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There is a correlation between long-term manganese (Mn) exposure and the Parkinson's-like disease (PD), with depression as an early symptom of PD. However, the direct relationship between Mn exposure and depression, and the mechanisms involved, remain unclear. We found that Mn exposure led to depressive-like behavior and mild cognitive impairment in mice, with Mn primarily accumulating in the cornu ammonis 3 (CA3) area of the hippocampus. Mice displayed a reduction in neuronal dendritic spines and damage to astrocytes specifically in the CA3 area. Spatial metabolomics revealed that Mn downregulated glutamic acid decarboxylase 1 (GAD1) expression in astrocytes, disrupting the Glutamine-Glutamate-γ-aminobutyric acid (GlnGluGABA) metabolic cycle in the hippocampus, leading to neurotoxicity. We established an in vitro astrocyte Gad1 overexpression (OEX) model and found that the cultured medium from Gad1 OEX astrocytes reversed neuronal synaptic damage and the expression of gamma-aminobutyric acid (GABA) related receptors. Using the astrocyte Gad1 OEX mouse model, results showed that OEX of Gad1 ameliorated depressive-like behavior and cognitive dysfunction in mice. These findings provide new insight into the important role of GAD1 mediated GlnGluGABA metabolism disorder in Mn exposure induced depressive-like behavior. This study offers a novel sight to understanding abnormal emotional states following central nervous system damage induced by Mn exposure.
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Despite increasing concerns regarding the harmful effects of plastic-induced gut injury, mechanisms underlying the initiation of plastic-derived intestinal toxicity remain unelucidated. Here, mice were subjected to long-term exposure to polystyrene nanoplastics (PS-NPs) of varying sizes (80, 200, and 1000 nm) at doses relevant to human dietary exposure. PS-NPs exposure did not induce a significant inflammatory response, histopathological damage, or intestinal epithelial dysfunction in mice at a dosage of 0.5 mg/kg/day for 28 days. However, PS-NPs were detected in the mouse intestine, coupled with observed microstructural changes in enterocytes, including mild villous lodging, mitochondrial membrane rupture, and endoplasmic reticulum (ER) dysfunction, suggesting that intestinal-accumulating PS-NPs resulted in the onset of intestinal epithelial injury in mice. Mechanistically, intragastric PS-NPs induced gut microbiota dysbiosis and specific bacteria alterations, accompanied by abnormal metabolic fingerprinting in the plasma. Furthermore, integrated data from mass spectrometry imaging-based spatial metabolomics and metallomics revealed that PS-NPs exposure led to gut dysbiosis-associated host metabolic reprogramming and initiated intestinal injury. These findings provide novel insights into the critical gut microbial-host metabolic remodeling events vital to nanoplastic-derived-initiated intestinal injury.
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Microbioma Gastrointestinal , Mucosa Intestinal , Poliestirenos , Animais , Poliestirenos/toxicidade , Camundongos , Mucosa Intestinal/metabolismo , Microbioma Gastrointestinal/efeitos dos fármacos , Nanopartículas/toxicidade , Disbiose/induzido quimicamente , Microplásticos/toxicidadeRESUMO
The origins of maize were the topic of vigorous debate for nearly a century, but neither the current genetic model nor earlier archaeological models account for the totality of available data, and recent work has highlighted the potential contribution of a wild relative, Zea mays ssp. mexicana. Our population genetic analysis reveals that the origin of modern maize can be traced to an admixture between ancient maize and Zea mays ssp. mexicana in the highlands of Mexico some 4000 years after domestication began. We show that variation in admixture is a key component of maize diversity, both at individual loci and for additive genetic variation underlying agronomic traits. Our results clarify the origin of modern maize and raise new questions about the anthropogenic mechanisms underlying dispersal throughout the Americas.
