RESUMEN
Mitochondria, which play central roles in immunometabolic diseases, have their own genome. However, the functions of mitochondria-located noncoding RNAs are largely unknown due to the absence of a specific delivery system. By circular RNA (circRNA) expression profile analysis of liver fibroblasts from patients with nonalcoholic steatohepatitis (NASH), we observe that mitochondrial circRNAs account for a considerable fraction of downregulated circRNAs in NASH fibroblasts. By constructing mitochondria-targeting nanoparticles, we observe that Steatohepatitis-associated circRNA ATP5B Regulator (SCAR), which is located in mitochondria, inhibits mitochondrial ROS (mROS) output and fibroblast activation. circRNA SCAR, mediated by PGC-1α, binds to ATP5B and shuts down mPTP by blocking CypD-mPTP interaction. Lipid overload inhibits PGC-1α by endoplasmic reticulum (ER) stress-induced CHOP. In vivo, targeting circRNA SCAR alleviates high fat diet-induced cirrhosis and insulin resistance. Clinically, circRNA SCAR is associated with steatosis-to-NASH progression. Collectively, we identify a mitochondrial circRNA that drives metaflammation and serves as a therapeutic target for NASH.
Asunto(s)
Mitocondrias/genética , ATPasas de Translocación de Protón Mitocondriales/genética , ARN Circular/genética , Animales , Línea Celular , Dieta Alta en Grasa , Estrés del Retículo Endoplásmico/fisiología , Fibroblastos/metabolismo , Fibroblastos/patología , Expresión Génica/genética , Humanos , Resistencia a la Insulina , Hígado/patología , Cirrosis Hepática/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Mitocondrias/metabolismo , Poro de Transición de la Permeabilidad Mitocondrial/metabolismo , ATPasas de Translocación de Protón Mitocondriales/metabolismo , Enfermedad del Hígado Graso no Alcohólico/genética , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismo , ARN Circular/metabolismo , Especies Reactivas de Oxígeno , Transcriptoma/genéticaRESUMEN
BACKGROUND: The Hippo-YAP (yes-associated protein) signaling pathway is modulated in response to various environmental cues. Activation of YAP in vascular smooth muscle cells conveys the extracellular matrix stiffness-induced changes in vascular smooth muscle cells phenotype and behavior. Recent studies have established a mechanoreceptive role of receptor tyrosine kinase DDR1 (discoidin domain receptor 1) in vascular smooth muscle cells. METHODS: We conduced 5/6 nephrectomy in vascular smooth muscle cells-specific Ddr1-knockout mice, accompanied by pharmacological inhibition of the Hippo pathway kinase LATS1 (large tumor suppressor 1), to investigate DDR1 in YAP activation. We utilized polyacrylamide gels of varying stiffness or the DDR1 ligand, type I collagen, to stimulate the cells. We employed multiple molecular biological techniques to explore the role of DDR1 in controlling the Hippo pathway and to determine the mechanistic basis by which DDR1 exerts this effect. RESULTS: We identified the requirement for DDR1 in stiffness/collagen-induced YAP activation. We uncovered that DDR1 underwent stiffness/collagen binding-stimulated liquid-liquid phase separation and co-condensed with LATS1 to inactivate LATS1. Mutagenesis experiments revealed that the transmembrane domain is responsible for DDR1 droplet formation. Purified DDR1 N-terminal and transmembrane domain was sufficient to drive its reversible condensation. Depletion of the DDR1 C-terminus led to failure in co-condensation with LATS1. Interaction between the DDR1 C-terminus and LATS1 competitively inhibited binding of MOB1 (Mps one binder 1) to LATS1 and thus the subsequent phosphorylation of LATS1. Introduction of the single-point mutants, histidine-745-proline and histidine-902-proline, to DDR1 on the C-terminus abolished the co-condensation. In mouse models, YAP activity was positively correlated with collagen I expression and arterial stiffness. LATS1 inhibition reactivated the YAP signaling in Ddr1-deficient vessels and abrogated the arterial softening effect of Ddr1 deficiency. CONCLUSIONS: These findings identify DDR1 as a mediator of YAP activation by mechanical and chemical stimuli and demonstrate that DDR1 regulates LATS1 phosphorylation in an liquid-liquid phase separation-dependent manner.
