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COVID-19 caused by SARS-CoV-2 has spread around the world. The receptor-binding domain (RBD) of the spike protein of SARS-CoV-2 is a critical component that directly interacts with host ACE2. Here, we simulate the ACE2 recognition processes of RBD of the WT, Delta, and OmicronBA.2 variants using our recently developed supervised Gaussian accelerated molecular dynamics (Su-GaMD) approach. We show that RBD recognizes ACE2 through three contact regions (regions I, II, and III), which aligns well with the anchor-locker mechanism. The higher binding free energy in State d of the RBDOmicronBA.2-ACE2 system correlates well with the increased infectivity of OmicronBA.2 in comparison with other variants. For RBDDelta, the T478K mutation affects the first step of recognition, while the L452R mutation, through its nearby Y449, affects the RBDDelta-ACE2 binding in the last step of recognition. For RBDOmicronBA.2, the E484A mutation affects the first step of recognition, the Q493R, N501Y, and Y505H mutations affect the binding free energy in the last step of recognition, mutations in the contact regions affect the recognition directly, and other mutations indirectly affect recognition through dynamic correlations with the contact regions. These results provide theoretical insights for RBD-ACE2 recognition and may facilitate drug design against SARS-CoV-2.
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Enzima Convertidora de Angiotensina 2 , Simulación de Dinámica Molecular , Unión Proteica , SARS-CoV-2 , Glicoproteína de la Espiga del Coronavirus , Glicoproteína de la Espiga del Coronavirus/metabolismo , Glicoproteína de la Espiga del Coronavirus/química , Glicoproteína de la Espiga del Coronavirus/genética , Enzima Convertidora de Angiotensina 2/metabolismo , Enzima Convertidora de Angiotensina 2/química , Enzima Convertidora de Angiotensina 2/genética , Humanos , SARS-CoV-2/metabolismo , SARS-CoV-2/genética , Sitios de Unión , COVID-19/virología , COVID-19/metabolismo , Dominios Proteicos , MutaciónRESUMEN
BACKGROUND: The chimeric antigen receptor (CAR)-T therapy has a limited therapeutic effect on solid tumors owing to the limited CAR-T cell infiltration into solid tumors and the inactivation of CAR-T cells by the immunosuppressive tumor microenvironment. Macrophage is an important component of the innate and adaptive immunity, and its unique phagocytic function has been explored to construct CAR macrophages (CAR-Ms) against solid tumors. This study aimed to investigate the therapeutic application of CAR-Ms in ovarian cancer. METHODS: In this study, we constructed novel CAR structures, which consisted of humanized anti-HER2 or CD47 scFv, CD8 hinge region and transmembrane domains, as well as the 4-1BB and CD3ζ intracellular domains. We examined the phagocytosis of HER2 CAR-M and CD47 CAR-M on ovarian cancer cells and the promotion of adaptive immunity. Two syngeneic tumor models were used to estimate the in vivo antitumor activity of HER2 CAR-M and CD47 CAR-M. RESULTS: We constructed CAR-Ms targeting HER2 and CD47 and verified their phagocytic ability to ovarian cancer cells in vivo and in vitro. The constructed CAR-Ms showed antigen-specific phagocytosis of ovarian cancer cells in vitro and could activate CD8+ cytotoxic T lymphocyte (CTL) to secrete various anti-tumor factors. For the in vivo model, mice with human-like immune systems were used. We found that CAR-Ms enhanced CD8+ T cell activation, affected tumor-associated macrophage (TAM) phenotype, and led to tumor regression. CONCLUSIONS: We demonstrated the inhibition effect of our constructed novel HER2 CAR-M and CD47 CAR-M on target antigen-positive ovarian cancer in vitro and in vivo, and preliminarily verified that this inhibitory effect is due to phagocytosis, promotion of adaptive immunity and effect on tumor microenvironment.