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Produtos Agrícolas , Domesticação , Hibridização Genética , Zea mays , México , Fenótipo , Zea mays/genética , Variação Genética , Produtos Agrícolas/genéticaRESUMO
Although therapeutic targets have been developed for colorectal cancer (CRC) therapy, the therapeutic effects are not ideal and the survival rate for CRC patients remains poor. Therefore, it is crucial to recognize a specific target and develop an efficacious delivery system for CRC therapy. Herein, we demonstrate that reduced ALKBH5 mediates aberrant m6A modification and tumor progression in CRC. Mechanically, histone deacetylase 2-mediated H3K27 deacetylation inhibits ALKBH5 transcription in CRC, whereas ectopic ALKBH5 expression decreases tumorigenesis of CRC cells and protects mice from colitis-associated tumor development. Further, METTL14/ALKBH5/IGF2BPs combine to modulate JMJD8 stability in an m6A-dependent manner, which increases glycolysis and accelerates the development of CRC by enhancing the enzymatic activity of PKM2. Moreover, ALKBH5 mRNA-loaded folic acid-modified exosome-liposome hybrid nanoparticles were synthesized and significantly inhibit the progression of CRC in preclinical tumor models by modulating the ALKBH5/JMJD8/PKM2 axis and inhibiting glycolysis. Overall, our research confirms the crucial function of ALKBH5 in regulating the m6A status in CRC and provides a direct preclinical approach for using ALKBH5 mRNA nanotherapeutics for CRC.
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Neoplasias Colorretais , Exossomos , Camundongos , Animais , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Lipossomos , Exossomos/metabolismo , Carcinogênese , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismoRESUMO
Albeit numerous studies have been conducted on the toxicity evaluation of engineered metal nanoparticles (NPs), significant knowledge gaps remain regarding the influence of oral exposure to metal NPs on the intestine system, especially the effects on the intestinal immune microenvironment. Herein, we examined the long-term effects of representative engineered metal NPs on the intestine through oral exposure and identified silver NPs (Ag NPs) that resulted in severe damage. Oral Ag NP exposure damaged the epithelial structure, reduced the thickness of the mucosal layer, and altered the intestinal microbiota. Particularly, the reduced thickness of the mucosal layer increased the phagocytosis of Ag NPs by dendritic cells (DCs). Comprehensive animal and in vitro experiments unraveled that Ag NPs directly interacted with DCs, resulting in the abnormal activation of DCs by generating reactive oxygen species and inducing uncontrolled apoptosis. Furthermore, our data unveiled that the interactions between Ag NPs and DCs reduced the proportion of CD103+CD11b+ DCs and induced Th17 cell activation with inhibition of regulatory T-cell differentiation, resulting in the disordered immune microenvironment in the intestine. Collectively, these results represent a new point of view on the cytotoxicity of Ag NPs on the intestine system. This study provides additional insights into the health risks of engineered metal NPs, especially Ag NPs.
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Nanopartículas Metálicas , Prata , Animais , Prata/toxicidade , Prata/química , Nanopartículas Metálicas/toxicidade , Nanopartículas Metálicas/química , Espécies Reativas de Oxigênio , Intestinos , Antígeno CD11bRESUMO
Oncogenic-driven lipogenic metabolism is a common hallmark of colorectal cancer (CRC) progression. Therefore, there is an urgent need to develop novel therapeutic strategies for metabolic reprogramming. Herein, the metabolic profiles in the plasma between CRC patients and paired healthy controls were compared using metabolomics assays. Matairesinol downregulation was evident in CRC patients, and matairesinol supplementation significantly represses CRC tumorigenesis in azoxymethane/dextran sulfate sodium (AOM/DSS) colitis-associated CRC mice. Matairesinol rewired lipid metabolism to improve the therapeutic efficacy in CRC by inducing mitochondrial damage and oxidative damage and blunting ATP production. Finally, matairesinol-loaded liposomes significantly promoted the enhanced antitumor activity of 5-Fu/leucovorin combined with oxaliplatin (FOLFOX) in CDX and PDX mouse models by restoring chemosensitivity to the FOLFOX regimen. Collectively our findings highlight matairesinol-mediated lipid metabolism reprogramming as a novel druggable strategy to restore CRC chemosensitivity, and this nanoenabled approach for matairesinol will improve the chemotherapeutic efficacy with good biosafety.
