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Background: Monkeypox virus (MPXV) is spreading globally and nearly half of the infected people were human immunodeficiency virus (HIV) positive. Therefore, an in-depth understanding of the effects of HIV infection on the outcomes of MPXV infection is urgently needed. This study aimed to explore the clinical features, viral dynamics, and antibody response to MPXV infections in men who had sex with men (MSM) with and without HIV co-infection. Design or methods: MPXV-infected patients diagnosed by PCR were recruited in this study and were divided into MPXV and MPXV + HIV groups based on whether they were co-infected with HIV. Clinical data and samples were collected during of the hospital stay and follow up interviews. The symptoms and signs, laboratory examinations, viral shedding in various body fluids or swabs, antibody dynamics were tracked and compared between the two groups. Results: A total of 41 MPXV patients were recruited through June 2023 to September 2023 in Guangzhou. The MPXV group and MPXV + HIV group comprised 20 and 21 MSM, respectively. Patients in the two groups exhibited similar clinical characteristics except for pruritus and eschar, both were significantly fewer in MPXV + HIV group than in MPXV only group. Among the 355 clinical samples collected, MPXV DNA was detected in 100% of scabs, 97.4% of skin swabs, and 92.3% of exudate swabs from lesions, while the positive rate was 87.5% from oropharyngeal swabs, 59% from saliva, 51.3% from anal swabs, 50% from feces, 30.6% from urine samples, 37.5% of semen, and 28.2% from sera. Dynamics analysis revealed that viral DNA was undetectable in most patients 20 days after symptom onset. IgM and IgG antibodies to MPXV were detected in all patients with 3-5 days earlier in the MPXV group than in the MPXV + HIV group. Conclusion: This cohort analysis based on a large outbreak among MSM in Guangzhou indicated no obvious differences in clinical symptoms, viral DNA data, but antibody responses were 3-5 days later in mpox patients with HIV infection.
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Anticuerpos Antivirales , Coinfección , Infecciones por VIH , Homosexualidad Masculina , Monkeypox virus , Mpox , Humanos , Masculino , Infecciones por VIH/complicaciones , Infecciones por VIH/inmunología , Infecciones por VIH/epidemiología , China/epidemiología , Adulto , Anticuerpos Antivirales/sangre , Coinfección/virología , Coinfección/epidemiología , Mpox/epidemiología , Mpox/inmunología , Monkeypox virus/inmunología , Monkeypox virus/genética , Esparcimiento de Virus , Persona de Mediana Edad , Formación de Anticuerpos , Carga Viral , Adulto JovenRESUMEN
Macrophage migration inhibitor factor (MIF), as a pro-inflammatory and oncogenic cytokine, is highly expressed in a variety of malignant tumors and recruits tumor cells or immune cells into the tumor microenvironment. MIF affects the development of tumor by altering the tumor microenvironment. In the process of tumor, MIF not only plays an anti-inflammatory role, but also promotes tumorigenesis by immune escape and immune tolerance.This is closely related to immune cells that play a role in the tumor immune response, mainly including natural killer (NK) cells, macrophages, dendritic cells, B cells, T cells and myeloid-derived suppressor cells. The article summarizes the role of MIF in tumor immune and the relationship between MIF and the development of malignant tumors, in order to provide new ideas and possible therapy for tumor treatment.
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Factores Inhibidores de la Migración de Macrófagos , Neoplasias , Microambiente Tumoral , Factores Inhibidores de la Migración de Macrófagos/inmunología , Humanos , Neoplasias/inmunología , Neoplasias/terapia , Animales , Microambiente Tumoral/inmunología , Células Asesinas Naturales/inmunología , Macrófagos/inmunología , Células Dendríticas/inmunología , Linfocitos T/inmunologíaRESUMEN
BACKGROUND: Cervical cancer (CC), closely linked to persistent human papillomavirus infection, represents a major health problem for women worldwide. The objective of this study is to elucidate KIF23's role in the development of CC and its regulatory mechanism. METHODS: The bioinformatics methods were utilized to extract pyroptosis-associated differentially expressed genes (DEGs) and pivot genes from the GSE9750 and GSE63678 datasets, followed by immune infiltration analysis and quantification of these genes' expression. The effects of kinesin family member 23 (KIF23) were verified through functional experiments in vitro and a mouse xenograft model. The NLPR3 activator, nigericin, was applied for further analyzing the potential regulatory mechanism of KIF23 in CC. RESULTS: A total of 8 pyroptosis-related DEGs were screened out, among which 4 candidate core genes were identified as candidate hub genes and confirmed upregulation in CC tissues and cells. These genes respectively showed a positive correlation with the infiltration of distinct immune cells or tumor purity. Downregulation of KIF23 could suppress the proliferation, migration, and invasion abilities in CC cells and tumorigenesis through enhancing pyroptosis. Conversely, KIF23 overexpression accelerated the malignant phenotypes of CC cells and inhibited pyroptosis activation, which was blocked by nigericin treatment. CONCLUSIONS: KIF23 may play an oncogenic role in CC progression via inhibition of the NLRP3-mediated pyroptosis pathway.