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Antígeno CD47 , Neoplasias Ováricas , Humanos , Femenino , Animales , Ratones , Neoplasias Ováricas/terapia , Macrófagos , Fagocitosis , Microambiente TumoralRESUMEN
BACKGROUND: Benevolent leadership is common in organizations, including hospitals, and is known to have positive effects on employees. Yet, nursing literature lacks sufficient research on its relationships with nurses' behavior. METHODS: In March to April 2022, a cross-sectional study was carried out involving 320 nurses employed across various hospitals in Sichuan Province, China. Benevolent leadership, affective commitment, work engagement, and helping behavior were evaluated using the Benevolent Leadership Scale, Affective Commitment Scale, Work Engagement Scale, and Helping Behavior Questionnaire, respectively. The study employed structural equation model and the bootstrap method to investigate the proposed relationships. RESULTS: The SEM analysis results indicated a positive association between benevolent leadership and several outcomes among nurses. Specifically, benevolent leadership was found to be positively associated with nurses' affective commitment (ß = 0.58, p < .001), work engagement (ß = 0.02, p < .001), and helping behavior (ß = 0.17, p = .001). Additionally, there was a significant indirect effect between benevolent leadership and nurses' work engagement through affective commitment (ß = 0.08, p = .007) as well as between benevolent leadership and helping behavior through affective commitment (ß = 0.16, p < .001). CONCLUSIONS: This study's findings emphasize the crucial role of benevolent leadership in fostering nurses' positive attitudes and behaviors in the workplace. Hospital administrators could promote the benevolent leadership of head nurses to enhance nurses' affective commitment, work engagement, and helping behaviors.
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BACKGROUND: As the first member of the metastasis-associated protein (MTA) family, MTA1 and another MTA family member, MTA2, have both been reported to promote breast cancer progression and metastasis. However, the difference and relationship between MTA1 and MTA2 have not been fully elucidated. METHODS: Transwell assays were used to assess the roles of MTA1 and MTA2 in the metastasis of ZR-75-30 luminal B breast cancer cells in vitro. Immunoblotting and qRT-PCR were used to evaluate the effect of MTA1 overexpression on MTA2. Proteases that cleave MTA2 were predicted using an online web server. The role of neutrophil elastase (NE) in MTA1 overexpression-induced MTA2 downregulation was confirmed by specific inhibitor treatment, knockdown, overexpression and immunocytochemistry, and NE cleavage sites in MTA2 were confirmed by MTA2 truncation and mutation. The effect of MTA1 overexpression on the intrinsic inhibitor of NE, elafin, was detected by qRT-PCR, immunoblotting and treatment with inhibitors. RESULTS: MTA1 overexpression inhibited, while MTA2 promoted the metastasis of ZR-75-30 cells in vitro. MTA1 overexpression downregulated MTA2 expression at the protein level rather than the mRNA level. NE was predicted to cleave MTA2 and was responsible for MTA1 overexpression-induced MTA2 degradation. NE was found to cleave MTA2 in the C-terminus at the 486, 497, 542, 583 and 621 sites. MTA1 overexpression activated NE by downregulating elafin in a histone deacetylase- and DNA methyltransferase-dependent manner. CONCLUSIONS: MTA1 and MTA2 play opposing roles in the metastasis of ZR-75-30 luminal B breast cancer cells in vitro. MTA1 downregulates MTA2 at the protein level by epigenetically repressing the expression of elafin and releasing the inhibition of neutrophil elastase, which cleaves MTA2 in the C-terminus at multiple specific sites.
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Histona Desacetilasas/metabolismo , Proteolisis , Proteínas Represoras/metabolismo , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Línea Celular Tumoral , ADN (Citosina-5-)-Metiltransferasa 1/metabolismo , Regulación hacia Abajo/genética , Elafina/farmacología , Histona Desacetilasas/química , Humanos , Elastasa de Leucocito/antagonistas & inhibidores , Elastasa de Leucocito/metabolismo , Modelos Biológicos , Metástasis de la Neoplasia , Proteínas Represoras/química , TransactivadoresRESUMEN
Bromate is a disinfection byproduct (DBP) that forms during the ozonation of bromide-containing natural water, which may cause health risks to humans. In this review, we provide an overview of the mechanism of bromate formation, microbial communities and bioreactors that are responsible for bromate reduction. Bromate can be formed through two pathways of bromide oxidation by ozone or by ·OH, and it can be removed by biological approaches. Members belonging to phyla of Spirochaetes, Proteobacteria, Firmicutes, Actinobacteria, Clostridium, Deinococcus-Thermus and Bacteroidetes have been identified as capable of reducing bromate to bromide. Multiple configurations of biofilm bioreactors have been employed to cultivate microbial communities to perform bromate removal. The rapid development of multiomics has and will continue to accelerate the elucidation of the mechanisms involved in bromate and other DBP conversions, as well as the interaction patterns among different bacterial subdivisions in the bioremoval of DBPs.
