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1.
BMC Nephrol ; 25(1): 298, 2024 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-39256647

RESUMO

BACKGROUND: Lipid droplets (LD) in renal clear cell carcinoma (ccRCC)play a crucial role in lipid metabolism and immune response modulation. The purpose of this study was to create a LD-related signature to predict prognosis and guide the immunotherapy and targeted therapy in ccRCC patients. METHODS: We conducted a comprehensive analysis using transcriptional profiles and clinical data obtained from The Cancer Genome Atlas (TCGA). LD-related genes were identified from existing literature and the GeneCards database, and differentially expressed genes were determined. Sequentially, we conducted Cox regression analysis and Lasso regression analysis, to establish a prognostic risk model. The performance of the risk model was evaluated using Kaplan-Meier (KM) analysis and time-dependent receiver operating characteristic (ROC) analysis. Additionally, gene set enrichment analysis (GSEA), ESTIMATE, CIBERSORT, and immunophenoscore (IPS) algorithm were used to assess the tumor microenvironment (TME) and treatment response. RESULTS: We constructed a risk signature with four LD-related genes in the TCGA dataset, which could be an independent prognostic factor in ccRCC patients. Then, patients were classified into two risk groups and exhibited notable differences in overall survival (OS), progression-free survival (PFS), and TME characteristics. Furthermore, we developed a comprehensive nomogram based on clinical features, which demonstrated good prognostic predictive value. According to the results of GSEA analysis, immune-related pathways were found to be significantly enriched in the high-risk group. Additionally, the high-risk group displayed high levels of immune cell infiltration, TMB and IPS scores, indicating better efficacy of immune checkpoint inhibitors (ICIs). Finally, high-risk demonstrated reduced IC50 values compared to the low-risk counterpart for specific targeted and chemotherapeutic drugs, suggesting that the patients receiving these targeted drugs in high-risk group had better treatment outcomes. CONCLUSIONS: Our findings suggested that the LD-related gene signature could potentially predict the prognosis of ccRCC patients. Additionally, it showed promise for predicting responses to immunotherapy and targeted therapy in ccRCC patients. These insights might potentially have guided the clinical management of these patients, but further validation and broader data analysis are needed to confirm these preliminary observations.


Assuntos
Carcinoma de Células Renais , Imunoterapia , Neoplasias Renais , Humanos , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/imunologia , Carcinoma de Células Renais/terapia , Neoplasias Renais/genética , Neoplasias Renais/terapia , Prognóstico , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia , Feminino , Masculino , Pessoa de Meia-Idade , Transcriptoma , Nomogramas
3.
PLoS One ; 19(8): e0308980, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39146317

RESUMO

BACKGROUND: Nocturia, a prevalent chronic condition, impacts individuals' quality of life but remains underexplored. This study aimed to assess the association between serum albumin levels and nocturia. METHODS: Based on the analysis of the National Health and Nutrition Examination Survey (NHANES) database (2005-2012), our study included a total of 6345 adults (≥20 years old). Nocturia was defined as ≥2 nocturnal voiding episodes. Logistic regression and smooth curve fitting analyzed the linear and nonlinear correlations between serum albumin and nocturia, with subgroup analysis. RESULTS: Among 6345 participants, 1821 (28.7%) experienced nocturia. Logistic regression analysis revealed a linear negative correlation between serum albumin and nocturia risk (OR = 0.9549, 95% CI = 0.9280 ~ 0.9827, P = 0.002). Even after quartile division of serum albumin concentration, this correlation persisted within each group, and a smooth curve fitting validated the nonlinear negative correlation between the two. Subgroup analysis further demonstrated significant impacts of body mass index (BMI), alcohol consumption, and age on this association. CONCLUSION: This cross-sectional study indicated that higher serum albumin levels were associated with a reduced risk of nocturia in U.S. adults aged 20 and older, highlighting the importance of serum albumin in the prevention and treatment of nocturia and providing clinical guidance.


Assuntos
Noctúria , Inquéritos Nutricionais , Humanos , Noctúria/epidemiologia , Noctúria/sangue , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Estados Unidos/epidemiologia , Estudos Transversais , Idoso , Albumina Sérica/análise , Adulto Jovem , Índice de Massa Corporal , Fatores de Risco
4.
Commun Biol ; 7(1): 936, 2024 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-39095441

RESUMO

The repair of DNA double-strand breaks (DSBs) through alternative non-homologous end-joining (alt-NHEJ) pathway significantly contributes to genetic instability. However, the mechanism governing alt-NHEJ pathway choice, particularly its association with DSB complexity, remains elusive due to the absence of a suitable reporter system. In this study, we established a unique Escherichia coli reporter system for detecting complex DSB-initiated alternative end-joining (A-EJ), an alt-NHEJ-like pathway. By utilizing various types of ionizing radiation to generate DSBs with varying degrees of complexity, we discovered that high complexity of DSBs might be a determinant for A-EJ choice. To facilitate efficient repair of high-complexity DSBs, A-EJ employs distinct molecular patterns such as longer micro-homologous junctions and non-templated nucleotide addition. Furthermore, the A-EJ choice is modulated by the degree of homology near DSB loci, competing with homologous recombination machinery. These findings further enhance the understanding of A-EJ/alt-NHEJ pathway choice.