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Regulación Neoplásica de la Expresión Génica , Proteína con Dominio Pirina 3 de la Familia NLR , Piroptosis , Neoplasias del Cuello Uterino , Piroptosis/genética , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Humanos , Femenino , Animales , Ratones , Neoplasias del Cuello Uterino/genética , Neoplasias del Cuello Uterino/patología , Neoplasias del Cuello Uterino/metabolismo , Ratones Desnudos , Cinesinas/genética , Cinesinas/metabolismo , Proliferación Celular , Línea Celular Tumoral , Progresión de la Enfermedad , Ratones Endogámicos BALB C , Proteínas Asociadas a MicrotúbulosRESUMEN
This study explore the molecular mechanism of the synergistic effect of Chinese Yam polysaccharides and nucleoside analogues(NAs) on hepatitis B virus(HBV) resistance. Different concentrations of Chinese Yam polysaccharide and entecavir were ad-ded to HepG2.2.15 cells. After the cytotoxicity was detected by cell counting kit-8(CCK-8), the optimal concentration and time of the two drugs to inhibit HepG2.2.15 cells were screened out. They were divided into control group, Chinese Yam polysaccharide group, entecavir group and combination drug group(Chinese Yam polysaccharide + entecavir). The drugs were added to HepG2.2.15 cells, ELISA was used to detect the effects of each group of drugs on the secretion of hepatitis B virus surface antigen(HBsAg) and hepatitis B virus e antigen(HBeAg) in cell supernatant, probe quantitative real-time PCR(probe qRT-PCR) was used to detect the effects of drugs on HBV-DNA in HepG2.2.15 cells, and Western blot was used to detect the effects of each group of drugs on the expression of p38 MAPK, p-p38 MAPK, NTCP proteins in HepG2.2.15 cells. The qRT-PCR was used to detect the effect of drugs on the expression of p38 MAPK and NTCP mRNA in HepG2.2.15 cells. The results showed that compared with control group, the concentrations of HBeAg and HBsAg in Chinese Yam polysaccharide group, entecavir group and combination group decreased(P<0.01 or P<0.001), and both of them inhibited HBV-DNA in HepG2.2.15 cells(P<0.01), and the HBV-DNA inhibition of HepG2.2.15 cells in the combination group was more obvious(P<0.001), and the protein expression levels of p-p38 MAPK and NTCP were significantly decreased(P<0.05 or P<0.01), the mRNA expression level of p38 MAPK increased, and the mRNA expression level of NTCP decreased(P<0.05 or P<0.01). To sum up, Chinese Yam polysaccharide can reduce the expression of NTCP protein and mRNA through p38 MAPK signaling pathway and cooperate with entecavir in anti-HBV.
