RESUMEN
In this study, we aim to investigate the role of enolase 1 (ENO1) in osteoarthritis (OA) pathogenic process and to uncover the underlying mechanism. To this end, we used IL-1ß to induce an in vitro OAlike chondrocyte model in human immortalized chondrocyte C-28/I2 cells. We manipulated the expression of ENO1 and cytokine receptor-like factor 1 (CRLF1) in IL-1ß-induced C-28/I2 cells using siRNA and/or overexpression and tested their effects on IL-1ß-induced pathologies including cell viability, apoptosis and inflammatory cytokine levels (IL-6 and TNF-α), and the expression of extracellular matrix-related enzymes and major mediators in the NF-κB signaling pathway (p-p65, p65, p-IκBα and IκBα). We used co-immunoprecipitation and immunofluorescence imaging to study a possible binding between ENO1 and CRLF1. Our data showed that IL-1ß induction elevated ENO1 and CRLF1 expression in C-28/I2 cells. Silencing ENO1 or CRLF1 inhibited the IL-1ß-induced cell viability damage, apoptosis, inflammation, and extracellular matrix degradation. The inhibitory effect of silencing ENO1 was reversed by CRLF1 overexpression, suggesting a functional connection between ENO1 and CRLF1, which could be attributed to a binding between these two partners. Our study could help validate the role of ENO1 in OA pathogenies and identify novel therapeutic targets for OA treatment.
RESUMEN
Background: African American patients frequently receive nonstandard treatment and demonstrate poorer overall survival (OS) outcomes compared to White patients. Our objective was to analysis whether racial/ethnic disparities in rectal cancer-specific mortality remain after accounting for clinical characteristics, treatment, and access-to-care-related factors. Methods: Individuals diagnosed with rectal cancer between 2011 and 2020 were identified using the Surveillance, Epidemiology, and End Results Database. The cumulative incidence of rectal cancer-specific mortality was computed. Sub-distribution hazard ratios (sdHRs) and 95% confidence intervals (CIs) for rectal cancer-specific mortality associated with race/ethnicity were estimated using Fine and Gray model with stepwise adjustments for clinical characteristics, treatment modalities, and factors related to access-to-care. Results: Among 54,370 patients, non-Hispanic (NH) Black individuals exhibited the highest cumulative incidence of rectal cancer-specific mortality (39%), followed by American Indian/Alaska Native (AI/AN) (35%), Hispanics (32%), NH-White (31%), and Asian/Pacific Islander (API) (30%). After adjusting for clinical characteristics, NH-Black patients had a 28% increased risk of rectal cancer mortality (sdHR, 1.28; 95% CI: 1.20-1.35) compared to NH-White patients. In contrast, mortality disparities between Hispanic-White, AI/AN-White, and API-White groups were not significant. The Black-White mortality differences persisted even after adjustments for treatment and access-to-care-related factors. In stratified analyses, among patients with a median household income below $59,999, AI/AN patients showed higher mortality than NH-Whites when adjusted for clinical characteristics (sdHR, 1.32; 95% CI: 1.03-1.70). Conclusions: Overall, the racial/ethnic disparities in rectal cancer-specific mortality were largely attributable to differences in clinical characteristics, treatment modalities, and factors related to access-to-care. These findings emphasize the critical need for equitable healthcare to effectively address and reduce the significant racial/ethnic disparities in rectal cancer outcomes.
RESUMEN
Immunotherapy has limited response rates in colorectal cancer (CRC) due to an immunosuppressive tumor microenvironment (TME). Combining transcriptome sequencing, clinical specimens, and functional experiments, we identified a unique group of CAF subpopulations (COX4I2 + ) with inhibited mitochondrial respiration and enhanced glycolysis. Through bioinformatics predictions and luciferase reporter assays, we determined that EBF1 can upstreamly regulate COX4I2 transcription. COX4I2 + CAFs functionally and phenotypically resemble myofibroblasts, are important for the formation of the fibrotic TME, and are capable of activating the M2 phenotype of macrophages. In vitro experiments demonstrated that COX4I2 + CAFs promote immunosuppressive TME by blocking CD8 + T cell infiltration and inducing CD8 + T cell dysfunction. Using multiple independent cohorts, we also found a strong correlation between the immunotherapy response rate of CRC patients and COX4I2 expression in their tumors. Our results identify a CAF subpopulation characterized by activation of the EBF1-COX4I2 axis, and this group of CAFs can be targeted to improve cancer immunotherapy outcomes.
