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The small G protein Arf1 has been identified as playing a selective role in supporting cancer stem cells (CSCs), making it an attractive target for cancer therapy. However, the current Arf1 inhibitors have limited translational potential due to their high toxicity and low specificity. In this study, two new potent small-molecule inhibitors of Arf1, identified as DU101 and DU102, for cancer therapy are introduced. Preclinical tumor models demonstrate that these inhibitors triggered a cascade of aging in CSCs and enhance anti-tumor immunity in mouse cancer and PDX models. Through single-cell sequencing, the remodeling of the tumor immune microenvironment induced by these new Arf1 inhibitors is analyzed and an increase in tumor-associated CD8+ CD4+ double-positive T (DPT) cells is identified. These DPT cells exhibit superior features of active CD8 single-positive T cells and a higher percentage of TCF1+PD-1+, characteristic of stem-like T cells. The frequency of tumor-infiltrating stem-like DPT cells correlates with better disease-free survival (DFS) in cancer patients, indicating that these inhibitors may offer a novel cancer immunotherapy strategy by converting the cold tumor immune microenvironment into a hot one, thus expanding the potential for immunotherapy in cancer patients.
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Excessive reactive oxygen species (ROS) is a hallmark of both the onset and progression of inflammatory bowel disease (IBD), where a continuous cycle of ROS and inflammation drives the progression of diseases. The design of oral antioxidant nanoenzymes for scavenging ROS has emerged as a promising strategy to intervene in IBD. However, the practical application of these nanoenzymes is limited due to their single catalytical property and significantly impacted by substantial leakage in the upper gastrointestinal tract. This study introduces a novel oral delivery system, SP@CS-SeNPs, combining natural microalgae Spirulina platensis (SP), which possesses superoxide dismutase (SOD)-like activity, with chitosan-functionalized selenium nanoparticles (CS-SeNPs) that exhibit catalase-like activity. The SP@CS-SeNPs system leverages the dual catalytic capabilities of these components to initiate a cascade reaction that first converts superoxide anion radicals (O2â¢-) into hydrogen peroxide (H2O2), and then catalyzes the decomposition of H2O2 into water and oxygen. This system not only utilizes the resistance of the microalgae carrier to gastric acid and its efficient capture by intestinal villi, thereby enhancing intestinal distribution and retention but also demonstrates significant anti-inflammatory effects and effective repair of the damaged intestinal barrier in a colitis mice model. These results demonstrate that this oral delivery system successfully combines the features of microalgae and nanozymes, exhibits excellent biocompatibility, and offers a novel approach for antioxidant nanozyme intervention in IBD.
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The global rate of Amphotericin B (AmB) resistance in Candida auris has surpassed 12%. However, there is limited data on available clinical treatments and microevolutionary analyses concerning reduced AmB sensitivity. In this study, we collected 18 C. auris isolates from five patients between 2019 and 2022. We employed clinical data mining, genomic, and transcriptomic analyses to identify genetic evolutionary features linked to reduced AmB sensitivity in these isolates during clinical treatment. We identified six isolates with a minimum inhibitory concentration (MIC) of AmB below 0.5â µg/mL (AmB0.5) and 12 isolates with an AmB-MIC of 1â µg/mL (AmB1) or ≥ 2â µg/mL (AmB2). All five patients received 24-hour AmB (5â mg/L) bladder irrigation treatment. Evolutionary analyses revealed an ERG3 (c923t) mutation in AmB1 C. auris. Additionally, AmB2 C. auris was found to contain a t2831c mutation in the RAD2 gene. In the AmB1 group, membrane lipid-related gene expression (ERG1, ERG2, ERG13, and ERG24) was upregulated, while in the AmB2 group, expression of DNA-related genes (e.g. DNA2 and PRI1) was up-regulated. In a series of C.auris strains with reduced susceptibility to AmB, five key genes were identified: two upregulated (IFF9 and PGA6) and three downregulated (HGT7, HGT13,and PRI32). In this study, we demonstrate the microevolution of reduced AmB sensitivity in vivo and further elucidate the relationship between reduced AmB sensitivity and low-concentration AmB bladder irrigation. These findings offer new insights into potential antifungal drug targets and clinical markers for the "super fungus", C. auris.
