RESUMEN
Aerobic glycolysis regulates T cell function. However, whether and how primary cancer alters T cell glycolytic metabolism and affects tumor immunity in cancer patients remains a question. Here we found that ovarian cancers imposed glucose restriction on T cells and dampened their function via maintaining high expression of microRNAs miR-101 and miR-26a, which constrained expression of the methyltransferase EZH2. EZH2 activated the Notch pathway by suppressing Notch repressors Numb and Fbxw7 via trimethylation of histone H3 at Lys27 and, consequently, stimulated T cell polyfunctional cytokine expression and promoted their survival via Bcl-2 signaling. Moreover, small hairpin RNA-mediated knockdown of human EZH2 in T cells elicited poor antitumor immunity. EZH2(+)CD8(+) T cells were associated with improved survival in patients. Together, these data unveil a metabolic target and mechanism of cancer immune evasion.
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Regulación Neoplásica de la Expresión Génica/inmunología , MicroARNs , Neoplasias/inmunología , Complejo Represivo Polycomb 2/inmunología , Linfocitos T/inmunología , Escape del Tumor/inmunología , Animales , Separación Celular , Inmunoprecipitación de Cromatina , Proteína Potenciadora del Homólogo Zeste 2 , Femenino , Citometría de Flujo , Técnica del Anticuerpo Fluorescente , Glucólisis , Humanos , Immunoblotting , Melanoma Experimental/inmunología , Ratones Endogámicos C57BL , Neoplasias Ováricas/inmunología , Reacción en Cadena en Tiempo Real de la Polimerasa , Análisis de Matrices Tisulares , TransfecciónRESUMEN
Stomata exert considerable effects on global carbon and water cycles by mediating gas exchange and water vapour1,2. Stomatal closure prevents water loss in response to dehydration and limits pathogen entry3,4. However, prolonged stomatal closure reduces photosynthesis and transpiration and creates aqueous apoplasts that promote colonization by pathogens. How plants dynamically regulate stomatal reopening in a changing climate is unclear. Here we show that the secreted peptides SMALL PHYTOCYTOKINES REGULATING DEFENSE AND WATER LOSS (SCREWs) and the cognate receptor kinase PLANT SCREW UNRESPONSIVE RECEPTOR (NUT) counter-regulate phytohormone abscisic acid (ABA)- and microbe-associated molecular pattern (MAMP)-induced stomatal closure. SCREWs sensed by NUT function as immunomodulatory phytocytokines and recruit SOMATIC EMBRYOGENESIS RECEPTOR-LIKE KINASE (SERK) co-receptors to relay immune signalling. SCREWs trigger the NUT-dependent phosphorylation of ABA INSENSITIVE 1 (ABI1) and ABI2, which leads to an increase in the activity of ABI phosphatases towards OPEN STOMATA 1 (OST1)-a key kinase that mediates ABA- and MAMP-induced stomatal closure5,6-and a reduction in the activity of S-type anion channels. After induction by dehydration and pathogen infection, SCREW-NUT signalling promotes apoplastic water loss and disrupts microorganism-rich aqueous habitats to limit pathogen colonization. The SCREW-NUT system is widely distributed across land plants, which suggests that it has an important role in preventing uncontrolled stomatal closure caused by abiotic and biotic stresses to optimize plant fitness.
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Ácido Abscísico , Reguladores del Crecimiento de las Plantas , Inmunidad de la Planta , Estomas de Plantas , Plantas , Agua , Proteínas de Arabidopsis , Deshidratación , DesecaciónRESUMEN
The anomalous metallic state (AMS) emerging from a quantum superconductor-to-metal transition is a subject of great current interest since this exotic quantum state exhibits unconventional transport properties that challenge the core physics principles of Fermi liquid theory. As the AMS concept is historically derived from disordered two-dimensional (2D) systems, related studies have predominately concentrated on 2D materials. The AMS behaviors in three-dimensional (3D) systems have been rarely reported to date, which raises intriguing questions on the fundamental nature of pertinent physics. Here, we report experimental evidence for a 3D AMS in highly compressed titanium metal that exhibits superconductivity with a critical temperature (Tc) reaching near-record 25.1 K among elemental superconductors, offering a favorable material template for exploring 3D AMS. At sufficiently strong magnetic fields, unusual transport behaviors set in over a wide pressure range, showcasing AMS hallmarks of a low-temperature saturation resistance below the Drude value and giant positive magnetoresistance. These findings reveal a 3D AMS in simple elemental systems and, more importantly, provide a fresh platform for probing the decades-long enigmatic underlying physics.
