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Chemotherapy has been the standard treatment for liver cancer. However, intrinsic or acquired drug resistance remains a major barrier to successful treatment. At present, the underlying molecular mechanisms of chemoresistance in liver cancer have not been elucidated. Dipeptidyl peptidase 9 (DPP9) is a member of the dipeptidyl peptidase IV family that has been found to be highly expressed in a variety of tumors, including liver cancer. It is unclear whether DPP9 affects chemoresistance in liver cancer. In this study, we find that DPP9 weakens the responses of liver cancer cells to chemotherapy drugs by up-regulating NQO1 and inhibiting intracellular ROS levels. In terms of mechanism, DPP9 inhibits ubiquitin-mediated degradation of NRF2 protein by binding to KEAP1, up-regulates NRF2 protein levels, promotes mRNA transcription of NQO1, and inhibits intracellular ROS levels. In addition, the NQO1 inhibitor dicoumarol can enhance the efficacy of chemotherapy drugs in liver cancer cells. Collectively, our findings suggest that inhibiting DPP9/NQO1 signaling can serve as a potential therapeutic strategy for liver cancer.
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Dipeptidil-Peptidasas y Tripeptidil-Peptidasas , Resistencia a Antineoplásicos , Regulación Neoplásica de la Expresión Génica , Neoplasias Hepáticas , NAD(P)H Deshidrogenasa (Quinona) , Factor 2 Relacionado con NF-E2 , Especies Reactivas de Oxígeno , Humanos , NAD(P)H Deshidrogenasa (Quinona)/metabolismo , NAD(P)H Deshidrogenasa (Quinona)/genética , Especies Reactivas de Oxígeno/metabolismo , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Factor 2 Relacionado con NF-E2/metabolismo , Factor 2 Relacionado con NF-E2/genética , Línea Celular Tumoral , Dipeptidil-Peptidasas y Tripeptidil-Peptidasas/metabolismo , Dipeptidil-Peptidasas y Tripeptidil-Peptidasas/genética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Proteína 1 Asociada A ECH Tipo Kelch/genética , Antineoplásicos/farmacología , Transducción de Señal/efectos de los fármacosRESUMEN
The chemical composition of dissolved organic matter (DOM) exerts significant influence on aquatic energy dynamics, pollutant transportation, and carbon storage, thereby playing pivotal roles in the local water quality and regional-global biogeochemical cycling. However, the effects of natural climate change and local human activities on watershed characteristics and in-river processes have led to uncertainties regarding their contributions to DOM chemistry in coastal rivers, creating challenges for effective water management and the study of organic matter cycling. In this investigation, we employed a combination of stable isotopic analysis, optical techniques, and Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR-MS) to elucidate the sources, optical properties, and molecular composition of DOM in three South China coastal rivers. Our results suggest that terrestrial DOM entering the three rivers through natural or anthropogenic pathways is gradually diluted by in situ primary production as it moves downstream, ultimately being influenced by seawater intrusion near the estuary. Additionally, terrestrial processes influenced by temperature likely govern DOC concentration, while seawater intrusion promotes the natural production of S-containing organic compounds. In contrast, human-altered landcover significantly impacts DOM molecular composition. Increased water areas lead to the enrichment of lignins with high disinfection byproduct formation potential, and agricultural residue burning appears to be the dominant source of pyrogenic DOM in these coastal rivers. Our distinct results suggest that the development of specific water management plans that consider the combined effects of temperature, seawater intrusion, landcover changes, and agricultural practices will be essential to ensure sustainable water resource.
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The mechanism governing sulfur cycling in nitrate reduction within sulfate-rich reservoirs during seasonal hypoxic conditions remains poorly understood. This study employs nitrogen and oxygen isotope fractionation in nitrate, along with metagenomic sequencing to elucidate the intricacies of the coupled sulfur oxidation and nitrate reduction process in the water column. In the Aha reservoir, a typical seasonally stratified water body, we observed the coexistence of denitrification, bacterial sulfide oxidation, and bacterial sulfate reduction in hypoxic conditions. This is substantiated by the presence of abundant N/S-related genes (nosZ and aprAB/dsrAB) and fluctuations in N/S species. The lower 15εNO3/18εNO3 ratio (0.60) observed in this study, compared to heterotrophic denitrification, strongly supports the occurrence of sulfur-driven denitrification. Furthermore, we found a robust positive correlation between the metabolic potential of bacterial sulfide oxidation and denitrification (p < 0.05), emphasizing the role of sulfide produced via sulfate reduction in enhancing denitrification. Sulfide-driven denitrification relied on ∑S2- as the primary electron donor preferentially oxidized by denitrification. The pivotal genus, Sulfuritalea, emerged as a central player in both denitrification and sulfide oxidation processes in hypoxic water bodies. Our study provides compelling evidence that sulfides assume a critical role in regulating denitrification in hypoxic water within an ecosystem where their contribution to the overall nitrogen cycle was previously underestimated.