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Anfotericina B , Antifúngicos , Candida auris , Candidiasis , Farmacorresistencia Fúngica , Pruebas de Sensibilidad Microbiana , Humanos , Anfotericina B/farmacología , Antifúngicos/farmacología , China/epidemiología , Farmacorresistencia Fúngica/genética , Candidiasis/microbiología , Candidiasis/tratamiento farmacológico , Candida auris/genética , Candida auris/efectos de los fármacos , Evolución Molecular , Masculino , Mutación , Femenino , Persona de Mediana Edad , Proteínas Fúngicas/genéticaRESUMEN
The development of intracerebral hemorrhage (ICH) is a dynamic process and intervention during the acute phase of ICH is critical for subsequent recovery. Therefore, it is crucial to screen potential signature genes and therapeutic target genes in the acute phase of ICH. In this study, based on the results of mRNA sequencing in mouse ICH and mRNA sequencing of human ICH from online databases, top five potential signature genes after ICH, Tyrobp, Itgb2, Tlr2, Ptprc and Itgam, were screened. Quantitative PCR results showed higher mRNA expression of Tyrobp, Itgb2, Tlr2, Ptprc, and Itgam in the 1-, 3- and 5-day mouse ICH groups compared to the sham-operated group. Immune infiltration correlation analysis shows that the top-ranked signature gene, Tyrobp, is negatively correlated with M2 macrophages and plasma cells, and Western blot analysis shows higher expression of the Tyrobp protein in the 1-, 3-, and 5-day mouse ICH groups compared to the sham-operated group. Furthermore, immunohistochemistry revealed that TYROBP protein expression was significantly higher in human ICH tissues than in normal brain tissues. Our results suggest that Tyrobp is a signature gene in the acute phase of ICH and may be a potential target for the treatment of the acute phase of ICH.
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Hemorragia Cerebral , Hemorragia Cerebral/genética , Animales , Humanos , Ratones , Masculino , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , Perfilación de la Expresión Génica , Encéfalo/metabolismo , Encéfalo/patología , Transcriptoma , Proteínas Adaptadoras Transductoras de SeñalesRESUMEN
INTRODUCTION: In the treatment of malocclusion, continuous monitoring of the three-dimensional relationship between dental roots and the surrounding alveolar bone is essential for preventing complications from orthodontic procedures. Cone-beam computed tomography (CBCT) provides detailed root and bone data, but its high radiation dose limits its frequent use, consequently necessitating an alternative for ongoing monitoring. OBJECTIVES: We aimed to develop a deep learning-based cross-temporal multimodal image fusion system for acquiring root and jawbone information without additional radiation, enhancing the ability of orthodontists to monitor risk. METHODS: Utilizing CBCT and intraoral scans (IOSs) as cross-temporal modalities, we integrated deep learning with multimodal fusion technologies to develop a system that includes a CBCT segmentation model for teeth and jawbones. This model incorporates a dynamic kernel prior model, resolution restoration, and an IOS segmentation network optimized for dense point clouds. Additionally, a coarse-to-fine registration module was developed. This system facilitates the integration of IOS and CBCT images across varying spatial and temporal dimensions, enabling the comprehensive reconstruction of root and jawbone information throughout the orthodontic treatment process. RESULTS: The experimental results demonstrate that our system not only maintains the original high resolution but also delivers outstanding segmentation performance on external testing datasets for CBCT and IOSs. CBCT achieved Dice coefficients of 94.1 % and 94.4 % for teeth and jawbones, respectively, and it achieved a Dice coefficient of 91.7 % for the IOSs. Additionally, in the context of real-world registration processes, the system achieved an average distance error (ADE) of 0.43 mm for teeth and 0.52 mm for jawbones, significantly reducing the processing time. CONCLUSION: We developed the first deep learning-based cross-temporal multimodal fusion system, addressing the critical challenge of continuous risk monitoring in orthodontic treatments without additional radiation exposure. We hope that this study will catalyze transformative advancements in risk management strategies and treatment modalities, fundamentally reshaping the landscape of future orthodontic practice.