Asunto(s)
Fibroblastos Asociados al Cáncer , Neoplasias Colorrectales , Miofibroblastos , Transducción de Señal , Transactivadores , Microambiente Tumoral , Microambiente Tumoral/inmunología , Humanos , Fibroblastos Asociados al Cáncer/metabolismo , Fibroblastos Asociados al Cáncer/inmunología , Neoplasias Colorrectales/inmunología , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/genética , Transactivadores/metabolismo , Transactivadores/genética , Miofibroblastos/inmunología , Miofibroblastos/metabolismo , Animales , Línea Celular Tumoral , Fenotipo , Linfocitos T CD8-positivos/inmunología , Ratones , Regulación Neoplásica de la Expresión Génica , Inmunoterapia/métodosRESUMEN
Goose astrovirus (GoAstV) is an emerging avian pathogen that induces gout in goslings with a mortality of up to 50%. Organ damage caused by GoAstV infection was considered the cause of gout, but it is still unclear whether other factors are involved. Human and murine studies have linked the gut microbiome-derived urate and gout, thus we hypothesized that gut microbiome may also play an important role in gout induced by GoAstV infection. This study tested the pathogenicity of our isolated GoAstV genotype 2 strain on goslings, while the appearance of clinical signs, histopathological changes, viral distribution and the blood level of cytokines were monitored for 18 d postinfection (dpi). The dynamics in the gut microbiome were profiled by 16S sequencing and then correlated with GoAstV infection. Results showed that this study successfully developed an experimental infection model for studying the pathogenicity of the GoAstV infection which induces typical symptoms of gout. GoAstV infection significantly altered the gut microbiome of goslings with the enrichment of potential proinflammatory bacteria and depletion of beneficial bacteria that can produce short-chain fatty acids. More importantly, the microbial pathway involved in urate production was significantly increased in goslings infected with GoAstV, suggesting that gut microbiome-derived urate may also contribute to the gout symptoms. Overall, this study demonstrated the role of gut microbiome in the pathogenesis of GoAstV infection, highlighting the potential of gut microbiome-based therapeutics against gout symptoms.
Asunto(s)
Infecciones por Astroviridae , Avastrovirus , Microbioma Gastrointestinal , Gansos , Enfermedades de las Aves de Corral , Animales , Infecciones por Astroviridae/veterinaria , Infecciones por Astroviridae/virología , Enfermedades de las Aves de Corral/virología , Enfermedades de las Aves de Corral/microbiología , Avastrovirus/fisiología , Gota/veterinaria , Gota/virología , Gota/microbiologíaRESUMEN
Cellular communication (CC) influences tumor development by mediating intercellular junctions between cells. However, the role and underlying mechanisms of CC in malignant transformation remain unknown. Here, we investigated the spatiotemporal heterogeneity of CC molecular expression during malignant transformation. It was found that although both tight junctions (TJs) and gap junctions (GJs) were involved in maintaining the tumor microenvironment (TME), they exhibited opposite characteristics. Mechanistically, for epithelial cells (parenchymal component), the expression of TJ molecules consistently decreased during normal-cancer transformation and is a potential oncogenic factor. For fibroblasts (mesenchymal component), the expression of GJs consistently increased during normal-cancer transformation and is a potential oncogenic factor. In addition, the molecular profiles of TJs and GJs were used to stratify colorectal cancer (CRC) patients, where subtypes characterized by high GJ levels and low TJ levels exhibited enhanced mesenchymal signals. Importantly, we propose that leiomodin 1 (LMOD1) is biphasic, with features of both TJs and GJs. LMOD1 not only promotes the activation of cancer-associated fibroblasts (CAFs) but also inhibits the Epithelial-mesenchymal transition (EMT) program in cancer cells. In conclusion, these findings demonstrate the molecular heterogeneity of CC and provide new insights into further understanding of TME heterogeneity.