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Desnitrificación , Metagenómica , Sulfatos , Sulfuros , Sulfatos/metabolismo , Sulfuros/metabolismo , Nitratos/metabolismo , Procesos Autotróficos , Oxidación-Reducción , Bacterias/metabolismoRESUMEN
Breast cancer (BC) is the most common malignant tumor worldwide. Despite enormous progress made in the past decades, the underlying mechanisms of BC remain further illustrated. Recently, TRIM family proteins proved to be engaged in BC progression through regulating various aspects. Here we reviewed the structures and basic functions of TRIM family members and first classified them into three groups according to canonical polyubiquitination forms that they could mediate: K48- only, K63- only, and both K48- and K63-linked ubiquitination. Afterwards, we focused on the specific biological functions and mechanisms of TRIMs in BCs, including tumorigenesis and invasiveness, drug sensitivity, tumor immune microenvironment (TIME), cell cycle, and metabolic reprogramming. We also explored the potential of TRIMs as novel biomarkers for predicting prognosis and future therapeutic targets in BC.
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Neoplasias de la Mama , Proteínas de Motivos Tripartitos , Ubiquitinación , Humanos , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Neoplasias de la Mama/genética , Femenino , Proteínas de Motivos Tripartitos/metabolismo , Proteínas de Motivos Tripartitos/genética , Microambiente Tumoral , Biomarcadores de Tumor/metabolismo , Pronóstico , Regulación Neoplásica de la Expresión Génica , AnimalesRESUMEN
AIMS: Despite aggressive treatment, the recurrence of glioma is an inevitable occurrence, leading to unsatisfactory clinical outcomes. A plausible explanation for this phenomenon is the phenotypic alterations that glioma cells undergo aggressive therapies, such as TMZ-therapy. However, the underlying mechanisms behind these changes are not well understood. METHODS: The TMZ chemotherapy resistance model was employed to assess the expression of intercellular adhesion molecule-1 (ICAM1) in both in vitro and in vivo settings. The potential role of ICAM1 in regulating TMZ chemotherapy resistance was investigated through knockout and overexpression techniques. Furthermore, the mechanism underlying ICAM1-mediated TMZ chemotherapy resistance was examined using diverse molecular biological methods, and the lipid raft protein was subsequently isolated to investigate the cellular subcomponents where ICAM1 operates. RESULTS: Acquired TMZ resistant (TMZ-R) glioma models heightened production of intercellular adhesion molecule-1 (ICAM1) in TMZ-R glioma cells. Additionally, we observed a significant suppression of TMZ-R glioma proliferation upon inhibition of ICAM1, which was attributed to the enhanced intracellular accumulation of TMZ. Our findings provide evidence supporting the role of ICAM1, a proinflammatory marker, in promoting the expression of ABCB1 on the cell membrane of TMZ-resistant cells. We have elucidated the mechanistic pathway by which ICAM1 modulates phosphorylated moesin, leading to an increase in ABCB1 expression on the membrane. Furthermore, our research has revealed that the regulation of moesin by ICAM1 was instrumental in facilitating the assembly of ABCB1 exclusively on the lipid raft of the membrane. CONCLUSIONS: Our findings suggest that ICAM1 is an important mediator in TMZ-resistant gliomas and targeting ICAM1 may provide a new strategy for enhancing the efficacy of TMZ therapy against glioma.
