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In this issue, Versluis et al.1 use a highly sensitive live-cell imaging system to examine transcription dynamics and functions of various key transcription elongation regulators at the Hsp70 loci.
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Cromosomas Politénicos , Elongación de la Transcripción Genética , Animales , Cromosomas Politénicos/genética , Cromosomas Politénicos/metabolismo , Proteínas HSP70 de Choque Térmico/genética , Proteínas HSP70 de Choque Térmico/metabolismo , Transcripción Genética , ARN Polimerasa II/metabolismo , ARN Polimerasa II/genética , Factores de Transcripción/metabolismo , Factores de Transcripción/genéticaRESUMEN
TGF-ß signaling can be pro-tumorigenic or tumor suppressive. We investigated this duality in pancreatic ductal adenocarcinoma (PDA), which, with other gastrointestinal cancers, exhibits frequent inactivation of the TGF-ß mediator Smad4. We show that TGF-ß induces an epithelial-mesenchymal transition (EMT), generally considered a pro-tumorigenic event. However, in TGF-ß-sensitive PDA cells, EMT becomes lethal by converting TGF-ß-induced Sox4 from an enforcer of tumorigenesis into a promoter of apoptosis. This is the result of an EMT-linked remodeling of the cellular transcription factor landscape, including the repression of the gastrointestinal lineage-master regulator Klf5. Klf5 cooperates with Sox4 in oncogenesis and prevents Sox4-induced apoptosis. Smad4 is required for EMT but dispensable for Sox4 induction by TGF-ß. TGF-ß-induced Sox4 is thus geared to bolster progenitor identity, whereas simultaneous Smad4-dependent EMT strips Sox4 of an essential partner in oncogenesis. Our work demonstrates that TGF-ß tumor suppression functions through an EMT-mediated disruption of a lineage-specific transcriptional network.
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Carcinoma Ductal/genética , Transición Epitelial-Mesenquimal , Redes Reguladoras de Genes , Neoplasias Pancreáticas/genética , Factor de Crecimiento Transformador beta/antagonistas & inhibidores , Adenocarcinoma/genética , Adenocarcinoma/patología , Animales , Apoptosis , Carcinoma Ductal/patología , Factores de Transcripción de Tipo Kruppel/metabolismo , Ratones , Organoides/metabolismo , Organoides/patología , Neoplasias Pancreáticas/patología , Factores de Transcripción SOXC/metabolismo , Proteína Smad4/metabolismoRESUMEN
Conn et al.1 identify circular RNAs (circRNAs) derived from mixed lineage leukemia (MLL) breakpoint cluster regions, demonstrating a causal role of circRNAs in MLL translocations. CircRNAs:DNA hybrids (circR-loops) trigger RNA polymerase pausing, driving oncogenic gene fusions via endogenous RNA-directed DNA damage.
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Leucemia , ARN Circular , Humanos , Proteína de la Leucemia Mieloide-Linfoide/genética , Leucemia/genética , Translocación Genética , Reordenamiento GénicoRESUMEN
Drug targets are specific molecules in biological tissues and body fluids that interact with drugs. Drug target discovery is a key component of drug discovery and is essential for the development of new drugs in areas such as cancer therapy and precision medicine. Traditional in vitro or in vivo target discovery methods are time-consuming and labor-intensive, limiting the pace of drug discovery. With the development of modern discovery methods, the discovery and application of various emerging technologies have greatly improved the efficiency of drug discovery, shortened the cycle time, and reduced the cost. This review provides a comprehensive overview of various emerging drug target discovery strategies, including computer-assisted approaches, drug affinity response target stability, multiomics analysis, gene editing, and nonsense-mediated mRNA degradation, and discusses the effectiveness and limitations of the various approaches, as well as their application in real cases. Through the review of the aforementioned contents, a general overview of the development of novel drug targets and disease treatment strategies will be provided, and a theoretical basis will be provided for those who are engaged in pharmaceutical science research. SIGNIFICANCE STATEMENT: Target-based drug discovery has been the main approach to drug discovery in the pharmaceutical industry for the past three decades. Traditional drug target discovery methods based on in vivo or in vitro validation are time-consuming and costly, greatly limiting the development of new drugs. Therefore, the development and selection of new methods in the drug target discovery process is crucial.