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Colite , Neoplasias Colorretais , Camundongos , Animais , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Metabolismo dos Lipídeos , Furanos/uso terapêutico , Modelos Animais de DoençasRESUMO
The Epstein-Barr virus (EBV) genome encodes a cluster of 22 viral microRNAs, called miR-BamHI-A rightward transcripts (miR-BARTs), which are shown to promote the development of cancer. Here, this study reports that EBV-miR-BART18-3p is highly expressed in colorectal cancer (CRC) and is closely associated with the pathological and advanced clinical stages of CRC. Ectopic expression of EBV-miR-BART18-3p leads to increased migration and invasion capacities of CRC cells in vitro and causes tumor metastasis in vivo. Mechanistically, EBV-miR-BART18-3p activates the hypoxia inducible factor 1 subunit alpha/lactate dehydrogenase A axis by targeting Sirtuin, which promotes lactate accumulation and acetyl-CoA production in CRC cells under hypoxic condition. Increased acetyl-CoA utilization subsequently leads to histone acetylation of fatty acid synthase and fatty acid synthase-dependent fat synthesis, which in turn drives de novo lipogenesis. The oncogenic role of EBV-miR-BART18-3p is confirmed in the patient-derived tumor xenograft mouse model. Altogether, the findings define a novel mechanism of EBV-miR-BART18-3p in CRC development through the lipogenesis pathway and provide a potential clinical intervention target for CRC.
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Neoplasias Colorretais , Infecções por Vírus Epstein-Barr , Herpesvirus Humano 4 , Lipogênese , MicroRNAs , RNA Viral , Animais , Humanos , Camundongos , Acetilcoenzima A/metabolismo , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Infecções por Vírus Epstein-Barr/virologia , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , RNA Viral/genética , RNA Viral/metabolismoRESUMO
Maize is a globally valuable commodity and one of the most extensively studied genetic model organisms. However, we know surprisingly little about the extent and potential utility of the genetic variation found in wild relatives of maize. Here, we characterize a high-density genomic variation map from 744 genomes encompassing maize and all wild taxa of the genus Zea, identifying over 70 million single-nucleotide polymorphisms. The variation map reveals evidence of selection within taxa displaying novel adaptations. We focus on adaptive alleles in highland teosinte and temperate maize, highlighting the key role of flowering-time-related pathways in their adaptation. To show the utility of variants in these data, we generate mutant alleles for two flowering-time candidate genes. This work provides an extensive sampling of the genetic diversity of Zea, resolving questions on evolution and identifying adaptive variants for direct use in modern breeding.
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Melhoramento Vegetal , Zea mays , Zea mays/genética , Adaptação Fisiológica/genética , Sequência de Bases , Alelos , Variação Genética/genéticaRESUMO
Ambient fine particulate matter (PM2.5) is linked to an increased risk of chronic obstructive pulmonary disease (COPD) exacerbations, which significantly increase the risk of mortality in COPD patients. Identifying the subtype of COPD patients who are sensitive to environmental aggressions is necessary. Using in vitro and in vivo PM2.5 exposure models, we demonstrate that exosomal hsa_circ_0005045 is upregulated by PM2.5 and binds to the protein cargo peroxiredoxin2, which functionally aggravates hallmarks of COPD by recruiting neutrophil elastase and triggering in situ release of tumor necrosis factor (TNF)-α by inflammatory cells. The biological function of hsa_circ_0005045 associated with aggravation of COPD is validated using exosome-transplantation and conditional circRNA-knockdown murine models. By sorting the major components of PM2.5, we find that PM2.5-bound heavy metals, which are distinguishable from the components of cigarette smoke, trigger the elevation of exosomal hsa_circ_0005045. Finally, using machine learning models in a cohort with 327 COPD patients, the PM2.5 exposure-sensitive COPD patients are characterized by relatively high hsa_circ_0005045 expression, non-smoking, and group C (mMRC 0-1 (or CAT < 10) and ≥ 2 exacerbations (or ≥ 1 exacerbation leading to hospital admission) in the past year). Thus, our results suggest that environmental reduction in PM2.5 emission provides a targeted approach to protecting non-smoking COPD patients against air pollution-related disease exacerbation.