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Subfamilia B de Transportador de Casetes de Unión a ATP , Neoplasias Encefálicas , Resistencia a Antineoplásicos , Glioma , Molécula 1 de Adhesión Intercelular , Temozolomida , Resistencia a Antineoplásicos/efectos de los fármacos , Glioma/tratamiento farmacológico , Glioma/patología , Glioma/genética , Glioma/metabolismo , Molécula 1 de Adhesión Intercelular/metabolismo , Molécula 1 de Adhesión Intercelular/genética , Humanos , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Temozolomida/farmacología , Línea Celular Tumoral , Animales , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/genética , Antineoplásicos Alquilantes/farmacología , Antineoplásicos Alquilantes/uso terapéutico , Proliferación Celular/efectos de los fármacos , Ratones , Microdominios de Membrana/metabolismo , Microdominios de Membrana/efectos de los fármacosRESUMEN
Cisplatin (DDP) resistance poses a significant challenge in the treatment of ovarian cancer. Studies have shown that the combination of certain polysaccharides derived from plants with DDP is an effective approach to overcoming drug resistance in some cancers. Angelica sinensis (Oliv.) Diels has been used for centuries in China to treat gynecological ailments. Numerous studies indicate that Angelica sinensis polysaccharide (ASP), an extract from Angelica sinensis, can inhibit various forms of cancer. However, the impact of ASP on ovarian cancer remains unexplored. Through both in vitro and in vivo experiments, our study revealed the capability of ASP to effectively reversing DDP resistance in cisplatin-resistant ovarian cancer cells, while exhibiting acceptable safety profiles in vivo. To elucidate the mechanism underlying drug resistance reversal, we employed RNA-seq analysis and identified GPX4 as a key gene. Considering the role of GPX4 in ferroptosis, we conducted additional research to explore the effects of combining ASP with DDP on SKOV3/DDP cells. In summary, our findings demonstrate that the combination of ASP and DDP effectively suppresses GPX4 expression in SKOV3/DDP cells, thereby reversing their resistance to DDP.
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Angelica sinensis , Cisplatino , Resistencia a Antineoplásicos , Ferroptosis , Neoplasias Ováricas , Fosfolípido Hidroperóxido Glutatión Peroxidasa , Polisacáridos , Cisplatino/farmacología , Femenino , Resistencia a Antineoplásicos/efectos de los fármacos , Humanos , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/patología , Ferroptosis/efectos de los fármacos , Polisacáridos/farmacología , Angelica sinensis/química , Línea Celular Tumoral , Fosfolípido Hidroperóxido Glutatión Peroxidasa/metabolismo , Animales , Ratones Desnudos , Ratones , Ratones Endogámicos BALB C , Ensayos Antitumor por Modelo de Xenoinjerto , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Antineoplásicos/farmacologíaRESUMEN
Given the safety, tumor tropism, and ease of genetic manipulation in non-pathogenic Escherichia coli (E. coli), we designed a novel approach to deliver biologics to overcome poor trafficking and exhaustion of immune cells in the tumor microenvironment, via the surface display of key immune-activating cytokines on the outer membrane of E. coli K-12 DH5α. Bacteria expressing murine decoy-resistant IL18 mutein (DR18) induced robust CD8+ T and NK cell-dependent immune responses leading to dramatic tumor control, extending survival, and curing a significant proportion of immune-competent mice with colorectal carcinoma and melanoma. The engineered bacteria demonstrated tumor tropism, while the abscopal and recall responses suggested epitope spreading and induction of immunologic memory. E. coli K-12 DH5α engineered to display human DR18 potently activated mesothelin-targeting CAR NK cells and safely enhanced their trafficking into the tumors, leading to improved control and survival in xenograft mice bearing mesothelioma tumor cells, otherwise resistant to NK cells. Gene expression analysis of the bacteria-primed CAR NK cells showed enhanced TNFα signaling via NFkB and upregulation of multiple activation markers. Our novel live bacteria-based immunotherapeutic platform safely and effectively induces potent anti-tumor responses in otherwise hard-to-treat solid tumors, motivating further evaluation of this approach in the clinic.
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PURPOSE: Increased expression of leukocyte immunoglobulin-like receptor subfamily B member 2 (LILRB2) is associated with immune evasion in breast cancer (BC). The aim of this study to elucidate the role of LILRB2 in BC progression. METHODS: LILRB2 expression in tumor tissues was detected by immunohistochemical staining. Human leukocyte antigen A (HLA-A) expression in BC cells was detected by Western blotting, and HLA-A ubiquitination was detected by immunoprecipitation and histidine pulldown assay. An in-situ tumor model was established in nude BALB/c mice to verify the role of LILRB2 in immune escape. Finally, the functions and potential mechanisms of LILRB2 in BC progression were explored using in silico data. RESULTS: LILRB2 was upregulated in BC tissues and cells, and correlated positively with poor prognosis. LILRB2 promoted BC progression by downregulating HLA-A expression. Mechanistically, LILRB2 facilitates the ubiquitination and subsequent degradation of HLA-A by promoting the interaction between the ubiquitin ligase membrane-associated ring finger protein 9 (MARCH9) and HLA-A. In syngeneic graft mouse models, LILRB2-expressing BC cells evaded CD8 + T cells and inhibited the secretion of cytokines by the cytotoxic CD8 + T cells. CONCLUSION: LILRB2 downregulates HLA-A to promote immune evasion in BC cells and is a promising new target for BC treatment.