Asunto(s)
Vía de Señalización Hippo , Histidina , Ratones , Animales , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Transducción de Señal , Colágeno , Colágeno Tipo IRESUMEN
Many real-world scenarios involve interfaces, particularly liquid-liquid interfaces, that can fundamentally alter the dynamics of colloids. This is poorly understood for chemically active colloids that release chemicals into their environment. We report here the surprising discovery that chemical micromotorsâcolloids that convert chemical fuels into self-propulsionâmove significantly faster at an oil-water interface than on a glass substrate. Typical speed increases ranged from 3 to 6 times up to an order of magnitude and were observed for different types of chemical motors and interfaces made with different oils. Such speed increases are likely caused by faster chemical reactions at an oil-water interface than at a glass-water interface, but the exact mechanism remains unknown. Our results provide valuable insights into the complex interactions between chemical micromotors and their environments, which are important for applications in the human body or in the removal of organic pollutants from water. In addition, this study also suggests that chemical reactions occur faster at an oil-water interface and that micromotors can serve as a probe for such an effect.
RESUMEN
Emerging evidence has demonstrated the significant contribution of mitochondrial metabolism dysfunction to promote cancer development and progression. Aberrant expression of mitochondrial genome (mtDNA)-encoded proteins widely involves mitochondrial metabolism dysfunction, and targeted regulation of their expression can be an effective strategy for cancer therapy, which however is challenged due to the protection by the mitochondrial double membrane. Herein, a mitochondria-targeted RNAi nanoparticle (NP) platform for effective regulation of mitochondrial metabolism and breast cancer (BCa) therapy is developed. This nanoplatform is composed of a hydrophilic polyethylene glycol (PEG) shell, a hydrophobic poly(2-(diisopropylamino)ethyl methacrylate) (PDPA) core, and charged-mediated complexes of mitochondria-targeting and membrane-penetrating peptide amphiphile (MMPA) and small interfering RNA (siRNA) embedded in the core. After tumor accumulation and internalization by tumor cells, these NPs can respond to the endosomal pH to expose the MMPA/siRNA complexes, which can specifically transport siRNA into the mitochondria to down-regulate mtDNA-encoded protein expression (e.g., ATP6 and CYB). More importantly, because ATP6 down-regulation can suppress ATP production and enhance reactive oxygen species (ROS) generation to induce mitochondrial damage and mtDNA leakage into tumor tissues, the NPs can combinatorially inhibit tumor growth via suppressing ATP production and repolarizing tumor-associated macrophages (TAMs) into tumor-inhibiting M1-like macrophages by mtDNA.
Asunto(s)
Neoplasias de la Mama , Nanopartículas , Propionatos , Compuestos de Sulfhidrilo , Humanos , Femenino , Interferencia de ARN , Neoplasias de la Mama/patología , ARN Interferente Pequeño/genética , Nanopartículas/química , Péptidos/metabolismo , Mitocondrias/metabolismo , ADN Mitocondrial , Adenosina Trifosfato , Línea Celular TumoralRESUMEN
Candida albicans is the most frequent pathogen of fungal sepsis associated with substantial mortality in critically ill patients and those who are immunocompromised. Identification of novel immune-based therapeutic targets from a better understanding of its molecular pathogenesis is required. Here, we reported that the production of progranulin (PGRN) levels was significantly increased in mice after invasive C.albicans infection. Mice that lacked PGRN exhibited attenuated kidney injury and increased survival upon a lethal systemic infection with C. albicans. In mice, PGRN deficiency protected against systemic candidiasis by decreasing aberrant inflammatory reactions that led to renal immune cell apoptosis and kidney injury, and by enhancing antifungal capacity of macrophages and neutrophils that limited fungal burden in the kidneys. PGRN in hematopoietic cell compartment was important for this effect. Moreover, anti-PGRN antibody treatment limited renal inflammation and fungal burden and prolonged survival after invasive C. albicans infection. In vitro, PGRN loss increased phagocytosis, phagosome formation, reactive oxygen species production, neutrophil extracellular traps release, and killing activity in macrophages or neutrophils. Mechanistic studies demonstrated that PGRN loss up-regulated Dectin-2 expression, and enhanced spleen tyrosine kinase phosphorylation and extracellular signal-regulated kinase activation in macrophages and neutrophils. In summary, we identified PGRN as a critical factor that contributes to the immunopathology of invasive C.albicans infection, suggesting that targeting PGRN might serve as a novel treatment for fungal infection.
