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OBJECTIVES: To investigate the changes in the serum levels of oxidized phospholipids (OxPLs) and endothelial nitric oxide synthase (eNOS) and their association with coronary artery disease (CAL) in children in the acute stage of Kawasaki disease (KD), as well as the clinical significance of OxPLs and eNOS. METHODS: A prospective study was conducted on 95 children in the acute stage of KD (KD group). According to the presence of absence of CAL, the KD group was further divided into a CAL subgroup and a non-CAL (NCAL) subgroup. Thirty children with fever due to lower respiratory tract infection were enrolled as the fever group. Thirty healthy children who underwent physical examination were enrolled as the healthy control group. The above groups were compared in terms of general information and serum levels of OxPLs, eNOS and other laboratory indexes, and the correlation between OxPLs level and eNOS level was analyzed. RESULTS: The KD group had a significantly higher level of OxPLs and a significantly lower level of eNOS compared with the fever group and the healthy control group (P<0.05). After treatment, the children with KD had a significantly decreased OxPLs level and a significantly increased eNOS level (P<0.05). Compared with the NCAL subgroup, the CAL subgroup had a significantly higher level of OxPLs and a significantly lower level of eNOS (P<0.05). Among the children of KD, the level of OxPLs was negatively correlated with that of eNOS (rs=-0.353, P<0.05). CONCLUSIONS: Serum OxPLs and eNOS in the acute stage of KD may be involved in the development of CAL in children with KD, and therefore, they may be used as the biomarkers to predict CAL in these children.
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Síndrome Mucocutáneo Linfonodular , Óxido Nítrico Sintasa de Tipo III , Fosfolípidos , Humanos , Síndrome Mucocutáneo Linfonodular/sangre , Masculino , Femenino , Óxido Nítrico Sintasa de Tipo III/sangre , Preescolar , Lactante , Estudios Prospectivos , Enfermedad Aguda , Fosfolípidos/sangre , Oxidación-Reducción , Niño , Enfermedad de la Arteria Coronaria/sangre , Enfermedad de la Arteria Coronaria/etiologíaRESUMEN
Precise targeting has become the main direction of anti-cancer drug development. Trophoblast cell surface antigen 2 (Trop-2) is highly expressed in different solid tumors but rarely in normal tissues, rendering it an attractive target. Trop-2-targeted antibody-drug conjugates (ADCs) have displayed promising efficacy in treating diverse solid tumors, especially breast cancer and urothelial carcinoma. However, their clinical application is still limited by insufficient efficacy, excessive toxicity, and the lack of biological markers related to effectiveness. This review summarizes the clinical trials and combination therapy strategies for Trop-2-targeted ADCs, discusses the current challenges, and provides new insights for future advancements.
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Over 120 small-molecule kinase inhibitors (SMKIs) have been approved worldwide for treating various diseases, with nearly 70 FDA approvals specifically for cancer treatment, focusing on targets like the epidermal growth factor receptor (EGFR) family. Kinase-targeted strategies encompass monoclonal antibodies and their derivatives, such as nanobodies and peptides, along with innovative approaches like the use of kinase degraders and protein kinase interaction inhibitors, which have recently demonstrated clinical progress and potential in overcoming resistance. Nevertheless, kinase-targeted strategies encounter significant hurdles, including drug resistance, which greatly impacts the clinical benefits for cancer patients, as well as concerning toxicity when combined with immunotherapy, which restricts the full utilization of current treatment modalities. Despite these challenges, the development of kinase inhibitors remains highly promising. The extensively studied tyrosine kinase family has 70% of its targets in various stages of development, while 30% of the kinase family remains inadequately explored. Computational technologies play a vital role in accelerating the development of novel kinase inhibitors and repurposing existing drugs. Recent FDA-approved SMKIs underscore the importance of blood-brain barrier permeability for long-term patient benefits. This review provides a comprehensive summary of recent FDA-approved SMKIs based on their mechanisms of action and targets. We summarize the latest developments in potential new targets and explore emerging kinase inhibition strategies from a clinical perspective. Lastly, we outline current obstacles and future prospects in kinase inhibition.