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Anaplastic large cell lymphoma (ALCL), a subgroup of mature T-cell neoplasms with an aggressive clinical course, is characterized by elevated expression of CD30 and anaplastic cytology. To achieve a comprehensive understanding of the molecular characteristics of ALCL pathology and to identify therapeutic vulnerabilities, we applied genome-wide CRISPR library screenings to both anaplastic lymphoma kinase positive (ALK+) and primary cutaneous (pC) ALK- ALCLs and identified an unexpected role of the interleukin-1R (IL-1R) inflammatory pathway in supporting the viability of pC ALK- ALCL. Importantly, this pathway is activated by IL-1α in an autocrine manner, which is essential for the induction and maintenance of protumorigenic inflammatory responses in pC-ALCL cell lines and primary cases. Hyperactivation of the IL-1R pathway is promoted by the A20 loss-of-function mutation in the pC-ALCL lines we analyze and is regulated by the nonproteolytic protein ubiquitination network. Furthermore, the IL-1R pathway promotes JAK-STAT3 signaling activation in ALCLs lacking STAT3 gain-of-function mutation or ALK translocation and enhances the sensitivity of JAK inhibitors in these tumors in vitro and in vivo. Finally, the JAK2/IRAK1 dual inhibitor, pacritinib, exhibited strong activities against pC ALK- ALCL, where the IL-1R pathway is hyperactivated in the cell line and xenograft mouse model. Thus, our studies revealed critical insights into the essential roles of the IL-1R pathway in pC-ALCL and provided opportunities for developing novel therapeutic strategies.
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Linfoma Anaplásico de Células Grandes , Linfoma Anaplásico Cutáneo Primario de Células Grandes , Neoplasias Cutáneas , Humanos , Animales , Ratones , Linfoma Anaplásico de Células Grandes/tratamiento farmacológico , Linfoma Anaplásico de Células Grandes/genética , Linfoma Anaplásico de Células Grandes/patología , Proteínas Tirosina Quinasas Receptoras/genética , Quinasa de Linfoma Anaplásico/genética , Interleucinas/metabolismoRESUMEN
Vemurafenib has been used as first-line therapy for unresectable or metastatic melanoma with BRAFV600E mutation. However, overall survival is still limited due to treatment resistance after about one year. Therefore, identifying new therapeutic targets for melanoma is crucial for improving clinical outcomes. In the present study, we found that lowering intracellular cholesterol by knocking down DHCR24, the limiting synthetase, impaired tumor cell proliferation and migration and abrogated the ability to xenotransplant tumors. More importantly, administration of DHCR24 or cholesterol mediated resistance to vemurafenib and promoted the growth of melanoma spheroids. Mechanistically, we identified that 27-hydroxycholesterol (27HC), a primary metabolite of cholesterol synthesized by the enzyme cytochrome P450 27A1 (CYP27A1), reproduces the phenotypes induced by DHCR24 or cholesterol administration and activates Rap1-PI3K/AKT signaling. Accordingly, CYP27A1 is highly expressed in melanoma patients and upregulated by DHCR24 induction. Dafadine-A, a CYP27A1 inhibitor, attenuates cholesterol-induced growth of melanoma spheroids and abrogates the resistance property of vemurafenib-resistant melanoma cells. Finally, we confirmed that the effects of cholesterol on melanoma resistance require its metabolite 27HC through CYP27A1 catalysis, and that 27HC further upregulates Rap1A/Rap1B expression and increases AKT phosphorylation. Thus, our results suggest that targeting 27HC may be a useful strategy to overcome treatment resistance in metastatic melanoma.
