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BACKGROUND AND AIMS: Cholangiocarcinoma (CCA) is an aggressive malignancy arising from the intrahepatic (iCCA) or extrahepatic (eCCA) bile ducts with poor prognosis and limited treatment options. Prior evidence highlighted a significant contribution of the non-canonical NF-κB signalling pathway in initiation and aggressiveness of different tumour types. Lymphotoxin-ß (LTß) stimulates the NF-κB-inducing kinase (NIK), resulting in the activation of the transcription factor RelB. However, the functional contribution of the non-canonical NF-κB signalling pathway via the LTß/NIK/RelB axis in CCA carcinogenesis and progression has not been established. METHODS: Human CCA-derived cell lines and organoids were examined to determine the expression of NF-κB pathway components upon activation or inhibition. Proliferation and cell death were analysed using real-time impedance measurement and flow cytometry. Immunoblot, qRT-PCR, RNA sequencing and in situ hybridization were employed to analyse gene and protein expression. Four in vivo models of iCCA were used to probe the activation and regulation of the non-canonical NF-κB pathway. RESULTS: Exposure to LTα1/ß2 activates the LTß/NIK/RelB axis and promotes proliferation in CCA. Inhibition of NIK with the small molecule inhibitor B022 efficiently suppresses RelB expression in patient-derived CCA organoids and nuclear co-translocation of RelB and p52 stimulated by LTα1/ß2 in CCA cell lines. In murine CCA, RelB expression is significantly increased and LTß is the predominant ligand of the non-canonical NF-κB signalling pathway. CONCLUSIONS: Our study confirms that the non-canonical NF-κB axis LTß/NIK/RelB drives cholangiocarcinogenesis and represents a candidate therapeutic target.
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BACKGROUND: Laparoscopic surgery has been endorsed by clinical guidelines for colon cancer, but not for rectal cancer on account of unapproved oncologic equivalence with open surgery. AIMS: We started this largest-to-date meta-analysis to comprehensively evaluate the safety and efficacy of laparoscopy in the treatment of rectal cancer compared with open surgery. MATERIALS & METHODS: Both randomized and nonrandomized controlled trials comparing laparoscopic proctectomy and open surgery between January 1990 and March 2020 were searched in PubMed, Cochrane Library and Embase Databases (PROSPERO registration number CRD42020211718). The data of intraoperative, pathological, postoperative and survival outcomes were compared between two groups. RESULTS: Twenty RCTs and 93 NRCTs including 216,615 patients fulfilled the inclusion criteria, with 48,888 patients received laparoscopic surgery and 167,727 patients underwent open surgery. Compared with open surgery, laparoscopic surgery group showed faster recovery, less complications and decreased mortality within 30 days. The positive rate of circumferential margin (RR = 0.79, 95% CI: 0.72 to 0.85, p < 0.0001) and distal margin (RR = 0.75, 95% CI: 0.66 to 0.85 p < 0.0001) was significantly reduced in the laparoscopic surgery group, but the completeness of total mesorectal excision showed no significant difference. The 3-year and 5-year local recurrence, disease-free survival and overall survival were all improved in the laparoscopic surgery group, while the distal recurrence did not differ significantly between the two approaches. CONCLUSION: Laparoscopy is non-inferior to open surgery for rectal cancer with respect to oncological outcomes and long-term survival. Moreover, laparoscopic surgery provides short-term advantages, including faster recovery and less complications.