Asunto(s)
Fibroblastos Asociados al Cáncer , Comunicación Celular , Neoplasias Colorrectales , Transición Epitelial-Mesenquimal , Regulación Neoplásica de la Expresión Génica , Microambiente Tumoral , Animales , Humanos , Fibroblastos Asociados al Cáncer/metabolismo , Fibroblastos Asociados al Cáncer/patología , Línea Celular Tumoral , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/genética , Transición Epitelial-Mesenquimal/genética , Uniones Comunicantes/metabolismo , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/genética , Análisis Espacio-Temporal , Uniones Estrechas/metabolismo , Proteínas del Citoesqueleto/genética , Proteínas del Citoesqueleto/metabolismo , Autoantígenos/genética , Autoantígenos/metabolismoRESUMEN
BACKGROUND: Streak artifacts induced by irregular arm positioning have been an issue in diagnosing the abdomen. PURPOSE: To illustrate the risk of misdiagnosis in abdominal computed tomography (CT) of patients with irregular arm positioning through a case-by-case evaluation and to test if it can be solved by the artificial intelligence iterative reconstruction (AIIR) algorithm. MATERIAL AND METHODS: By reviewing 5220 cases of chest and thoracoabdominal CT, 64 patients with irregular arm positioning were enrolled, whose image data were reconstructed using AIIR in addition to routine hybrid iterative reconstruction (HIR). Lesion detection for livers, spleens, kidneys, gallbladders, and pancreas on AIIR images, performed by two radiologists, was compared with those on HIR images. Discrepancies arising from AIIR images included both cases with additional abnormalities and those with corrections made on previous detections. For cases with discrepancies, artifact scores for organs where discrepancies were found, and contrast-to-noise ratios (CNRs) of cysts with discrepancies were compared between two image sets. RESULTS: Additional abnormalities were detected for 15 cases: additional liver cirrhosis (n=2); additional gallbladder stone (n=1); additional cholecystitis (n=1), additional spleen nodule (n=1); additional kidney cysts (n=8); additional liver cysts (3); and additional spleen cyst (n=1). A spleen contusion was corrected for one case. All involved artifact scores were improved on AIIR images. CNRs of involved liver, kidney, and spleen cysts were improved by up to 539.7%, 538.5%, and 245.5%, respectively. CONCLUSION: Irregular arm positioning may induce a variety of misdiagnoses in abdominal CT, which is almost totally avoidable by the AIIR algorithm.
RESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Wumei Wan (WMW), a traditional Chinese medicine prescription, has been proved to be effective in treating Colitis-associated colorectal cancer (CAC), but it has not been proven to be effective in different stages of CAC. AIM OF THE STUDY: The purpose of our study is to investigate the therapeutic effect and mechanism of WMW on the progression of CAC. MATERIALS AND METHODS: Azioximethane (AOM) and dextran sulfate sodium (DSS) were used to treat mice for the purpose of establishing CAC models. WMW was administered in different stages of CAC. The presentative chemical components in WMW were confirmed by LC-MS/MS under the optimized conditions. The detection of inflammatory cytokines in the serum and colon of mice were estimated by qRT-PCR and ELISA. The changes of T cells and myeloid-derived suppressor cells (MDSCs) in each group were detected by flow cytometry. The metabolic components in serum of mice were detected by UPLC-MS/MS. Expression of genes and proteins were detected by eukaryotic transcriptomics and Western blot to explore the key pathway of WMW in preventing CAC. RESULTS: WMW had significant effect on inhibiting inflammatory responses and tumors during the early development stage of CAC when compared to other times. WMW increased the length of mice's colons, reduced the level of IL-1ß, IL-6, TNF-α in colon tissues, and effectively alleviated colonic inflammation, and improved the pathological damage of colon tissues. WMW could significantly reduce the infiltration of MDSCs in the spleen, increase CD4+ T cells and CD8+ T cells in the spleen of CAC mice, and effectively reform the immune microenvironment in CAC mice. Transcriptomics analysis revealed that 2204 genes had different patterns of overlap in the colon tissues of mice between control group, AOM + DSS group, and early administration of WMW group. And KEGG enrichment analysis showed that PI3K/Akt signaling pathway, ECM-receptor interaction, IL-17 signaling pathway, MAPK signaling pathway, pancreatic secretion, thermogenesis, and Rap1 signaling pathway were all involved. The serum metabolomics results of WMW showed that the metabolic compositions of the control group, AOM + DSS group and the early stage of WMW were different, and 42 differential metabolites with the opposite trends of changes were screened. The metabolic pathways mainly included pyrimidine metabolism, glycine, serine and threonine metabolism, tryptophan metabolism, and purine metabolism. And amino acids and related metabolites may play an important role in WMW prevention of CAC. CONCLUSION: WMW can effectively prevent the occurrence and development of CAC, especially in the initial stage. WMW can reduce the immune infiltration of MDSCs in the early stage. Early intervention of WMW can improve the metabolic disorder caused by AOM + DSS, especially correct the amino acid metabolism. PI3K/Akt signaling pathway was inhabited in early administration of WMW, which can regulate the amplification and function of MDSCs.