Asunto(s)
Candida albicans , Sepsis , Animales , Antifúngicos , Quinasas MAP Reguladas por Señal Extracelular , Ratones , Neutrófilos , Progranulinas , Especies Reactivas de Oxígeno/metabolismo , Sepsis/patología , Quinasa SykRESUMEN
The members of the classic B7 family regulate the immune microenvironment of several malignant tumors. However, the potential relationship between the B7 family and the breast cancer (BrCa) tumor immune microenvironment has remained elusive. In the present study, we provide a comprehensive explanation of the expression, clinical significance, mutation, and immune cell infiltration of B7 family molecules in BrCa. First, we recruited 10 patients with BrCa surgery from the Wuxi Maternal and Child Health Hospital and performed single-cell RNA sequencing (scRNA-seq) analysis to investigate the distribution of B7 family members in multiple immune cell subsets. We focused on B7-2, B7-H3, and B7-H5 molecules of the B7 family and constructed tumor microarrays by self-recruiting patients to perform multiple immunohistochemical (mIHC) analyses and study tumor expression of B7-2, B7-H3, B7-H5 and CD8+ immune cell infiltration. B7-H5 displayed a strong correlation with CD8+ immune cell infiltration. In summary, B7-H5 provides a new perspective for the identification of immunothermal subtypes of BrCa and could function as a switch to reverse BrCa from an "immunologically cold" state to an "immunologically hot" state.
RESUMEN
Breast cancer (BC) is the second-leading factor of mortality for women globally and is brought on by a variety of genetic and environmental causes. The conventional treatments for this disease have limitations, making it difficult to improve the lifespan of breast cancer patients. As a result, extensive research has been conducted over the past decade to find innovative solutions to these challenges. Targeting of the antitumor immune response through the immunomodulatory checkpoint protein B7 family has revolutionized cancer treatment and led to intermittent patient responses. B7-H3 has recently received attention because of its significant demodulation and its immunomodulatory effects in many cancers. Uncontrolled B7-H3 expression and a bad outlook are strongly associated, according to a substantial body of cancer research. Numerous studies have shown that BC has significant B7-H3 expression, and B7-H3 induces an immune evasion phenotype, consequently enhancing the survival, proliferation, metastasis, and drug resistance of BC cells. Thus, an innovative target for immunotherapy against BC may be the B7-H3 checkpoint.In this review, we discuss the structure and regulation of B7-H3 and its double costimulatory/coinhibitory function within the framework of cancer and normal physiology. Then we expound the malignant behavior of B7-H3 in BC and its role in the tumor microenvironment (TME) and finally focus on targeted drugs against B7-H3 that have opened new therapeutic opportunities in BC.
Asunto(s)
Neoplasias de la Mama , Humanos , Femenino , Neoplasias de la Mama/tratamiento farmacológico , Antígenos B7/metabolismo , Inmunoterapia , Inmunomodulación , Microambiente TumoralRESUMEN
Cyclic GMP-AMP synthase (cGAS) functions as a key sensor for microbial invasion and cellular damage by detecting emerging cytosolic DNA. Here, we report that GTPase-activating protein-(SH3 domain)-binding protein 1 (G3BP1) primes cGAS for its prompt activation by engaging cGAS in a primary liquid-phase condensation state. Using high-resolution microscopy, we show that in resting cells, cGAS exhibits particle-like morphological characteristics, which are markedly weakened when G3BP1 is deleted. Upon DNA challenge, the pre-condensed cGAS undergoes liquid-liquid phase separation (LLPS) more efficiently. Importantly, G3BP1 deficiency or its inhibition dramatically diminishes DNA-induced LLPS and the subsequent activation of cGAS. Interestingly, RNA, previously reported to form condensates with cGAS, does not activate cGAS. Accordingly, we find that DNA - but not RNA - treatment leads to the dissociation of G3BP1 from cGAS. Taken together, our study shows that the primary condensation state of cGAS is critical for its rapid response to DNA.