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Laparoscopía , Neoplasias del Recto , Humanos , Laparoscopía/métodos , Laparoscopía/efectos adversos , Márgenes de Escisión , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/etiología , Proctectomía/métodos , Proctectomía/efectos adversos , Ensayos Clínicos Controlados Aleatorios como Asunto , Neoplasias del Recto/cirugía , Neoplasias del Recto/mortalidad , Neoplasias del Recto/patología , Resultado del TratamientoRESUMEN
BACKGROUND AND AIMS: HCC is the most common primary liver tumor, with an increasing incidence worldwide. HCC is a heterogeneous malignancy and usually develops in a chronically injured liver. The NF-κB signaling network consists of a canonical and a noncanonical branch. Activation of canonical NF-κB in HCC is documented. However, a functional and clinically relevant role of noncanonical NF-κB and its downstream effectors is not established. APPROACH AND RESULTS: Four human HCC cohorts (total n = 1462) and 4 mouse HCC models were assessed for expression and localization of NF-κB signaling components and activating ligands. In vitro , NF-κB signaling, proliferation, and cell death were measured, proving a pro-proliferative role of v-rel avian reticuloendotheliosis viral oncogene homolog B (RELB) activated by means of NF-κB-inducing kinase. In vivo , lymphotoxin beta was identified as the predominant inducer of RELB activation. Importantly, hepatocyte-specific RELB knockout in a murine HCC model led to a lower incidence compared to controls and lower maximal tumor diameters. In silico , RELB activity and RELB-directed transcriptomics were validated on the The Cancer Genome Atlas HCC cohort using inferred protein activity and Gene Set Enrichment Analysis. In RELB-active HCC, pathways mediating proliferation were significantly activated. In contrast to v-rel avian reticuloendotheliosis viral oncogene homolog A, nuclear enrichment of noncanonical RELB expression identified patients with a poor prognosis in an etiology-independent manner. Moreover, RELB activation was associated with malignant features metastasis and recurrence. CONCLUSIONS: This study demonstrates a prognostically relevant, etiology-independent, and cross-species consistent activation of a lymphotoxin beta/LTßR/RELB axis in hepatocarcinogenesis. These observations may harbor broad implications for HCC, including possible clinical exploitation.
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Exosomes in the body fluid are effective cell-derived membranous structures transferring various molecules to mediate intercellular communication. The expression of protein in the urinary exosomes from the colorectal cancer (CRC) patients could reflect the characteristics of tumorigenesis. The urinary exosomes with globular membrane structure, the size of 30 ~ 100 nm and positive expression of CD9, CD63 and CD81 were successfully isolated from 9 CRC patients and 3 heathy adults using the density gradient ultracentrifugation. Proteome profiles revealed by label-free liquid chromatography-tandem mass spectrometry (LC-MS/MS) indicated that several proteins were differentially expressed among different stages of CRC. Compared with normal controls, 67 proteins in CRC urinary exosomes were upregulated and 74 proteins were downregulated. The bioinformatics analysis revealed the decreased proteins were related to ESCRT III complex disassembly. The CHMP family was further determined to be the hub of interaction network of proteins enriched in ESCRT signaling. The significant decrease of CHMP4A, CHMP4B, CHMP2A, CHMP2B and CHMP1B were respectively found in the total CRC group and distant metastasis group compared with NC group. Moreover, the CEACAM family also showed significant aberrant changes in the urinary exosomes of CRC patients. The CEACAM7 and CEACAM1 were increased in the CRC patients compared with healthy individuals (P < 0.05). Significant changes of proteomic profile could be found in the urinary exosomes in the CRC patients. The differential expressed urinary exosomes derived proteins showed potential usage in diagnosis and prognosis of CRC.
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Intrahepatic, perihilar, and distal cholangiocarcinoma (iCCA, pCCA, dCCA) are highly malignant tumours with increasing mortality rates due to therapy resistances. Among the mechanisms mediating resistance, overexpression of anti-apoptotic Bcl-2 proteins (Bcl-2, Bcl-xL , Mcl-1) is particularly important. In this study, we investigated whether antiapoptotic protein patterns are prognostically relevant and potential therapeutic targets in CCA. Bcl-2 proteins were analysed in a pan-cancer cohort from the NCT/DKFZ/DKTK MASTER registry trial (n = 1140, CCA n = 72) via RNA-sequencing and transcriptome-based protein activity interference revealing high ranks of CCA for Bcl-xL and Mcl-1. Expression of Bcl-xL , Mcl-1, and Bcl-2 was assessed in human CCA tissue and cell lines compared with cholangiocytes by immunohistochemistry, immunoblotting, and quantitative-RT-PCR. Immunohistochemistry confirmed the upregulation of Bcl-xL and Mcl-1 in iCCA tissues. Cell death of CCA cell lines upon treatment with specific small molecule inhibitors of Bcl-xL (Wehi-539), of Mcl-1 (S63845), and Bcl-2 (ABT-199), either alone, in combination with each other or together with chemotherapeutics was assessed by flow cytometry. Targeting Bcl-xL induced cell death and augmented the effect of chemotherapy in CCA cells. Combined inhibition of Bcl-xL and Mcl-1 led to a synergistic increase in cell death in CCA cell lines. Correlation between Bcl-2 protein expression and survival was analysed within three independent patient cohorts from cancer centers in Germany comprising 656 CCA cases indicating a prognostic value of Bcl-xL in CCA depending on the CCA subtype. Collectively, these observations identify Bcl-xL as a key protein in cell death resistance of CCA and may pave the way for clinical application.