Asunto(s)
Neoplasias Asociadas a Colitis , Sulfato de Dextran , Medicamentos Herbarios Chinos , Células Supresoras de Origen Mieloide , Proteínas Proto-Oncogénicas c-akt , Transducción de Señal , Animales , Proteínas Proto-Oncogénicas c-akt/metabolismo , Medicamentos Herbarios Chinos/farmacología , Ratones , Transducción de Señal/efectos de los fármacos , Neoplasias Asociadas a Colitis/tratamiento farmacológico , Neoplasias Asociadas a Colitis/prevención & control , Células Supresoras de Origen Mieloide/efectos de los fármacos , Células Supresoras de Origen Mieloide/metabolismo , Masculino , Fosfatidilinositol 3-Quinasas/metabolismo , Citocinas/metabolismo , Neoplasias Colorrectales/tratamiento farmacológico , Colitis/tratamiento farmacológico , Colitis/complicaciones , Colitis/metabolismo , Ratones Endogámicos BALB C , Modelos Animales de Enfermedad , Colon/efectos de los fármacos , Colon/metabolismo , Colon/patología , Ratones Endogámicos C57BLRESUMEN
BACKGROUND: Hematological metastasis has been recognized as a crucial factor contributing to the high rates of metastasis and mortality observed in colorectal cancer (CRC). Notably, exosomes derived from cancer cells participate in the formation of CRC pre-metastatic niches; however, the mechanisms underlying their effects are largely unknown. While our preliminary research revealed the role of exosome-derived disintegrin and metalloproteinase 17 (ADAM17) in the early stages of CRC metastasis, the role of exosomal ADAM17 in CRC hematogenous metastasis remains unclear. METHODS: In the present study, we isolated and purified exosomes using ultracentrifugation and identified exosomal proteins through quantitative mass spectrometry. In vitro, co-culture assays were conducted to evaluate the impact of exosomal ADAM17 on the permeability of the blood vessel endothelium. Vascular endothelial cell resistance, the cell index, membrane protein separation, flow cytometry, and immunofluorescence were employed to investigate the mechanisms underlying exosomal ADAM17-induced vascular permeability. Additionally, a mouse model was established to elucidate the role of exosomal ADAM17 in the modulation of blood vessel permeability and pre-metastatic niche formation in vivo. RESULTS: Our clinical data indicated that ADAM17 derived from the circulating exosomes of patients with CRC could serve as a blood-based biomarker for predicting metastasis. The CRC-derived exosomal ADAM17 targeted vascular endothelial cells, thus enhancing vascular permeability by influencing vascular endothelial cadherin cell membrane localization. Moreover, exosomal ADAM17 mediated the formation of a pre-metastatic niche in nude mice by inducing vascular leakage, thereby promoting CRC metastasis. Nonetheless, ADAM17 selective inhibitors effectively reduced CRC metastasis in vivo. CONCLUSIONS: Our results suggest that exosomal ADAM17 plays a pivotal role in the hematogenous metastasis of CRC. Thus, this protein may serve as a valuable blood-based biomarker and potential drug target for CRC metastasis intervention.
Asunto(s)
Neoplasias Colorrectales , Exosomas , MicroARNs , Animales , Ratones , Humanos , MicroARNs/metabolismo , Células Endoteliales/metabolismo , Permeabilidad Capilar , Ratones Desnudos , Biomarcadores/metabolismo , Neoplasias Colorrectales/patología , Exosomas/metabolismo , Línea Celular Tumoral , Proliferación Celular , Proteína ADAM17/metabolismoRESUMEN
Dendrite-free Zn metal anodes with high depth-of-discharge (DoD) and robust cycle performances are highly desired for the practical application of aqueous Zn-ion batteries. Herein, the zincophobic/hydrophilic nature of Metal-N-C through manipulating the electronic interactions between metal and coordination atoms is successfully reversed, thereby fabricating a zincophilic/hydrophobic asymmetric Zn-N3Py+1Pr-C (consisting of a Zn center coordinated with 3 pyridinic N atoms and 1 pyrrolic N atom) host, which realizes uniformed Zn deposition and a long lifespan with high DoD. The experimental and theoretical investigations demonstrate weakened interaction between pyrrolic N and metal center in the asymmetric Zn-N3Py+1Pr-C triggers downshift of the Zn 3d-band-center and a new localization nonbonding state in the N and C 2p-band, resulting in preferred Zn adsorption to water adsorption. Consequently, the asymmetric Zn-N3Py+1Pr-C host delivers small Zn nucleation overpotential and high Coulombic efficiency of 98.3% over 500 cycles. The symmetric cells with Zn-N3Py+1Pr-C@Zn anode demonstrate 500 h dendrite-free cycles at DoD up to 50%. The Zn-N3Py+1Pr-C@Zn/S-PANI full cell also shows a robust long-term cycle performance of 1000 cycles at 10 A g-1. This strategy of constructing zincophilic/hydrophobic Metal-N-C may open up their application for the dendrite-free metal anode.