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Neoplasias , Inhibidores de Proteínas Quinasas , Humanos , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/química , Neoplasias/tratamiento farmacológico , Terapia Molecular Dirigida/métodos , Antineoplásicos/uso terapéutico , Antineoplásicos/farmacología , AnimalesRESUMEN
Background: No standardized criteria for surgical resection of parasagittal sinus meningiomas (PSM) have been established, and different surgical strategies have been proposed. The aim of the present study was to investigate the efficacy and safety of a "radical" surgical strategy in the treatment of PSM. Methods: The clinical histories, radiological findings, pathologic features, and surgical records of 53 patients with PSM admitted by the same surgical team using the "radical" surgical strategy were retrospectively analyzed between 2018 and 2023. Results: Among the 53 PSM cases, 16 (30.2%) had a patent sinus proper, 28 (52.8%) had partial obstruction of the sinus proper, and 9 (17.0%) had complete obstruction of the sinus proper before the operation. During operation, Simpson grade I resection was performed in 34 (64.2%) cases and Simpson grade II in 19 (35.8%) cases. Postoperative pathologic examination suggested tumors of WHO grade I in 47 (88.7%) cases, WHO grade II in 4 (7.5%) cases, and WHO grade III in 2 (3.8%) cases. Postoperative complications primarily included a small amount of delayed intracerebral hemorrhage in 3 (5.7%) cases, exacerbation of cerebral edema in 3 (5.7%) cases, exacerbation of motor and sensory deficits in 4 (7.5%) cases, and intracranial infection in 2 (3.8%) cases. There were no cases of death or new-onset neurological dysfunction. Dizziness and headache symptoms improved to varying degrees, and a seizure-free status was achieved postoperatively. Excluding one case lost to follow-up, the average follow-up period was 33 months, and there were no cases of recurrence. Conclusion: A "radical" strategy for the surgical management of PSM is effective, safe, and simple to perform, provided that the sagittal sinus is properly managed and its associated veins are protected.
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Paradoxical embolism is a medical condition characterized by the migration of an embolus from a venous source into the systemic circulation. This occurs through a specific cardiac abnormality known as a right-to-left shunt, ultimately resulting in the possibility of arterial embolism. Patent foramen ovale (PFO) is the most common cause of intracardiac shunting. We reported a rare case of a 56-year-old man on hemodialysis with PFO and arteriovenous fistula dysfunction who suffered a paradoxical embolic ischemic stroke after percutaneous transluminal angioplasty. This case emphasized the potential risk of paradoxical embolism in hemodialysis patients with vascular access problems. We aimed to highlight the importance of searching for PFO, as it may serve as a possible source of embolism in these patients.
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Angioplastia , Embolia Paradójica , Diálisis Renal , Humanos , Masculino , Persona de Mediana Edad , Diálisis Renal/efectos adversos , Embolia Paradójica/etiología , Embolia Paradójica/diagnóstico , Accidente Cerebrovascular Embólico/etiología , Fallo Renal Crónico/terapia , Fallo Renal Crónico/complicaciones , Foramen Oval Permeable/complicaciones , Foramen Oval Permeable/terapia , Derivación Arteriovenosa Quirúrgica/efectos adversosRESUMEN
Zika virus (ZIKV) is an enveloped, single-stranded and positive-stranded RNA virus of the genus Flavivirus in the family Flaviviridae. ZIKV can cross the placental barrier and infect the fetus, causing microcephaly, congenital ZIKV syndrome, and even fetal death. ZIKV infection can also lead to testicular damage and male sterility. But no effective drugs and vaccines are available up to now. Previous studies have shown that the cathelicidin antimicrobial peptide LL-37 can protect against ZIKV infection. However, LL-37 is a secreted peptide, which can be easily degraded in vivo. We herein constructed exosome-loaded LL-37 (named LL-37-TM-exo and TM-LL-37-exo) using the transmembrane protein TM to load LL-37 onto the membrane of exosome. We found that exosome-loaded LL-37 could significantly inhibit ZIKV infection in vitro and in vivo, and LL-37-TM-exo had stronger antiviral activity than that of TM-LL-37-exo, which could significantly reduce ZIKV-induced testicular injury and sperm injury, and had broad-spectrum antiviral effect. Compared to free LL-37, exosome-loaded LL-37 showed a better serum stability, higher efficiency to cross the placental barrier, and stronger antiviral activity. The mechanism of exosome-loaded LL-37 against ZIKV infection was consistent with that of free LL-37, which could directly inactivate viral particles, reduce the susceptibility of host cells, and act on viral replication stage. Our study provides a novel strategy for the development of LL-37 against viral infection.