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Proliferación Celular , Colestanotriol 26-Monooxigenasa , Colesterol , Hidroxicolesteroles , Melanoma , Células Madre Neoplásicas , Vemurafenib , Vemurafenib/farmacología , Vemurafenib/uso terapéutico , Humanos , Melanoma/tratamiento farmacológico , Melanoma/patología , Melanoma/metabolismo , Melanoma/genética , Hidroxicolesteroles/metabolismo , Hidroxicolesteroles/farmacología , Animales , Proliferación Celular/efectos de los fármacos , Colestanotriol 26-Monooxigenasa/metabolismo , Colestanotriol 26-Monooxigenasa/genética , Colesterol/metabolismo , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/patología , Línea Celular Tumoral , Ratones , Resistencia a Antineoplásicos/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Proteolysis targeting chimera (PROTAC) technology is an innovative strategy for cancer therapy, which, however, suffers from poor targeting delivery and limited capability for protein of interest (POI) degradation. Here, we report a strategy for the in situ formulation of antineoplastic Supra-PROTACs via intracellular sulfatase-responsive assembly of peptides. Coassembling a sulfated peptide with two ligands binding to ubiquitin VHL and Bcl-xL leads to the formation of a pro-Supra-PROTAC, in which the ratio of the two ligands is rationally optimized based on their protein binding affinity. The resulting pro-Supra-PROTAC precisely undergoes enzyme-responsive assembly into nanofibrous Supra-PROTACs in cancer cells overexpressing sulfatase. Mechanistic studies reveal that the pro-Supra-PROTACs selectively cause apparent cytotoxicity to cancer cells through the degradation of Bcl-xL and the activation of caspase-dependent apoptosis, during which the rationally optimized ligand ratio improves the bioactivity for POI degradation and cell death. In vivo studies show that in situ formulation enhanced the tumor accumulation and retention of the pro-Supra-PROTACs, as well as the capability for inhibiting tumor growth with excellent biosafety when coadministrating with chemodrugs. Our findings provide a new approach for enzyme-regulated assembly of peptides in living cells and the development of PROTACs with high targeting delivering and POI degradation efficiency.
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Antineoplásicos , Neoplasias , Humanos , Quimera Dirigida a la Proteólisis , Antineoplásicos/farmacología , Sulfatasas , Proteolisis , Péptidos , Ubiquitina-Proteína LigasasRESUMEN
Hydrides are promising candidates for achieving room-temperature superconductivity, but a formidable challenge remains in reducing the stabilization pressure below a megabar. In this study, we successfully synthesized a ternary lanthanum borohydride by introducing the nonmetallic element B into the La-H system, forming robust B-H covalent bonds that lower the pressure required to stabilize the superconducting phase. Electrical transport measurements confirm the presence of superconductivity with a critical temperature (Tc) of up to 106 K at 90 GPa, as evidenced by zero resistance and Tc shift under an external magnetic field. X-ray diffraction and transport measurements identify the superconducting compound as LaB2H8, a nonclathrate hydride, whose crystal structure remains stable at pressures as low as â¼ half megabar (59 GPa). Stabilizing superconductive stoichiometric LaB2H8 in a submegabar pressure regime marks a substantial advancement in the quest for high-Tc superconductivity in polynary hydrides, bringing us closer to the ambient pressure conditions.
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Long noncoding RNA urothelial carcinoma associated 1 (UCA1) has been identified as a key molecule in human cancers. However, its functional implications remain unspecified in the context of cervical cancer (CC). This research aims to identify the regulatory mechanism of UCA1 in CC. UCA1 was identified through microarray and confirmed through a quantitative real-time polymerase chain reaction. Proteins that bind with UCA1 were recognized using RNA pull-down assays along with RNA immunoprecipitation. Ubiquitination assays and coimmunoprecipitation were performed to explore the molecular mechanisms of the SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily d, member 3 (SMARCD3) downregulated in CC. The effects of UCA1 and SMARCD3 on the progression of CC were investigated through gain- and loss-of-function assays and xenograft tumor formation in vivo. In this study, UCA1 was found to be upregulated in CC cells as well as in human plasma exosomes for the first time. Functional studies indicated that UCA1 promotes CC progression. Mechanically, UCA1 downregulated the SMARCD3 protein stabilization by promoting SMARCD3 ubiquitination. Taken together, we revealed that the UCA1/SMARCD3 axis promoted CC progression, which could provide a new therapeutic target for CC.