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Tomografía Computarizada de Haz Cónico , Aprendizaje Profundo , Humanos , Tomografía Computarizada de Haz Cónico/métodos , Ortodoncia/métodos , Maloclusión/diagnóstico por imagen , Maloclusión/terapiaRESUMEN
Ubiquitination, a prevalent and highly dynamic reversible post-translational modification, is tightly regulated by the deubiquitinating enzymes (DUBs) superfamily. Among them, OTU Domain-Containing Ubiquitin Aldehyde-Binding Protein 1 (OTUB1) stands out as a critical member of the OTU deubiquitinating family, playing a pivotal role as a tumor regulator across various cancers. However, its specific involvement in BLCA (BLCA) and its clinical significance have remained ambiguous. This study aimed to elucidate the biofunctions of OTUB1 in BLCA and its implications for clinical prognosis. Our investigation revealed heightened OTUB1 expression in BLCA, correlating with unfavorable clinical outcomes. Through in vivo and in vitro experiments, we demonstrated that increased OTUB1 levels promote BLCA tumorigenesis and progression, along with conferring resistance to cisplatin treatment. Notably, we established a comprehensive network involving OTUB1, ß-catenin, necroptosis, and BLCA, delineating their regulatory interplay. Mechanistically, we uncovered that OTUB1 exerts its influence by deubiquitinating and stabilizing ß-catenin, leading to its nuclear translocation. Subsequently, nuclear ß-catenin enhances the transcriptional activity of c-myc and cyclin D1 while suppressing the expression of RIPK3 and MLKL, thereby fostering BLCA progression and cisplatin resistance. Importantly, our clinical data suggest that the OTUB1/ß-catenin/RIPK3/MLKL axis holds promise as a potential biomarker for BLCA.
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Cisteína Endopeptidasas , Transducción de Señal , beta Catenina , Humanos , beta Catenina/metabolismo , Animales , Cisteína Endopeptidasas/metabolismo , Cisteína Endopeptidasas/genética , Ratones , Enzimas Desubicuitinizantes/metabolismo , Línea Celular Tumoral , Ratones Desnudos , Ubiquitinación , Cisplatino/farmacología , Cisplatino/uso terapéuticoRESUMEN
OBJECTIVE: Lindqvist-type polyoxometalates (POMs) exhibit potential antitumor activities. This study aimed to examine the effects of Lindqvist-type POMs against breast cancer and the underlying mechanism. METHODS: Using different cancer cell lines, the present study evaluated the antitumor activities of POM analogues that were modified at the body skeleton based on molybdenum-vanadium-centered negative oxygen ion polycondensations with different side strains. Cell colony formation assay, autophagy detection, mitochondrial observation, qRT-PCR, Western blotting, and animal model were used to evaluate the antitumor activities of POMs against breast cancer cells and the related mechanism. RESULTS: MO-4, a Lindqvist-type POM linking a proline at its side strain, was selected for subsequent experiments due to its low half maximal inhibitory concentration in the inhibition of proliferation of breast cancer cells. It was found that MO-4 induced the apoptosis of multiple types of breast cancer cells. Mechanistically, MO-4 activated intracellular mitophagy by elevating mitochondrial reactive oxygen species (ROS) levels and resulting in apoptosis. In vivo, breast tumor growth and distant metastasis were significantly reduced following MO-4 treatment. CONCLUSION: Collectively, the results of the present study demonstrated that the novel Lindqvist-type POM MO-4 may exhibit potential in the treatment of breast cancer.
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Antineoplásicos , Apoptosis , Neoplasias de la Mama , Mitofagia , Especies Reactivas de Oxígeno , Compuestos de Tungsteno , Humanos , Mitofagia/efectos de los fármacos , Femenino , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/genética , Apoptosis/efectos de los fármacos , Compuestos de Tungsteno/farmacología , Animales , Ratones , Antineoplásicos/farmacología , Línea Celular Tumoral , Especies Reactivas de Oxígeno/metabolismo , Proliferación Celular/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto , Molibdeno/farmacología , Polielectrolitos , AnionesRESUMEN
Neutrophils and macrophages confine pathogens by entrapping them in extracellular traps (ETs) through activating TLR9 function. However, plasmodial parasites secreted TatD-like DNases (TatD) to counteract ETs-mediated immune clearance. We found that TLR9 mutant mice increased susceptibility to rodent malaria, suggesting TLR9 is a key protein for host defense. We found that the proportion of neutrophils and macrophages in response to plasmodial parasite infection in the TLR9 mutant mice was significantly reduced compared to that of the WT mice. Importantly, PbTatD can directly bind to the surface TLR9 (sTLR9) on macrophages, which blocking the phosphorylation of mitogen-activated protein kinase and nuclear factor-κB, negatively regulated the signaling of ETs formation by both macrophages and neutrophils. Such, P. berghei TatD is a parasite virulence factor that can inhibit the proliferation of macrophages and neutrophils through directly binding to TLR9 receptors on the cell surface, thereby blocking the activation of the downstream MyD88-NF-kB pathways.