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Catelicidinas , Exosomas , Infección por el Virus Zika , Virus Zika , Femenino , Humanos , Masculino , Embarazo , Antivirales/uso terapéutico , Exosomas/metabolismo , Placenta , Replicación Viral , Virus Zika/efectos de los fármacos , Virus Zika/fisiología , Infección por el Virus Zika/prevención & control , Infección por el Virus Zika/virologíaRESUMEN
BACKGROUND: SLC25A17, a peroxisomal solute carrier, has been implicated in various physiological and pathological processes. However, its precise roles and underlying mechanisms in triple-negative breast cancer (TNBC) remain incompletely understood. METHODS: The expression and survival data of breast cancer were derived from TCGA and GEO databases. A variety of in vitro assays were conducted, including proliferation, apoptosis, cell cycle, migration, and invasion. Reactive oxygen species (ROS) were measured by immunofluorescence microscopy and flow cytometry. The levels of autophagy were assessed by mRFP-GFP-LC3 confocal microscopy scanning, western blotting, and electron microscopy. RESULTS: SLC25A17 was highly expressed in breast cancer tissues, which was found to be associated with unfavorable prognosis. Functional assays demonstrated that SLC25A17 knockdown suppressed proliferation, epithelial-mesenchymal transition (EMT), migration, and invasion. Moreover, it prompted apoptosis and autophagy. On the other hand, SLC25A17 knockdown promoted autophagy through triggering ROS accumulation, which was counteracted by N-acetyl-l-cysteine (NAC). Furthermore, the pro-apoptotic effect of SLC25A17 knockdown was reversed when treated with autophagy inhibitor 3-MA in TNBC cells, suggesting that SLC25A17 knockdown-induced autophagic cell death. Mechanistically, SLC25A17 performed its function through regulation JAK2/STAT3 signaling in TNBC. In a nude mice xenograft study, SLC25A17 knockdown markedly decreased breast tumor growth and metastasis. CONCLUSION: SLC25A17 up-regulation may be a critical factor driving TNBC progression by modulating ROS production and autophagy. Consequently, targeting SLC25A17 could be an effective therapeutic strategy against TNBC.
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Identification of cytotoxic T lymphocyte (CTL) epitopes from tumor related antigens is a promising approach for malignant tumor immunotherapy. TC2N, a recently identified tumor associated antigen from human glioblastoma, is regarded as a promising target of tumor-specific immunotherapy. As one of the most widely used histocompatibility molecules in Chinese is HLA-A*0201, we were able to identify the TC2N peptides that are provided by this molecular type. A panel of antigenic peptides produced from TC2N were predicted by using a computer tool. The binding affinities of three peptides with the highest predicted score to the HLA-A*0201 molecule were evaluated after synthesis. In vitro and in vivo stimulation of the main T-cell response against the predicted peptides. The results demonstrated that TC2N (152-160) was able to release IFN-γ and lyse U251 cells in vitro as well as in vivo by eliciting peptide-specific CTLs. Our results indicated that peptide TC2N (152-160) (RLYGSVCDL) was a novel HLA-A2.1-restricted CTL epitope capable of inducing TC2N specific CTLs in vitro. As TC2N might qualify as a viable target for immunotherapeutic approaches for patients with GBM, we speculated that the newly identified epitope RLYGSVCDL would be of potential use in peptide-based, cancer-specific immunotherapy against GBM.