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Carcinoma de Células Transicionales , MicroARNs , ARN Largo no Codificante , Neoplasias de la Vejiga Urinaria , Neoplasias del Cuello Uterino , Femenino , Humanos , Neoplasias de la Vejiga Urinaria/genética , Neoplasias de la Vejiga Urinaria/patología , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Neoplasias del Cuello Uterino/genética , Invasividad Neoplásica/genética , Proliferación Celular/genética , MicroARNs/genética , Regulación Neoplásica de la Expresión Génica , Línea Celular TumoralRESUMEN
Substantial numbers of B cell leukemia and lymphoma patients relapse due to antigen loss or heterogeneity after anti-CD19 chimeric antigen receptor (CAR) T cell therapy. To overcome antigen escape and address antigen heterogeneity, we engineered induced pluripotent stem cell-derived NK cells to express both an NK cell-optimized anti-CD19 CAR for direct targeting and a high affinity, non-cleavable CD16 to augment antibody-dependent cellular cytotoxicity. In addition, we introduced a membrane-bound IL-15/IL-15R fusion protein to promote in vivo persistence. These engineered cells, termed iDuo NK cells, displayed robust CAR-mediated cytotoxic activity that could be further enhanced with therapeutic antibodies targeting B cell malignancies. In multiple in vitro and xenogeneic adoptive transfer models, iDuo NK cells exhibited robust anti-lymphoma activity. Furthermore, iDuo NK cells effectively eliminated both CD19+ and CD19- lymphoma cells and displayed a unique propensity for targeting malignant cells over healthy cells that expressed CD19, features not achievable with anti-CAR19 T cells. iDuo NK cells combined with therapeutic antibodies represent a promising approach to prevent relapse due to antigen loss and tumor heterogeneity in patients with B cell malignancies.
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Leucemia , Neoplasias , Humanos , Deriva y Cambio Antigénico , Leucemia/terapia , Células Asesinas NaturalesRESUMEN
BACKGROUND: Melanin-concentrating hormone (MCH) is a hypothalamic neuropeptide that projects throughout the central nervous system, including the noradrenergic locus coeruleus (LC). Our previous study suggested that MCH/MCH receptor 1 (MCHR1) in the LC may be involved in the regulation of depression. The present study investigated whether the role of MCH/MCHR1 in the LC in depression-like behaviors is associated with the regulation of norepinephrine. METHOD: Chronic unpredictable stress (CUS) and an acute intra-LC microinjection of MCH induced depression-like behaviors in rats. The MCHR1 antagonist SNAP-94847 was also microinjected in the LC in rats that were suffering CUS or treated with MCH. The sucrose preference, forced swim, and locomotor tests were used for behavioral evaluation. Immunofluorescence staining, enzyme-linked immunosorbent assay, western blot, and high-performance liquid chromatography with electrochemical detection were used to explore the mechanism of MCH/MCHR1 in the regulation of depression-like behaviors. RESULTS: CUS induced an abnormal elevation of MCH levels and downregulated MCHR1 in the LC, which was highly correlated with the formation of depression-like behaviors. SNAP-94847 exerted antidepressant effects in CUS-exposed rats by normalizing tyrosine hydroxylase, dopamine ß hydroxylase, and norepinephrine in the LC. An acute microinjection of MCH induced depression-like behaviors through its action on MCHR1. MCHR1 antagonism in the LC significantly reversed the MCH-induced downregulation of norepinephrine production by normalizing MCHR1-medicated cAMP-PKA signaling. CONCLUSIONS: Our study confirmed that the MCH/MCHR1 system in the LC may be involved in depression-like behaviors by downregulating norepinephrine production. These results improve our understanding of the pathogenesis of depression that is related to the MCH/MCHR1 system in the LC.
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Hormonas Hipotalámicas , Locus Coeruleus , Ratas , Animales , Depresión/inducido químicamente , Depresión/tratamiento farmacológico , Norepinefrina , Hormonas Hipotalámicas/metabolismo , Hormonas Hipofisarias/farmacología , Melaninas/farmacologíaRESUMEN
Heterogeneous cancer-associated fibroblasts (CAFs) play important roles in cancer progression. However, the specific biological functions and regulatory mechanisms involved in endometrial cancer have yet to be elucidated. We aimed to explore the potential mechanisms of heterogeneous CAFs in promoting endometrial cancer progression. The presence of melanoma cell adhesion molecule (MCAM; CD146) positive CAFs was confirmed by tissue multi-immunofluorescence (mIF), and fluorescence activated cell sorting (FACS). The biological functions were determined by wound healing assays, tuber formation assays and cord formation assays. The effects of CD146+CAFs on endometrial cancer cells were studied in vitro and in vivo. The expression level of interleukin 10 (IL-10) was measured by quantitative real time polymerase chain reaction (qRT-PCR), western boltting and enzyme linked immunosorbent assays (ELISAs). In addition, the transcription factor STAT3 was identified by bioinformatics methods and chromatin immunoprecipitation (ChIP). A subtype of CAFs marked with CD146 was found in endometrial cancer and correlated with poor prognosis. CD146+CAFs promoted angiogenesis and vasculogenic mimicry (VM) in vitro. A xenograft tumour model also showed that CD146+CAFs can facilitate tumour progression. The expression of IL-10 was elevated in CD146+CAFs. IL-10 promoted epithelial-endothelial transformation (EET) and further VM formation in endometrial cancer cells via the janus kinase 1/signal transducer and activator of transcription 3 (JAK1/STAT3) signalling pathway. This process could be blocked by the JAK1/STAT3 inhibitor niclosamide. Mechanically, STAT3 can bind to the promoter of cadherin5 (CDH5) to promote its transcription which may be stimulated by IL-10. We concluded that CD146+CAFs could promote angiogenesis and VM formation via the IL-10/JAK1/STAT3 signalling pathway. These findings may lead to the identification of potential targets for antiangiogenic therapeutic strategies for endometrial cancers.