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Descubrimiento de Drogas , Humanos , Descubrimiento de Drogas/métodos , Animales , Terapia Molecular DirigidaRESUMEN
Alternative splicing (AS) regulates gene expression and increases proteomic diversity for the fine tuning of stress responses in plants, but the exact mechanism through which AS functions in plant stress responses is not thoroughly understood. Here, we investigated how AS functions in poplar (Populus trichocarpa), a popular plant for bioremediation, in response to lead (Pb) stress. Using a proteogenomic analysis, we determine that Pb stress induced alterations in AS patterns that are characterized by an increased use of nonconventional splice sites and a higher abundance of Pb-responsive splicing factors (SFs) associated with Pb-responsive transcription factors. A strong Pb(II)-inducible chaperone protein, PtHSP70, that undergoes AS was further characterized. Overexpression of its two spliced isoforms, PtHSP70-AS1 and PtHSP70-AS2, in poplar and Arabidopsis significantly enhances the tolerance to Pb. Further characterization shows that both isoforms can directly bind to Pb(II), and PtHSP70-AS2 exhibits 10-fold higher binding capacities and a greater increase in expression under Pb stress, thereby reducing cellular toxicity through Pb(II) extrusion and conferring Pb tolerance. AS of PtHSP70 is found to be regulated by PtU1-70K, a Pb(II)-inducible core SF involved in 5'-splice site recognition. Because the same splicing pattern is also found in HSP70 orthologs in other plant species, AS of HSP70 may be a common regulatory mechanism to cope with Pb(II) toxicity. Overall, we have revealed a novel post-transcriptional machinery that mediates heavy metal tolerance in diverse plant species. Our findings offer new molecular targets and bioengineering strategies for phytoremediation and provide new insight for future directions in AS research.
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Arabidopsis , Populus , Proteogenómica , Empalme Alternativo , Proteómica , Populus/genética , Populus/metabolismo , Plomo/toxicidad , Plomo/metabolismo , Arabidopsis/genética , Arabidopsis/metabolismo , Factores de Transcripción/metabolismo , Estrés Fisiológico/genética , Regulación de la Expresión Génica de las Plantas , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismoRESUMEN
Transcription factors (TFs) play critical roles in hematopoiesis, and their aberrant expression can lead to various types of leukemia. The t(8;21) leukemogenic fusion protein AML1-ETO (AE) is the most common fusion protein in acute myeloid leukemia and can enhance hematopoietic stem cell renewal while blocking differentiation. A key question in understanding AE-mediated leukemia is what determines the choice of AE to activate self-renewal genes or repress differentiation genes. Toward the resolution of this problem, we earlier showed that AE resides in the stable AETFC complex and that its components colocalize on up- or down-regulated target genes and are essential for leukemogenesis. In the current study, using biochemical and genomic approaches, we show that AE-containing complexes are heterogeneous, and that assembly of the larger AETFC (containing AE, CBFß, HEB, E2A, LYL1, LMO2, and LDB1) requires LYL1. Furthermore, we provide strong evidence that the LYL1-containing AETFC preferentially binds to active enhancers and promotes AE-dependent gene activation. Moreover, we show that coactivator CARM1 interacts with AETFC and facilitates gene activation by AETFC. Collectively, this study describes a role of oncoprotein LYL1 in AETFC assembly and gene activation by recruiting CARM1 to chromatin for AML cell survival.