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Colangiocarcinoma , Proteína bcl-X , Humanos , Proteína bcl-X/genética , Proteína bcl-X/metabolismo , Neoplasias de los Conductos Biliares/diagnóstico , Neoplasias de los Conductos Biliares/tratamiento farmacológico , Conductos Biliares Intrahepáticos , Línea Celular Tumoral , Colangiocarcinoma/diagnóstico , Colangiocarcinoma/tratamiento farmacológico , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/genética , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/metabolismo , Pronóstico , Proteínas Proto-Oncogénicas c-bcl-2/genéticaRESUMEN
Alzheimer's disease (AD) is the common neurodegenerative disease in the center never system and the typical dementia in old people. The major pathological changes of AD are the accumulation of amyloid-ß (Aß) plaques, neurofibrillary tangles, loss of cholinergic neurons, inflammation and metabolism dysfunction. However, the molecular mechanism leading to AD pathogenesis is not clear. More and more studies reported that long non-coding RNAs (lncRNAs) play important roles in AD. In this review, we briefly introduce the recent research progress on lncRNAs in AD, including their regulation of clearance of the Aß plaques, synaptic function, inflammation reaction and mitochondrial function, and thus providing the references for that lncRNAs can serve as a potential diagnostic biomarker and therapeutic target in AD.
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Enfermedad de Alzheimer , Enfermedades Neurodegenerativas , ARN Largo no Codificante , Enfermedad de Alzheimer/genética , Péptidos beta-Amiloides/metabolismo , Humanos , ARN Largo no Codificante/genéticaRESUMEN
Type 2 diabetes (T2D) is an independent risk factor for acute ischemic stroke (AIS), but the underlying mechanisms remain elusive. Because the gut microbiota plays a causal role in both T2D and AIS, we wondered whether gut dysbiosis in T2D aggravates stroke progression. We recruited 35 T2D, 90 AIS, 60 AIS with T2D (AIS_T2D) patients, and 55 healthy controls and found that AIS and T2D had an additive effect on AIS_T2D patient gut dysbiosis by exhibiting the largest difference from the heathy controls. In addition, we found that the degree of gut dysbiosis associated with T2D was positively correlated with the National Institutes of Health Stroke Scale (NIHSS), modified Rankin score (mRS), and Essen stroke risk score in patients with AIS, including AIS and AIS_T2D patients. Compared with mice colonized with gut microbiota from healthy controls poststroke modeling, germfree (GF) mice colonized with gut microbiota from T2D patients showed exacerbated cerebral injury and impaired gut barrier function. Specifically, exacerbated brain injury and gut barrier dysfunction in T2D-treated GF mice were significantly associated with a reduction in short-chain fatty acid (SCFA)-producing bacteria. Our study showed that T2D and AIS have an additive effect on AIS_T2D patient gut microbiota dysbiosis. T2D-associated gut microbiota dysbiosis is associated with stroke severity in AIS patients and aggravates stroke progression in mice. IMPORTANCE We demonstrated an additive effect of type 2 diabetes (T2D) and acute ischemic stroke (AIS) on AIS with T2D (AIS_T2D) patient gut microbiota dysbiosis, and gut dysbiosis associated with T2D was positively correlated with stroke severity in AIS patients. Through animal experiments, we found that cerebral injury was exacerbated by fecal microbiota transplantation from T2D patients compared with that from healthy controls, which was associated with a reduction in short-chain fatty acid (SCFA)-producing bacteria. This study provided a novel view that links T2D and AIS through gut microbial dysbiosis.