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Poluentes Atmosféricos , Poluição do Ar , Doença Pulmonar Obstrutiva Crônica , Humanos , Animais , Camundongos , Poluentes Atmosféricos/toxicidade , Poluentes Atmosféricos/análise , RNA Circular , Poluição do Ar/análise , Material Particulado/toxicidade , Material Particulado/análise , Doença Pulmonar Obstrutiva Crônica/induzido quimicamente , Fator de Necrose Tumoral alfa , Exposição Ambiental/análiseRESUMO
BACKGROUND: Maize (Zea mays L.) is at the vanguard facing the upcoming breeding challenges. However, both a super pan-genome for the Zea genus and a comprehensive genetic variation map for maize breeding are still lacking. RESULTS: Here, we construct an approximately 6.71-Gb pan-Zea genome that contains around 4.57-Gb non-B73 reference sequences from fragmented de novo assemblies of 721 pan-Zea individuals. We annotate a total of 58,944 pan-Zea genes and find around 44.34% of them are dispensable in the pan-Zea population. Moreover, 255,821 common structural variations are identified and genotyped in a maize association mapping panel. Further analyses reveal gene presence/absence variants and their potential roles during domestication of maize. Combining genetic analyses with multi-omics data, we demonstrate how structural variants are associated with complex agronomic traits. CONCLUSIONS: Our results highlight the underexplored role of the pan-Zea genome and structural variations to further understand domestication of maize and explore their potential utilization in crop improvement.
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Genoma de Planta , Zea mays , Mapeamento Cromossômico/métodos , Domesticação , Humanos , Melhoramento Vegetal/métodos , Zea mays/genéticaRESUMO
Recent studies have identified that long noncoding RNA (lncRNA) might affect the responses to anticancer drug treatment, including colorectal cancer (CRC). However, the association between single-nucleotide polymorphisms (SNPs) in PVT1 and the chemotherapy response in metastatic colorectal cancer has yet to be clarified. In this study, the PVT1 rs2278176 CT/TT genotypes were found to be associated with an increased overall survival (OS) and progression-free survival (PFS) compared with the CC genotype. Furthermore, patients harboring the rs2278176 CT/TT genotypes had a greater chance of achieving clinical benefit from 5-Fluorouracil/leucovorin combined with oxaliplatin (FOLFOX). In vivo nude mice experiments demonstrated that the CRISPR/Cas9 mediated rs2278176 C to T mutation significantly inhibited the tumorigenesis of colorectal cancer cells treated with 5-Fu, but not control DMSO treated cells. Furthermore, the apoptotic rate was significantly enhanced by treatment with 5-Fu in the CRC cells carrying with the CT/TT genotypes. Functional studies demonstrated that the PVT1 rs2278176 C to T mutation altered the binding site for hsa-miR-297, and that hsa-miR-297 downregulated Glutathione S-Transferase Alpha 2(GSTA2), a member of phase II detoxification enzyme, in an Argonaute 2(Ago2)-dependent manner. Moreover, GSTA2 levels were downregulated in the cancer tissues of patients carrying rs2278176 CT/TT genotypes. High GSTA2 expression predicted poor clinical outcome in metastatic colorectal cancer treated with FOLFOX. In conclusion, this study provided that PVT1 with rs2278176 T allele altered the binding affinity with hsa-miR-297, leading to decreased GSTA2 expression and sensitized CRC cells to FOLFOX chemotherapy, suggesting rs2278176 CT/TT genotypes might serve as a predictive biomarker to improve prognosis in patients with metastatic CRC treated with FOLFOX.