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Antivirales , Dioscorea , Virus de la Hepatitis B , Polisacáridos , Proteínas Quinasas p38 Activadas por Mitógenos , Humanos , Virus de la Hepatitis B/efectos de los fármacos , Virus de la Hepatitis B/genética , Polisacáridos/farmacología , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/genética , Células Hep G2 , Antivirales/farmacología , Dioscorea/química , Sinergismo Farmacológico , Nucleósidos/farmacología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Antígenos de Superficie de la Hepatitis B/metabolismo , Antígenos de Superficie de la Hepatitis B/genética , Antígenos e de la Hepatitis B/metabolismo , Hepatitis B/tratamiento farmacológico , Hepatitis B/virología , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/química , Guanina/análogos & derivados , Guanina/farmacologíaRESUMEN
Breast cancer is still the leading cause of death among women worldwide. Due to the lack of effective drug targets, triple-negative breast cancer has a worse prognosis and higher mortality compared with other types of breast cancer, and chemotherapy is still the main treatment for triple-negative breast cancer at present. Quercetin (QUE) is a flavonoid compound found in a variety of fruits and vegetables. The mechanism of QUE has been extensively studied, such as prostate cancer, colon cancer, ovarian cancer, etc. However, the anti-tumor immune mechanism of QUE in triple-negative breast cancer remains unclear. Therefore, we assessed the anti-tumor immune effects of QUE on triple-negative breast cancer using both 4T1 cells and a xenograft mouse model of 4T1 cells. In vitro, we examined the inhibitory effects of QUE on 4T1 cells and its molecular mechanisms through MTT, Transwell, ELISA, and Western blotting. In vivo, by establishing a xenograft mouse model, we utilized flow cytometry, immunohistochemistry, ELISA, and Western blotting to evaluate the anti-tumor immune effects of QUE on triple-negative breast cancer. The results indicate that QUE inhibits the proliferation, migration, and invasion of 4T1 cells, concurrently significantly suppressing the IL-6/JAK2/STAT3 signaling pathway. Furthermore, it depletes Treg cell content in 4T1 xenograft mice, thereby improving the tumor immune microenvironment and promoting the cytotoxicity of relevant tumor immune cells. These findings suggest that QUE may serve as a potential adjuvant for immune therapy in triple-negative breast cancer.
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Interleucina-6 , Janus Quinasa 2 , Quercetina , Factor de Transcripción STAT3 , Transducción de Señal , Linfocitos T Reguladores , Neoplasias de la Mama Triple Negativas , Animales , Femenino , Humanos , Ratones , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Interleucina-6/metabolismo , Janus Quinasa 2/efectos de los fármacos , Janus Quinasa 2/metabolismo , Ratones Endogámicos BALB C , Quercetina/farmacología , Transducción de Señal/efectos de los fármacos , Factor de Transcripción STAT3/efectos de los fármacos , Factor de Transcripción STAT3/metabolismo , Linfocitos T Reguladores/efectos de los fármacos , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Human immunodeficiency virus (HIV) infection is strongly associated with a heightened incidence of lymphomas. To mirror the natural course of human HIV infection, animal models have been developed. These models serve as valuable tools to investigate disease pathobiology, assess antiretroviral and immunomodulatory drugs, explore viral reservoirs, and develop eradication strategies. However, there are currently no validated in vivo models of HIV-associated lymphoma (HAL), hampering progress in this crucial domain, and scant attention has been given to developing animal models dedicated to studying HAL, despite their pivotal role in advancing knowledge. This review provides a comprehensive overview of the existing animal models of HAL, which may enhance our understanding of the underlying pathogenesis and approaches for malignancies linked to HIV infection.
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This study aims to investigate the role of industrial Internet platform in facilitating the digital transformation of traditional manufacturing enterprises. While prior research has predominantly focused on industrial Internet platform enterprises, there is a noticeable dearth of research concerning traditional manufacturing enterprises lacking the resources to establish such platforms. To address this research gap, we conduct an exploratory case study and propose an affordances upgrade model that elucidates the digital business transformation process of these manufacturing enterprises leveraging industrial Internet platforms. The research findings can be summarized from two key perspectives. Firstly, the industrial Internet platform offers valuable technical support and potential opportunities for manufacturing enterprises to achieve digital business transformation through three distinct affordances: consonance, resonance, and adaptation. These affordances enable enterprises to align their operations with the capabilities and possibilities provided by the platform, thus facilitating their digital transformation. Secondly, to effectively harness these affordances, enterprises must strategically leverage the platform's technical services and systems in their production and operational practices. Through the accumulation of practical experiences, enterprises gradually transition their production modes from experience institutionalization and standardization to a state of refinement. The dynamic leapfrogging process of digital transformation in traditional manufacturing enterprises, facilitated by the industrial Internet platform, is reflected in the realization of these three affordances and their underlying resource capabilities. This research significantly contributes to the field by expanding the scope of inquiry to encompass traditional manufacturing enterprises and presenting a stage model for their digital transformation utilizing industrial Internet platform.