RESUMEN
Objective: To establish a nomogram prediction model (based on clinicopathological and radiological features) for the development of metachronous liver metastasis (MLM) in patients with colorectal cancer (CRC). Methods: This retrospective study included patients with CRC who underwent surgery at Changshu No.1 People's Hospital and the Second Affiliated Hospital of Soochow University between January 2016 and December 2018. The clinical, pathological, and radiological features of each patient were investigated. Risk factors for MLM were identified by univariable and multivariable analyses. The predictive nomogram for MLM development was constructed. The predictive performance of the nomogram was estimated by the receiver operating characteristics curve, calibration curve, and decision curve analysis. Results: This study included 161 patients with CRC [median age: 66 (range, 33-87) years]. Fifty-nine developed MLM after a median of 12 (range, 2-52) months after surgery. The multivariable logistic regression analysis showed that age >66 years (OR=3.471, 95% CI: 1.272-9.473, P=0.015), N2 stage (OR=6.534, 95% CI: 1.456-29.317, P=0.014), positive vascular invasion (OR=2.995, 95% CI: 1.132-7.926, P=0.027), positive tumor deposit (OR=4.451, 95% CI: 1.153-17.179, P=0.030), and linear (OR=6.774, 95% CI: 1.306-35.135, P=0.023) and nodal pericolic fat infiltration patterns (OR=8.762, 95% CI: 1.521-50.457, P=0.015) were independently associated with MLM. These five factors were used to create a nomogram. The area under the receiver operating characteristics curve of the nomogram was 0.866 (95% CI: 0.803-0.914), indicating favorable prediction performance. The calibration curve of the nomogram showed a satisfactory agreement between the predicted and actual probabilities. Conclusions: A nomogram prediction model based on five clinicopathological and radiological features might have favorable prediction performance for MLM in patients who underwent surgery for CRC. Hence, the present study proposes a nomogram that can easily be used to predict MLM after CRC surgery based on readily available features.
RESUMEN
Longstranded noncoding RNAs (lncRNAs) are RNAs that consist of >200 nucleotides. The majority of lncRNAs do not encode proteins but have been revealed to mediate a variety of important physiological functions. AntisenselncRNAs (ASlncRNAs) are transcribed from the opposite strand of a protein or nonprotein coding gene as part of the antisense strand of the coding gene. ASlncRNAs can serve an important role in the tumorigenesis, prognosis, metastasis and drug resistance of a number of malignancies. This has been reported to be exerted through various mechanisms, such as endogenous competition, promoter interactions, direct interactions with mRNAs, acting as 'scaffolds' to regulate mRNA halflife, interactions with 5untranslated regions and regulation of sense mRNAs. ASlncRNAs have been found to either inhibit or promote tumor aggressiveness by regulating cell proliferation, energy metabolism, inflammation, inflammatorycarcinoma transformation, invasion, migration and angiogenesis. In addition, accumulating evidence has documented that ASlncRNAs can regulate tumor therapy resistance. Therefore, targeting aberrantly expressed ASlncRNAs for cancer treatment may prove to be a promising approach to reverse therapy resistance. In the present review, research advances on the role of ASlncRNAs in tumor occurrence and development were summarized, with the aim of providing novel ideas for further research in this field.
Asunto(s)
Neoplasias , ARN Largo no Codificante , Humanos , ARN Largo no Codificante/genética , Neoplasias/genética , Regulación Neoplásica de la Expresión GénicaRESUMEN
Breast cancer is commonly diagnosed with mammography. Using image segmentation algorithms to separate lesion areas in mammography can facilitate diagnosis by doctors and reduce their workload, which has important clinical significance. Because large, accurately labeled medical image datasets are difficult to obtain, traditional clustering algorithms are widely used in medical image segmentation as an unsupervised model. Traditional unsupervised clustering algorithms have limited learning knowledge. Moreover, some semi-supervised fuzzy clustering algorithms cannot fully mine the information of labeled samples, which results in insufficient supervision. When faced with complex mammography images, the above algorithms cannot accurately segment lesion areas. To address this, a semi-supervised fuzzy clustering based on knowledge weighting and cluster center learning (WSFCM_V) is presented. According to prior knowledge, three learning modes are proposed: a knowledge weighting method for cluster centers, Euclidean distance weights for unlabeled samples, and learning from the cluster centers of labeled sample sets. These strategies improve the clustering performance. On real breast molybdenum target images, the WSFCM_V algorithm is compared with currently popular semi-supervised and unsupervised clustering algorithms. WSFCM_V has the best evaluation index values. Experimental results demonstrate that compared with the existing clustering algorithms, WSFCM_V has a higher segmentation accuracy than other clustering algorithms, both for larger lesion regions like tumor areas and for smaller lesion areas like calcification point areas.