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Ozono , Contaminantes Químicos del Agua , Purificación del Agua , Biodegradación Ambiental , BromatosRESUMEN
Bromate is a weakly carcinogenic disinfection by-product generated from naturally existing bromide during ozonation. In order to uncover the phylogenetic diversity of bromate-reducing aquatic bacteria, the microbial mixed cultures were enriched anaerobically from various activated sludge samples with a high concentration of 3.6â¯mmol/L bromate which served as the electron acceptor in batch-fed reactors. Then the phylogenetic diversity was characterized by employing 16S rRNA gene-based clone libraries and high-throughput sequencing. Results showed that as highest as 48.65â¯mg/L [BrO3--Br] (0.61â¯mmol/L) could be reduced to Br- within an operational cycle of 48â¯h, indicating the presence of bromate-reducing bacteria. The microbial analysis based on 16S rRNA gene clone libraries indicated that the dominant bacteria in the enriched consortium were affiliated to the genera of Aeromonas, which had been reported and implied its functional application to reduce bromate. In addition, some other subdivisions of bromate-reducing bacteria were enriched at different operational cycles. The abundance of the genus Rivibacter belonging to Comamonadaceae were increased after 10 cycles enrichment, which might represent another type of novel bromate bio-reducers. The study provided new insights for the phylogenetic diversity of the bromate-reducing microorganisms while further researches are required to verify the bromate bio-reduction mechanism.
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Bacterias/clasificación , Bromatos/metabolismo , Filogenia , Aguas del Alcantarillado/microbiología , Contaminantes Químicos del Agua/metabolismo , Bacterias/genética , Bacterias/aislamiento & purificación , Bacterias/metabolismo , Biodegradación Ambiental , Reactores Biológicos/microbiología , Consorcios Microbianos/genética , Oxidación-Reducción , ARN Ribosómico 16S/genéticaRESUMEN
This study evaluated the biocontrol effect of isolated epiphytic yeasts (Papiliotrema terrestris, Hanseniaspora uvarum, and Rhodosporidium glutinis) against Botrytis cinerea and Alternaria alternata in blueberry fruits and its possible mechanisms. Our findings indicated that the three tested yeasts exerted a good biocontrol effect on postharvest diseases in blueberry, and that H. uvarum was the most effective. In addition, the three tested yeasts could improve the postharvest storage quality of blueberry fruits to some extent. H. uvarum demonstrated the strongest direct inhibitory effect on pathogens by suppressing spore germination, mycelial growth, and antifungal volatile organic compound (VOC) production. P. terrestris showed the highest extracellular lytic enzymes activities. It also had better adaptation to low temperature in fruit wounds at 4 °C. The biofilm formation capacity was suggested to be the main action mechanism of R. glutinis, which rapidly colonized fruit wounds at 20 °C. Several action mechanisms are employed by the superb biocontrol yeasts, while yeast strains possess distinctive characteristics and have substantially different action mechanisms.
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Acute lung injury (ALI) is a life-threatening disease characterized by severe lung inflammation and intestinal microbiota disorder. The GPR18 receptor has been demonstrated to be a potential therapeutic target against ALI. Extracting Naringin dihydrochalcone (NDC) from the life-sustaining orange peel is known for its diverse anti-inflammatory properties, yet the specific action target remains uncertain. In the present study, we identified NDC as a potential agonist of the GPR18 receptor using virtual screening and investigated the pharmacological effects of NDC on sepsis-induced acute lung injury in rats and explored underlying mechanisms. In in vivo experiments, CLP-induced ALI model was established by cecum puncture and treated with NDC gavage one hour prior to drug administration, lung histopathology and inflammatory cytokines were evaluated, and feces were subjected to 16s rRNA sequencing and untargeted metabolomics analysis. In in vitro experiments, the anti-inflammatory properties were exerted by evaluating NDC targeting the GPR18 receptor to inhibit lipopolysaccharide (LPS)-induced secretion of TNF-α, IL-6, IL-1ß and activation of inflammatory signaling pathways in MH-S cells. Our findings showed that NDC significantly ameliorated lung damage and pro-inflammatory cytokine levels (TNF-α, IL-6, IL-1ß) in both cells and lung tissues via inhibiting the activation of STAT3, NF-κB, and NLRP3 inflammatory signaling pathways through GRP18 receptor activation. In addition, NDC can also partly reverse the imbalance of gut microbiota composition caused by CLP via increasing the proportion of Firmicutes/Bacteroidetes and Lactobacillus and decreasing the relative abundance of Proteobacteria. Meanwhile, the fecal metabolites in the NDC treatment group also significantly were changed, including decreased secretion of Phenylalanin, Glycine, and bile secretion, and increased secretion of Lysine. In conclusion, these findings suggest that NDC can alleviate sepsis-induced ALI via improving gut microbial homeostasis and metabolism and mitigate inflammation via activating GPR18 receptor. In conclusion, the results indicate that NDC, derived from the typical orange peel of food, could significantly contribute to development by enhancing intestinal microbial balance and metabolic processes, and reducing inflammation by activating the GPR18 receptor, thus mitigating sepsis-induced ALI and expanding the range of functional foods.