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Lung cancer is one of the most lethal cancers with high incidence worldwide. The prevention of lung cancer is of great significance to reducing the social harm caused by this disease. An in-depth understanding of the molecular changes underlying precancerous lesions is essential for the targeted chemoprevention against lung cancer. Here, we discovered an increased NQO1 level over time within pulmonary premalignant lesions in both the KrasG12D-driven and nicotine-derived nitrosamine ketone (NNK)-induced mouse models of lung cancer, as well as in KrasG12D-driven and NNK-induced malignant transformed human bronchial epithelial cells (BEAS-2B and 16HBE). This suggests a potential correlation between the NQO1 expression and lung carcinogenesis. Based on this finding, we utilized ß-Lapachone (ß-Lap), an NQO1 bioactivatable drug, to suppress lung tumorigenesis. In this study, the efficacy and safety of low-dose ß-Lap were demonstrated in preventing lung tumorigenesis in vivo. In conclusion, our study suggests that long-term consumption of low-dose ß-Lap could potentially be an effective therapeutic strategy for the prevention of lung premalignant lesions. However, further studies and clinical trials are necessary to validate our findings, determine the safety of long-term ß-Lap usage in humans, and promote the use of ß-Lap in high-risk populations.
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Neoplasias Pulmonares , NAD(P)H Deshidrogenasa (Quinona) , Naftoquinonas , Animales , Naftoquinonas/farmacología , Naftoquinonas/uso terapéutico , NAD(P)H Deshidrogenasa (Quinona)/metabolismo , Neoplasias Pulmonares/prevención & control , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/inducido químicamente , Neoplasias Pulmonares/metabolismo , Humanos , Ratones , Carcinogénesis/efectos de los fármacos , Transformación Celular Neoplásica/efectos de los fármacos , Transformación Celular Neoplásica/inducido químicamente , Transformación Celular Neoplásica/metabolismo , Femenino , Línea CelularRESUMEN
Thermal stability and iron saturation of lactoferrin (LF) are of great significance not only for the evaluation of the biological activities of LF but also for the optimization of the isolation and drying process parameters. Differential scanning calorimetry (DSC) is a well-established and efficient method for thermal stability and iron saturation detection in LF. However, multiple DSC measurements are typically performed sequentially, thus time-consuming and low throughput. Herein, we introduced the differential scanning fluorimetry (DSF) approach to overcome such limitations. The DSF can monitor LF thermal unfolding with a commonly available real-time PCR instrument and a fluorescent dye (SYPRO orange or Glomelt), and the measured melting temperature of LF is consistent with that determined by DSC. On the basis of that, a new quantification method was established for determination of iron saturation levels using the linear correlation of the degree of ion saturation of LF with DSF measurements. Such DSF method is simple, inexpensive, rapid (<15 min), and high throughput (>96 samples per experiment), and provides a valuable alternative tool for thermal stability detection of LF and other whey proteins.
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Fluorometría , Hierro , Lactoferrina , Estabilidad Proteica , Lactoferrina/química , Lactoferrina/análisis , Hierro/química , Fluorometría/métodos , Rastreo Diferencial de Calorimetría/métodos , Temperatura , Ensayos Analíticos de Alto Rendimiento/métodosRESUMEN
Artemisia annua L. (A. annua), a Traditional Chinese Medicine (TCM) that has been utilized in China for centuries, is known for its potential anticancer properties. However, the main components and mechanism of action of A. annua on endometrial carcinoma have not been reported. We used the TCMSP database to identify the active components of A. annua and their corresponding gene targets. We then obtained the gene targets specific to endometrial cancer from The Cancer Genome Atlas (TCGA) and GeneCards databases. The gene targets common to three databases were selected, and a "component-target" network was constructed. Protein-protein interaction (PPI) network analysis and ranking of the target proteins identified the key protein PTGS2 network analysis, and ranking of the target proteins identified the key protein PTGS2. We also screened the active components of A. annua and found that quercetin, kaempferol, luteolin, isorhamnetin, artemisin, and stigmasterol had the most targets. Molecular docking models were established for these six components with PTGS2, revealing strong binding activity for all of them. Finally, we conducted validation experiments to assess the effects of quercetin, an active component of A. annua, on endometrial cancer cells (HEC-1-A and Ishikawa cells). Our findings demonstrate that quercetin has the potential to inhibit both cell growth and migration, while also suppressing the expression of PTGS2.