Asunto(s)
Lógica Difusa , Molibdeno , Humanos , Mamografía , Algoritmos , Análisis por Conglomerados , Procesamiento de Imagen Asistido por Computador/métodosRESUMEN
BACKGROUND AND STUDY OBJECTIVES: A higher b-value Diffusion-weighted imaging (DWI) would improve the contrast between cancerous and noncancerous tissue. Apparent diffusion coefficient (ADC)-histogram analysis is a method that can provide statistical data and quantitative information on tumor heterogeneity. This study aimed to compare two high b-values (1000 and 2000 sec/mm2) DWI in tumor detection and diagnostic performance in identifying early-stage tumor rectal cancer. PATIENTS AND METHODS: This blinded and blinded retrospective study involved 56 patients with rectal cancer and 45 patients. Two radiologists evaluated the qualitative detection parameters and quantitative parameters of the ADC evaluated histogram and compared them between two DWI sequences (b-value for 1000 sec/mm2 and 2000 sec/mm2). The characteristic curves were used to assess diagnostic administration for the ADC histogram in discriminating early-stage tumors. RESULTS: The b-value for 2000 sec/mm2 DWI significantly improved AUCs, sensitivity, specificity, and precision and decreased false-positive rate for detection compared to the b-value for 1000 sec/mm2 (p < 0.05). The mean and fifth percentile ADC value for stage I using the b-value for 1000 sec/mm2 DWI was significantly higher than stage ≥ II (p = 0.036II and 0.016 respectively), as the well as fifth, 10th, mean ADC of the fifth, 10th, and 25th ADC percentile at b-value for 2000 sec/mm2 (p = 0.031, 0.014, 0.035 and 0.025 respectively). The AUCs of the fifth percentile ADC at b-value for 2000 sec/mm2 DWI in both readers in differentiating the stage â tumor were the highest (0.732 and 0.751). CONCLUSION: The b-value for 2000 sec/mm2 DWI could improve the accurate detection of rectal cancer. The fifth percentile ADC at b-value for 2000 sec/mm2 sec/mm2 DWI was more useful for discriminating early stage than the b-value for 1000 sec/mm2 DWI.
Asunto(s)
Neoplasias del Recto , Humanos , Estudios Retrospectivos , Neoplasias del Recto/diagnóstico por imagen , Neoplasias del Recto/patología , Imagen de Difusión por Resonancia Magnética/métodosRESUMEN
Nephropathogenic infectious bronchitis virus (NIBV) infections continue to pose a significant hazard in the poultry industry. Baicalin is a natural flavonoid that has been reported to have antiviral activity, but its function in NIBV infection largely remains unclear. In this study, the antiviral mechanism of baicalin in the spleen of NIBV-infected chicks was mainly elucidated in mitophagy and macrophage polarization. 28-day-old Hy-Line brown chicks were randomly divided into four groups: the group of chicks was treated intranasally (in) with normal saline (0.2 mL) and subsequently divided into two groups: the Con group (basic diet), the Con+BA group (basic diet+10 mg/kg Baicalin); another group of chicks was intranasally infected with SX9 (10-5/0.2 mL) and subsequently divided into two groups: the Dis group (basic diet), the Dis+BA group (basic diet+10 mg/kg Baicalin). Spleen tissues were collected at 3, 7, and 11 days post infection (dpi). NIBV copy number was strikingly decreased in the spleens under BA treatment with infectious time. Histopathological examination showed enlarged and hemorrhagic white pulp and no clearly defined boundary between white pulp and red pulp in the Dis group, which could be improved by BA treatment. Meanwhile, the loss of cristae structure and vacuolization in mitochondria caused by NIBV infection was repaired in the Dis+BA group by ultrastructure observation. In addition, BA treatment inhibited the induction of mitophagy by NIBV infection. BA treatment also promoted innate immunity by enhancing type I IFN levels. Moreover, BA treatment up-regulated M1-related cytokines (iNOS, TNF-α, IL-1ß, IL-6) and inhibited M2-related cytokines (ARG2, IL-4, IL-10, Pparg) at the mRNA and protein levels. However, the results from the splenic tissues at 11 dpi are opposite results from 3 and 7 dpi. Immunofluorescence analysis for M1 macrophage marker iNOS and M2 macrophage marker CD163 further validated this result. Collectively, BA inhibited mitophagy and triggered IFN activation, and M1 polarization, which contributed to the inhibition of NIBV infection.