Asunto(s)
ADN Helicasas , Nucleotidiltransferasas , Proteínas de Unión a Poli-ADP-Ribosa , ARN Helicasas , Proteínas con Motivos de Reconocimiento de ARN , ADN/metabolismo , ADN Helicasas/genética , ADN Helicasas/metabolismo , Nucleotidiltransferasas/metabolismo , Proteínas de Unión a Poli-ADP-Ribosa/genética , Proteínas de Unión a Poli-ADP-Ribosa/metabolismo , ARN Helicasas/genética , ARN Helicasas/metabolismo , Proteínas con Motivos de Reconocimiento de ARN/genética , Proteínas con Motivos de Reconocimiento de ARN/metabolismo , Gránulos de EstrésRESUMEN
Highly efficient and practical carbon-chalcogen (S, Se) and amide bonds formation methodologies for the synthesis of thio- and seleno-acetamides were developed, via the base-promoted one-pot two-step reactions of 2-amino(benzo)thiazoles and aryl acetyl chlorides with dichalcogenides. This cross-coupling reaction afforded the goal products that had been chalcogenated regioselectively in moderate to good yields. Further transformations of the new synthesized compounds, DFT calculations and preliminary mechanism studies are discussed as well.
RESUMEN
Exploring a novel photocatalyst for catalytic oxidation of toluene is a sustainable strategy for energy conversion in times of an energy crisis. However, designing an effective photocatalyst for the conversion of toluene remains challenging. Herein, a novel organic monophosphonate-modified high nucleus Cu-incorporated polyoxotungstate, K8H33[{Cu0.5(H2O)4}{Cu2(O3PCH2COO)(1,4,9-α-P2W15O56)}]4·Cl·60H2O (1), has been intentionally synthesized by a self-assembly process utilizing conventional aqueous method. It reveals that 1 contains a polyanion of [{Cu0.5(H2O)}4{Cu2(O3PCH2COO)(1,4,9-α-P2W15O56)}]440- composed of four Dawson-type {1,4,9-α-P2W15} subunits, forming an oval-shaped structure and further connecting into a three-dimensional (3D) framework by lateral {Cu(H2O)4}2+. Interestingly, the trivacant {1,4,9-α-P2W15} subunits were observed in the organophosphonate acid-functionalized polyoxometalates for the first time. Notably, 1 exhibits a wonderful performance in catalytic oxidation of the recalcitrant C(sp3)-H bond of toluene to benzoic acid with a conversion as high as 97% under visible light utilizing O2 as an oxidant.
RESUMEN
Under xenon lamps, ZnFe2O4 (ZFO) has been shown to be effective in removing uranium through photocatalysis. However, its performance is still inadequate in low-light environments due to low photon utilization and high electron-hole complexation. Herein, S-doped hollow ZnFe2O4 microcubes (Sx-H-ZFO, x = 1, 3, 6, 9) were synthesized using the MOF precursor template method. The hollow morphology improves the utilization of visible light by refracting and reflecting the incident light multiple times within the confined domain. S doping narrows the band gap and shifts the conduction band position negatively, which enhances the separation, migration, and accumulation of photogenerated charges. Additionally, S doping increases the number of adsorption sites, ultimately promoting efficient surface reactions. Consequently, Sx-H-ZFO is capable of removing U(VI) in low-light environments. Under cloudy and rainy weather conditions, the photocatalytic rate of S3-H-ZFO was 100.31 µmol/(g·h), while under LED lamps (5000 Lux) it was 72.70 µmol/(g·h). More interestingly, a systematic mechanistic investigation has revealed that S doping replaces some of the oxygen atoms to enhance electron transfers and adsorption of O2. This process initiates the formation of hydrogen peroxide, which reacts directly with UO22+ to form solid studtite (UO2)O2·2H2O. Additionally, the promising magnetic separation capability of Sx-H-ZFO facilitates the recycling and reusability of the material. This work demonstrates the potential of ZnFe2O4 extraction uranium from nuclear wastewater.