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Background: Chemotherapy-induced thrombocytopenia (CIT) is a common hematological complication in patients with cancer. Hetrombopag is a novel thrombopoietin receptor agonist that has shown an additive effect in stimulating platelet production when combined with recombinant human thrombopoietin (rhTPO). Objectives: This multicenter retrospective cohort study aimed to evaluate the efficacy and safety of hetrombopag plus rhTPO compared with rhTPO alone for CIT. Methods: A total of 294 patients with solid tumors and CIT (platelet count, <50 × 109/L) who received either rhTPO plus hetrombopag (146 patients) or rhTPO alone (148 patients) at 3 centers from January to December 2022 were included in the study. The primary outcome was a platelet count at least 50 × 109/L higher than the baseline value within 14 days. Chemotherapy dose reductions/delays, bleeding, and adverse events were reported. Results: One hundred twenty patients (82.2%) in the rhTPO-hetrombopag group vs 100 patients (67.6%) in the rhTPO group achieved the primary outcome (P = .005). This significant difference persisted in adjusted analysis (odds ratio, 2.01; 95% CI, 1.12-3.60). A total of 115 patients (78.8%) in the rhTPO-hetrombopag group and 101 patients (68.2%) in the rhTPO group avoided chemotherapy dose reductions/delays (P = .041). There was no significant difference in bleeding rates, and adverse events were mild and similar between the 2 groups. No deaths occurred. Conclusion: Compared to rhTPO alone, our findings suggest that the combination of hetrombopag and rhTPO is safe and more effective in patients with CIT.
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BACKGROUND: Intracerebral hemorrhage (ICH) is a serious medical problem, and promising strategy is limited. Macrophage initiated brain inflammatory injury following ICH, but the molecular mechanism had not been well identified. E3 ligase Nedd4L is implicated in the pathogenesis of the inflammatory immune response. METHODS: In the present study, we detected the levels of Nedd4L in macrophages following ICH. Furthermore, Macrophage M1 polarization, pro-inflammatory cytokine production, BBB disruption, brain water content and neurological function were examined in ICH mice. RESULTS: Here, we demonstrated that E3 ligase Nedd4L levels of macrophage increased following ICH, promoted M1 polarization inflammation by TRAF3. Nedd4L promoted BBB disruption, as well as neurological deficits. Inhibition of Nedd4L significantly attenuated M1 polarization in vivo. Inhibition of Nedd4L decreased TRAF3 and TBK1 levels, and subsequent phosphorylation of p38 and NF-κB p65 subunit following ICH. CONCLUSIONS: Our data demonstrated that Nedd4L was involved in the pathogenesis of ICH, which promoted inflammatory responses and exacerbated brain damage by TRAF3 following ICH.
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Encéfalo , Hemorragia Cerebral , Ubiquitina-Proteína Ligasas Nedd4 , Factor 3 Asociado a Receptor de TNF , Animales , Ratones , Encéfalo/inmunología , Encéfalo/patología , Hemorragia Cerebral/inmunología , Hemorragia Cerebral/patología , Macrófagos/enzimología , Macrófagos/inmunología , Transducción de Señal/fisiología , Factor 3 Asociado a Receptor de TNF/metabolismo , Ubiquitina-Proteína Ligasas Nedd4/metabolismoRESUMEN
Developing antibiotic-free treatment strategies to cope with the crisis on drug-resistant bacteria, are urgently needed. Antibiotics-independent physical approaches, especially the non-invasive phototherapies, worked through the assistance of photosensitizer (PS), have geared intensive attention and interests. Here, composite porphyrin-based conjugated microporous polymer/graphene oxide, denoted as GO-TAPP, combining the advantages of each component perfectly, was developed as broad-spectrum antibacterial agent. GO-TAPP, prepared via the self-oxidation coupling of tetraethynyl porphyrin on the surface of graphene oxide, could exert synergistic photothermal (PTT, ascribed to the graphene) and photodynamic (PDT, derived from the Porphyrin polymer) antimicrobial effectiveness. Both the in vivo and in vitro experiments have confirmed GO-TAPP are extremely potent against the Gram-positive (Staphylococcus aureus) and Gram-negative (Escherichia coli) pathogens, which presents a remarkably enhanced sterilizing effect in comparison with its counterparts (the bare GO, and TAPP). Meanwhile, the synergistic effect of GO-TAPP could significantly accelerate the healing of open wound infected by bacterial. Altogether, this work proposed a new approach for the rational preparation of highly biocompatible graphene-based composite materials as antibiotic-free agents with synergistic antibacterial effect to combat bacterial infections.