Asunto(s)
Virus de la Bronquitis Infecciosa , Animales , Bazo , Mitofagia , Pollos , Flavonoides/farmacología , Citocinas/genética , Macrófagos , AntiviralesRESUMEN
Beclin1, also known as ATG6, has been shown to be closely related to coronavirus, however, the link between Beclin1 and nephropathogenic infectious bronchitis virus (NIBV) has been poorly investigated and there are no available antibodies specifically targeting the chicken Beclin1 protein. The study aimed to prepare and assay a polyclonal antibody to Beclin1, enabling a deeper understanding of the mechanism of action of Beclin1 in NIBV. In this study, we amplified the chicken Beclin1 target gene and constructed a recombinant plasmid using prokaryotic expression techniques, then obtained the recombinant target protein by induced expression. Finally, the serum is obtained by immunizing rabbits with the purified and concentrated protein. The results show that the antiserum potency of the ELISA assay was >1:204800. By western blotting and immunofluorescence, the antibodies we prepared specifically recognized the chicken Beclin1 protein, which is mainly found in the nucleus of trachea, lung, kidney, spleen and fabricant cells. NIBV infection significantly decreased the expression of Beclin1 in the trachea, but increased in others. We have successfully prepared specific rabbit anti-chicken Beclin1 polyclonal antibodies, and detected changes in tissues of diseased chickens infected with NIBV, laying the foundation for further studies on the role of Beclin1 in avian diseases.
Asunto(s)
Pollos , Virus de la Bronquitis Infecciosa , Animales , Conejos , Virus de la Bronquitis Infecciosa/genética , Beclina-1/genética , Beclina-1/metabolismo , Anticuerpos , Riñón/metabolismo , Western BlottingRESUMEN
Flexible conductive sensor materials have received great attention for their sensitive electrical response to external conditions and their promising applications in flexible wearable and robotic applications. In this work, a highly stretchable force sensitive and temperature sensitive sensor material with a sandwich structure was prepared from the polydimethylsiloxane (PDMS) and the liquid metal (LM) gallium-indium-tin alloy (GaInSn). The sandwich structure (PDMS + PDMS/GaInSn + PDMS) was proven to prevent the "leakage" of LM. The preparation method of the sensing material was simple and time-saving (less than 1.5 h) and can be used for industrial production. The electrical performance analysis results confirmed that the resistance (R) of the material was sensitive to the external force, such as repeated stretching, compressing, bending, and impacting. The ΔR/R changed periodically and stably with the repeated stretching, when the GaInSn/Part A ≥ 0.4, the cyclic tensile strain ≤ 50%, and the cyclic tensile rate ≤ 2.5 mm/min. The R of the sensor materials was also responsive to the temperature, such as hot air and liquid nitrogen. In conclusion, this work provides a method for preparing sensing materials with the sandwich structure, which was confirmed to be sensitive to force and temperature without leaking LM, and it produced different types of R signals under different deformations and different temperatures.
RESUMEN
Background: As the most common gastrointestinal malignancy worldwide, liver metastases occur in half colorectal cancer (CRC) patients. Early detection can help treat them early and reduce mortality in patients with colorectal cancer liver metastases (CRLM). Finding useful biomarkers for CRLM is thus essential. Methods: The TCGA and GEO databases were used to download the expression profiles and clinical data of the patients. Differential analysis screened for genes associated with CRLM, and univariate Cox regression analysis identified genes associated with prognosis. The least absolute shrinkage and selection operator (LASSO) method further preferred genes to construct a prognostic signature. Kaplan-Meier survival curves were used to show patients' overall survival (OS). Receiver operating characteristic (ROC) curves showed the accuracy of the model. Risk scores and clinical characteristics of patients were included in multivariate Cox regression analysis to identify independent risk factors, and a nomogram was constructed. The proportion of immune cells and infiltration were assessed using the 'CIBERSORT' package and the 'ESTIMATE' package. Results: We constructed a signature consisting of seven CRLM-associated genes, and signature-based risk scores have great potential in estimating the prognosis of CRC patients. Moreover, the poor response to immunotherapy in high-risk patients might contribute to the poor prognosis of individuals. Furthermore, we found that overexpression of Hepcidin antimicrobial peptide (HAMP), the only gene highly expressed in CRC and liver metastatic tissues, promoted CRC development and that it was associated with tumor mutation burden (TMB), DNA mismatch repair (MMR) genes, and microsatellite instability (MSI) in various tumors. Finally, we found that in CRC patients, low expression of HAMP also represented a better immunotherapeutic outcome, reflecting the critical role of HAMP in guiding immunotherapy. Conclusion: We identified a prognostic signature containing 7 CRLM-associated genes, and the signature was specified as an independent predictor and a nomogram containing the risk score was built accordingly. In addition, the derived gene HAMP could help guide the exploration of profitable immunotherapeutic strategies.