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BACKGROUND: Generating chromosome-scale haplotype resolved assembly is important for functional studies. However, current de novo assemblers are either haploid assemblers that discard allelic information, or diploid assemblers that can only tackle genomes of low complexity. RESULTS: Here, Using robust programs, we build a diploid genome assembly pipeline called gcaPDA (gamete cells assisted Phased Diploid Assembler), which exploits haploid gamete cells to assist in resolving haplotypes. We demonstrate the effectiveness of gcaPDA based on simulated HiFi reads of maize genome which is highly heterozygous and repetitive, and real data from rice. CONCLUSIONS: With applicability of coping with complex genomes and fewer restrictions on application than most of diploid assemblers, gcaPDA is likely to find broad applications in studies of eukaryotic genomes.
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Cromossomos , Diploide , Alelos , Haploidia , Haplótipos , Sequenciamento de Nucleotídeos em Larga Escala , Análise de Sequência de DNARESUMO
Due to its wide applications in tire and rubber products, carbon black (CB) implicates concerns on its safety during production, collection, and handling. Here we report that exposure CB, increases coagulation-thrombosis potential in a splenic extramedullary hemopoiesis (EMH)-dependent manner. Adult C57BL/6 mice are kept in whole-body inhalation chambers, and exposed to filtered room air (FRA) or CB for 28 consecutive days. CB exposure resulted in splenic EMH characterized with platelet precursor cells, megakaryocytes (MKs), hyperplasia and enhanced in vivo blood coagulation ability. Metabolomics analysis suggests significant enhance in PGE2 production but reduction in folic acid (FA) levels in murine serum following CB exposure. Mechanistically, activation of COX-dependent PGE2 production promotes IL-6 expression in splenic macrophages, which subsequently results in splenic EMH and increased platelet counts in circulation. Administration of FA protects the mice against CB-induced splenic EMH through inhibiting prostaglandin-endoperoxide synthase 2 (Ptgs2 or Cox2) and prostaglandin E synthase (Ptges) expression in splenic macrophages, eventually recover the coagulation capacity to normal level. The results strongly suggest the involvement of splenic EMH in response to CB exposure and subsequently increased coagulation-thrombosis potential. Supplementation with FA may be a candidate to prevent thrombosis potential attributable to CB exposure.
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Fuligem , Trombose , Animais , Coagulação Sanguínea , Ácido Fólico , Camundongos , Camundongos Endogâmicos C57BL , Trombose/induzido quimicamenteRESUMO
Considerable investigations have been carried out to address the relationship between ambient fine particulate matter (PM2.5) and blood pressure (BP) in patients with hypertension. However, few studies have explored the influence of PM2.5 and its constituents on Trimethylamine N-oxide (TMAO), an established risk factor for hypertension and cardiovascular disease (CVD), particularly in severely air-polluted areas. To explore the potential impact of PM2.5 constituents on BP, plasma hormones, and TMAO, a panel study was conducted to investigate changes in BP, plasma hormones, and TMAO in response to ambient air pollution exposure in stage 1 hypertensive young adults. Linear mixed effect models were used to estimate the cumulative effects of fine particulate matters (PM2.5) and its constituents on BP, plasma hormones and TMAO. We found that one interquartile range (IQR) (35 µg/m3) increase in 0-1 day moving-average PM2.5 concentrations was statistically significantly associated with elevated systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial pressure (MAP) with estimated values of 0.13 (95% confidence interval (CI): 0.03 to 0.23) mmHg, 0.18 (95% CI: 0.08 to 0.28) mmHg, and 0.17 (95% CI: 0.09 to 0.26) mmHg, respectively. Hormone disturbance in the renin-angiotensin-aldosterone system was also associated with PM2.5 exposure. Elevated TMAO levels with an IQR increase for 0-4, 0-5, 0-6 moving-average concentrations of PM2.5 were found, and the increased values ranged from 26.28 (95% CI: 2.92 to 49.64) to 60.78 (31.95-89.61) ng/ml. More importantly, the PM2.5-bound metal constituents, such as manganese (Mn), titanium (Ti), and selenium (Se) showed robust associations with elevated BP and plasma TMAO levels. This study demonstrates associations between PM2.5 metal constituents and increased BP, changes in plasma hormones and TMAO, in stage 1 hypertensive young adults. Source control, aiming to reduce the emission of PM2.5-bound metals should be implemented to reduce the risk of hypertension and CVD.