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Desoxirribonucleasas , Inmunidad Innata , Macrófagos , Malaria , Neutrófilos , Plasmodium berghei , Transducción de Señal , Animales , Humanos , Ratones , Desoxirribonucleasas/metabolismo , Trampas Extracelulares/inmunología , Trampas Extracelulares/metabolismo , Macrófagos/inmunología , Macrófagos/metabolismo , Malaria/inmunología , Malaria/parasitología , Ratones Endogámicos C57BL , Ratones Noqueados , Factor 88 de Diferenciación Mieloide/metabolismo , Factor 88 de Diferenciación Mieloide/genética , Neutrófilos/inmunología , FN-kappa B/metabolismo , Plasmodium berghei/inmunología , Proteínas Protozoarias/metabolismo , Proteínas Protozoarias/inmunología , Proteínas Protozoarias/genética , Receptor Toll-Like 9/metabolismoRESUMEN
Toxoplasma gondii, the causative parasite of toxoplasmosis, is an apicomplexan parasite that infects warm-blooded mammals. The ability of the calcium-binding proteins (CBPs) to transport large amounts of Ca2+ appears to be critical for the biological activity of T. gondii. However, the functions of some members of the CBP family have not yet been deciphered. Here, we characterized a putative CBP of T. gondii, TgpCaBP (TGME49_229480), which is composed of four EF-hand motifs with Ca2+-binding capability. TgpCaBP was localized in the cytosol and ER of T. gondii, and parasites lacking the TgpCaBP gene exhibited diminished abilities in cell invasion, intracellular growth, egress, and motility. These phenomena were due to the abnormalities in intracellular Ca2+ efflux and ER Ca2+ storage, and the reduction in motility was associated with a decrease in the discharge of secretory proteins. Therefore, we propose that TgpCaBP is a Ca2+ transporter and signaling molecule involved in Ca2+ regulation and parasitization in the hosts.IMPORTANCECa2+ signaling is essential in the development of T. gondii. In this study, we identified a calcium-binding protein in T. gondii, named TgpCaBP, which actively regulates intracellular Ca2+ levels in the parasite. Deletion of the gene coding for TgpCaBP caused serious deficits in the parasite's ability to maintain a stable intracellular calcium environment, which also impaired the secretory protein discharged from the parasite, and its capacity of gliding motility, cell invasion, intracellular growth, and egress from host cells. In summary, we have identified a novel calcium-binding protein, TgpCaBP, in the zoonotic parasite T. gondii, which is a potential therapeutic target for toxoplasmosis.
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Weaning is an important period in the growth and development of lambs. Thus, effectively reducing the occurrence of weaning stress is critical for maintaining lamb production. Coated sodium butyrate has been shown to reduce inflammation, promote intestinal health, and maintain homeostasis. However, the application and potential mechanism of coated sodium butyrate in alleviating weaning stress in lambs are still unclear. To evaluate the effects of coated sodium butyrate on the growth performance, antioxidant capacity, and gut microbiota of weaned lambs, 10 weaned lambs of 21-day-old were randomly divided into two groups: the CON group (basal diet) and the NaB group (basal diet +3 g/kg of coated sodium butyrate). The trial lasted 21 days. The experimental results showed that compared to the CON group, coated sodium butyrate supplementation in the diet significantly increased the average daily weight gain and daily feed intake of lambs (p < 0.05). In addition, compared to the CON group, the addition of coated sodium butyrate also significantly decreased the serum MDA level of lambs (p < 0.05). Notably, the addition of coated sodium butyrate did not have a significant effect on the cecal microbiota, while increasing the diversity of colonic microbiota and promoting the abundance of Lachnospiraceae, Verrucomicrobiota, Akkermansia, Roseburia, and Sinobacteraceae, which are associated with the nutrient absorption of lambs (p < 0.05). These results indicate that dietary supplementation with coated sodium butyrate could promote the growth and antioxidant capacity of weaned lambs and alleviate weaning stress.