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Lesión Pulmonar Aguda , Antiinflamatorios , Chalconas , Citocinas , Microbioma Gastrointestinal , Receptores Acoplados a Proteínas G , Sepsis , Animales , Receptores Acoplados a Proteínas G/metabolismo , Microbioma Gastrointestinal/efectos de los fármacos , Lesión Pulmonar Aguda/tratamiento farmacológico , Lesión Pulmonar Aguda/patología , Lesión Pulmonar Aguda/etiología , Lesión Pulmonar Aguda/microbiología , Lesión Pulmonar Aguda/metabolismo , Masculino , Sepsis/tratamiento farmacológico , Sepsis/complicaciones , Citocinas/metabolismo , Ratas , Chalconas/farmacología , Chalconas/uso terapéutico , Antiinflamatorios/uso terapéutico , Antiinflamatorios/farmacología , Ratas Sprague-Dawley , Homeostasis/efectos de los fármacos , Línea Celular , Pulmón/patología , Pulmón/efectos de los fármacos , Modelos Animales de Enfermedad , Lipopolisacáridos , Humanos , FlavanonasRESUMEN
ABSTRACT: Excessively activated or dysregulated complement activation may contribute to the pathogenesis of a wide range of human diseases, thus leading to a surge in complement inhibitors. Herein, we developed a human-derived and antibody-like C3b-targeted fusion protein (CRIg-FH-Fc) x2, termed CG001, that could potently block all 3 complement pathways. Complement receptor of the immunoglobulin superfamily (CRIg) and factor H (FH) bind to distinct sites in C3b and synergistically inhibit complement activation. CRIg occupancy in C3b prevents the recruitment of C3 and C5 substrates, whereas FH occupancy in C3b accelerates the decay of C3/C5 convertases and promotes the factor I-mediated degradation and inactivation of C3b. CG001 also showed therapeutic effects in alternative pathways-induced hemolytic mouse and classical pathways-induced mesangial proliferative glomerulonephritis rat models. In the pharmacological/toxicological evaluation in rats and cynomolgus monkeys, CG001 displayed an antibody-like pharmacokinetic profile, a convincing complement inhibitory effect, and no observable toxic effects. Therefore, CG001 holds substantial potential for human clinical studies.
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Complemento C3b , Animales , Humanos , Ratas , Ratones , Complemento C3b/metabolismo , Inactivadores del Complemento/farmacología , Inactivadores del Complemento/uso terapéutico , Macaca fascicularis , Activación de Complemento/efectos de los fármacos , Proteínas Recombinantes de Fusión/farmacología , Proteínas Recombinantes de Fusión/uso terapéutico , Factor H de Complemento/metabolismo , Modelos Animales de Enfermedad , Evaluación Preclínica de MedicamentosRESUMEN
Echinococcosis poses a significant concern in the fields of public health and veterinary care as it can be transmitted between animals and humans. The primary endemic subtypes are cystic echinococcosis (CE) and alveolar echinococcosis (AE), which result from infestation by Echinococcus granulosus and Echinococcus multilocularis, respectively. A prominent epidemic of echinococcosis greatly affects the Tibet Autonomous Region (TAR) in China. A new technique called the loop-mediated isothermal amplification-lateral flow dipstick (LAMP-LFD) test is introduced in this research to differentiate between E. granulosus and E. multilocularis using their repetitive genetic sequences. The test is characterized by its portable nature, simple operation, quick result production, high sensitivity, and low susceptibility to aerosol contamination. The LAMP-LFD method demonstrated an exceptional minimal detection limit, reaching levels as low as approximately 1 fg/µL (femtogram per microliter) of genomic DNA. The assay's specificity was assessed, and no cross-reactivity was seen. A total of 982 dog fecal samples were collected from 54 counties in the TAR region between July 2021 and June 2022. The established method underwent validation using a commercially available ELISA kit. The agreement rate between the LAMP-LFD and ELISA methods was 97.25%, with a sensitivity of 96.05% and a specificity of 97.35%. The assay described in this study improves specificity by using a double-labeled probe, and it reduces the risk of false-positive results caused by aerosol contamination through the use of a sealed device. This makes it a suitable choice for quickly and accurately identifying the two main types of Echinococcus in field settings.