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Fibroblastos Asociados al Cáncer , Neoplasias Endometriales , Femenino , Humanos , Angiogénesis , Fibroblastos Asociados al Cáncer/metabolismo , Antígeno CD146/metabolismo , Línea Celular Tumoral , Neoplasias Endometriales/metabolismo , Interleucina-10 , Janus Quinasa 1 , Factor de Transcripción STAT3/metabolismoRESUMEN
The activation of the nucleotide oligomerization domain (NOD)-like receptor (NLR) family, pyrin domain-containing protein 3 (NLRP3) inflammasome is related to the pathogenesis of a wide range of inflammatory diseases, but drugs targeting the NLRP3 inflammasome are still scarce. In the present study, we demonstrated that Licochalcone B (LicoB), a main component of the traditional medicinal herb licorice, is a specific inhibitor of the NLRP3 inflammasome. LicoB inhibits the activation of the NLRP3 inflammasome in macrophages but has no effect on the activation of AIM2 or NLRC4 inflammasome. Mechanistically, LicoB directly binds to NEK7 and inhibits the interaction between NLRP3 and NEK7, thus suppressing NLRP3 inflammasome activation. Furthermore, LicoB exhibits protective effects in mouse models of NLRP3 inflammasome-mediated diseases, including lipopolysaccharide (LPS)-induced septic shock, MSU-induced peritonitis and non-alcoholic steatohepatitis (NASH). Our findings indicate that LicoB is a specific NLRP3 inhibitor and a promising candidate for treating NLRP3 inflammasome-related diseases.
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Chalconas , Inflamasomas , Animales , Chalconas/farmacología , Inflamasomas/metabolismo , Ratones , Ratones Endogámicos C57BL , Quinasas Relacionadas con NIMA/genética , Quinasas Relacionadas con NIMA/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLRRESUMEN
Sevoflurane exposure in the neonatal period causes long-term developmental neuropsychological dysfunction, including memory impairment and anxiety-like behaviors. However, the molecular mechanisms underlying such effects have not been fully elucidated. In this study, we investigated the effect of neonatal exposure to sevoflurane on neurobehavioral profiles in adolescent rats, and applied an integrated approach of lipidomics and proteomics to investigate the molecular network implicated in neurobehavioral dysfunction. We found that neonatal exposure to sevoflurane caused cognitive impairment and social behavior deficits in adolescent rats. Lipidomics analyses revealed that sevoflurane significantly remodeled hippocampal lipid metabolism, including lysophatidylcholine (LPC) metabolism, phospholipid carbon chain length and carbon chain saturation. Through a combined proteomics analysis, we found that neonatal exposure to sevoflurane significantly downregulated the expression of lysophosphatidylcholine acyltransferase 1 (LPCAT1), a key enzyme in the regulation of phospholipid metabolism, in the hippocampus of adolescent rats. Importantly, hippocampal LPCAT1 overexpression restored the dysregulated glycerophospholipid (GP) metabolism and alleviated the learning and memory deficits caused by sevoflurane. Collectively, our evidence that neonatal exposure to sevoflurane downregulates LPCAT1 expression and dysregulates GP metabolism in the hippocampus, which may contribute to the neurobehavioral dysfunction in the adolescent rats.