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BACKGROUND: More effective methods are urgently needed for predicting the pathological grade and lymph node metastasis of cT1-stage lung adenocarcinoma. METHODS: We analyzed the relationships between CT quantitative parameters (including three-dimensional parameters) and pathological grade and lymph node metastasis in cT1-stage lung adenocarcinoma patients of our center between January 2015 and December 2023. RESULTS: A total of 343 patients were included, of which there were 233 males and 110 females, aged 61.8 ± 9.4 (30-82) years. The area under the receiver operating characteristic (ROC) curve for predicting the pathological grade of lung adenocarcinoma using the consolidation tumor ratio (CTR) and the solid volume ratio (SVR) were 0.761 and 0.777, respectively. The areas under the ROC curves (AUCs) for predicting lymph node metastasis were 0.804 and 0.873, respectively. Multivariate logistic regression analysis suggested that the SVR is an independent predictor of highly malignant lung adenocarcinoma pathology, while the SVR and pathological grade are independent predictors of lymph node metastasis. The sensitivity of predicting the pathological grading of lung adenocarcinoma based on SVR>5% is 97.2%, with a negative predictive value of 96%. The sensitivity of predicting lymph node metastasis based on SVR>47.1% is 97.3%, and the negative predictive value is 99.5%. CONCLUSIONS: The SVR has greater diagnostic value than the CTR in the preoperative prediction of pathologic grade and lymph node metastasis in stage cT1-stage lung adenocarcinoma patients, and the SVR may replace the diameter and CTR as better criteria for guiding surgical implementation.
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Metal-organic frameworks (MOFs) offer diverse applications in the food industry, facilitating loading, protection, and controlled release of functional ingredients despite encountering loading capacity and functional activity limitations. This study focuses on curcuminzinc MOFs, harnessing curcumin's renowned health benefits and zinc to enhance pharmacological properties. We evaluated their synthesis efficiency, stability under varying conditions (pH, salt concentration, temperature), loading and antioxidant capacity. The results showed that microwave synthesis yielded MOFs with a 23.2 ± 4.5% yield, stable within pH 4-10, gradually decomposing in PBS. DPPH, ABTS, and H2O2 assays revealed varying free radical scavenging abilities. MOFs disintegrate in either acidic environments or contain H2O2 (at a concentration threshold of 10 µM). Post-disintegration, these MOFs significantly inhibiting the secretion of TNF-α by RAW264.7 cells induced by LPS. These findings highlight the potential of novel curcuminzinc MOF materials for nutrient delivery, addressing challenges in effectively delivering functional ingredients.
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Antioxidantes , Curcumina , Estructuras Metalorgánicas , Zinc , Curcumina/química , Curcumina/farmacología , Estructuras Metalorgánicas/química , Ratones , Zinc/química , Antioxidantes/química , Antioxidantes/farmacología , Animales , Células RAW 264.7 , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
T-cell receptor therapy (TCR-T) has demonstrated efficacy, durability, and safety advantages in certain solid tumors (such as human papillomavirus-related tumors, synovial sarcoma, and melanoma). This study aimed to provide careful considerations for developing TCR-T for solid tumors. Therefore, in this review, we have summarized the current clinical application, advantage of TCR-T modalities and explored efficacy/safety-related parameters, particularly avidity, pharmacokinetics/pharmacodynamics, and indications, for solid tumors. Furthermore, we have investigated critical factors related to avidity, including antigen selection, T-cell receptor acquisition, optimization, and co-receptor engagement. Moreover, we have re-examined the expression of tumor antigens for a potentially higher coverage rate of solid tumors based on the current RNA-seq datasets. Finally, we have discussed the current limitations and future directions of TCR-Ts.