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Poluentes Atmosféricos , Poluição do Ar , Poluentes Atmosféricos/análise , Poluição do Ar/análise , Poluição do Ar/estatística & dados numéricos , Pressão Sanguínea , China , Exposição Ambiental/análise , Hormônios , Humanos , Metilaminas , Material Particulado/análiseRESUMO
Background: Anterior cervical discectomy and fusion (ACDF) has been established as a classic procedure for the management of cervical radiculopathy. However, it is unclear whether combined uncinate process resection (UPR) is necessary for treating cervical radiculopathy. Here, we investigated the clinical outcome of ACDF combined with UPR compared to ACDF alone to determine the necessity of UPR in treating cervical radiculopathy. Hypothesis: Uncinate process resection may be necessary in certain patients along with ACDF to achieve better clinical outcomes of cervical radiculopathy. Patients and Methods: Fifty-five patients underwent ACDF with UPR, and 126 patients without UPR were reviewed. The width and height of the intervertebral foramen were measured by 45° oblique X-rays. We also measured the Japanese Orthopedic Association (JOA) score and visual analog scale (VAS) score. C2-C7 Cobb angles were obtained from all patients pre- and post-operatively. Meanwhile, linear regression analysis was used to evaluate the relationship between the clinical outcomes and the intervertebral foramen width before surgery. Results: Linear regression analysis indicated that the improvement in the JOA and VAS scores was irrelevant to both the pre-operative width of the intervertebral foramen (wIVF) and the height of the intervertebral foramen (hIVF) in the ACDF+UPR group. However, pre-operative wIVF was associated with post-operative JOA and VAS scores in the ACDF alone group. Those with pre-operative wIVF <3 mm in the ACDF group had the least improvement in post-operative clinical symptoms due to the change in wIVF (P > 0.05). The ACDF group whose wIVF was over 3 mm showed similar clinical outcomes to the ACDF + UPR group, and wIVF significantly increased post-operatively (P < 0.05). The fusion rate and C2-C7 Cobb angles did not show significant differences between the two groups (P > 0.05). Discussion: Our current findings suggest that UPR should be considered when wIVF is <3 mm pre-operatively. However, there is no need to sacrifice the uncovertebral joint in ACDF when the pre-operative wIVF is over 3 mm. Level of Evidence: Level III.
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Chimeric antigen receptor (CAR) - T cell therapy is a new class of cellular immunotherapies, which has made great achievements in the treatment of malignant tumors. Despite improvements in colorectal cancer (CRC) therapy, treatment of many patients fails because of metastasis and recurrence. The human epidermal growth factor receptor 2 (HER2) is a substantiated target for CAR-T therapy, and has been reported recently to be over-expressed in CRC, which may provide a potential therapeutic target for CRC treatment. Herein, HER2 was a promising target of metastatic colorectal cancer (mCRC) in CAR-T therapy as assessed by flow cytometry and tissue microarray (TMA) with 9-year survival follow-up data. Furthermore, HER2-specific CAR-T cells exhibited strong cytotoxicity and cytokine-secreting ability against CRC cells in vitro. Moreover, through the tumor-bearing model of the NOD-Prkdcem26cd52Il2rgem26Cd22/Nju (NCG) mice, HER2 CAR-T cells showed signs of effectively preventing CRC progression in three different xenograft models. Notably, HER2 CAR-T cells displayed greater aggressiveness in HER2+ CRC in the patient-derived tumor xenograft (PDX) models and had potent immunotherapeutic capacity for mCRC in the metastatic xenograft mouse models. In conclusion, our studies provide scientific evidence that HER2 CAR-T cells represent an emerging immunotherapy for the treatment of mCRC.