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A number of neurotransmitters have been detected in tumor microenvironment and proved to modulate cancer oncogenesis and progression. We previously found that biosynthesis and secretion of neurotransmitter 5-hydroxytryptamine (5-HT) was elevated in colorectal cancer cells. In this study, we discovered that the HTR2B receptor of 5-HT was highly expressed in colorectal cancer tumor tissues, which was further identified as a strong risk factor for colorectal cancer prognostic outcomes. Both pharmacological blocking and genetic knocking down HTR2B impaired migration of colorectal cancer cell, as well as the epithelial-mesenchymal transition (EMT) process. Mechanistically, HTR2B signaling induced ribosomal protein S6 kinase B1 (S6K1) activation via the Akt/mTOR pathway, which triggered cAMP-responsive element-binding protein 1 (CREB1) phosphorylation (Ser 133) and translocation into the nucleus, then the phosphorylated CREB1 acts as an activator for ZEB1 transcription after binding to CREB1 half-site (GTCA) at ZEB1 promoter. As a key regulator of EMT, ZEB1, therefore, enhances migration and EMT process in colorectal cancer cells. We also found that HTR2B-specific antagonist (RS127445) treatment significantly ameliorated metastasis and reversed EMT process in both HCT116 cell tail-vein-injected pulmonary metastasis and CT26 cell intrasplenic-injected hepatic metastasis mouse models. IMPLICATIONS: These findings uncover a novel regulatory role of HTR2B signaling on colorectal cancer metastasis, which provide experimental evidences for potential HTR2B-targeted anti-colorectal cancer metastasis therapy.
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Neoplasias Colorrectales , Proteína de Unión a Elemento de Respuesta al AMP Cíclico , Transición Epitelial-Mesenquimal , Receptor de Serotonina 5-HT2B , Homeobox 1 de Unión a la E-Box con Dedos de Zinc , Humanos , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Animales , Ratones , Homeobox 1 de Unión a la E-Box con Dedos de Zinc/metabolismo , Homeobox 1 de Unión a la E-Box con Dedos de Zinc/genética , Receptor de Serotonina 5-HT2B/metabolismo , Receptor de Serotonina 5-HT2B/genética , Línea Celular Tumoral , Movimiento Celular , Metástasis de la Neoplasia , Transducción de Señal , Regulación Neoplásica de la Expresión Génica , Masculino , FemeninoRESUMEN
Arsenic (As) has been widely detected in surface media on the Qinghai-Tibetan Plateau (QTP); however, the differences in the As distribution and partitioning characteristics between freshwater and saltwater lakes remain poorly understood. To determine the distribution and partitioning characteristics of As, multimedia environmental samples were collected from a typical small watershed consisting of a river, wetland, and both freshwater and saltwater lakes on the QTP. Results showed that freshwater systems, represented by Hurleg Lake, were high in particulate arsenic (PAs) and low in dissolved arsenic (DAs), whereas the saltwater system represented by Tosen Lake, exhibited the reverse distribution. This discrepancy in As distribution was primarily attributed to evaporation enrichment, competitive adsorption of HCO3- and pH variations, as suggested by correlation analysis and stable isotopic composition of water. In the stratified Tosen Lake, an increasing trend of DAs in the water column was observed, potentially driven by the reductive dissolution of Fe (hydr)oxides and bacterial sulfate reduction in the anoxic bottom hypolimnion. Conversely, Hurleg Lake maintained oxic conditions with stable DAs concentrations. Notably, PAs was elevated in the bottom layer of both lakes, possibly due to uptake/adsorption by biogenic particles, as indicated by high levels of chl.α and suspended particulate matter. These findings offer insights into the potential future impact of climate change on As mobilization/redistribution in arid plateau lakes, with implications for management policies that regulate As pollution.