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OBJECTIVE: Stroke is a leading cause of death and disability worldwide. Neuroprotective approaches have failed in clinical trials, thus warranting therapeutic innovations with alternative targets. The gut microbiota is an important contributor to many risk factors for stroke. However, the bidirectional interactions between stroke and gut microbiota remain largely unknown. DESIGN: We performed two clinical cohort studies to capture the gut dysbiosis dynamics after stroke and their relationship with stroke prognosis. Then, we used a middle cerebral artery occlusion model to explore gut dysbiosis post-stroke in mice and address the causative relationship between acute ischaemic stroke and gut dysbiosis. Finally, we tested whether aminoguanidine, superoxide dismutase and tungstate can alleviate post-stroke brain infarction by restoring gut dysbiosis. RESULTS: Brain ischaemia rapidly induced intestinal ischaemia and produced excessive nitrate through free radical reactions, resulting in gut dysbiosis with Enterobacteriaceae expansion. Enterobacteriaceae enrichment exacerbated brain infarction by enhancing systemic inflammation and is an independent risk factor for the primary poor outcome of patients with stroke. Administering aminoguanidine or superoxide dismutase to diminish nitrate generation or administering tungstate to inhibit nitrate respiration all resulted in suppressed Enterobacteriaceae overgrowth, reduced systemic inflammation and alleviated brain infarction. These effects were gut microbiome dependent and indicated the translational value of the brain-gut axis in stroke treatment. CONCLUSIONS: This study reveals a reciprocal relationship between stroke and gut dysbiosis. Ischaemic stroke rapidly triggers gut microbiome dysbiosis with Enterobacteriaceae overgrowth that in turn exacerbates brain infarction.
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Mammalian brain presents extraordinary complexity reflected in the structure, function, and dynamic changes in the biological and physiological processes of development, maturity, and aging. Recent transcriptomic profiles from the brain tissues of distinct species have described a novel class of transcripts with a covalently closed-loop structure, called circular RNAs (circRNAs), which are produced by alternative back-splicing and derived from genes associated with synaptogenesis and neural activities. Brain is a tightly regulated and largely unexplored organ where circRNAs are highly enriched and expressed in the cell type-, spatiotemporal-specific, sex-biased, and age-related manner. Although the biological functions of most of the circRNAs in the brain remain elusive, increased evidence suggests that dynamic changes in circRNA expression are critical for brain function and the maintenance of physiological homeostasis in the brain. Here, we review the latest immense progresses in the understanding of circRNA expression and function in the mammalian brain. We also discuss possibly biological functions of circRNAs in the brain, which may provide new sights of understanding brain development and aging, as well as the pathogenesis of mental diseases.
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Encéfalo/metabolismo , ARN Circular/metabolismo , Envejecimiento , Animales , Biomarcadores/metabolismo , Encéfalo/citología , Encéfalo/crecimiento & desarrollo , Humanos , Trastornos Mentales/genética , Trastornos Mentales/metabolismo , Trastornos Mentales/patología , Células-Madre Neurales/citología , Células-Madre Neurales/metabolismo , Enfermedades Neurodegenerativas/genética , Enfermedades Neurodegenerativas/metabolismo , Enfermedades Neurodegenerativas/patologíaRESUMEN
The cleaning potential of selected Chinese bituminous coals during coal preparation was evaluated in terms of coal quality, cleaning grade, and cleanability. The cleaning potentials were determined for coals sampled from a total of six seams, two each in three different general exploration areas in southern Shanxi, China. Distribution maps of resources with different cleaning potential characteristics were prepared using mapping and geographical information software. In each case, the area and calculated reserves for coals having different classifications of cleaning potentials were determined. The total areal extent of the six coals studied is about 410 million m2, and the total reserves of these coals amount to about 1460 million tonnes, which include coals of poor, fair, good, and proficient cleanabilities. The proportion of high-quality coals is about 28.9%. Coals that can be processed into high-quality coals account for about 69.2%. A cleaning potential gradient is proposed for indicating the cleaning potential level, and an equation for calculating it is established. The necessity of processing raw coal of good quality is also to be considered in terms of economics. It does not make economic sense to process coal with an organic sulfur content more than 1.5%, even though it may have a good cleanability.