RESUMEN
AIMS: Elevated levels of adipokine chemerin have been identified in oral squamous cell carcinoma (OSCC) and found to be associated with metastasis to the cervical lymph nodes. The underlying mechanism through which chemerin affects OSCC progression is unclear. The aims of this study were firstly to determine chemerin levels and cytokine concentrations in serum from patients with OSCC and in OSCC cell cultures, and secondly to observe chemerin effects on OSCC cell cytokine secretion, migration, and invasion in vitro. METHODS: Serum samples were collected from 20 patients diagnosed with OSCC, including groups with (LN+) and without (LN-) cervical lymph node metastasis. A Luminex liquid suspension assay was used to quantify serum concentrations of 27 types of cytokines. Correlations between chemerin and cytokines (i.e., IL-6, IL-15, GM-CSF, RANTES, TNF-α, and VEGF) were analyzed. ELISAs (enzyme-linked immunosorbent assays) were used to determine concentrations of chemerin and selected cytokines in serum and in supernatants of OSCC cell cultures (SCC9 and SCC25 cell lines). OSCC cells were stimulated with human recombinant chemerin, STAT3 inhibitor, or IL-6 together with TNF-α neutralizing antibodies. Phosphorylated STAT3 protein levels were measured with western blot analysis. OSCC cell migration and invasion were investigated with Transwell assays. RESULTS: Compared to the LN- group, OSCC patients with cervical lymph node metastasis had higher levels of IL-6 (P = 0.006), IL-15 (P = 0.020), GM-CSF (P = 0.036), RANTES (P = 0.032), TNF-α (P = 0.005), VEGF (P = 0.006), and chemerin (P = 0.001). Patients' serum chemerin levels correlated directly with IL-6, GM-CSF, TNF-α, and VEGF levels in OSCC patients. Exogenous recombinant chemerin treatment promoted secretion of IL-6 and TNF-α via activation of STAT3 in OSCC cells. Chemerin induced OSCC-cell migration and invasion, and these effects were reduced by IL-6 and TNF-α neutralizing antibodies. CONCLUSION: Our findings indicate that chemerin may play a role in advancing OSCC progression by increasing production of IL-6 and TNF-α, perhaps via a mechanism involving STAT3 signaling.
Asunto(s)
Carcinoma de Células Escamosas , Quimiocinas , Neoplasias de Cabeza y Cuello , Neoplasias de la Boca , Humanos , Anticuerpos Neutralizantes , Carcinoma de Células Escamosas/patología , Línea Celular Tumoral , Movimiento Celular , Citocinas/metabolismo , Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Interleucina-15/metabolismo , Interleucina-15/farmacología , Interleucina-6/metabolismo , Metástasis Linfática , Neoplasias de la Boca/patología , Carcinoma de Células Escamosas de Cabeza y Cuello , Factor de Transcripción STAT3/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo , Quimiocinas/metabolismoRESUMEN
The T cell immunoglobulin and ITAM domain (TIGIT) is a recently discovered synergistic co-suppressor molecule that plays an important role in immune response and tumor immune escape in the context of cancer. Importantly, CD155 acts as a receptor for TIGIT, and CD155 signaling to immune cells is mediated through interactions with the co-stimulatory immune receptor CD226 (DNAM-1) and the inhibitory checkpoint receptors TIGIT and CD96. Aspirin (ASA) has been shown to reduce the growth and survival of colorectal cancer (CRC) cells, but the immunological mechanisms involved have not been sufficiently elucidated. In the present study the effects of aspirin on CRC in mice and on Jurkat cells were investigated. Aspirin may suppress the expression of TIGIT on T cells and Regulatory T cells (Tregs) and inhibit T cell viability, and therefore induce tumor cell apoptosis. TIGIT is expressed at higher levels on infiltrating lymphocytes within CRC tumor tissue than adjacent. Further, aspirin could inhibit Jurkat cell proliferation and induce apoptosis via downregulation of TIGIT expression and the anti-apoptosis B cell lymphoma 2 (BCL2) protein and upregulation of BCL2-associated X protein (BAX) expression. The present study suggests that aspirin can inhibit specific aspects of T cell function by reducing interleukin-10 and transforming growth factor-ß1 secretion via the TIGIT-BCL2-BAX signaling pathway, resulting in improved effector T cell function that inhibits tumor progression.