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Patients with Philadelphia chromosome-like acute lymphoblastic leukaemia (Ph-like ALL) often face a grim prognosis, with PDGFRB gene fusions being commonly detected in this subgroup. Our study has unveiled a newfound fusion gene, TERF2::PDGFRB, and we have found that patients carrying this fusion gene exhibit sensitivity to dasatinib. Ba/F3 cells harbouring the TERF2::PDGFRB fusion display IL-3-independent cell proliferation through activation of the p-PDGFRB and p-STAT5 signalling pathways. These cells exhibit reduced apoptosis and demonstrate sensitivity to imatinib in vitro. When transfused into mice, Ba/F3 cells with the TERF2::PDGFRB fusion gene induce tumorigenesis and a shortened lifespan in cell-derived graft models, but this outcome can be improved with imatinib treatment. In summary, we have identified the novel TERF2::PDGFRB fusion gene, which exhibits oncogenic potential both in vitro and in vivo, making it a potential therapeutic target for tyrosine kinase inhibitors (TKIs).
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Proteínas de Fusión Oncogénica , Leucemia-Linfoma Linfoblástico de Células Precursoras , Receptor beta de Factor de Crecimiento Derivado de Plaquetas , Proteína 2 de Unión a Repeticiones Teloméricas , Animales , Humanos , Ratones , Carcinogénesis , Transformación Celular Neoplásica , Mesilato de Imatinib , Inhibidores de Proteínas Quinasas/farmacología , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/genética , Transducción de Señal , Factor de Transcripción STAT5/genética , Proteína 2 de Unión a Repeticiones Teloméricas/genética , Proteínas de Fusión Oncogénica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genéticaRESUMEN
As transcription factors derived from transposase, FAR-RED IMPAIRED RESPONSE1 (FAR1) and its homolog FHY3 play crucial roles in the regulation of light signaling and various stress responses by coordinating the expression of downstream target genes. Despite the extensive investigation of the FAR1/FHY3 family in Arabidopsis thaliana and other species, a comprehensive examination of these genes in maize has not been conducted thus far. In this study, we employed a genomic mining approach to identify 16 ZmFAR1 genes in the maize inbred line B73, which were further classified into five subgroups based on their phylogenetic relationships. The present study characterized the predicted polypeptide sequences, molecular weights, isoelectric points, chromosomal distribution, gene structure, conserved motifs, subcellular localizations, phylogenetic relationships, and cis-regulatory elements of all members belonging to the ZmFAR1 family. Furthermore, the tissue-specific expression of the 16 ZmFAR1 genes was analyzed using RNA-seq, and their expression patterns under far-red light conditions were validated in the ear and tassel through qRT-qPCR. The observed highly temporal and spatial expression patterns of these ZmFAR1 genes were likely associated with their specific functional capabilities under different light conditions. Further analysis revealed that six ZmFAR1 genes (ZmFAR1-1, ZmFAR1-10, ZmFAR1-11, ZmFAR1-12, ZmFAR1-14, and ZmFAR1-15) exhibited a response to simulated shading treatment and actively contributed to the development of maize ears. Through the integration of expression quantitative trait loci (eQTL) analyses and population genetics, we identified the presence of potential causal variations in ZmFAR1-14 and ZmFAR1-9, which play a crucial role in regulating the kernel row number and kernel volume weight, respectively. In summary, this study represents the initial identification and characterization of ZmFAR1 family members in maize, uncovering the functional variation in candidate regulatory genes associated with the improvement of significant agronomic traits during modern maize breeding.
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ABSTRACT: Growth factor independence 1 (GFI1) is a DNA-binding transcription factor and a key regulator of hematopoiesis. GFI1-36N is a germ line variant, causing a change of serine (S) to asparagine (N) at position 36. We previously reported that the GFI1-36N allele has a prevalence of 10% to 15% among patients with acute myeloid leukemia (AML) and 5% to 7% among healthy Caucasians and promotes the development of this disease. Using a multiomics approach, we show here that GFI1-36N expression is associated with increased frequencies of chromosomal aberrations, mutational burden, and mutational signatures in both murine and human AML and impedes homologous recombination (HR)-directed DNA repair in leukemic cells. GFI1-36N exhibits impaired binding to N-Myc downstream-regulated gene 1 (Ndrg1) regulatory elements, causing decreased NDRG1 levels, which leads to a reduction of O6-methylguanine-DNA-methyltransferase (MGMT) expression levels, as illustrated by both transcriptome and proteome analyses. Targeting MGMT via temozolomide, a DNA alkylating drug, and HR via olaparib, a poly-ADP ribose polymerase 1 inhibitor, caused synthetic lethality in human and murine AML samples expressing GFI1-36N, whereas the effects were insignificant in nonmalignant GFI1-36S or GFI1-36N cells. In addition, mice that received transplantation with GFI1-36N leukemic cells treated with a combination of temozolomide and olaparib had significantly longer AML-free survival than mice that received transplantation with GFI1-36S leukemic cells. This suggests that reduced MGMT expression leaves GFI1-36N leukemic cells particularly vulnerable to DNA damage initiating chemotherapeutics. Our data provide critical insights into novel options to treat patients with AML carrying the GFI1-36N variant.