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5-hydroxymethylcytosine (5hmC) is an intermediate stage of DNA de-methylation. Its location in the genome also serves as an important regulatory signal for many biological processes and its levels change significantly with the etiology of Alzheimer's disease (AD). In keeping with this relationship, the TET family of enzymes which convert 5-methylcytosine (5mC) to 5hmC are responsive to the presence of Aß. Using hMeDIP-seq, we show that there is a genome-wide reduction of 5hmC that is found in neurons but not in astrocytes from 3xTg mice (an AD mouse model). Decreased TET enzymatic activities in the brains of persons who died with AD suggest that this reduction is the main cause for the loss of 5hmC. Overexpression of human TET catalytic domains (hTETCDs) from the TET family members, especially for hTET3CD, significantly attenuates the neurodegenerative process, including reduced Aß accumulation as well as tau hyperphosphorylation, and improve synaptic dysfunction in 3xTg mouse brain. Our findings define a crucial role of deregulated 5hmC epigenetics in the events leading to AD neurodegeneration.
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5-Metilcitosina/análogos & derivados , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Enfermedades Neurodegenerativas/metabolismo , 5-Metilcitosina/metabolismo , Animales , Astrocitos/metabolismo , Encéfalo/metabolismo , Línea Celular , Metilación de ADN/genética , Modelos Animales de Enfermedad , Epigénesis Genética/genética , Epigenómica/métodos , Genoma/genética , Células HEK293 , Humanos , Ratones , Enfermedades Neurodegenerativas/genética , Neuronas/metabolismoRESUMEN
Circular RNAs (circRNAs) are abundant in mammalian brain and some show age-dependent expression patterns. Here, we report that circGRIA1, a conserved circRNA isoform derived from the genomic loci of α-mino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor subunit Gria1, shows an age-related and male-specific increase in expression in the rhesus macaque prefrontal cortex and hippocampus. We show circGRIA1 is predominantly localized to the nucleus, and find an age-related increase in its association with the promoter region of Gria1 gene, suggesting it has a regulatory role in Gria1 transcription. In vitro and in vivo manipulation of circGRIA1 negatively regulates Gria1 mRNA and protein levels. Knockdown of circGRIA1 results in an age-related improvement of synaptogenesis, and GluR1 activity-dependent synaptic plasticity in the hippocampal neurons in males. Our findings underscore the importance of circRNA regulation and offer an insight into the biology of brain aging.
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Encéfalo/fisiología , Macaca mulatta/metabolismo , Plasticidad Neuronal , ARN Circular/metabolismo , Receptores AMPA/genética , Sinapsis/metabolismo , Factores de Edad , Envejecimiento , Animales , Femenino , Hipocampo/metabolismo , Macaca mulatta/genética , Macaca mulatta/crecimiento & desarrollo , Masculino , ARN Circular/genética , Receptores AMPA/metabolismo , Sinapsis/genéticaRESUMEN
Background: Significant dysbiosis occurs in the gut microbiome of stroke patients. Condensing these broad, complex changes into one index would greatly facilitate the clinical usage of gut microbiome data. Here, we formulated a gut microbiota index in patients with acute ischemic stroke based on their gut microbiota dysbiosis patterns and tested whether the index was correlated with brain injury and early outcome. Methods: A total of 104 patients with acute ischemic stroke and 90 healthy individuals were recruited, and their gut microbiotas were compared and to model a Stroke Dysbiosis Index (SDI), which representing stroke-associated dysbiosis patterns overall. Another 83 patients and 70 controls were recruited for validation. The association of SDI with stroke severity (National Institutes of Health Stroke Scale [NIHSS] score) and outcome (modified Rankin scale [mRS] score: favorable, 0-2; unfavorable, >2) at discharge was also assessed. A middle cerebral artery occlusion (MCAO) model was used in human flora-associated (HFA) animals to explore the causal relationship between gut dysbiosis and stroke outcome. Results: Eighteen genera were significantly different between stroke patients and healthy individuals. The SDI formula was devised based on these microbiome differences; SDI was significantly higher in stroke patients than in healthy controls. SDI alone discriminated stroke patients from controls with AUCs of 74.9% in the training cohort and 84.3% in the validation cohort. SDI was significantly and positively correlated with NIHSS score on admission and mRS score at discharge. Logistic regression analysis showed that SDI was an independent predictor of severe stroke (NIHSS ≥8) and early unfavorable outcome (mRS >2). Mice receiving fecal transplants from high-SDI patients developed severe brain injury with elevated IL-17+ γδ T cells in gut compared to mice receiving transplants from low-SDI patients (all P < 0.05). Conclusions: We developed an index to measure gut microbiota dysbiosis in stroke patients; this index was significantly correlated with patients' outcome and was causally related to outcome in a mouse model of stroke. Our model facilitates the potential clinical application of gut microbiota data in stroke and adds quantitative evidence linking the gut microbiota to stroke.