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Behavioral and clinical studies have revealed a critical role of substance P (SP) in aggression; however, the neural circuit mechanisms underlying SP and aggression remain elusive. Here, we show that tachykinin-expressing neurons in the medial amygdala (MeATac1 neurons) are activated during aggressive behaviors in male mice. We identified MeATac1 neurons as a key mediator of aggression and found that MeATac1âventrolateral part of the ventromedial hypothalamic nucleus (VMHvl) projections are critical to the regulation of aggression. Moreover, SP/neurokinin-1 receptor (NK-1R) signaling in the VMHvl modulates aggressive behaviors in male mice. SP/NK-1R signaling regulates aggression by influencing glutamate transmission in neurons in the VMHvl. In summary, these findings place SP as a key node in aggression circuits.
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Catenin alpha 1 (CTNNA1), encoding α-catenin, is involved in several physiological activities, such as adherens junction synthesis and signal transduction. Recent studies have suggested additional functions for CTNNA1 malignancies. This review systematically summarizes the varying functions of CTNNA1 in different tumors and briefly describes the diverse pathways and mechanisms involved in different types of tumors. CTNNA1 is abnormally expressed in leukemia and solid tumor such as cancers of digestive system, genitourinary system and breast, and it's related to the occurrence, development, and prognosis of tumors. In addition, the possible physiological processes involving CTNNA1, such as methylation, miRNA interference, or regulatory axes, similar to those of CDH1, SETD2, and hsa-miR-30d-5p/GJA1 are also summarized here. The precise mechanism of CTNNA1 in most cancers remains uncertain; hence, additional pre-clinical studies of CTNNA1 are warranted for potential early tumor diagnosis, prognosis, and treatment.
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BACKGROUND: Artesunate (ART) has been reported to have an antifibrotic effect in various organs. The underlying mechanism has not been systematically elucidated. We aimed to clarify the effect of ART on liver fibrosis induced by Schistosoma japonicum (S. japonicum) in an experimentally infected rodent model and the potential underlying mechanisms. METHODS: The effect of ART on hepatic stellate cells (HSCs) was assessed using CCK-8 and Annexin V-FITC/PI staining assays. The experimental model of liver fibrosis was established in the Mongolian gerbil model infected with S. japonicum cercariae and then treated with 20 mg/kg or 40 mg/kg ART. The hydroxyproline (Hyp) content, malondialdehyde (MDA) content, superoxide dismutase (SOD) and glutathione peroxidase (GPX) activities in liver tissue were measured and histopathological changes of liver tissues were observed. Whole-transcriptome RNA sequencing (RNA-seq) of the liver tissues was performed. Differentially expressed genes (DEGs) were identified using bioinformatic analysis and verified by quantitative PCR (qPCR) and western blot assay. RESULTS: ART significantly inhibited the proliferation and induce the apoptosis of HSCs in a dose-dependent manner. In vivo, Hyp content decreased significantly in the ART-H group compared to the model (MOD) group and GPX activity was significantly higher in the ART-H group than in the MOD group. Besides, ART treatment significantly reduced collagen production (p <0.05). A total of 158 DEGs and 44 differentially expressed miRNAs related to ART-induced anti-schistosomiasis liver fibrosis were identified. The qPCR and western blot results of selected DEGs were consistent with the sequencing results. These DEGs were implicated in key pathways such as immune and inflammatory response, integrin-mediated signaling and toll-like receptor signaling pathways. CONCLUSION: ART is effective against liver fibrosis using Mongolian gerbil model induced by S. japonicum infection. We identified host candidate regulators of schistosomiasis-induced liver fibrosis in response to ART through transcriptomics approach.