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Proteínas de Unión al ADN , Leucemia Mieloide Aguda , Humanos , Ratones , Animales , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Temozolomida , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Daño del ADN , Reparación del ADN , Células Germinativas/metabolismo , ADN , Factores de Transcripción/genéticaRESUMEN
Maize grain yield can be greatly reduced when flowering time coincides with drought conditions, which delays silking and consequently increases the anthesis-silking interval. Although the genetic basis of delayed flowering time under water-stressed conditions has been elucidated in maize-maize populations, little is known in this regard about maize-teosinte populations. Here, 16 quantitative trait loci (QTL) for three flowering-time traits, namely days to anthesis, days to silk, and the anthesis-silking interval, were identified in a maize-teosinte introgression population under well-watered and water-stressed conditions; these QTL explained 3.98-32.61% of phenotypic variations. Six of these QTL were considered to be sensitive to drought stress, and the effect of any individual QTL was small, indicating the complex genetic nature of drought resistance in maize. To resolve which genes underlie the six QTL, 11 candidate genes were identified via colocalization analysis of known associations with flowering-time-related drought traits. Among the 11 candidate genes, five were found to be differentially expressed in response to drought stress or under selection during maize domestication, and thus represented the most likely candidates underlying the drought-sensitive QTL. The results lay a foundation for further studies of the genetic mechanisms of drought resistance and provide valuable information for improving drought resistance during maize breeding. Supplementary Information: The online version contains supplementary material available at 10.1007/s11032-023-01413-0.
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Growth factor independence 1 (GFI1) is a transcriptional repressor protein that plays an essential role in the differentiation of myeloid and lymphoid progenitors. We and other groups have shown that GFI1 has a dose-dependent role in the initiation, progression, and prognosis of acute myeloid leukaemia (AML) patients by inducing epigenetic changes. We now demonstrate a novel role for dose-dependent GFI1 expression in regulating metabolism in haematopoietic progenitor and leukaemic cells. Using in-vitro and ex-vivo murine models of MLL::AF9-induced human AML and extra-cellular flux assays, we now demonstrate that a lower GFI1 expression enhances oxidative phosphorylation rate via upregulation of the FOXO1- MYC axis. Our findings underscore the significance of therapeutic exploitation in GFI1-low-expressing leukaemia cells by targeting oxidative phosphorylation and glutamine metabolism.
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Leucemia Mieloide Aguda , Factores de Transcripción , Humanos , Ratones , Animales , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Diferenciación Celular , Pronóstico , Epigénesis Genética , Proteína de la Leucemia Mieloide-Linfoide/genética , Proteínas de Fusión Oncogénica/metabolismo , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismoRESUMEN
GFI1 is a transcriptional repressor and plays a pivotal role in regulating the differentiation of hematopoietic stem cells (HSCs) towards myeloid and lymphoid cells. Serial transplantation of Gfi1 deficient HSCs repopulated whole hematopoietic system but in a competitive setting involving wild-type HSCs, they lose this ability. The underlying mechanisms to this end are poorly understood. To better understand this, we used different mouse strains that express either loss of both Gfi1 alleles (Gfi1-KO), with reduced expression of GFI1 (GFI1-KD) or wild-type Gfi1/GFI1 (Gfi1-/GFI1-WT; corresponding to the mouse and human alleles). We observed that loss of Gfi1 or reduced expression of GFI1 led to a two to four fold lower number of HSCs (defined as Lin-Sca1+c-Kit+CD150+CD48-) compared to GFI1-WT mice. To study the functional influence of different levels of GFI1 expression on HSCs function, HSCs from Gfi1-WT (expressing CD45.1 + surface antigens) and HSCs from GFI1-KD or -KO (expressing CD45.2 + surface antigens) mice were sorted and co-transplanted into lethally irradiated host mice. Every 4 weeks, CD45.1+ and CD45.2 + on different lineage mature cells were analyzed by flow cytometry. At least 16 weeks later, mice were sacrificed, and the percentage of HSCs and progenitors including GMPs, CMPs and MEPs in the total bone marrow cells was calculated as well as their CD45.1 and CD45.2 expression. In the case of co-transplantation of GFI1-KD with Gfi1-WT HSCs, the majority of HSCs (81% ± 6%) as well as the majority of mature cells (88% ± 10%) originated from CD45.2 + GFI1-KD HSCs. In the case of co-transplantation of Gfi1-KO HSCs with Gfi1-WT HSCs, the majority of HSCs originated from CD45.2+ and therefore from Gfi1-KO (61% ± 20%); however, only a small fraction of progenitors and mature cells originated from Gfi1-KO HSCs (<1%). We therefore in summary propose that GFI1 has a dose-dependent role in the self-renewal and differentiation of HSCs.