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Leucemia Mieloide Aguda , Proteínas de Fusión Oncogénica , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Proteínas Adaptadoras de Señalización CARD , Cromatina , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Subunidad alfa 2 del Factor de Unión al Sitio Principal/metabolismo , Guanilato Ciclasa , Humanos , Proteínas con Homeodominio LIM/genética , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Proteínas de Neoplasias/genética , Proteínas de Fusión Oncogénica/genética , Proteínas de Fusión Oncogénica/metabolismo , Proteína-Arginina N-Metiltransferasas , Activación TranscripcionalRESUMEN
BACKGROUND: There are large differences in clinical manifestations and biological markers between elderly patients with rheumatoid arthritis (EPRA, age >60) and younger patients with RA (YPRA, age ≤60), partly owing to variations in the immune system of different age groups. Here, we focused on the changes of immune cell infiltration in YPRA and EPRA. METHODS: The R packages "ssGSEA" and "GSEA" were used to identify the changes in immune cell infiltration and immune-related pathways between the two groups. The R packages "WGCNA" and "DEseq2" were used to screen and verify age-related differentially expressed genes (DEGs). Hub genes were identified using Cytoscape and cytoHubba. Spearman correlation coefficient was conducted to evaluate correlations between hub age-related genes and immune cells. RESULTS: Compared with 54 established YPRA, several immune cells and immune-related pathways were markedly decreased in 29 EPRA synovial tissues. Moreover, 78 age-related DEGs related to amino acid and glycosphingolipid synthesis and metabolism were identified. USP2 and ARG2 were verified to be upregulated in EPRA, signifying that these two genes could effectively distinguish YPRA and EPRA and have potential as biomarkers. In addition, we found that USP2 was significantly negatively correlated with B cells and monocytes, while there was a significant negative association between ARG2 and T cells. CONCLUSIONS: In conclusion, this study is the first to systematically analyze changes in immune cell infiltration between YPRA and EPRA patients and obtain hub age-related genes, which may provide the basis for illuminating the pathogenesis of EPRA and informing treatment strategies.
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Artritis Reumatoide , Anciano , Humanos , Aminoácidos , Artritis Reumatoide/genética , Linfocitos B , Biología Computacional , Membrana Sinovial , Ubiquitina TiolesterasaRESUMEN
According to statistics, the incidence of liver cancer is increasing yearly, and effective treatment of liver cancer is imminent. For early liver cancer, resection surgery is currently the most effective treatment. However, resection does not treat the disease in advanced patients, so finding a method with a better prognosis is necessary. In recent years, ferroptosis and cuproptosis have been gradually defined, and related studies have proved that they show excellent results in the therapy of liver cancer. Cuproptosis is a new form of cell death, and the use of cuproptosis combined with ferroptosis to inhibit the production of hepatocellular carcinoma cells has good development prospects and is worthy of in-depth discussion by researchers. In this review, we summarize the research progress on cuproptosis combined with ferroptosis in treating liver cancer, analyze the value of cuproptosis and ferroptosis in the immune of liver cancer, and propose potential pathways in oncotherapy with the combination of cuproptosis and ferroptosis, which can provide background knowledge for subsequent related research.
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BACKGROUND: Hematopoietic stem cell (HSC) regeneration underlies hematopoietic recovery from myelosuppression, which is a life-threatening side effect of cytotoxicity. HSC niche is profoundly disrupted after myelosuppressive injury, while if and how the niche is reshaped and regulates HSC regeneration are poorly understood. METHODS: A mouse model of radiation injury-induced myelosuppression was built by exposing mice to a sublethal dose of ionizing radiation. The dynamic changes in the number, distribution and functionality of HSCs and megakaryocytes were determined by flow cytometry, immunofluorescence, colony assay and bone marrow transplantation, in combination with transcriptomic analysis. The communication between HSCs and megakaryocytes was determined using a coculture system and adoptive transfer. The signaling mechanism was investigated both in vivo and in vitro, and was consolidated using megakaryocyte-specific knockout mice and transgenic mice. RESULTS: Megakaryocytes become a predominant component of HSC niche and localize closer to HSCs after radiation injury. Meanwhile, transient insulin-like growth factor 1 (IGF1) hypersecretion is predominantly provoked in megakaryocytes after radiation injury, whereas HSCs regenerate paralleling megakaryocytic IGF1 hypersecretion. Mechanistically, HSCs are particularly susceptible to megakaryocytic IGF1 hypersecretion, and mTOR downstream of IGF1 signaling not only promotes activation including proliferation and mitochondrial oxidative metabolism of HSCs, but also inhibits ferritinophagy to restrict HSC ferroptosis. Consequently, the delicate coordination between proliferation, mitochondrial oxidative metabolism and ferroptosis ensures functional HSC expansion after radiation injury. Importantly, punctual IGF1 administration simultaneously promotes HSC regeneration and hematopoietic recovery after radiation injury, representing a superior therapeutic approach for myelosuppression. CONCLUSIONS: Our study identifies megakaryocytes as a last line of defense against myelosuppressive injury and megakaryocytic IGF1 as a novel niche signal safeguarding HSC regeneration.