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Anestésicos por Inhalación , Animales , Ratas , Sevoflurano/metabolismo , Sevoflurano/farmacología , Animales Recién Nacidos , Anestésicos por Inhalación/farmacología , Ratas Sprague-Dawley , Aprendizaje por Laberinto , Trastornos de la Memoria/metabolismo , Hipocampo/metabolismo , Fosfolípidos/metabolismoRESUMEN
BACKGROUND: Low-grade appendiceal mucinous neoplasms (LAMN) are very rare, accounting for approximately 0.2%-0.5% of gastrointestinal tumors. We conducted a multicenter retrospective study to explore the impact of different surgical procedures combined with HIPEC on the short-term outcomes and long-term survival of patients. METHODS: We retrospectively analyzed the clinicopathological data of 91 LAMN perforation patients from 9 teaching hospitals over a 10-year period, and divided them into HIPEC group and non-HIPEC group based on whether or not underwent HIPEC. RESULTS: Of the 91 patients with LAMN, 52 were in the HIPEC group and 39 in the non-HIPEC group. The Kaplan-Meier method predicted that 52 patients in the HIPEC group had 5- and 10-year overall survival rates of 82.7% and 76.9%, respectively, compared with predicted survival rates of 51.3% and 46.2% for the 39 patients in the non-HIPEC group, with a statistically significant difference between the two groups (χ2 = 10.622, p = 0.001; χ2 = 10.995, p = 0.001). Compared to the 5-year and 10-year relapse-free survival rates of 75.0% and 65.4% in the HIPEC group, respectively, the 5-year and 10-year relapse-free survival rates of 48.7% and 46.2% in the non-HIPEC group were significant different between the two outcomes (χ2 = 8.063, p = 0.005; χ2 = 6.775, p = 0.009). The incidence of postoperative electrolyte disturbances and hypoalbuminemia was significantly higher in the HIPEC group than in the non-HIPEC group (p = 0.023; p = 0.044). CONCLUSIONS: This study shows that surgery combined with HIPEC can significantly improve 5-year and 10-year overall survival rates and relapse-free survival rates of LAMN perforation patients, without affecting their short-term clinical outcomes.
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Adenocarcinoma Mucinoso , Neoplasias del Apéndice , Quimioterapia Intraperitoneal Hipertérmica , Humanos , Estudios Retrospectivos , Masculino , Femenino , Neoplasias del Apéndice/terapia , Neoplasias del Apéndice/mortalidad , Neoplasias del Apéndice/patología , Persona de Mediana Edad , Adulto , Adenocarcinoma Mucinoso/terapia , Adenocarcinoma Mucinoso/mortalidad , Adenocarcinoma Mucinoso/patología , Anciano , Terapia Combinada , Resultado del Tratamiento , Tasa de Supervivencia , Clasificación del Tumor , Perforación Intestinal/etiología , Neoplasias Peritoneales/terapia , Neoplasias Peritoneales/mortalidadRESUMEN
Endometrial cancer is considered to be the second most common tumor of the female reproductive system, and patients diagnosed with advanced endometrial cancer have a poor prognosis. The influence of fatty acid metabolism in the prognosis of patients with endometrial cancer remains unclear. We constructed a prognostic risk model using transcriptome sequencing data of endometrial cancer and clinical information of patients from The Cancer Genome Atlas (TCGA) database via least absolute shrinkage and selection operator regression analysis. The tumor immune microenvironment was analyzed using the CIBERSORT algorithm, followed by functional analysis and immunotherapy efficacy prediction by gene set variation analysis. The role of model genes in regulating endometrial cancer in vitro was verified by CCK-8, colony formation, wound healing, and transabdominal invasion assays, and verified in vivo by subcutaneous tumor transplantation in nude mice. A prognostic model containing 14 genes was constructed and validated in 3 cohorts and clinical samples. The results showed differences in the infiltration of immune cells between the high-risk and low-risk groups, and that the high-risk group may respond better to immunotherapy. Experiments in vitro confirmed that knockdown of epoxide hydrolase 2 (EPHX2) and acyl-CoA oxidase like (ACOXL) had an inhibitory effect on EC cells, as did overexpression of hematopoietic prostaglandin D synthase (HPGDS). The same results were obtained in experiments in vivo. Prognostic models related to fatty acid metabolism can be used for the risk assessment of endometrial cancer patients. Experiments in vitro and in vivo confirmed that the key genes HPGDS, EPHX2, and ACOXL in the prognostic model may affect the development of endometrial cancer.