Asunto(s)
Apoptosis , Aspirina , Neoplasias Colorrectales , Proteínas Proto-Oncogénicas c-bcl-2 , Receptores Inmunológicos , Transducción de Señal , Receptores Inmunológicos/metabolismo , Humanos , Animales , Aspirina/farmacología , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/inmunología , Ratones , Células Jurkat , Apoptosis/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Proteína X Asociada a bcl-2/metabolismo , Proliferación Celular/efectos de los fármacos , Linfocitos T Reguladores/efectos de los fármacos , Linfocitos T Reguladores/inmunología , Receptores Virales/metabolismo , Antígenos de Diferenciación de Linfocitos T/metabolismo , Regulación Neoplásica de la Expresión Génica/efectos de los fármacosRESUMEN
The reproduction toxicity of pubertal exposure to Microcystin-LR (MC-LR) and the underlying mechanism needs to be further investigated. In the current study, pubertal male ICR mice were intraperitoneally injected with 2⯵g/kg MC-LR for four weeks. Pubertal exposure to MC-LR decreased epididymal sperm concentration and blocked spermatogonia proliferation. In-vitro studies found MC-LR inhibited cell proliferation of GC-1 cells and arrested cell cycle in G2/M phase. Mechanistically, MC-LR exposure evoked excessive reactive oxygen species (ROS) and induced DNA double-strand break in GC-1 cells. Besides, MC-LR inhibited DNA repair by reducing PolyADP-ribosylation (PARylation) activity of PARP1. Further study found MC-LR caused proteasomal degradation of SIRT6, a monoADP-ribosylation enzyme which is essential for PARP1 PARylation activity, due to destruction of SIRT6-USP10 interaction. Additionally, MG132 pretreatment alleviated MC-LR-induced SIRT6 degradation and promoted DNA repair, leading to the restoration of cell proliferation inhibition. Correspondingly, N-Acetylcysteine (NAC) pre-treatment mitigated the disturbed SIRT6-USP10 interaction and SIRT6 degradation, causing recovered DNA repair and subsequently restoration of cell proliferation inhibition in MC-LR treated GC-1 cells. Together, pubertal exposure to MC-LR induced spermatogonia cell cycle arrest and sperm count reduction by oxidative DNA damage and simultaneous SIRT6-mediated DNA repair failing. This study reports the effect of pubertal exposure to MC-LR on spermatogenesis and complex mechanism how MC-LR induces spermatogonia cell proliferation inhibition.
Asunto(s)
Toxinas Marinas , Microcistinas , Sirtuinas , Espermatogonias , Animales , Masculino , Ratones , Apoptosis , Proliferación Celular , Roturas del ADN de Doble Cadena/efectos de los fármacos , Reparación del ADN , Toxinas Marinas/metabolismo , Toxinas Marinas/toxicidad , Ratones Endogámicos ICR , Microcistinas/metabolismo , Microcistinas/toxicidad , Semen , Sirtuinas/efectos de los fármacos , Sirtuinas/metabolismo , Espermatogonias/efectos de los fármacos , Espermatogonias/metabolismoRESUMEN
Heavy metals can negatively affect children's neurodevelopment, yet the relationship between heavy metals exposure and attention deficit hyperactivity disorder (ADHD) in children remains unclear. We aimed to examine associations between exposure to five common heavy metals (lead, arsenic, mercury, cadmium, and manganese) with neurodevelopmental toxicity and the risk of ADHD in children. Online databases of PubMed, Web of Science, and Embase were searched before February 29, 2024. A total of 31 studies involving 25,258 children were included in the final analysis. Our findings revealed that lead exposure was positively associated with ADHD risk in children (OR = 1.95, 95% CI: 1.57-2.41) overall, while the associations varied among different WHO regions, with the strongest in the Americas. Sensitivity analyses revealed significant associations between arsenic (OR = 1.53, 95% CI: 1.01-2.32) and manganese (OR = 1.79, 95% CI: 1.28-2.49) exposure and ADHD risk after omitting one study. Arsenic exposure was positively associated with ADHD risk in studies conducted in the Americas and adjusted for environmental smoke exposure. Positive associations between manganese exposure and ADHD risk were also found in several subgroup analyses. No significant associations were found for mercury and cadmium exposure. Dose-response meta-analysis suggested that children with higher blood lead levels exhibited a higher probability of ADHD diagnosis. Lead exposure consistently increases the risk of ADHD in children, while arsenic and manganese exposure may be associated with ADHD under different occasions. More research is required to understand heavy metals' impact on ADHD across varying exposure levels, particularly in less contaminated regions.