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Ferroptosis , Células Madre Hematopoyéticas , Factor I del Crecimiento Similar a la Insulina , Megacariocitos , Regeneración , Animales , Células Madre Hematopoyéticas/metabolismo , Megacariocitos/metabolismo , Megacariocitos/efectos de la radiación , Factor I del Crecimiento Similar a la Insulina/metabolismo , Factor I del Crecimiento Similar a la Insulina/genética , Ferroptosis/genética , Ratones , Ratones Endogámicos C57BL , Traumatismos por Radiación/metabolismo , Traumatismos por Radiación/patología , Traumatismos por Radiación/genética , Transducción de Señal/efectos de la radiaciónRESUMEN
Staphylococcus xylosus has emerged as a bovine mastitis pathogen with increasing drug resistance, resulting in substantial economic impacts. This study utilized iTRAQ analysis to investigate the mechanisms driving resistance evolution in S. xylosus under ceftiofur sodium stress. Findings revealed notable variations in the expression of 143 proteins, particularly glycolysis-related proteins (TpiA, Eno, GlpD, Ldh) and peptidoglycan (PG) hydrolase Atl. Following the induction of ceftiofur sodium resistance in S. xylosus, the emergence of resistant strains displaying characteristics of small colony variants (SCVs) was observed. The transcript levels of TpiA, Eno, GlpD and Ldh were up-regulated, TCA cycle proteins (ICDH, MDH) and Atl were down-regulated, lactate content was increased, and NADH concentration was decreased in SCV compared to the wild strain. That indicates a potential role of carbon metabolism, specifically PG hydrolysis, glycolysis, and the TCA cycle, in the development of resistance to ceftiofur sodium in S. xylosus.
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Antibacterianos , Carbono , Cefalosporinas , Farmacorresistencia Bacteriana , Staphylococcus , Cefalosporinas/farmacología , Cefalosporinas/metabolismo , Antibacterianos/farmacología , Staphylococcus/efectos de los fármacos , Staphylococcus/genética , Staphylococcus/metabolismo , Carbono/metabolismo , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Animales , Bovinos , Glucólisis/efectos de los fármacos , Ciclo del Ácido Cítrico , Mastitis Bovina/microbiología , Infecciones Estafilocócicas/microbiología , Pruebas de Sensibilidad Microbiana , FemeninoRESUMEN
Hematopoietic toxicity due to ionizing radiation (IR) is a leading cause of death in nuclear incidents, occupational hazards, and cancer therapy. Oxymatrine (OM), an extract originating from the root of Sophora flavescens (Kushen), possesses extensive pharmacological properties. In this study, we demonstrate that OM treatment accelerates hematological recovery and increases the survival rate of mice subjected to irradiation. This outcome is accompanied by an increase in functional hematopoietic stem cells (HSCs), resulting in enhanced hematopoietic reconstitution abilities. Mechanistically, we observed significant activation of the MAPK signaling pathway, accelerated cellular proliferation, and decreased cell apoptosis. Notably, we identified marked increases in the cell cycle transcriptional regulator Cyclin D1 (Ccnd1) and the anti-apoptotic protein BCL2 in HSCs after OM treatment. Further investigation revealed that the expression of Ccnd1 transcript and BCL2 levels were reversed upon specific inhibition of ERK1/2 phosphorylation, effectively negating the rescuing effect of OM. Moreover, we determined that targeted inhibition of ERK1/2 activation significantly counteracted the regenerative effect of OM on human HSCs. Taken together, our results suggest a crucial role for OM in hematopoietic reconstitution following IR via MAPK signaling pathway-mediated mechanisms, providing theoretical support for innovative therapeutic applications of OM in addressing IR-induced injuries in humans.