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Neoplasias Endometriales , Ácidos Grasos , Femenino , Neoplasias Endometriales/patología , Neoplasias Endometriales/genética , Neoplasias Endometriales/metabolismo , Neoplasias Endometriales/inmunología , Humanos , Ratones , Ácidos Grasos/metabolismo , Animales , Pronóstico , Ratones Desnudos , Microambiente Tumoral/inmunología , Línea Celular TumoralRESUMEN
BACKGROUND: Ovarian cancer (OC) has the highest fatality rate among all gynecological malignancies, necessitating the exploration of novel, efficient, and low-toxicity therapeutic strategies. Ferroptosis is a type of programmed cell death induced by iron-dependent lipid peroxidation and can potentially activate antitumor immunity. Developing highly effective ferroptosis inducers may improve OC prognosis. RESULTS: In this study, we developed an ultrasonically controllable two-dimensional (2D) piezoelectric nanoagonist (Bi2MoO6-MXene) to induce ferroptosis. A Schottky heterojunction between Bi2MoO6 (BMO) and MXene reduced the bandgap width by 0.44 eV, increased the carrier-separation efficiency, and decreased the recombination rate of electron-hole pairs under ultrasound stimulation. Therefore, the reactive oxygen species yield was enhanced. Under spatiotemporal ultrasound excitation, BMO-MXene effectively inhibited OC proliferation by more than 90%, induced lipid peroxidation, decreased mitochondrial-membrane potential, and inactivated the glutathione peroxidase and cystathionine transporter protein system, thereby causing ferroptosis in tumor cells. Ferroptosis in OC cells further activated immunogenic cell death, facilitating dendritic cell maturation and stimulating antitumor immunity. CONCLUSION: We have succeeded in developing a highly potent ferroptosis inducer (BMO-MXene), capable of inhibiting OC progression through the sonodynamic-ferroptosis-immunogenic cell death pathway.
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Ferroptosis , Muerte Celular Inmunogénica , Neoplasias Ováricas , Ferroptosis/efectos de los fármacos , Femenino , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/patología , Humanos , Animales , Línea Celular Tumoral , Muerte Celular Inmunogénica/efectos de los fármacos , Ratones , Especies Reactivas de Oxígeno/metabolismo , Peroxidación de Lípido/efectos de los fármacos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Bismuto/farmacología , Bismuto/químicaRESUMEN
Pulmonary Fibrosis (PF) is a fatal disease in the interstitial lung associated with high mortality, morbidity, and poor prognosis. Transforming growth factor-ß1 (TGF-ß1) is a fibroblast-activating protein that promotes fibrous diseases. Herein, an inhalable system was first developed using milk exosomes (M-Exos) encapsulating siRNA against TGF-ß1 (MsiTGF-ß1), and their therapeutic potential for bleomycin (BLM)-induced PF was investigated. M-siTGF-ß1 was introduced into the lungs of mice with PF through nebulization. The collagen penetration effect and lysosomal escape ability were verified in vitro. Inhaled MsiTGF-ß1 notably alleviated inflammatory infiltration, attenuated extracellular matrix (ECM) deposition, and increased the survival rate of PF mice by 4.7-fold. M-siTGF-ß1 protected lung tissue from BLM toxicity by efficiently delivering specific siRNA to the lungs, leading to TGF-ß1 mRNA silencing and epithelial mesenchymal transition pathway inhibition. Therefore, M-siTGF-ß1 offers a promising avenue for therapeutic intervention in fibrosis-related disorders.