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Grafito , Porfirinas , Grafito/farmacología , Porfirinas/farmacología , Antibacterianos/farmacología , Escherichia coli , Cicatrización de HeridasRESUMEN
HER2 is highly expressed in a variety of malignant tumors and affects the prognosis of patients, making it a highly sensitive target for cancer therapy. Since the approval of the first HER2 inhibitor, trastuzumab, in 1998, HER2-targeted drugs have rapidly evolved. Currently, targeting HER2 drugs mainly include monoclonal antibodies (mAbs), tyrosine kinase inhibitors (TKIs), and antibody-drug conjugates (ADCs). This article reviews the development of HER2 inhibitors for various tumors over the past 20 years.
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PURPOSE: This study aimed to analyze the interindividual differences of the maximal oxygen uptake (VÌO 2max ) response to 12 wk of high-intensity interval training (HIIT), and the genotype-phenotype models were constructed to predict the effect of HIIT on VÌO 2max . METHODS: A total of 228 physically inactive adults who completed a 12-wk HIIT were analyzed. A genome-wide association study (GWAS) was conducted to identify genetic variants associated with the VÌO 2max response. Nonresponders, responders, and the highest training responders were defined as the effect sizes (ES) <0.2, ≥0.2, and ≥0.8, respectively. We generated polygenic predictor score (PPS) using lead variants and constructed a predictive model for VÌO 2max response based on a linear stepwise regression analysis. RESULTS: The VÌO 2max increased significantly after HIIT (~14%, P < 0.001), but with interindividual differences (-7.8 to 17.9 mL·kg -1 ·min -1 ). In 27% of participants, the VÌO 2max showed no improvement. We identified one genetic locus near the γ-aminobutyric acid type A receptor subunit beta 3 gene ( GABRB3 , rs17116985) associated with VÌO 2max response at the genome-wide significance level ( P < 5 × 10 -8 ), and an additional nine single nucleotide polymorphisms (SNPs) at the suggestive significance level ( P < 1 × 10 -5 ). The SNPs rs474377, rs9365605, and rs17116985, respectively, explained 11%, 9%, and 6.2% of variance in VÌO 2max response. The 13 SNPs ( P < 1 × 10 -5 ) were found on chromosome 6 (position: 148209316-148223568). Individuals with a PPS greater than 1.757 had the highest response, and those with a PPS lower than -3.712 were nonresponders. The PPS, baseline VÌO 2max , sex, and body mass explained 56.4% of the variance in the VÌO 2max response; the major predictor was the PPS, which explained 39.4% of the variance. CONCLUSIONS: The PPS, baseline VÌO 2max , sex, and body mass could explain the variance in VÌO 2max response. Individuals who had a PPS greater than 1.757 had the highest training response after 12 wk of HIIT. Genetic variants in a region on chromosome 6, especially the sterile alpha motif domain containing 5 gene ( SAMD5 ), which had been explored influencing angiogenesis, might have a potential role in the VÌO 2max response.