RESUMEN
Prostate cancer (PCa) is a common malignant cancer in elderly males in Western countries. Whole-genome sequencing confirmed that long non-coding RNAs (lncRNAs) are frequently altered in castration-resistant prostate cancer (CRPC) and promote drug resistance to cancer therapy. Therefore, elucidating the prospective role of lncRNAs in PCa oncogenesis and progression is of remarkable clinical significance. In this study, gene expression in prostate tissues was determined using RNA-sequencing datasets, and the gene diagnostic and prognostic values of CRPC were analyzed using bioinformatics. Further, the expression levels and clinical significance of MAGI2 Antisense RNA 3 (MAGI2-AS3) in PCa clinical specimens were evaluated. The tumor-suppressive activity of MAGI2-AS3 was functionally explored in PCa cell lines and animal xenograft models. MAGI2-AS3 was found to be aberrantly decreased in CRPC and was negatively correlated with Gleason score and lymph node status. Notably, low MAGI2-AS3 expression positively correlated with poorer survival in patients with PCa. The overexpression of MAGI2-AS3 significantly inhibited the proliferation and migration of PCa in vitro and in vivo. Mechanistically, MAGI2-AS3 could play a tumor suppressor function in CRPC through a novel miR-106a-5p/RAB31 regulatory network and could be a target for future cancer therapy.
Asunto(s)
MicroARNs , Neoplasias de la Próstata Resistentes a la Castración , ARN Largo no Codificante , Masculino , Animales , Humanos , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Neoplasias de la Próstata Resistentes a la Castración/genética , MicroARNs/genética , MicroARNs/metabolismo , Pronóstico , Proliferación Celular/genética , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , Proteínas de Unión al GTP rab/genética , Proteínas de Unión al GTP rab/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Guanilato-Quinasas/genética , Guanilato-Quinasas/metabolismoRESUMEN
Kagome superconductors AV3Sb5 (A = K, Rb, Cs) provide a fertile playground for studying intriguing phenomena, including nontrivial band topology, superconductivity, giant anomalous Hall effect, and charge density wave (CDW). Recently, a C2 symmetric nematic phase prior to the superconducting state in AV3Sb5 drew enormous attention due to its potential inheritance of the symmetry of the unusual superconductivity. However, direct evidence of the rotation symmetry breaking of the electronic structure in the CDW state from the reciprocal space is still rare, and the underlying mechanism remains ambiguous. The observation shows unconventional unidirectionality, indicative of rotation symmetry breaking from six-fold to two-fold. The interlayer coupling between adjacent planes with π-phase offset in the 2 × 2 × 2 CDW phase leads to the preferred two-fold symmetric electronic structure. These rarely observed unidirectional back-folded bands in KV3Sb5 may provide important insights into its peculiar charge order and superconductivity.
RESUMEN
The removal of organic pollutants in water environments and the resource utilization of solid waste are two pressing issues around the world. Facing the increasing pollution induced by discharge of mining effluents containing sodium isopropyl xanthate (SIPX), in this work, municipal solid waste incineration fly ash (MSWI FA) was pretreated by hydrothermal method to produce stabilized FA, which was then innovatively used as support for the construction of FA/TiO2/BiOCl nanocomposite (FTB) with promoted photocatalytic activity under visible light and natural sunlight. When the content of FA was 20 wt% and the mass ratio of TiO2 to BiOCl was 4:6, a remarkable performance for the optimal FTB (20-FTB-2) was achieved. Characterizations demonstrated that TiO2 and BiOCl uniformly dispersed on FA contributing to high surface area and broad light adsorption of FTB, which exhibits excellent adsorption capacity and light response ability. Build in electric field formed in the interface of TiO2/BiOCl heterojunction revealed by density functional theory calculations accelerated the separation of photoinduced e- and h+, leading to high efficiency for SIPX degradation. The synergetic effect combined with adsorption and photocatalytic degradation endowed 20-FTB-2 superior SIPX removal efficiency over 99% within 30 min under visible light and natural sunlight irradiation. The photocatalytic degradation pathways of SIPX were determined through theoretical calculations and characterizations, and the toxic byproduct CS2 was effectively eliminated through oxidation of â¢O2-. For 20-FTB-2, reusability of photocatalyst was showed by cycle tests, also the concentrations of main heavy metals (Pb, Zn, Cu, Cr, and Cd) in the liquid phases released during photocatalyst preparation process (< 1 mg/L) and photodegradation process (< 8.5 µg/L) proved the satisfactory stability with low toxicity. This work proposed a novel strategy to develop efficient and stable support-based photocatalysts by utilizing MSWI FA and realize its resource utilization.