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Arsénico , Lagos , Lagos/química , Arsénico/análisis , Tibet , Monitoreo del Ambiente/métodos , Agua , ChinaRESUMEN
Lactic acid or lactate, a key byproduct of anaerobic glycolysis, plays pivotal roles in routine metabolism. An increase in lactic acid is observed in various pathological conditions such as cancer, diabetes, genetic mitochondrial disease, and aging. While several groups have proposed small molecule inhibitors to reduce circulating lactic acid, there are few clinically relevant ways to manage acute or chronic elevations in lactic acid in patients. In addition, recent evidence suggests that lactic acid exchanges between the gut, blood, and peripheral tissues, and professional marathon runners harbor specific gut microbial species that more efficiently metabolize lactic acid. Inspired by these findings, this work sought to engineer probiotic B. subtilis strains to express lactate oxidase that could increase circulating lactic acid catabolism after delivery to the gut. After optimization, oral administration of engineered B. subtilis to the gut of mice reduced the elevation in blood lactic acid levels after exogenous lactic acid challenge without affecting normal gut microbiota composition, inflammation or liver enzymes. Taken together, through the oral delivery of engineered probiotics to the gastrointestinal tract, our proof-of-concept study offers a new opportunity to therapeutically target diseases where blood lactic acid is elevated, and provides a new approach to "knocking down" metabolites to help understand the roles of metabolites in host physiological and pathological processes.
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Hypertension and osteoporosis are common comorbidities among elderly individuals. Drug therapy has been widely used in clinical practice as the preferred antihypertensive treatment. Therefore, antihypertensive drugs have become some of the most commonly prescribed drugs in healthcare settings. However, antihypertensive drugs have different effects on bone metabolism. The results of animal and clinical studies on the effects of antihypertensive drugs on osteoporosis or fracture risk are controversial and have aroused widespread concern among clinicians. Recent studies found that angiotensin receptor blockers, selective ß-adrenergic receptor blockers, and thiazide diuretics might improve bone trabecular number and bone mineral density by stimulating osteoblast differentiation, reducing osteoclast generation, and other mechanism. Furthermore, nonselective ß-adrenergic receptor blockers and dihydropyridine calcium channel blockers were found to have no significant relationship with bone mineral density or bone strength, and α-adrenergic receptor blockers and loop diuretics might increase fracture risk by decreasing bone mineral density. This article aimed to review previous animal experiments, clinical studies, and meta-analyses focusing on the effects of different antihypertensive drugs on bone metabolism, and to provide a new approach for the prevention and treatment of osteoporosis.
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Fracturas Óseas , Hipertensión , Osteoporosis , Humanos , Anciano , Antihipertensivos/farmacología , Antihipertensivos/uso terapéutico , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Bloqueadores de los Canales de Calcio/uso terapéutico , Hipertensión/tratamiento farmacológico , Antagonistas Adrenérgicos beta/uso terapéutico , Antagonistas Adrenérgicos alfa/uso terapéutico , Fracturas Óseas/epidemiología , Fracturas Óseas/etiología , Fracturas Óseas/prevención & control , Osteoporosis/inducido químicamente , Osteoporosis/tratamiento farmacológico , Receptores Adrenérgicos beta , Diuréticos/uso terapéuticoRESUMEN
ABSTRACT: Background: Previous data have suggested the involvement of circular RNA (circRNA) in ulcerative colitis (UC) development. However, the role and mechanism of circ_0085323 in UC occurrence have not been reported. Methods: Normal human colonic epithelial cells (NCM460) were treated with TNF-α to simulate UC-like cell inflammation and injury in vitro. The expression of circ_0085323, microRNA-495-3p (miR-495-3p), and TNF receptor-associated factor 3 (TRAF3) was detected by quantitative real-time polymerase chain reaction. Protein expression was checked by western blotting analysis. Cell viability, cell proliferation, and cell apoptosis were investigated by cell counting kit-8 assay, 5-ethynyl-29-deoxyuridine assay, and flow cytometry analysis, respectively. IL-1ß, IL-6, and IL-8 production were analyzed by enzyme-linked immunosorbent assays. Lactate dehydrogenase activity was assessed by a lactate dehydrogenase activity detection assay. The interactions among circ_0085323, miR-495-3p, and TRAF3 were identified by dual-luciferase reporter assay and RNA immunoprecipitation assay. Results: Circ_0085323 was overexpressed in the colonic mucosal tissues of UC patients and TNF-α-stimulated NCM460 cells. Circ_0085323 knockdown relieved TNF-α-induced inhibitory effect on the proliferation of NCM460 cells and promoting effects on cell apoptosis and inflammation. Circ_0085323 acted as a miR-495-3p sponge, and the effects of circ_0085323 silencing on TNF-α-induced NCM460 cell injury were attenuated by decreasing miR-495-3p expression. TRAF3 was targeted by miR-495-3p, and circ_0085323 combined with miR-495-3p to regulate TRAF3. TRAF3 depletion not only alleviated TNF-α-induced NCM460 cell damage but also partially revoked the effect of circ_0085323 silencing combined with miR-495-3p depletion on TNF-α-induced NCM460 cell injury. Conclusions: Circ_0085323 knockdown ameliorated TNF-α-induced NCM460 cell injury by regulating the miR-495-3p/TRAF3 axis, which suggested that circ_0085323 might be a therapeutic target for UC.