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In addition to the classical role as a serum effector system of innate immunity, accumulating evidence suggests that intracellular complement components have indispensable functions in immune defense, T cell homeostasis, and tumor cell proliferation and metastasis. Here, we revealed that complement component 3 (C3) is remarkably upregulated in paclitaxel (PTX)-resistant non-small cell lung cancer (NSCLC) cells and that knockdown of C3 promoted PTX-induced cell apoptosis, sensitizing resistant cells to PTX therapy. Ectopic C3 decreased PTX-induced apoptosis and induced resistance to PTX treatment in original NSCLC cells. Interestingly, C3b, the activated fragment of C3, was found to translocate into the nucleus and physically associate with the HDAC1/2-containing SIN3A complex to repress the expression of GADD45A, which plays an important role in cell growth inhibition and apoptosis induction. Importantly, C3 downregulated GADD45A by enhancing the binding of the SIN3A complex with the promoter of GADD45A, thus decreasing the H3Ac level to compress chromatin around the GADD45A locus. Subsequently, ectopic GADD45A promoted PTX-induced cell apoptosis, sensitizing resistant cells to PTX therapy, and insufficiency of GADD45A in original cancer cells induced resistance to PTX treatment. These findings identify a previously unknown nucleus location and oncogenic property for C3 in chemotherapy and provide a potential therapeutic opportunity to overcome PTX resistance.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Paclitaxel , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Complemento C3b , Resistencia a Antineoplásicos , Proliferación Celular , Apoptosis , Línea Celular Tumoral , Histona Desacetilasa 1/genéticaRESUMEN
Sufficient evidence has linked many different types of cancers and T2D through shared risk factors; however, the underlying mechanisms are not fully understood. α-Hydroxybutyrate (α-HB), a byproduct metabolite increased in diabetes and cancer, including colorectal cancer (CRC), triggers lactate dehydrogenase A (LDHA) nuclear translocation. Nuclear LDHA markedly extends NF-κB nuclear retention by interacting with phosphorylated p65, leading to an increase in TNF-α production, impaired insulin secretion and the exacerbation of azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced CRC and high-fat diet (HFD)-induced type 2 diabetes. Furthermore, metformin interrupted this process by inhibiting the transcription of FOXM1 and c-MYC, the resultant downregulation of LDHA expression and α-HB-induced LDHA nuclear translocation. Thus, the results reveal the elevated α-HB level could be a novel shared risk factor of linking CRC, diabetes and the use of metformin treatment, as well as highlight the importance of preventing NF-κB activation for protecting against cancer and diabetes.
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Neoplasias Colorrectales , Diabetes Mellitus Tipo 2 , Humanos , FN-kappa B/metabolismo , Diabetes Mellitus Tipo 2/complicaciones , Neoplasias Colorrectales/metabolismo , Transducción de SeñalRESUMEN
Apolipoprotein M (ApoM) is considered a protective factor that inhibits the occurrence and development of liver cancer, but the specific underlying mechanisms require further investigation. Previous studies have demonstrated that ApoM gene knockout promotes the expression of the transcription factor sterol regulatory element-binding protein 1 (SREBP1; also known as SREBF1) in the livers of mice. SREBF1 is closely associated with factors involved in fatty acid synthesis and has a role in the promotion of tumor progression. The present study initially confirmed that the expression levels of ApoM in cancer tissues were significantly decreased compared with those in normal tissue, while the expression levels of SREBF1 were significantly increased. In addition, ApoM gene knockout significantly increased the expression levels of SREBF1 and the key glycolytic enzyme ATP-dependent 6-phosphofructokinase, liver type (PFKL). Binding site prediction and a dual-luciferase reporter gene assay indicated that SREBF1 regulates the promoter region of PFKL. To the best of our knowledge, the present study was the first to propose the regulation of glycolytic enzyme transcription levels by SREBF1. Furthermore, cell proliferation and Transwell assays demonstrated that ApoM gene knockout increased the expression levels of SREBF1 and further enhanced the activity of the promoter region of PFKL, ultimately promoting the proliferation, migration and invasion of liver cancer cells.