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Inmunoterapia Adoptiva , Neoplasias , Receptores de Antígenos de Linfocitos T , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/inmunología , Receptores de Antígenos de Linfocitos T/inmunología , Receptores de Antígenos de Linfocitos T/uso terapéutico , Receptores de Antígenos de Linfocitos T/metabolismo , Inmunoterapia Adoptiva/métodos , Linfocitos T/inmunologíaRESUMEN
BACKGROUND: The development of gut-liver axis metabolic immune crosstalk is intimately associated with intestinal barrier disorder, intestinal SCFAs-Th17/Treg immunological imbalance, and disorders of the gut microbiota. Prior research has discovered that Dendrobium officinale National Herbal Drink (NHD), a traditional Chinese medicine drink with enhanced immunity, may enhance the immunological response in animals with impaired immune systems brought on by cyclophosphamide by repairing intestinal barrier function and controlling turbulence in the gut microbiota. However, whether NHD can further improve the gut-liver axis metabolic immune crosstalk and its related mechanisms need to be systematically studied. OBJECTIVES: The purpose of this study is to clarify the function and mechanism of NHD in enhancing the gut-liver axis metabolic immunological crosstalk brought on by excessive alcohol intake. METHODS: In this work, we set up a mouse model to analyze the metabolic and immunological crosstalk involving the gut-liver axis across 7 weeks of continuous, excessive drinking. At the same time, high and low doses (20,10 ml/kg) of NHD were given by gavage. The effect of NHD on improving the metabolism of gut-liver axis was evaluated by blood lipid, liver lipid deposition, liver function and intestinal pathophysiology. By measuring serum immunological indices, intestinal barrier, and intestinal immune barrier, the impact of NHD on enhancing immune and intestinal barrier function was assessed. Furthermore, immunohistochemistry, immunofluorescence, 16S rRNA, Western blot, q-PCR and other methods were used to detect gut microbiota, SCFAs-GPR41/43 pathway, intestinal Th17/Treg immune cells and PPAR-α-NPC1L1/SREBP1 pathway to elucidate the mechanism by which NHD enhances the gut-liver axis' metabolic immune crosstalk. RESULTS: Our study demonstrated that NHD has the potential to improve the pathophysiological damage caused by gut-liver axis in model mice. NHD also ameliorated the disorder of lipid metabolism. In addition, it regulated the levels of peripheral blood T cell immunity and serum immune factors. And NHD can restore intestinal mechanical and immune barrier damage. NHD has a favorable impact on the quantity of beneficial bacteria, including uncultured_bacterium_g__norank_f__muribaculacea and uncultured_bacterium_g__Turicibacter. Additionally, it raised the model mice's levels of SCFAs (n-butyric acid, isovaleric acid, etc.). This resulted in the promotion of intestinal GPR41/43-ERK1/2 expression and the reshaping of intestinal CD4+T cell Th17/Treg homeostasis. As a consequence, colon IL-22 and IL-10 levels increased, while colon IL-17A levels decreased. Lastly, NHD raised the amount of intestinal IAP/LPS, regulated the development of PPAR-α-NPC1L1/SREBP1 pathway in gut-liver axis, and improve lipid metabolism disorder. CONCLUSIONS: Our study found that NHD can improve the gut-liver axis metabolic immune crosstalk in model mice caused by excessive drinking. The mechanism might be connected to how NHD controls gut microbiota disorders in model mice, the activation of intestinal SCFAs-GPR41/43 pathway, the remodeling of Th17/Treg immune homeostasis of intestinal CD4+T cells, the improvement of IAP/LPS abnormality, and further mediating the PPAR-α-NPC1L1/SREBP1 pathway of lipid metabolism in gut-liver axis.