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Entrenamiento de Intervalos de Alta Intensidad , Adulto , Humanos , Estudio de Asociación del Genoma Completo , Pueblos del Este de Asia , Consumo de Oxígeno/fisiología , Fenotipo , GenotipoRESUMEN
The intercalation of cetyltrimethylammonium bromide (CTMAB) into montmorillonite will cause interlayer expansion and surface charge reversal. In this study, CTMAB-Mt is prepared by adding CTMAB with different multiples of montmorillonite cation exchange capacity (CEC), and the intercalated CTMAB structural arrangement, as well as the dynamics behavior, are investigated by combining molecular dynamics (MD) simulation with experimental characterization. According to RDF analysis of MD simulations, the interaction between CTMA+ and the surface of montmorillonite is mostly electrostatic interaction and hydrogen bond production. At low loading (≤1.00CEC), the XRD profile exhibits a peak value corresponding to one type of intercalation structure and interlayer spacing, but at high loading (>1.00CEC), two peaks are visible, each of which has a fixed value but a varied strength, corresponding to the existence of two types of expanded structures. The d-spacing (d 001) values obtained from MD simulations are quite close to XRD values when CTMAB loading is lower than 1.00CEC. Density distribution profiles obtained from MD analysis reveal that as loading increases, CTMA+ is arranged in the interlayer from a monolayer to a bilayer and then to a pseudo-trilayer. At high loadings (>1.00CEC), due to the fact that the excess loading leads to inhomogenous intercalation, XRD demonstrates the existence of two different arrangements: bilayer and pseudo-trilayer. The self-diffusion coefficients of MD simulations show that the dynamic behavior of CTMA+ is influenced by both the interlayer space and the electrostatic interaction of the montmorillonite clay. The abrupt rise in interlayer spacing increases mobility, whereas the increased interaction between alkyl chains decreases mobility.
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Background: Elevated expression of Copine-1 (CPNE1) has been proved in various cancers; however, the underlying mechanisms by which it affects clear cell renal cell carcinoma (ccRCC) are unclear. Methods: In this study, we applied multiple bioinformatic databases to analyze the expression and clinical significance of CPNE1 in ccRCC. Co-expression analysis and functional enrichment analysis were investigated by LinkedOmics, cBioPortal and Metascape. The relationships between CPNE1 and tumor immunology were explored using ESTIMATE and CIBERSORT method. In vitro experiments, CCK-8, wound healing, transwell assays and western blotting were conducted to investigate the effects of gain- or loss-of-function of CPNE1 in ccRCC cells. Results: The expression of CPNE1 was notably elevated in ccRCC tissues and cells, and significantly correlated with grade, invasion range, stage and distant metastasis. Kaplan-Meier and Cox regression analysis displayed that CPNE1 expression was an independent prognostic factor for ccRCC patients. Functional enrichment analysis revealed that CPNE1 and its co-expressed genes mainly regulated cancer-related and immune-related pathways. Immune correlation analysis showed that CPNE1 expression was significantly related to immune and estimate scores. CPNE1 expression was positively related to higher infiltrations of immune cells, such as CD8+ T cells, plasma cells and regulatory T cells, exhibited lower infiltrations of neutrophils. Meanwhile, elevated expression of CPNE1 was characterized by high immune infiltration levels, increased expression levels of CD8+ T cell exhaustion markers (CTLA4, PDCD1 and LAG3) and worse response to immunotherapy. In vitro functional studies demonstrated that CPNE1 promoted proliferation, migration and invasion of ccRCC cells through EGFR/STAT3 pathway. Conclusion: CPNE1 is a reliable clinical predictor for the prognosis of ccRCC and promotes proliferation and migration by activating EGFR/STAT3 signaling. Moreover, CPNE1 significantly correlates with immune infiltration in ccRCC.
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Background: Acute thrombus in atrial septal defect occluders is a rare complication that requires aggressive, effective, and safe management. Tirofiban, a platelet glycoprotein IIb/IIIa receptor antagonist, is widely used for the management of thromboembolic diseases, such as coronary heart disease and stroke. To date, there is no report using the GPIIb/IIIa receptor antagonist tirofiban for the management of ASD closure-related thrombosis in children. Case presentation: Herein, we reported a case of a 5-year-old girl with ASD who presented with acute thrombus on the left disc of the occluder device immediately after transcatheter closure of ASD. The thrombus was successfully dissolved 24â h after a combined infusion of heparin and tirofiban, followed by 1 months of aspirin and clopidogrel and 5 months of aspirin alone. No thromboembolism or hemorrhage events occurred during follow-up for more than 2 years. Conclusion: The continuous infusion of GPIIb/IIIa receptor antagonist tirofiban combined with heparin may have beneficial effects for the management of thrombosis during ASD closure procedure.