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Neoplasias Colorretais/genética , Receptor ErbB-2/metabolismo , Receptores de Antígenos Quiméricos/metabolismo , Animais , Biomarcadores Tumorais , Estudos de Casos e Controles , Neoplasias Colorretais/patologia , Feminino , Humanos , Camundongos , Metástase NeoplásicaRESUMO
BACKGROUND AND AIMS: Liver metastasis is a frequent occurrence in patients with colorectal cancer (CRC), with 15%-25% of CRC patients having liver metastases at the time of initial diagnosis. Specifically, some regional-stage patients with mild symptoms (stage 1 or 2) will also advance to liver metastases rapidly, even if the CRC lesion in situ is resected in time. Nevertheless, the precise mechanism of liver metastasis is still unclear. APPROACH AND RESULTS: Fresh tumor tissues from patients with CRC, adjacent noncancerous tissues, and colorectal adenoma tissues were subjected to microarray analysis to identify differentially expressed microRNA. Exosomes from human serum and cell culture medium were separated, quantitated, and verified by transmission electronic microscopy and Zetasizer Nano. Luciferase reporter assay, real-time quantitative PCR, western blot, immunoprecipitation, chromatin and re-chromatin immunoprecipitation, migration and invasion assay, PDX mouse model, flow cytometry, immunohistochemistry, and immunofluorescence staining were employed to explore the regulation among CRC liver metastases, immunosuppression, and cell adhesion. In this study, we demonstrated that the hypoxic microenvironment in primary CRC lesions boosted exosome release, selectively initiated favorable premetastatic niche formation in the liver but not in other organs. Mechanistically, Kupffer cells (KCs) can phagocytose exosomes containing highly expressed miR-135a-5p from the blood circulation into the liver. Exosomal miR-135a-5p initiated the large tumor suppressor kinase 2-yes-associated protein-matrix metalloproteinase 7 axis to promote the occurrence of CRC liver metastasis, and cluster of differentiation 30-TNF receptor-associated factor 2-p65-mediated immunosuppression signaling also contributed to this process. CONCLUSIONS: Hypoxia-induced exosomal miR-135a-5p correlates with the development, clinical severity, and prognosis of CRC liver metastases through the premetastatic niche; and our findings revealed that miR-135a-5p might be a promising target in halting CRC liver metastases.
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Neoplasias Colorretais/patologia , Regulação Neoplásica da Expressão Gênica , Neoplasias Hepáticas/genética , MicroRNAs/metabolismo , Hipóxia Tumoral/genética , Idoso , Animais , Linhagem Celular Tumoral , Neoplasias Colorretais/sangue , Neoplasias Colorretais/genética , Neoplasias Colorretais/mortalidade , Exossomos/metabolismo , Feminino , Seguimentos , Perfilação da Expressão Gênica , Humanos , Fígado/patologia , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/secundário , Masculino , Metaloproteinase 7 da Matriz/metabolismo , Camundongos , MicroRNAs/sangue , Pessoa de Meia-Idade , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais/genética , Proteínas Supressoras de Tumor/metabolismo , Regulação para Cima , Ensaios Antitumorais Modelo de Xenoenxerto , Proteínas de Sinalização YAP/metabolismoRESUMO
Low grain moisture at harvest is crucial for safe production, transport and storage, but the genetic architecture of this trait in maize (Zea mays) remains elusive. Here, we measured the dynamic changes in grain moisture content in an association-mapping panel of 513 diverse maize inbred lines at five successive stages across five geographical environments. Genome-wide association study (GWAS) revealed 71 quantitative trait loci (QTLs) that influence grain moisture in maize. Epistatic effects play vital roles in the variability in moisture levels, even outperforming main-effect QTLs during the early dry-down stages. Distinct QTL-environment interactions influence the spatio-temporal variability of maize grain moisture, which is primarily triggered at specific times. By combining genetic population analysis, transcriptomic profiling and gene editing, we identified GRMZM5G805627 and GRMZM2G137211 as candidate genes underlying major QTLs for grain moisture in maize. Our results provide insights into the genetic architecture of dynamic changes in grain moisture, which should facilitate maize breeding.