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Dendrobium , Medicamentos Herbarios Chinos , Ácidos Grasos Volátiles , Microbioma Gastrointestinal , Hígado , Linfocitos T Reguladores , Células Th17 , Animales , Dendrobium/química , Linfocitos T Reguladores/efectos de los fármacos , Células Th17/efectos de los fármacos , Masculino , Microbioma Gastrointestinal/efectos de los fármacos , Hígado/efectos de los fármacos , Hígado/metabolismo , Ratones , Medicamentos Herbarios Chinos/farmacología , Ácidos Grasos Volátiles/metabolismo , Ratones Endogámicos C57BLRESUMEN
BACKGROUND: Drug resistance, including Adriamycin-based therapeutic resistance, remains a challenge in breast cancer (BC) treatment. Studies have revealed that macrophages could play a pivotal role in mediating the chemoresistance of cancer cells. Accumulating evidence suggests that tRNA-Derived small RNAs (tDRs) are associated the physiological and pathological processes in multiple cancers. However, the underlying mechanisms of tDRs on chemoresistance of BC in tumor-associated macrophages remain largely unknown. METHODS: The high-throughput sequencing technique was used to screen tDRs expression profile in BC cells. Gain- and loss-of-function experiments and xenograft models were performed to verify the biological function of 3'tRF-Ala-AGC in BC cells. The CIBERSORT algorithm was used to investigate immune cell infiltration in BC tissues. To explore the role of 3'tRF-Ala-AGC in macrophages, M2 macrophages transfected with 3'tRF-Ala-AGC mimic or inhibitor were co-cultured with BC cells. Effects on Nuclear factor-κb (NF-κb) pathway were investigated by NF-κb nuclear translocation assay and western blot analysis. RNA pull-down assay was performed to identify 3'tRF-Ala-AGC interacting proteins. RESULTS: A 3'tRF fragment of 3'tRF-AlaAGC was screened, which is significantly overexpressed in BC specimens and Adriamycin-resistant cells. 3'tRF-AlaAGC could promote cell malignant activity and facilitate M2 polarization of macrophages in vitro and in vivo. Higher expression of M2 macrophages were more likely to have lymph node metastasis and deeper invasion in BC patients. Mechanistically, 3'tRF-AlaAGC binds Type 1-associated death domain protein (TRADD) in BC cells, and suppression of TRADD partially abolished the enhanced effect of 3'tRF-AlaAGC mimic on phenotype of M2. The NF-κb signaling pathway was activated in BC cells co-cultured with M2 macrophages transfected with 3'tRF-AlaAGC mimic. CONCLUSIONS: 3'tRF-AlaAGC might modulate macrophage polarization via binding to TRADD and increase the effect of M2 on promoting the chemoresistance in BC cells through NF-κb signaling pathway.
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Neoplasias de la Mama , Resistencia a Antineoplásicos , Macrófagos , FN-kappa B , Neoplasias de la Mama/patología , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Humanos , Resistencia a Antineoplásicos/genética , Femenino , Macrófagos/metabolismo , Animales , Línea Celular Tumoral , FN-kappa B/metabolismo , Unión Proteica/efectos de los fármacos , ARN de Transferencia/metabolismo , ARN de Transferencia/genética , Polaridad Celular/efectos de los fármacos , Ratones , Transducción de Señal , Ratones Desnudos , Doxorrubicina/farmacología , Ratones Endogámicos BALB CRESUMEN
Background: Several respiratory infections outbreaks have been observed in mainland China after reduction of non-pharmaceutical interventions. Other countries have seen increases in respiratory infections outside typical seasons post-COVID-19, warranting investigation into underlying causes. Methods: We established monitoring networks for suspected respiratory infection in 14 tertiary hospitals nationwide. PCR for SARS-CoV-2, influenza A and B were performed on 3708 respiratory specimens and deep sequencing were conducted to identify co-infections or newly emerging microbes in 2023. Viral evolutionary analysis was completed. We retrospectively detected serum antibody level for various respiratory pathogens from 4324 adults without respiratory infections over 7 years to observe its dynamic curves. Findings: SARS-CoV-2 and influenza A were the main pathogens during outbreaks in 2023, bacterial-virus and bacterial-bacterial co-infections were most detected, but community co-infections didn't significantly increase pneumonia incidence. Different SARS-CoV-2 and influenza variants were present in different outbreaks, and no novel pathogens were found. The epidemiological patterns of influenza A, COVID-19 and etc. were altered, exhibiting characteristics of being "staggered" compared to most global regions, and potentially led to "overlapping prevalence". Binding antibody testing showed regular fluctuation, without significant decrease against common respiratory pathogens in adults. Influenza A antibody stimulation was attenuated during the 2023 outbreak. Conclusions: "Misaligned" alteration in seasonal respiratory disease patterns possibly caused combined epidemics, leading to cases spike in China, 2023. In adults, antibody levels didn't show significant decline, but reduced immune response to influenza during 2020-2023 emphasizes the need for consistent vaccination during pandemics.
