotansanjiefang medication treated groups. We also found the high concentration of Xiaotansanjiefang medication could suppress the migration and promote the apoptosis of HCT116 cell spheres. Moreover, we found the expression of Jagged 1, Notch 3, Snail, and Hes 1 were decreased in HCT116 cell spheres treated with Xiaotansanjiefang medication. Furthermore, the proliferation and apoptosis behaviors of HCT116 cell spheres treated with Xiaotansanjiefang medication were reversed with the addition of Jagged 1 Fc chimera protein. The expression of Jagged 1, Notch 3, Snail, and Hes 1 were also increased again in HCT116 cells treated with Xiaotansanjiefang medication plus with Jagged 1 Fc chimera protein. The presented study may provide a promising strategy to treat and prevent colorectal cancer.

A rapid and sensitive ultra-performance liquid chromatography tandem mass spectrometry method for determination of anlotinib in plasma and dried blood spots: Method development, validation, and clinical application.

RATIONALE: Anlotinib is a multi-target tyrosine kinase inhibitor, approved in China for treating several cancer types. Dose individualization based on therapeutic drug monitoring (TDM) is a useful tool to reduce toxicity. However, it is not convenient for patients to go to hospital for routine TDM via venous blood sampling at a certain time. METHODS: An ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method was developed and validated for determination of anlotinib in human plasma and dried blood spot (DBS), characterized by simple sample preparation, high sensitivity, and short analysis time. The assay was validated in the concentration range of 0.2-200 ng/mL in plasma and 5-1000 ng/mL in DBS. This method was applied to monitor anlotinib exposure levels in patients with advanced biliary tract cancer (BTC) and non-small cell lung cancer (NSCLC). RESULTS: The trough plasma concentration (Ctrough ) of anlotinib was highly variable among BTC patients with coefficients of variation (CV) of 47.5%. DBS and venous blood samples were also collected from NSCLC patients to determine whether DBS sampling is a viable alternative sampling approach. Pearson correlation coefficient (R) between DBS and plasma concentration was 0.985. Bland-Altman plot demonstrated that the difference between estimated and measured plasma concentration was -2.9%. And 87% of sample pairs had a maximal deviation of ±20%. CONCLUSIONS: Anlotinib exhibits a high inter-individual variability in plasma exposure, and DBS sampling could be a promising tool for TDM of anlotinib.

Tumor Necrosis Factor-α-Induced Protein 8-Like 2 Ameliorates Cardiac Hypertrophy by Targeting TLR4 in Macrophages.

Background: Tumor necrosis factor-α-induced protein 8-like 2 (TIPE2), a novel immunoregulatory protein, has been reported to regulate inflammation and apoptosis. The role of TIPE2 in cardiovascular disease, especially cardiac hypertrophy, has not been elucidated. Thus, the aim of the present study was to explore the role of TIPE2 in cardiac hypertrophy. Methods: Mice were subjected to aortic banding (AB) to induce an adverse hypertrophic model. To overexpress TIPE2, mice were injected with a lentiviral vector expressing TIPE2. Echocardiographic and hemodynamic analyses were used to evaluate cardiac function. Neonatal rat cardiomyocytes (NRCMs) and mouse peritoneal macrophages (MPMs) were isolated and stimulated with angiotensin II. NRCMs and MPM were also cocultured and stimulated with angiotensin II. Cells were transfected with Lenti-TIPE2 to overexpress TIPE2. Results: TIPE2 expression levels were downregulated in hypertrophic mouse hearts and in macrophages in heart tissue. TIPE2 overexpression attenuated pressure overload-induced cardiac hypertrophy, fibrosis, and cardiac dysfunction. Moreover, we found that TIPE2 overexpression in neonatal cardiomyocytes did not relieve the angiotensin II-induced hypertrophic response in vitro. Furthermore, TIPE2 overexpression downregulated TLR4 and NF-κB signaling in macrophages but not in cardiomyocytes, which led to diminished inflammation in macrophages and consequently reduced the activation of hypertrophic Akt signaling in cardiomyocytes. TLR4 inhibition by TAK-242 did not enhance the antihypertrophic effect of TIPE2 overexpression. Conclusions: The present study indicated that TIPE2 represses macrophage activation by targeting TLR4, subsequently inhibiting cardiac hypertrophy.