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The abundance and function of circular RNAs (circRNAs) in mammalian brain have been reported, but their alterations in the biology of brain aging remain elusive. Here, using deep RNA profiling with linear RNA digestion by RNase R we explored a comprehensive map of changes in circRNA expression in rhesus macaque (macaca mulatta) brain in two age groups from adult (10 y) to aged (20 y) periods. Total 17,050 well expressed, stable circRNAs were identified. Cluster analysis reveals that dynamic changes in circRNA expression show the spatial-, sex- and age-biased specificities. On the basis of separate profiling of the RNAs, age-related circRNAs show differential correlation to host mRNA expression. Furthermore, two voltage-dependent L- and R-type calcium channel gene-derived circCACNA2D1 and circCACNA1E negatively regulate their host mRNA expression. Our results demonstrate the power of changes in circRNA expression to reveal insights into a potentially circRNA-mediated regulatory mechanism underlying the biology of brain aging.
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While extensive studies report that neonatal hypoxia-ischemia (HI) induces long-term cognitive impairment via inflammatory responses in the brain, little is known about the role of early peripheral inflammation response in HI injury. Here we used a neonatal hypoxia rodent model by subjecting postnatal day 0 (P0d) rat pups to systemic hypoxia (3.5 h), a condition that is commonly seen in clinic neonates, Then, an initial dose of minocycline (45 mg/kg) was injected intraperitoneally (i.p.) 2 h after the hypoxia exposure ended, followed by half dosage (22.5 mg/kg) minocycline treatment for next 6 consecutive days daily. Saline was injected as vehicle control. To examine how early peripheral inflammation responded to hypoxia and whether this peripheral inflammation response was associated to cognitive deficits. We found that neonatal hypoxia significantly increased leukocytes not only in blood, but also increased the monocytes in central nervous system (CNS), indicated by presence of C-C chemokine receptor type 2 (CCR2+)/CD11b+CD45+ positive cells and CCR2 protein expression level. The early onset of peripheral inflammation response was followed by a late onset of brain inflammation that was demonstrated by level of cytokine IL-1ß and ionized calcium binding adapter molecule 1(Iba-1; activated microglial cell marker). Interrupted blood-brain barrier (BBB), hypomyelination and learning and memory deficits were seen after hypoxia. Interestingly, the cognitive function was highly correlated with hypoxia-induced leukocyte response. Notably, administration of minocycline even after the onset of hypoxia significantly suppressed leukocyte-mediated inflammation as well as brain inflammation, demonstrating neuroprotection in systemic hypoxia-induced brain damage. Our data provided new insights that systemic hypoxia induces cognitive dysfunction, which involves the leukocyte-mediated peripheral inflammation response.
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Long noncoding RNAs (lncRNAs) mediate important epigenetic regulation in a wide range of biological processes and diseases. We applied comprehensive analyses of RNA-seq and CAGE-seq (cap analysis of gene expression and sequencing) to characterize the dynamic changes in lncRNA expression in rhesus macaque (Macaca mulatta) brain in four representative age groups. We identified 18 anatomically diverse lncRNA modules and 14 mRNA modules representing spatial, age, and sex specificities. Spatiotemporal- and sex-biased changes in lncRNA expression were generally higher than those observed in mRNA expression. A negative correlation between lncRNA and mRNA expression in cerebral cortex was observed and functionally validated. Our findings offer a fresh insight into spatial-, age-, and sex-biased changes in lncRNA expression in macaque brain and suggest that the changes represent a previously unappreciated regulatory system that potentially contributes to brain development and aging.