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Alcaloides , Ratones , Humanos , Animales , Fosforilación , Alcaloides/farmacología , Transducción de Señal , Apoptosis , Proteínas Proto-Oncogénicas c-bcl-2/genéticaRESUMEN
In optical systems, diffraction limits significantly impact spot simulations. This study addresses this problem by applying the Fourier transform to calculate spots in imaging systems. Typically, a 1 mm image plane suffices; however, mosaic aperture telescopes with notable wavefront discontinuities require an approximately 10 mm simulation image plane. This necessitates high sampling rates for pupils, posing challenges for conventional methods. Our model overcomes this challenge by leveraging an interpolation technique to align multiwavelength spots on a uniform image plane grid, thus effectively analyzing spot translation and spreading in imaging systems with diffraction limits.
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INTRODUCTION AND OBJECTIVES: Cholangiocarcinoma (CCA) is characterized by early distant invasion and metastasis, whereas the underlying mechanism is still obscure. Increasing evidence shows that collagen type Ι alpha 1 (COL1A1) is a gene associated with the progression of multiple diseases. Here, we attempted to investigate the role of COL1A1 in CCA. MATERIALS AND METHODS: The expression of COL1A1 between tumor tissues and adjacent normal tissues obtained from CCA patients was detected by Western blot and immunofluorescence, followed by analysis of its clinical significance. Then, the biological effects of COL1A1 overexpression or knockdown on CCA cells were evaluated in vitro and in vivo. Finally, molecular mechanism of COL1A1 in regulating the invasion and metastasis of CCA cells was determined by a series of experiments. RESULTS: COL1A1 expression was significantly higher in CCA pathological tissues than in corresponding adjacent normal tissues. Analysis of 83 CCA patients showed that higher expression of COL1A1 was correlated with poorer patient prognosis. Notably, overexpression or knockdown experiments revealed that COL1A1 contributed to the migration and invasion, as well as epithelial-to-mesenchymal transition (EMT), in CCA cells. Further investigations demonstrated that matrix metalloproteinase-2 (MMP2) promoted COL1A1 upregulation via the integrin alpha â ¤ pathway, therefore affecting ECM remodelling and inducing EMT in CCA cells. Moreover, COL1A1 expression was positively related to PD-1 and PD-L1 in CCA, and COL1A1 increased PD-L1 expression by activating the NF-κB pathway. CONCLUSIONS: COL1A1 plays an important role in regulating CCA progression and may act as a promising biomarker and therapeutic target for CCA.
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Neoplasias de los Conductos Biliares , Colangiocarcinoma , Humanos , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Neoplasias de los Conductos Biliares/patología , Conductos Biliares Intrahepáticos/patología , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Colangiocarcinoma/patología , Regulación Neoplásica de la Expresión Génica , Integrina alfaV/genética , Integrina alfaV/metabolismo , Metaloproteinasa 2 de la Matriz/genética , Metaloproteinasa 2 de la Matriz/metabolismoRESUMEN
OBJECTIVE: To identify standard clinical parameters that can predict the presence and severity of obstructive sleep apnea. SUBJECTS AND METHODS: Adult patients with habitual snoring completed comprehensive polysomnography and anthropometric measurements, including sex, age, body mass index (BMI), neck circumference, tonsil size grading, modified Mallampati score, and nasofibroscopy-assisted Muller's maneuver (NMM). Spearman's correlation coefficient was used to screen the significant variables. Stepwise multiple linear regression analysis was then conducted to identify the independent variables. receiver operating characteristic (ROC) curve analysis was used to quantify the predictability of the formed oropharyngeal obstruction scoring system. RESULTS: A total of 163 adults (127 men) were enrolled in the study. Tonsil size grading, modified Mallampati score, and NMM grading maneuver were predictive of OSA and incorporated into a scoring system. This score ranged between 3 and 12, and threshold values of ≥ 8 and ≥ 9 seemed to be appropriate to identify patients at an increased risk of at least mild (AHI ≥ 5/h; AUROC = 0.935, 95%CI = 0.900-0.970, P < 0.001) and severe OSA (AHI ≥ 30/h; AUROC = 0.939, 95%CI = 0.899-0.969, P < 0.001), respectively. CONCLUSION: This study established an evaluation score for assessing the degree of oropharhygeal obstruction. The findings of the study suggest that the score may help identify patients at risk of oropharyngeal-related OSA who should have a full sleep evaluation.