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As a representative product of advanced glycation end products, NÉ-carboxymethyllysine (CML) exists in free and bound forms in vivo and in food with different bioavailability. To thoroughly understand the bioavailability of free NÉ-carboxymethyllysine (CML) and bovine serum albumin (BSA)-CML in vivo after intragastric administration, pharmacokinetics, biodistribution, and excretion of CML in rats were investigated by high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). Pharmacokinetics results revealed that free CML peaked at 1.83 h (1684.72 ± 78.08 ng/mL) and 1.33 h (1440.84 ± 72.48 ng/mL) in serum after intragastric administration of free CML and BSA-CML, demonstrating the higher absorption of free CML than BSA-CML. Besides, dietary free CML exhibited a relatively lower body clearance and tissue distribution than dietary BSA-CML based on the apparent volume of distribution and body clearance. Moreover, free CML was concentrated in the kidneys, indicating that kidneys were the target organ for the uptake of absorbed free CML. Additionally, the total excretion rate of CML in urine and feces were 37% and 60% after oral administration of free CML and BSA-CML. These results shed pivotal light on a better understanding of the biological effects of free and bound CML on health.
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Lisina , Espectrometría de Masas en Tándem , Ratas , Animales , Cromatografía Líquida de Alta Presión , Distribución Tisular , Espectrometría de Masas en Tándem/métodos , Lisina/análisis , Albúmina Sérica Bovina/metabolismoRESUMEN
Only a small proportion of patients with triple-negative breast cancer benefit from immune checkpoint inhibitor (ICI) targeting PD-1/PD-L1 signaling in combination with chemotherapy. Here, we discovered that therapeutic response to ICI plus paclitaxel was associated with subcellular redistribution of PD-L1. In our immunotherapy cohort of ICI in combination with nab-paclitaxel, tumor samples from responders showed significant distribution of PD-L1 at mitochondria, while non-responders showed increased accumulation of PD-L1 on tumor cell membrane instead of mitochondria. Our results also revealed that the distribution pattern of PD-L1 was regulated by an ATAD3A-PINK1 axis. Mechanistically, PINK1 recruited PD-L1 to mitochondria for degradation via a mitophagy pathway. Importantly, paclitaxel increased ATAD3A expression to disrupt proteostasis of PD-L1 by restraining PINK1-dependent mitophagy. Clinically, patients with tumors exhibiting high expression of ATAD3A detected before the treatment with ICI in combination with paclitaxel had markedly shorter progression-free survival compared with those with ATAD3A-low tumors. Preclinical results further demonstrated that targeting ATAD3A reset a favorable antitumor immune microenvironment and increased the efficacy of combination therapy of ICI plus paclitaxel. In summary, our results indicate that ATAD3A serves not only as a resistant factor for the combination therapy of ICI plus paclitaxel through preventing PD-L1 mitochondrial distribution, but also as a promising target for increasing the therapeutic responses to chemoimmunotherapy.