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Background: Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) is a mitochondrial bifunctional enzyme encoded in the nucleus. It plays a significant role in the regulation of glucose, nucleic acid, and folate metabolism, and maintains redox balance in the cells. The present study aimed at elucidating the potential function and mechanisms of MTHFD2 and explored the correlation between ferroptosis and MTHFD2 in triple-negative breast cancer. Methods: MTHFD2 expression, survival analysis, and clinical correlation were performed using data from various online databases including TCGA, GEO, HPA, GTEX, Kaplan-Meier Plotter, PrognoScan, and UALCAN databases. Genomic alterations and CNV analysis were performed using the cBioPortal and GSCA databases. Potential functions and mechanisms were explored by enrichment analysis. The tumor microenvironment was identified by the TIMER database. In vitro, RT-qPCR and western blot assays were utilized to identify the MTHFD2 expression and the knockdown effects in breast cancer. CCK8, cell wound healing, transwell, and flow cytometry assays were used to identify the potential function of MTHFD2 in TNBC cells. MDA, GSH detection, and flow cytometry assays were performed to identify ferroptosis. Western blot assays were performed to measure the protein expression of all target genes. Results: MTHFD2 expression levels were up-regulated in the majority of cancers and particularly in TNBC, in which higher expression levels indicated a poorer prognosis. Enrichment analyses showed that MTHFD2 is involved in various tumor-related biological processes. MTHFD2 expression was found to strongly correlate with multiple immune cell infiltration. In vitro, the knockdown of MTHFD2 suppresses the proliferation, apoptosis, migration, and invasion in TNBC cells. In addition, the MTHFD2 knockdown significantly enhanced intracellular ROS and lipid peroxidation and decreased intracellular GSH. The expressions of SLC7A11, GPX4, and NRF2 were down-regulated by the MTHFD2 knockdown. Conclusion: MTHFD2 could be a crucial molecular biomarker for predicting patient prognosis and a novel therapeutic target in TNBC. In addition, MTHFD2 is a potential ferroptosis regulatory gene in TNBC.
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BACKGROUND: Intracerebral hemorrhage (ICH) is a serious disease with high mortality and morbidity, and effective treatment is limited. A large amount of evidence suggests that the inflammatory response contributes to secondary brain damage following ICH. TIPE2 is an essential negative regulator of both innate and adaptive immunity, and depletion of TIPE2 causes inflammatory disease. However, the possible role of TIPE2 following ICH has not been reported. METHODS: In this study, we investigated TIPE2 levels and inflammation in microglia treated with erythrocyte lysate in vitro. In addition, we analyzed the role of Bcl-2/Bax/cleaved caspase-3 apoptotic pathways in ICH mice. Furthermore, we observed proinflammatory cytokine production, BBB disruption, cerebral water content and neurological damage in ICH mice. RESULTS: We found that TIPE2 levels were significantly decreased in erythrocyte lysate-treated microglia compared to control microglia.Upregulation of TIPE2 decreased microglia activation and cytokine production and accelerated brain damage in ICH mice. Furthermore, upregulation of TIPE2 decreased the higher ratio of Blc-2/Bax and increased cleaved caspase-3 levels in ICH mice. In addition, upregulation of TIPE2 attenuated proinflammatory cytokine production, BBB disruption, and severe brain inflammation after ICH. CONCLUSION: These results demonstrated that TIPE2 was negatively correlated with the pathogenesis of ICH, which prevented brain injury and attenuated deleterious inflammatory responses following ICH. TIPE2 might serve as a novel target for ICH therapy.