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Polisomnografía , Apnea Obstructiva del Sueño , Humanos , Masculino , Femenino , Apnea Obstructiva del Sueño/diagnóstico , Adulto , Persona de Mediana Edad , Orofaringe/fisiopatología , Obstrucción de las Vías Aéreas/diagnóstico , Índice de Severidad de la Enfermedad , Ronquido/diagnóstico , Reproducibilidad de los ResultadosRESUMEN
OBJECTIVE: To reinterpret the surgical anatomy of paracolpium in radical hysterectomy and to explore its implications for the surgery. SETTING: The term "paracolpium" first defined by Fothergill in 1907, is essential in radical hysterectomy. However, several challenges remain unresolved. These include: (1) inconsistent terminology in relation to its defined attributes; (2) the lack of consensus on anatomical landmarks; (3) unclear associations with the cardinal and sacral ligaments; and (4) the critical implications and requirements of paracolpium resection in radical hysterectomy practices. PARTICIPANTS: A patient in her 60s diagnosed with stage IB2 cervical cancer was enrolled in a clinical trial and assigned to the laparoscopic surgery group. A step-by-step, narrated video demonstration. INTERVENTIONS: During the procedure, post-excision of the uterosacral, cardinal, and vesicovaginal ligaments, we identified a ligament-like structure situated between the middle third of the vagina and the pelvic wall. We have termed this structure the "paracolpium ligament." A detailed anatomical description was performed, outlining its crucial attachments: ⢠Medial attachment: middle third of the vagina ⢠Lateral attachment: tendinous arch of the pelvic fascia (TAPF) ⢠Cranial attachment: cardinal-uterosacral ligaments confluence ⢠Caudal attachment: pubococcygeus muscle fascia ⢠Dorsal: paravaginal space ⢠Ventral: pararectal space To ensure a safe dissection, the paracolpium ligament was exposed by removing anterior and posterior fat tissue. The extent of surgical resection was adapted based on the tumor's location. Extensive resection of the paracolpium ligament was essential when the tumor was localized to one side of the vagina to ensure complete removal of the disease; otherwise, preservation of the ligament was considered feasible. CONCLUSION: In this video, we meticulously name and define the "paracolpium ligament," providing groundbreaking insights into its anatomical and surgical implications in radical hysterectomy. Our findings contribute to a better understanding of surgical anatomy for cervical cancer.
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BACKGROUND/PURPOSE: Hepatocellular carcinoma (HCC) can be noninvasively diagnosed through dynamic computed tomography (CT) and magnetic resonance imaging (MRI). We compared the diagnostic performance of CT and gadoxetic acid-enhanced MRI (EOB-MRI) in categorizing tumors by using the 2018 version of the Liver Imaging Reporting And Data System (LI-RADS v2018) and assessing liver tumors before resection. METHODS: Data from a prospective cohort from October 2011 to March 2019 on 106 hepatic tumors in 96 patients with suspected malignancy were included in this study. We performed preoperative CT and EOB-MRI, and reviewed these images retrospectively. Ninety-seven tumors from 87 patients were pathologically diagnosed as HCC, and nine tumors were non-HCC. The clinical data, imaging characteristics, diagnostic performance, and outcomes of CT and EOB-MRI were analyzed and compared. RESULTS: EOB-MRI had more favorable diagnostic performance (area under curve: 0.920 vs. 0.868) and significantly higher sensitivity (86.87% vs. 69.70%, p = 0.005) than did CT. However, the specificity of EOB-MRI did not differ from that of CT (88.89% vs. 88.89%, p > 0.999). Fourteen (14.5%) patients with pathologically verified HCC had lesions categorized as LI-RADS 4 through CT and as LI-RADS 5 through EOB-MRI. Patients with EOB-MRI-categorized but not CT-categorized LI-RADS 5 lesions had significantly longer overall survival than did those with LI-RADS 4 lesions (p < 0.001). CONCLUSION: EOB-MRI had higher sensitivity than did CT in diagnosing HCC. Patients with EOB-MRI-categorized LI-RADS 5 lesions had more favorable outcomes than did those with LI-RADS 4 lesions after liver resection.