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Epigénesis Genética , Macaca mulatta/genética , Familia de Multigenes/genética , ARN Largo no Codificante/genética , Animales , Encéfalo/crecimiento & desarrollo , Encéfalo/metabolismo , Femenino , Regulación de la Expresión Génica/genética , Humanos , Macaca mulatta/crecimiento & desarrollo , Masculino , Anotación de Secuencia Molecular , ARN Largo no Codificante/biosíntesis , ARN Mensajero/genética , ARN Mensajero/metabolismoRESUMEN
Chronic kidney disease (CKD) patients have an increased risk of cardiovascular diseases (CVDs). The present study aimed to investigate the gut microbiota and blood trimethylamine-N-oxide concentration (TMAO) in Chinese CKD patients and explore the underlying explanations through the animal experiment. The median plasma TMAO level was 30.33 µmol/L in the CKD patients, which was significantly higher than the 2.08 µmol/L concentration measured in the healthy controls. Next-generation sequence revealed obvious dysbiosis of the gut microbiome in CKD patients, with reduced bacterial diversity and biased community constitutions. CKD patients had higher percentages of opportunistic pathogens from gamma-Proteobacteria and reduced percentages of beneficial microbes, such as Roseburia, Coprococcus, and Ruminococcaceae. The PICRUSt analysis demonstrated that eight genes involved in choline, betaine, L-carnitine and trimethylamine (TMA) metabolism were changed in the CKD patients. Moreover, we transferred faecal samples from CKD patients and healthy controls into antibiotic-treated C57BL/6 mice and found that the mice that received gut microbes from the CKD patients had significantly higher plasma TMAO levels and different composition of gut microbiota than did the comparative mouse group. Our present study demonstrated that CKD patients had increased plasma TMAO levels due to contributions from both impaired renal functions and dysbiosis of the gut microbiota.
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Clostridiaceae/metabolismo , Disbiosis/metabolismo , Gammaproteobacteria/metabolismo , Microbioma Gastrointestinal/genética , Metilaminas/sangre , Insuficiencia Renal Crónica/metabolismo , Adulto , Anciano , Animales , Betaína/metabolismo , Carnitina/metabolismo , Estudios de Casos y Controles , Colina/metabolismo , Clostridiaceae/clasificación , Clostridiaceae/genética , Disbiosis/microbiología , Disbiosis/patología , Trasplante de Microbiota Fecal , Femenino , Gammaproteobacteria/clasificación , Gammaproteobacteria/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Pruebas de Función Renal , Masculino , Ratones , Ratones Endogámicos C57BL , Persona de Mediana Edad , Insuficiencia Renal Crónica/microbiología , Insuficiencia Renal Crónica/patologíaRESUMEN
Iron is an essential element for nervous system development, and maintaining a normal iron level in nervous system is controlled by multiple factors. Recent studies reported that iron dysregulation and the following iron metabolic pathways played an important role in hypoxic ischemic brain damage (HIBD) in neonates. Circulatory iron level is altered after hypoxia-ischemia exposure, which may cause abnormal iron deposition in the nervous system followed by neuronal injury. Finding the causing factors for abnormal iron metabolism after hypoxia-ischemia exposure, as well as understanding the mechanisms how iron metabolism contributes to HIBD, will shed lights on HIBD prevention and treatment. In this mini-review, we summarized changes in iron metabolism after neonatal hypoxia-ischemia exposure, its possible regulatory factors and how iron abnormalities contribute to HIBD.