Asunto(s)
Ceniza del Carbón , Nanocompuestos , Titanio , Nanocompuestos/química , Titanio/química , Ceniza del Carbón/química , Catálisis , Adsorción , Residuos Sólidos , Contaminantes Químicos del Agua/químicaRESUMEN
BACKGROUND: It has been acknowledged that the tumour immune microenvironment (TIME) plays a critical role in determining therapeutic responses and clinical outcomes in breast cancer (BrCa). Thus, the identification of the TIME features is essential for guiding therapy and prognostic assessment for BrCa. METHODS: The heterogeneous cellular composition of the TIME in BrCa by single-cell RNA sequencing (scRNA-seq). Two subtype-special genes upregulated in the tumour-rich subtype and the immune-infiltrating subtype were extracted, respectively. The CRABP2/CD69 signature was established based on CRABP2 and CD69 expression, and its predictive values for the clinical outcome and the neoadjuvant chemotherapy (NAT) responses were validated in multiple cohorts. Moreover, the oncogenic role of CRABP2 was explored in BrCa cells. RESULTS: Based on the heterogeneous cellular composition of the TIME in BrCa, the BrCa samples could be divided into the tumour-rich subtype and the immune-infiltrating subtype, which exhibited distinct prognosis and chemotherapeutic responses. Next, we extracted CRABP2 as the biomarker for the tumour-rich subtype and CD69 as the biomarker for the immune-infiltrating subtype. Based on the CRABP2/CD69 signature, BrCa samples were re-divided into three subtypes, and the CRABP2highCD69low subtype exhibited the worst prognosis and the lowest chemotherapeutic response, while the CRABP2lowCD69high subtype showed the opposite results. Furthermore, CARBP2 functioned as a novel oncogene in BrCa, which promoted tumour cell proliferation, migration, and invasion, and CRABP2 inhibition triggered the activation of cytotoxic T lymphocytes (CTLs). CONCLUSION: The CRABP2/CD69 signature is significantly associated with the TIME features and could effectively predict the clinical outcome. Also, CRABP2 is determined to be a novel oncogene, which could be a therapeutic target in BrCa.
Asunto(s)
Neoplasias de la Mama , Femenino , Humanos , Biomarcadores , Neoplasias de la Mama/genética , Proliferación Celular , Terapia Neoadyuvante , Oncogenes , Pronóstico , Microambiente Tumoral/genéticaRESUMEN
A high-nuclearity carboxylic-modified heteropolyoxovanadate, Na2K10H15[P8VIV24(tart)15(H2O)15(OH)O51]·58H2O [1, tart = C4H2O6], has been successfully synthesized by a conventional aqueous method under mild conditions. The crystallographic study reveals that compound 1 crystallizes in the tetragonal I41/a space group and is composed by a trilayer saddle-like polyoxoanion {P8V24}. Two {V3(tart)(H2O)O11} as linking units bridge the top {P4VIV9(tart)7(H2O)4(OH)O23} and the bottom {P4VIV9(tart)6(H2O)9O22} layers via tartrate ligands and {PO4} tetrahedra, resulting in a 24-nuclearity POV skeleton structure. More interestingly, compound 1 serves as a heterogeneous catalyst for the selective oxidation of diphenylmethanes with 96.2% conversion and 93.6% selectivity under the optimized conditions.