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Carcinoma Hepatocelular , Gadolinio DTPA , Neoplasias Hepáticas , Humanos , Neoplasias Hepáticas/diagnóstico por imagen , Neoplasias Hepáticas/cirugía , Carcinoma Hepatocelular/diagnóstico por imagen , Carcinoma Hepatocelular/cirugía , Estudios Retrospectivos , Estudios Prospectivos , Medios de Contraste , Imagen por Resonancia Magnética/métodos , Tomografía Computarizada por Rayos X/métodos , Sensibilidad y EspecificidadRESUMEN
As a ROS scavenger, resveratrol exerts a neuroprotective effect by polarizing the M1 microglia to the anti-inflammatory M2 phenotype for ischemic stroke treatment. However, the obstruction of the blood-brain barrier (BBB) seriously impairs the efficacy of resveratrol. Herein, we develop a stepwise targeting nanoplatform for enhanced ischemic stroke therapy, which is fabricated by pH-responsive poly(ethylene glycol)-acetal-polycaprolactone-poly(ethylene glycol) (PEG-Acetal-PCL-PEG) and modified with cRGD and triphenylphosphine (TPP) on a long PEG chain and a short PEG chain, respectively. The as-designed micelle system features effective BBB penetration through cRGD-mediated transcytosis. Once entering the ischemic brain tissues and endocytosed by microglia, the long PEG shell can be detached from the micelles in the acidic lysosomes, subsequently exposing TPP to target mitochondria. Thus, the micelles can effectively alleviate oxidative stress and inflammation by enhanced delivery of resveratrol to microglia mitochondria, reversing the microglia phenotype through the scavenging of ROS. This work offers a promising strategy to treat ischemia-reperfusion injury.
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Accidente Cerebrovascular Isquémico , Micelas , Humanos , Especies Reactivas de Oxígeno , Acetales , Resveratrol/farmacología , Resveratrol/uso terapéutico , Polímeros/uso terapéutico , Polietilenglicoles/uso terapéutico , Estrés Oxidativo , Inflamación/tratamiento farmacológicoRESUMEN
We report an experimental study of proximity induced superconductivity in planar Josephson junction devices made from free-standing InAs nanosheets. The nanosheets are grown by molecular beam epitaxy, and the Josephson junction devices are fabricated by directly contacting the nanosheets with superconductor Al electrodes. The fabricated devices are explored by low-temperature carrier transport measurements. The measurements show that the devices exhibit a gate-tunable supercurrent, multiple Andreev reflections, and a good quality superconductor-semiconductor interface. The superconducting characteristics of the Josephson junctions are investigated at different magnetic fields and temperatures and are analyzed based on the Bardeen-Cooper-Schrieffer (BCS) theory. The measurements of the ac Josephson effect are also conducted under microwave radiations with different radiation powers and frequencies, and integer Shapiro steps are observed. Our work demonstrates that InAs nanosheet based hybrid devices are desired systems for investigating the forefront of physics, such as two-dimensional topological superconductivity.