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Colitis Ulcerosa , MicroARNs , Humanos , Factor 3 Asociado a Receptor de TNF/genética , Factor de Necrosis Tumoral alfa/farmacología , Inflamación/genética , Apoptosis/genética , Células Epiteliales , Lactato Deshidrogenasas , MicroARNs/genéticaRESUMEN
The most widely used technique for psychiatric diagnosis is a contemporary manual-based procedure based on prevailing culture-bound data for the classification of mental disorders. However, it has several inherent faults, including the misdiagnosis of complex patient phenomena and others. A potential mental patient from a minority culture could present with atypical symptoms that would be missed by the standard approach. Using the three-way decisions (3WD) as a framework, we propose a unified model that represents the subjective approach (CSA) of clinicians (psychiatrists and psychologists) consisting of three components: qualitative analysis, quantitative analysis, and evaluation-based analysis. The results of the qualitative and quantitative investigation are a classification list and a set of numerical weights based on malady severity levels according to the clinician's highest level of assumptions. Moreover, we construct a comparative classification of diseases into three categories with varying levels of importance; a three-way evaluation-based model is utilized in this study in order to better comprehend and communicate these results. This proposed method enables clinicians to consider identical data-driven individual behavioral symptoms of patients to be integrated with the current manual-based process as a complementary diagnostic instrument to improve the accuracy of mental disorder diagnosis.
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BACKGROUND: Immune checkpoint inhibitors (ICIs) shed new light on triple-negative breast cancer (TNBC), but only a minority of patients demonstrate response. Therefore, adaptive immune resistance (AIR) needs to be further defined to guide the development of ICI regimens. METHODS: Databases, including The Cancer Genome Atlas, Gene Ontology Resource, University of California Santa Cruz Genome Browser, and Pubmed, were used to screen epigenetic modulators, regulators for CD8+ T cells, and transcriptional regulators of programmed cell death-ligand 1 (PD-L1). Human peripheral blood mononuclear cell (Hu-PBMC) reconstruction mice were adopted for xenograft transplantation. Tumor specimens from a TNBC cohort and the clinical trial CTR20191353 were retrospectively analyzed. RNA-sequencing, Western blotting, qPCR and immunohistochemistry were used to assess gene expression. Coculture assays were performed to evaluate the regulation of TNBC cells on T cells. Chromatin immunoprecipitation and transposase-accessible chromatin sequencing were used to determine chromatin-binding and accessibility. RESULTS: The epigenetic modulator AT-rich interaction domain 1A (ARID1A) gene demonstrated the highest expression association with AIR relative to other epigenetic modulators in TNBC patients. Low ARID1A expression in TNBC, causing an immunosuppressive microenvironment, promoted AIR and inhibited CD8+ T cell infiltration and activity through upregulating PD-L1. However, ARID1A did not directly regulate PD-L1 expression. We found that ARID1A directly bound the promoter of nucleophosmin 1 (NPM1) and that low ARID1A expression increased NPM1 chromatin accessibility as well as gene expression, further activating PD-L1 transcription. In Hu-PBMC mice, atezolizumab demonstrated the potential to reverse ARID1A deficiency-induced AIR in TNBC by reducing tumor malignancy and activating anti-tumor immunity. In CTR20191353, ARID1A-low patients derived more benefit from pucotenlimab compared to ARID1A-high patients. CONCLUSIONS: In AIR epigenetics, low ARID1A expression in TNBC contributed to AIR via the ARID1A/NPM1/PD-L1 axis, leading to poor outcome but sensitivity to ICI treatment.