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The ever-increasing morbidity associated with gynecological malignancies constantly endangers the physical and psychological health of women. Since a long time, there has been an urgent need for a deeper understanding of the tumorigenesis and the development of gynecological cancer to identify new molecular markers for early diagnosis and metastatic disease prognosis and for the development of therapeutic targets. MicroRNAs are crucial cellular regulators. The microRNA-10 (miR-10) family has been found to play an integral role in the evolution of numerous cancer types. A comprehensive understanding of current studies on miR-10 could provide better insights into future research and clinical applications in related fields. This article reviews the latest research on the role of the miR-10 family in gynecological malignancies and the relevant molecular mechanism, mainly focusing on endometrial, cervical, and ovarian cancers.
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BACKGROUND: RE1-silencing transcription factor (REST) is known to silence target genes involved in synaptic plasticity and neuronal differentiation. Although previous studies implicate REST in neurodegenerative diseases, its function in the progression of Alzheimer's disease (AD) is uncertain. OBJECTIVE: The aim of the present work was to explore the mechanisms of AD and determine whether and how REST was involved in the pathogenesis of AD. METHODS: We investigated the differentially expressed genes and key transcription factors in AD using bioinformatics analysis. In addition, we assessed the expression of REST under the influence of AD-related factors. Mice overexpressing REST were generated and analyzed by proteomics analysis. We used transmission electron microscopy, Golgi-cox staining, immunohistochemistry, and western blotting to examine the impact of REST on neurons. RESULTS: The results of bioinformatics analysis revealed REST as a hub transcriptional regulator in AD. We demonstrate that the mRNA expression of REST was significantly upregulated compared with that in the control groups, not only in AD patients but also in APP/PS1 transgenic mice, lipopolysaccharide-induced neuroinflammatory mice, and oxidative and glutamate stressed neurons. Using proteomics analysis, we showed that the upregulation of REST increased the expression of genes involved in apoptotic and mitochondrial pathways. Long-term overexpression of REST significantly reduced the number of dendritic spines and increased the mitochondrial defect and apoptosis. Reduction of the cofilin phosphorylation may be one of its mechanisms, and cofilin activity could be affected through the P38 MAPK/CREB signaling pathway. CONCLUSION: These results demonstrated the possible mechanism underlying AD and indicated REST as a potential therapeutic target for AD.
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Factores Despolimerizantes de la Actina , Enfermedad de Alzheimer , Proteínas Represoras , Factores Despolimerizantes de la Actina/metabolismo , Enfermedad de Alzheimer/patología , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animales , Modelos Animales de Enfermedad , Humanos , Ratones , Ratones Transgénicos , Neuronas/metabolismo , Fosforilación , Proteínas Represoras/genéticaRESUMEN
Bromate, a possible human carcinogen, can be reduced to innocuous bromide by microorganisms. To characterize bromate reducers, microbes were enriched anaerobically from activated sludge by using bromate as the sole electron acceptor and different carbon sources as the electron donor. Bacteria that showed significant bromate-reducing activity but not coupled to cell growth were isolated. Two whole genomes of the isolates, namely, Raoultella electrica Lac1 and Klebsiella variicola Glu3, were reconstructed by Illumina and Nanopore sequencing. Transcriptomic analysis suggested that neither the respiratory nitrate reductase, the selenate reductase, nor the dimethylsulfoxide reductase was involved in the bromate reduction process, and strain K. variicola Glu3 reduced bromate via a yet undiscovered enzymatic mechanism. The results provide novel phylogenetic insights into bromate-reducing microorganisms and clues in putative genes encoding enzymes related to bromate reduction.
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Sea urchin nowadays serves as a delicacy around the world, and its gonads accumulate abundant polysaccharides before gametogenesis. However, the structure and bioactivity of these polysaccharides remain less well understood. Herein, a water soluble polysaccharide (HPP-1S) with a molecular weight of 2.996 × 107 Da was purified from the gonads of Hemicentrotus pulcherrimus. Chemical, spectroscopic and oligosaccharide sequencing analyses revealed that HPP-1S was a highly homogeneous polysaccharide featuring a linear backbone of 1,4-linked α-d-glucose with 1,6-α-d-glucose and 1,6-α-D-glucuronic acid side chains grafted on the backbone in an alternating pattern. In vitro, HPP-1S can arrest the cell cycle at G2/M and sub-G1 phases, and induce apoptosis in Hela cells potentially by increasing expression ratio of Bax/Bcl-2. In vivo, HPP-1S exhibited obvious antitumor efficacy in Hela xenograft-bearing nude mice with low toxicity. These findings indicated that HPP-1S might serve as a potential low toxic antitumor agent.