RESUMEN
Background: Given the key role of integrins in maintaining intestinal homeostasis, anti-integrin biologics in inflammatory bowel disease (IBD) are being investigated in full swing. However, the unsatisfactory efficacy and safety of current anti-integrin biologics in clinical trials limit their widespread use in clinic. Therefore, it is particularly important to find a target that is highly and specifically expressed in the intestinal epithelium of patients with IBD. Methods: The function of integrin αvß6 in IBD and colitis-associated carcinoma (CAC) with the underlying mechanisms has been less studied. In the present study, we detected the level of integrin ß6 within inflammation including colitis tissues in human and mouse. To investigate the role of integrin ß6 in IBD and CAC, integrin ß6 deficient mice were hence generated based on the construction of colitis and CAC model. Results: We noted that integrin ß6 was significantly upregulated in inflammatory epithelium of patients with IBD. Integrin ß6 deletion not only reduced infiltration of pro-inflammatory cytokines, but also attenuated disruption of tight junctions between colonic epithelial cells. Meanwhile, lack of integrin ß6 affected macrophage infiltration in mice with colitis. This study further revealed that lack of integrin ß6 could inhibit tumorigenesis and tumor progression in CAC model by influencing macrophage polarization, which was also involved in attenuating the degree of intestinal symptoms and inflammatory responses in mice suffering from colitis. Conclusions: The present research provides a potentially new perspective and option for the treatment of IBD and CAC.
RESUMEN
OBJECTIVES: Polycyclic aromatic hydrocarbons (PAHs) are environmental endocrine-disrupting compounds, which have been widely recognised as a risk factor for human health. However, the relationship between PAHs exposure and the risk of osteoarthritis has rarely been reported. This study aimed to investigate the association between individual and mixed exposure to PAHs and osteoarthritis. METHODS: In this cross-sectional study, participants aged ≥20 years with data on urinary PAHs and osteoarthritis were extracted from the National Health and Nutrition Examination Survey (NHANES) between 2001 and 2016. Logistic regression analysis was utilised to assess the relationship between individual PAHs exposure and osteoarthritis. The quantile-based g computation (qgcomp) analysis and Bayesian kernel machine regression (BKMR) analysis were performed to assess the effect of mixed exposure to PAHs on osteoarthritis, respectively. RESULTS: A total of 10,613 participants were enrolled, 980 (9.23%) of whom had osteoarthritis. Exposure to high levels of 1-hydroxynaphthalene (1-NAP) [odds ratio (OR)=1.06, 95% confidence interval (CI): 1.01-1.10], 3-hydroxyfluorene (3-FLU) (OR=1.09, 95%CI: 1.02-1.17), and 2-hydroxyfluorene (2-FLU) (OR=1.06, 95%CI: 1.01-1.13) were all associated with greater odds of osteoarthritis after adjusting for age, sex, body mass index, drinking alcohol, and hypertension. The qgcomp analysis showed that the joint weighted value of mixed PAHs exposure (OR=1.11, 95%CI: 1.02-1.22; p=0.017) was significantly related to higher odds of osteoarthritis. The BKMR analysis demonstrated that mixed exposure to PAHs was positively correlated with the risk of osteoarthritis. CONCLUSIONS: Both individual and mixed exposure to PAHs were positively correlated with the risk of osteoarthritis.
Asunto(s)
Osteoartritis , Hidrocarburos Policíclicos Aromáticos , Adulto , Humanos , Hidrocarburos Policíclicos Aromáticos/efectos adversos , Encuestas Nutricionales , Estudios Transversales , Teorema de Bayes , Biomarcadores , Osteoartritis/inducido químicamente , Osteoartritis/epidemiologíaRESUMEN
Hepatocellular carcinoma (HCC) is a common malignancy that is associated with poor prognosis in humans. Despite the development of targeted drugs, overall survival remains a significant challenge, and new therapeutic strategies are urgently needed. The aim of this study was to investigate the function of miR-552-5p in ferroptosis and the underlying mechanism, as well as to explore novel strategies for HCC treatment. CCK8 assay results showed that the viability of Huh-7 and Hep3B cells decreased significantly after transfection of the miR-552-5p inhibitor. In addition, we found that glutathione levels were depleted, intracellular Fe2+ levels were elevated, and the mean fluorescence intensity of C11-BODIPY was increased after miR-552-5p transfection. Transmission electron microscopy revealed that mitochondria became smaller and mitochondrial membrane intensity was increased in the inhibitor+RSL3 group. Mechanistically, a dual-luciferase reporter assay confirmed that miR-552-5p interacted with the 3' untranslated region (3' UTR) of acyl-CoA synthetase long-chain family member 4 (ACSL4) mRNA. qPCR and Western blotting results verified that miR-552-5p negatively regulated ACSL4 expression. In addition, we found that overexpression of ZNF8, which is a transcription factor, reduced intracellular miR-552-5p levels and enhanced sensitivity to ferroptosis. miR-552-5p reduces sensitivity to ferroptosis by targeting the 3' UTR of ACSL4 in HCC. The ZNF8-miR-552-5p-ACSL4 axis is involved in regulation of ferroptosis in HCC, and these findings may provide a new therapeutic target for treatment of HCC.