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Inhibidores de Puntos de Control Inmunológico , Neoplasias de la Mama Triple Negativas , Humanos , Animales , Ratones , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Linfocitos T CD8-positivos/metabolismo , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/genética , Neoplasias de la Mama Triple Negativas/patología , Leucocitos Mononucleares/metabolismo , Leucocitos Mononucleares/patología , Antígeno B7-H1 , Estudios Retrospectivos , Proteínas Nucleares , Microambiente Tumoral/genética , Proteínas de Unión al ADN , Factores de TranscripciónRESUMEN
Host mucosal barriers possess an arsenal of defense molecules to maintain host-microbe homeostasis such as antimicrobial peptides and immunoglobulins. In addition to these well-established defense molecules, we recently reported small RNAs (sRNAs)-mediated interactions between human oral keratinocytes and Fusobacterium nucleatum (Fn), an oral pathobiont with increasing implications in extra-oral diseases. Specifically, upon Fn infection, oral keratinocytes released Fn-targeting tRNA-derived sRNAs (tsRNAs), an emerging class of noncoding sRNAs with gene regulatory functions. To explore potential antimicrobial activities of tsRNAs, we chemically modify the nucleotides of the Fn-targeting tsRNAs and demonstrate that the resultant tsRNA derivatives, termed MOD-tsRNAs, exhibit growth inhibitory effect against various Fn type strains and clinical tumor isolates without any delivery vehicle in the nanomolar concentration range. In contrast, the same MOD-tsRNAs do not inhibit other representative oral bacteria. Further mechanistic studies uncover the ribosome-targeting functions of MOD-tsRNAs in inhibiting Fn. Taken together, our work provides an engineering approach to targeting pathobionts through co-opting host-derived extracellular tsRNAs.
Asunto(s)
MicroARNs , ARN Pequeño no Traducido , Humanos , Fusobacterium nucleatum/genética , ARN de Transferencia/genética , MicroARNs/genéticaRESUMEN
BACKGROUND AND OBJECTIVE: Data on the association between early-life famine exposure and osteoporosis and fractures remain limited and inconclusive. The aim of this study was to investigate the correlation between famine exposure and osteoporosis and fractures. METHODS: We performed a cross-sectional analysis using the first follow-up survey data from the China Cardiometabolic Disease and Cancer Cohort Study from 2014 to 2016. We classified 4807 Lanzhou participants into seven groups based on their birthday (non-exposed or exposed in the fetal stage, early childhood, mid-childhood, late childhood, adolescence, or early adulthood). And we combined the non-exposed and early-adulthood exposed groups as a control group, which was called "age balanced group". This age-balanced group was used as the control group to further evaluate the risk of osteoporosis and fracture. We used multiple logistic regression to estimate the association between famine exposure and the risk of osteoporosis (T-score ≤ -1.8 by QUS) and self-reported fracture. RESULTS: In women, compared to the age-balanced group, the odds ratios (95 % CI) for the risk of osteoporosis were 1.400(1.034, 1.897), 1.630(1.268, 2.095), 1.707(1.314, 2.218), 2.150(1.732.2.668) and 2.885(2.286,3.641) in the fetal stage, early childhood, mid-childhood, late childhood and adolescence famine-exposed cohorts. In men, no association between famine and osteoporosis was noted with exposed cohort compared with the age-balanced control cohort (p > 0.05). Interestingly, the association between famine exposure and fractures was slightly different from the above results: in women, the odds ratios (95 % CI) for fractures in mid-childhood famine exposure was 1.461(1.082,1.973), in late childhood famine exposure was 1.333(1.035,1.718) and in adolescence famine exposure was 1.607(1.239,2.085). However, compared to the age-balanced control cohort, men exposed to famine in early childhood (OR: 1.801, 95 % CI: 1.010,3.211) had a higher risk of fracture. CONCLUSION: Famine exposure in different life stage has adverse effects on bone health. Famine exposure in not only the period from gestation to infancy, but also childhood and adolescence was associated with an increased risk of osteoporosis, especially in women. Exposure to famine in childhood- (mid and late) and adolescence- life period is associated with fracture in women. But, in men early-childhood famine exposure was only associated with fracture.