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Red rice, a variety of pigmented grain, serves dual purposes as both a food and medicinal resource. In recent years, we have witnessed an increasing interest in the dermatological benefits of fermented rice extracts, particularly their whitening and hydrating effects. However, data on the skincare advantages derived from fermenting red rice with Aspergillus oryzae remain sparse. This study utilized red rice as a substrate for fermentation by Aspergillus oryzae, producing a substance known as red rice Aspergillus oryzae fermentation (RRFA). We conducted a preliminary analysis of RRFA's composition followed by an evaluation of its skincare potential through various in vitro tests. Our objective was to develop a safe and highly effective skincare component for potential cosmetic applications. RRFA's constituents were assessed using high-performance liquid chromatography (HPLC), Kjeldahl nitrogen determination, the phenol-sulfuric acid method, and enzyme-linked immunosorbent assay (ELISA). We employed human dermal fibroblasts (FB) to assess RRFA's anti-aging and antioxidative properties, immortalized keratinocytes (HaCaT cells) and 3D epidermal models to examine its moisturizing and reparative capabilities, and human primary melanocytes (MCs) to study its effects on skin lightening. Our findings revealed that RRFA encompasses several bioactive compounds beneficial for skin health. RRFA can significantly promote the proliferation of FB cells. And it markedly enhances the mRNA expression of ECM-related anti-aging genes and reduces reactive oxygen species production. Furthermore, RRFA significantly boosts the expression of Aquaporin 3 (AQP3), Filaggrin (FLG), and Hyaluronan Synthase 1 (HAS1) mRNA, alongside elevating moisture levels in a 3D epidermal model. Increases were also observed in the mRNA expression of Claudin 1 (CLDN1), Involucrin (IVL), and Zonula Occludens-1 (ZO-1) in keratinocytes. Additionally, RRFA demonstrated an inhibitory effect on melanin synthesis. Collectively, RRFA contains diverse ingredients which are beneficial for skin health and showcases multifaceted skincare effects in terms of anti-aging, antioxidant, moisturizing, repairing, and whitening capabilities in vitro, highlighting its potential for future cosmetic applications.
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Aspergillus oryzae , Fermentación , Proteínas Filagrina , Oryza , Aspergillus oryzae/metabolismo , Oryza/química , Oryza/metabolismo , Humanos , Antioxidantes/farmacología , Antioxidantes/metabolismo , Queratinocitos/metabolismo , Queratinocitos/efectos de los fármacos , Células HaCaT , Fibroblastos/metabolismo , Fibroblastos/efectos de los fármacos , Melanocitos/metabolismo , Melanocitos/efectos de los fármacos , Cuidados de la Piel/métodos , Piel/metabolismoRESUMEN
BACKGROUND: Carboxymethylpachymaran (CMP) is created by carboxymethylating pachyman (PM), which increases its water solubility and enhances a number of biological activities. Traditional polysaccharides modified by carboxymethylation employ strong chemical techniques. Carboxymethylcellulose (CMC) has been used previously for liquid fermentation to carboxymethyl modify bacterial polysaccharides. This theory can be applied to fungal polysaccharides because Poria cocos has the ability to naturally utilize cellulose. RESULTS: CMC with different degrees of substitution (DS) (0.7, 0.9 and 1.2) were added to P. cocos fermentation medium, and CMPs with different DS (0.38, 0.56 and 0.78, respectively) were prepared by liquid fermentation. The physical and chemical properties and biological activities of the CMPs were determined. Their structures were confirmed by Fourier transform infrared (FTIR) spectroscopy and monosaccharide composition. With the increase of DS, the viscosity and viscosity-average molecular weight of CMPs decreased, whereas polysaccharide content and water solubility increased, although the triple helix structure was not affected. The results of bioactivity assay showed that the higher the DS of CMPs, the higher the 2,2-diphenyl-1-picrylhydrazyl radical scavenging ability, and the stronger the bacterial inhibition ability. CONCLUSION: The present study has developed a method for producing CMPs by P. cocos liquid fermentation. The results of the study confirm that enhancing the DS of CMP could effectively enhance its potential biological activity. The findings provide safe and reliable raw materials for creating CMP-related foods and encourage CMP application in the functional food industry. © 2024 Society of Chemical Industry.