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Antígeno B7-H1 , Mitofagia , Humanos , ATPasas Asociadas con Actividades Celulares Diversas , Inmunoterapia , Proteínas de la Membrana , Mitocondrias , Proteínas Mitocondriales , Paclitaxel/farmacología , Proteínas QuinasasRESUMEN
Advanced glycation end products (AGEs) are increasingly recognized as potentially pathogenic components of processed foods, and long-term consumption of dietary AGEs triggers disruption of the intestinal barrier integrity and increases the risk of chronic diseases. Galactooligosaccharides (GOS) as prebiotics can modulate the intestinal microbiota and improve the intestinal barrier integrity. In this study, we aimed to investigate whether GOS could ameliorate the intestinal barrier damage induced by AGEs. The results showed an increased number of goblet cells (AGEs vs. H-GOS, 133.4 vs. 174.7, p < 0.05) and neutral mucin area (PAS positive area, 7.29% vs. 10.05%, p < 0.05). Upregulated expressions of occludin and claudin-1 and improved intestinal barrier integrity were observed in the H-GOS group. Using 16S rRNA sequencing analysis, we found that GOS significantly reduced the high enrichment of Akkermansia (16.95% vs. 1.29%, p < 0.05) induced by dietary AGEs while increasing the content of short-chain fatty acids. Fecal microbiota transplantation (FMT) showed that AGE-induced damage to the intestinal mucus barrier was reversed in the H-GOS transplanted group. Collectively, GOS ameliorated dietary AGE-induced intestinal barrier damage by reversing the dysregulated state of the intestinal microbiota. Our study lays the foundation for further research on dietary guidelines for populations with high AGE diets.
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Productos Dietéticos Finales de Glicación Avanzada , Microbioma Gastrointestinal , Animales , Ratones , ARN Ribosómico 16S , Oligosacáridos/farmacología , Ratones Endogámicos C57BLRESUMEN
[This retracts the article DOI: 10.21037/atm-20-4558.].
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Non-alcoholic fatty liver disease (NAFLD) has become a public health burden. Controlling bile acids (BAs) metabolism and energy expenditure are potential therapies for NAFLD. Because one of the main health effects of cereal ß-glucan (BG) is its ability to lower cholesterol by interacting with BAs, BG may regulate imbalances of the metabolism of BAs during NAFLD. Therefore, by using metabolic tests coupled with the profiling of hepatic BAs, we have assessed the effect of BG from highland barley on western diet (WD) induced NAFLD mice. BG treatment prevented fat accumulation and increased adipose lipolysis. These moderating effects were associated with an increased energy expenditure. Moreover, BG-treated mice enhanced the production of hepatic BAs, which may be connected with the activation of farnesoid X receptor (FXR) signaling in the liver and inhibition of FXR signaling in the ileum. Our results suggest that BG prevents fat accumulation by increasing energy expenditure, a mechanism associated with major changes in the composition of hepatic BAs.
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Hordeum , Enfermedad del Hígado Graso no Alcohólico , beta-Glucanos , Ratones , Animales , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Ácidos y Sales Biliares/metabolismo , beta-Glucanos/farmacología , beta-Glucanos/metabolismo , Dieta Occidental/efectos adversos , Metabolismo de los Lípidos , Hígado/metabolismo , Metabolismo Energético , Ratones Endogámicos C57BLRESUMEN
The zinc finger protein Growth Factor Independence 1 (GFI1) acts as a transcriptional repressor regulating differentiation of myeloid and lymphoid cells. A single nucleotide polymorphism of GFI1, GFI1-36N, has a prevalence of 7% in healthy Caucasians and 15% in acute myeloid leukemia (AML) patients, hence most probably predisposing to AML. One reason for this is that GFI1-36N differs from the wildtype form GFI1-36S regarding its ability to induce epigenetic changes resulting in a derepression of oncogenes. Using proteomics, immunofluorescence, and immunoblotting we have now gained evidence that murine GFI1-36N leukemic cells exhibit a higher protein level of the pro-proliferative protein arginine N-methyltransferase 5 (PRMT5) as well as increased levels of the cell cycle propagating cyclin-dependent kinases 4 (CDK4) and 6 (CDK6) leading to a faster proliferation of GFI1-36N leukemic cells in vitro. As a therapeutic approach, we subsequently treated leukemic GFI1-36S and GFI1-36N cells with the CDK4/6 inhibitor palbociclib and observed that GFI1-36N leukemic cells were more susceptible to this treatment. The findings suggest that presence of the GFI1-36N variant increases proliferation of leukemic cells and could possibly be a marker for a specific subset of AML patients sensitive to CDK4/6 inhibitors such as palbociclib.