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Bleomicina , Colágeno , Transición Epitelial-Mesenquimal , Exosomas , Pulmón , Leche , Fibrosis Pulmonar , ARN Interferente Pequeño , Factor de Crecimiento Transformador beta1 , Animales , Exosomas/metabolismo , Factor de Crecimiento Transformador beta1/metabolismo , Fibrosis Pulmonar/tratamiento farmacológico , Ratones , Colágeno/metabolismo , Bleomicina/farmacología , Transición Epitelial-Mesenquimal/efectos de los fármacos , Pulmón/patología , Pulmón/metabolismo , Pulmón/efectos de los fármacos , Leche/química , Ratones Endogámicos C57BL , Humanos , Permeabilidad , Masculino , Nebulizadores y VaporizadoresRESUMEN
Although CRISPR-Cas12a [clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein 12a] combining pre-amplification technology has the advantage of high sensitivity in biosensing, its generality and specificity are insufficient, which greatly restrains its application range. Here, we discovered a new targeting substrate for LbaCas12a (Lachnospiraceae bacterium Cas12a), namely double-stranded DNA (dsDNA) with a sticky-end region (PAM-SE+ dsDNA). We discovered that CRISPR-Cas12a had special enzymatic properties for this substrate DNA, including the ability to recognize and cleave it without needing a protospacer adjacent motif (PAM) sequence and a high sensitivity to single-base mismatches in that substrate. Further mechanism studies revealed that guide RNA (gRNA) formed a triple-stranded flap structure with the substrate dsDNA. We also discovered the property of low-temperature activation of CRISPR-Cas12a and, by coupling with the unique DNA hybridization kinetics at low temperature, we constructed a complete workflow for low-abundance point mutation detection in real samples, which was fast, convenient and free of single-stranded DNA (ssDNA) transformation. The detection limits were 0.005-0.01% for synthesized strands and 0.01-0.05% for plasmid genomic DNA, and the mutation abundances provided by our system for 28 clinical samples were in accordance with next-generation sequencing results. We believe that our work not only reveals novel information about the target recognition mechanism of the CRISPR-Cas12a system, but also greatly broadens its application scenarios.
Asunto(s)
Proteínas Asociadas a CRISPR , Sistemas CRISPR-Cas , Proteínas Asociadas a CRISPR/metabolismo , Proteínas Bacterianas/metabolismo , ADN/química , ADN de Cadena Simple/genéticaRESUMEN
In recent years, with the increasing global focus on environmental protection, the issue of microfiber release from denim during the washing process has gained attention. In this study, a programmable washing device simulating household drum washing was designed and developed, microfibers and indigo dyes released from denim washing were quantitatively detected, and we have also developed a novel method for estimating the release of microfibers during washing. The effects of washing time, washing temperature, and washing load on microfiber and indigo dye release from denim were explored. The results showed that the effect of washing load on microfiber and indigo dye release was greater than washing temperature and washing time. The research findings indicate that with an increase in washing time (35-95 min) and washing load (100-250 g), the shedding of microfibers and indigo dye significantly increases, reaching peak release levels of 343.6 µg/g fabric and 0.027 mg/L, respectively. However, there is a decreasing trend in the release of microfibers and indigo dye when the washing temperature exceeds 50 °C. Furthermore, our data suggests that an increase in washing load leads to a significant change in the number of microfibers (from 978 items/g fabric to 1997 items/g fabric) and their mass (from 156.87 µg/g fabric to 343.56 µg/g fabric). The influence of washing time, washing temperature, and washing load on microfiber length shows relatively small fluctuations within the range of 600-900 µm. This study provides new ideas and methods for estimating the release of microfiber and indigo dye in denim washing around the world.
Asunto(s)
Carmin de Índigo , TextilesRESUMEN
To establish a predictive model incorporating conventional ultrasound, strain elastography and clinicopathological features for Ki-67 expression in small breast cancer (SBC) which defined as maximum diameter less than2 cm. In this retrospective study, 165 SBC patients from our hospital were allocated to a high Ki-67 group (n = 104) and a low Ki-67 group (n = 61). Multivariate regression analysis was performed to identify independent indicators for developing predictive models. The area under the receiver operating characteristic (AUC) curve was also determined to establish the diagnostic performance of different predictive models. The corresponding sensitivities and specificities of different models at the cutoff value were compared. Conventional ultrasound parameters (spiculated margin, absence of posterior shadowing and Adler grade 2-3), strain elastic scores and clinicopathological information (HER2 positive) were significantly correlated with high expression of Ki-67 in SBC (all p < .05). Model 2, which incorporated conventional ultrasound features and strain elastic scores, yielded good diagnostic performance (AUC = 0.774) with better sensitivity than model 1, which only incorporated ultrasound characteristics (78.85%vs. 55.77%, p = .000), with specificities of 77.05% and 62.30% (p = .035), respectively. Model 3, which incorporated conventional ultrasound, strain elastography and clinicopathological features, yielded better performance (AUC = 0.853) than model 1 (AUC = 0.694) and model 2 (AUC = 0.774), and the specificity was higher than model 1 (86.89% vs. 77.05%, p = .001). The predictive model combining conventional ultrasound, strain elastic scores and clinicopathological features could improve the predictive performance of Ki-67 expression in SBC.