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Background: Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) is a rare autosomal dominant disorder with a low incidence in Asia. The most frequent clinical manifestations include fever, rash, myalgia, joint pain and abdominal pain. Misdiagnosis rates are high because of the clinical and genetic variability of the disease. The pathogenesis of TRAPS is complex and yet to be fully defined. Early genetic diagnosis is the key to precise treatment. Methods: In this study, a Chinese family with suspected TRAPS were analyzed by genome-wide SNP genotyping, linkage analysis and targeted sequencing for identification of mutations in causative genes. To study the pathogenicity of the identified gene mutation, we performed a conservation analysis of the mutation site and protein structure analysis. Flow cytometry was used to detect TNFRSF1A shedding and quantitative real-time PCR were used to assess the activation of unfolded protein response (UPR) in the mutation carriers and healthy individuals. Results: A typical TRAPS family history, with a pattern of autosomal dominant inheritance, led to the identification of a rare mutation in the TNFRSF1A gene (c.G374A [p.Cys125Tyr]) with unknown significance. The patient responded well to corticosteroids, and long-term therapy with colchicine effectively reduced the inflammatory attacks. No amyloid complications occurred during the 6-year follow-up. In silico protein analysis showed that the mutation site is highly conversed and the mutation prevents the formation of intrachain disulfide bonds in the protein. Despite a normal shedding of the TNFRSF1A protein from stimulated monocytes in the TRAPS patients with p.C125Y mutation, the expression of CHOP and the splicing of XBP1 was significantly higher than healthy controls, suggesting the presence of an activation UPR. Conclusion: This is the first report of a Chinese family with the rare p.C125Y mutation in TNFRSF1A. The p.C125Y mutation does not result in aberrant receptor shedding, but instead is associated with an activated UPR in these TRAPS patients, which may provide new insights into the pathogenesis of this rare mutation in TRAPS.
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Prussian blue analogs (PBAs) have been widely recognized as superior cathode materials for sodium-ion batteries (SIBs) owing to numerous merits. However, originating from the rapid crystal growth, PBAs still suffer from considerable vacancy defects and interstitial water, making the preparation of long-cycle-life PBAs the greatest challenge for its practical application. Herein, a novel equilibrium chelation strategy is first proposed to synthesize a high crystallinity (94.7%) PBAs, which is realized by modulating the chelating potency of strong chelating agents via "acid effect" to achieve a moderate chelating effect, forcefully breaking through the bottleneck of poor cyclic stability for PBAs cathodes. Impressively, the as-prepared highly crystalline PBAs represent an unprecedented level of electrochemical performance including ultra-long lifespan (10000 cycles with 86.32% capacity maintenance at 6 A g-1), excellent rate capability (82.0 mAh g-1 at 6 A g-1). Meanwhile, by pairing with commercial hard carbon, the as-prepared PBAs-based SIBs exhibit high energy density (350 Wh kg-1) and excellent capacity retention (82.4% after 1500 cycles), highlighting its promising potential for large-scale energy storage applications.
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Low-dimensional lead halide perovskites demonstrate remarkable nonlinear optical characteristics attributed to their distinctive physical structures and electronic properties. Nevertheless, the investigation into their nonlinear optical properties remains in its incipient stages. This study addresses this gap by precisely controlling solvent volumes to synthesize both 0D Cs4PbBr6 and Cs4PbBr6/CsPbBr3 perovskites. Remarkably, as saturable absorbers, both pure Cs4PbBr6 and Cs4PbBr6/CsPbBr3 composites exhibit favorable nonlinear optical properties within the C-band, showcasing modulation depths of 9.22% and 16.83%, respectively. Moreover, for the first time, Cs4PbBr6 and Cs4PbBr6/CsPbBr3 composites have been successfully integrated into erbium-doped fiber lasers to realize the mode-locking operations. The utilization of the Cs4PbBr6/CsPbBr3 composites as a saturable absorber that enables the generation of conventional soliton mode-locked laser pulses with a pulse duration of 688 fs, and a repetition frequency of 10.947 MHz at a central wavelength of 1557 nm. Cs4PbBr6 is instrumental in generating laser pulses at a frequency of 10.899 MHz, producing pulse widths of 642 fs at the central wavelength of 1531.2 nm and 1.02 ps at the central wavelength of 1565.3 nm, respectively. The findings of this investigation underscore the potential utility of 0D Cs4PbBr6 and Cs4PbBr6/CsPbBr3 composites as promising materials for optical modulation within fiber laser applications.