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Lesiones Encefálicas , Enfermedades Neuroinflamatorias , Animales , Ratones , Caspasa 3/metabolismo , Proteína X Asociada a bcl-2/metabolismo , Ratones Endogámicos C57BL , Hemorragia Cerebral/metabolismo , Lesiones Encefálicas/complicaciones , Microglía/metabolismo , Citocinas/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismoRESUMEN
BACKGROUND: Mild hypothermia has been identified to reduce brain injury following intracerebral hemorrhage (ICH) by protecting neuron cells through several pathways. However, the role of hypothermia in brain function following ICH and the related mechanisms have not been well identified. Ubiquitination-mediated inflammation plays important roles in the pathogenesis of immune diseases. The experiment analyzed anti-inflammatory effects of mild hypothermia following ICH. METHODS: The model of ICH was induced by injecting autologous blood. Neuregulin receptor degradation protein-1 (Nrdp1) and downstream molecule were analyzed. In addition, brain inflammatory response, brain edema, and neurological functions of ICH mice were also assessed. RESULTS: We found that mild hypothermia attenuated proinflammatory factors production after ICH. Mild hypothermia significantly inhibited BBB injury, water content, and neurological damage following ICH in vivo. Moreover, mild hypothermia also increased Nrdp1/MyD88 levels and thus affect neuronal apoptosis and inflammation. CONCLUSIONS: Taken together, these results suggest that mild hypothermia can attenuate the neuroinflammatory response and neuronal apoptosis after ICH through the regulation of the Nrdp1 levels.
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Edema Encefálico , Lesiones Encefálicas , Hipotermia , Ratones , Animales , Factor 88 de Diferenciación Mieloide/metabolismo , Neurregulinas/metabolismo , Hipotermia/complicaciones , Hemorragia Cerebral/patología , Lesiones Encefálicas/patología , Edema Encefálico/prevención & control , Edema Encefálico/complicaciones , Inflamación/patología , Transducción de SeñalRESUMEN
BACKGROUND: The status of children's early motor skills play an important role during childhood and across lifetime. This study described FMS proficiency among boys (n = 189) and girls (n = 179) kindergarten children from 3 to 6 years old (4.4 s 0.7, mean ± SD) in northwest China. The differences in FMS proficiency of boys and girls from different environments, ethnic groups were analyzed respectively. METHODS: TGMD-3 was used to assess FMS. FMS mastery level was defined according to the correct performance of all criteria over two trials. The correlation between BMI and FMS and the interaction of environmental and ethnic on FMS were analyzed. The general linear model was used to evaluate the differences of boys and girls among environment groups (urban/suburban/county), and ethnic groups (Han/Hui/Tibetan) on the FMS subsets respectively. RESULTS: FMS proficiency was assessed in 368 3- to 6-year-old children (n = 156 urban, n = 101 suburban, n = 111 county)/(n = 208 Han, n = 107 Hui, n = 53 Tibetan). Overall, the highest skill performance was the run, with 86% achieving mastery level, and the poorest performance was the FH strike, at only 19%. Correlation between BMI and FMS is minimal. According to TGMD-3 scores, there was no significant difference between boys and girls in total FMS (p = 0.38). In terms of locomotor skills, boys performed better than girls in the hop, skip and slide (p < 0.05). County children performed significantly difference than urban and suburban children. Some skills performed less proficiently, (boys in 6 of 13 skills: run, HJ, slide, TH strike, FH strike and kick; girls in 4 of 13 skills: run, slide, TH strike and kick) and some skills performed more proficiently (boys in dribble; girls in hop and dribble). Tibetan children performed significantly difference than Han and Hui children. Some skills performed less proficiently, (boys in 6 of 13 skills: run, HJ, slide, TH strike, FH strike and kick; girls in TH strike) and some skills performed more proficiently (boys and girls were all in dribble). CONCLUSION: Children in northwest China showed certain characteristics in FMS, the county/Tibetan boys and girls performed poorer than others in ability to execute particular process characteristics of some skills and performed more outstanding in other skills. It suggests that a certain group population may need specific focus on interventions to improve their FMS level.