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Hipoxia-Isquemia Encefálica/sangre , Hierro/aislamiento & purificación , Animales , Animales Recién Nacidos , Encéfalo , Humanos , NeuronasRESUMEN
BACKGROUND: The role of Th17 cells in colorectal tumorigenesis and development still remains unclear, despite the fact that it has been established in the pathogenesis of autoimmune diseases. METHODS: We first analyzed Th17 cells and Treg cells using flow cytometry in the circulation of colorectal adenoma (CRA) and colorectal carcinoma (CRC) patients and healthy controls, and the frequency of Th17 cells in peripheral blood mononuclear cells (PBMCs) stimulated by anti-CD3 plus anti-CD28 and treated by IL-1ß, IL-6, and TGF-ß in different concentrations. We then detected cytokines IL-1ß, IL-6, IL-17A, IL-21, IL-23 or TGF-ß by ELISA in sera and supernatants from both normal and tumor tissues cultured ex vivo. RESULTS: It was found that the percentage of Th17 and Treg cells increased in the circulation of both CRA and CRC patients; the increase of Th17 cells in the circulation occurred in early stages, whereas the increase of Treg cells in the circulation and the increase of Th17 cells in tumor tissues occurred in advanced stages. The subsequent cytokine profiling showed that, along CRC progression, IL-1ß, IL-17A and IL-23 underwent a similar change, while IL-6 in CRC exhibited an opposite change, with Th17 cells. In addition, high levels of TGF-ß and IL-17A were detected in tumor tissues rather than in normal mucosa. The in vitro experiment further demonstrated that IL-1ß, IL-6 or TGF-ß modulated Th17 cell expansion in PBMC. CONCLUSIONS: Our study reveals a unique change of Th17 cells, which is regulated possibly by IL-1ß, IL-6 and TGF-ß in the progression of CRC.
Asunto(s)
Adenoma/inmunología , Neoplasias Colorrectales/inmunología , Neoplasias Colorrectales/metabolismo , Citocinas/metabolismo , Células Th17/inmunología , Adenoma/metabolismo , Adenoma/patología , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma/inmunología , Carcinoma/metabolismo , Carcinoma/patología , Neoplasias Colorrectales/patología , Citocinas/sangre , Citocinas/farmacología , Progresión de la Enfermedad , Femenino , Humanos , Inmunofenotipificación , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/inmunología , Leucocitos Mononucleares/metabolismo , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/metabolismo , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Células Th17/efectos de los fármacos , Células Th17/metabolismoRESUMEN
OBJECTIVE: To investigate the expression of TROP2 in the left-sided and right-sided colon cancer and its clinical significance. METHODS: A total of eighty patients, who received radical resection of colon cancer between June 2001 and April 2005 and were staged as II( and III(, were identified, including forty with left-sided colon cancer(LSCC) and forty with right-sided colon cancer (RSCC). The expression of TROP2 was detected by real-time quantitative RT-PCR in paired cancer and normal tissue. Subsequently, the relationship between TROP2 expression and clinicopathological variables as well as the effect on the patients' prognosis were analyzed. RESULTS: The expression of TROP2 mRNA in the cancer tissue was significantly higher than that in normal tissue(P<0.01, paired Wilcoxon test). However, its expression in LSCC was markedly higher than that in RSCC with significant difference (P=0.009, Mann-Whitney U test). The patients with TROP2 high expression were found more frequently in LSCC than in RSCC(67.5% vs 32.5%, P=0.002, chi(2) test). Cancer-related mortality of the patients with TROP2 high expression was four times as high as low expression(40% vs 10%, P=0.002, chi(2) test). From the stratified survival analysis through Kaplan-Meier curve, the TROP2 high expression group had a significantly poorer median survival time than the low expression group for the patients with LSCC(45.9:63.1 months, P=0.032, log-rank test). By contrast, for the patients with RSCC, TROP2 expression had no marked effect on the survival time(P=0.235, log-rank test). In multivariable analysis, for the cohort of the present study, serosal invasion and lymphatic/vascular invasion were the independent prognostic factors of RSCC. Serosal invasion, lymph node metastasis and lymphatic/vascular invasion were the independent prognostic factors of LSCC. TROP2 high expression showed marginal significance(RR:6.244, 95% CI:0.755-51.636, P=0.089). CONCLUSION: (1)TROP2 is a differentially expressed gene between RSCC and LSCC. (2)TROP2 high expression is closely related to the factors indicating poor prognosis. (3)TROP2 has distinct clinical significance to the patients with different tumor sites. TROP2 high expression is potentially an independent prognostic factor of LSCC. (4)LSCC and RSCC seem to be two distinct diseases with significant molecular heterogeneity.