Assuntos
Quebras de DNA de Cadeia Dupla , Reparo do DNA por Junção de Extremidades , Escherichia coli , Escherichia coli/genética , Escherichia coli/metabolismo , Recombinação Homóloga
5.
J Prosthet Dent ; 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38955600

RESUMO

STATEMENT OF PROBLEM: Three-dimensional (3D) printing has had extensive applications across dentistry, but a comprehensive bibliometric analysis relating to the application of 3D printing in dentistry is lacking. PURPOSE: The purpose of this study was to conduct a comprehensive bibliometric analysis of the scientific literature concerning the application of 3D printing in dentistry from 2012 to 2023. MATERIAL AND METHODS: The literature search was conducted in the Web of Science Core Collection Database. The retrieved literature data were downloaded as plain text file in "full record and cited references" format, with software programs (VOSviewer, CiteSpace, Biblioshiny, RStudio, Carrot2, and Microsoft Excel) used for bibliometric analysis and quantitative assessment. RESULTS: The bibliometric analysis incorporated 1911 publications. Revilla-León, Marta was the most productive author. Zurich University had the highest number of publications and citations. The United States dominated the research landscape with the highest publication volume and H-index. The Journal of Prosthetic Dentistry was the leading journal in both publication volume and citation frequency. Co-occurrence analysis of keyword and co-cited analysis of reference indicated a robust research environment, characterized by a strong focus on the pursuit of accuracy in dental restorative solutions, biocompatibility of materials, and clinical applications. CONCLUSIONS: Research on 3D printing in the field of dentistry continues to grow. Collaborations with leading organizations and countries have been established, with Revilla-León, Marta et al playing a pivotal role. Top journals represented included the Journal of Prosthetic Dentistry and Dental Materials. Main research domain resided in prosthodontics and implantology. Hot research topics included improvements in accuracy, dental materials, and clinical applications centered on implant guide design.

6.
Bioresour Technol ; 406: 130965, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38876280

RESUMO

Microalgae's superior ability to fix carbon dioxide into biomass and high-value bioproducts remains underutilized in biotechnological applications due to a lack of comprehensive understanding of their carbon metabolism and energy conversion. In this work, the strain improvement technique heavy-ion beams (HIB) mutagenesis was employed on the environmentally adaptable microalgae Scenedesmus quadricauda. After several rounds of screening, two contrasting mutants were identified. S-#4 showed low photosynthetic activity and biomass productivity, while S-#26 exhibited adaptability to prolonged high light stress, achieving a 28.34 % increase in biomass yield compared to the wild-type strain. Integrating their photosynthetic characteristics and comparative proteomic analysis revealed that the contrasting protein regulations from central carbon metabolism mainly affects the two mutants' opposite biomass accumulation. Therefore, the divergent regulation of the tricarboxylic acid cycle following HIB mutagenesis could be potential targets for engineering microalgae with superior biomass and high-value products.


Assuntos
Biomassa , Carbono , Metabolismo Energético , Íons Pesados , Mutação , Fotossíntese , Proteômica , Scenedesmus , Scenedesmus/metabolismo , Carbono/metabolismo , Proteômica/métodos , Mutação/genética , Mutagênese
7.
PLoS One ; 19(5): e0303927, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38768158

RESUMO

BACKGROUND: Nocturia, the most common lower urinary tract symptom (LUTS), significantly impacts socioeconomic factors and individuals' quality of life and is closely related to many diseases. This study utilized data from NHANES 2005-2010 to explore the relationship between family income to poverty ratio (PIR) and the presence of nocturia symptoms in adults aged 20 or older in the United States. METHODS: Data from the National Health and Nutrition Examination Survey (NHANES) in 2005-2010, including 6,662 adults aged 20 or older, were utilized for this cross-sectional study. The baseline data was used to display the distribution of each characteristic visually. Multiple linear regression and smooth curve fitting were used to study the linear and non-linear correlations between PIR and nocturia. Subgroup analysis and interaction tests were conducted to examine the stability of intergroup relationships. RESULTS: Out of the 6,662 adult participants aged 20 or older, 1,300 households were categorized as living in poverty, 3,671 households had a moderate income, and 1,691 households were classified as affluent. Among these participants, 3,139 individuals experienced nocturia, representing 47.12% of the total, while 3,523 individuals were nocturia-free, constituting 52.88% of the total population. After adjusting for all other covariates, it was found that PIR was significantly negatively correlated with nocturia (OR: 0.875, 95%CI: 0.836-0.916 P<0.0001). This trend persisted when PIR was divided into three groups (PIR <1, PIR 1-4, PIR > 4) or quartiles. There was a non-linear negative correlation between PIR and nocturia. CONCLUSION: Our findings indicated that lower PlR was associated with a higher risk of nocturia in adults aged 20 or older in the United States. These findings highlight the importance of considering socioeconomic factors in preventing and managing nocturia. Nonetheless, further exploration of the causal nexus between these factors was precluded due to the constraints of a cross-sectional design.


Assuntos
Renda , Noctúria , Inquéritos Nutricionais , Pobreza , Humanos , Adulto , Noctúria/epidemiologia , Masculino , Feminino , Pessoa de Meia-Idade , Renda/estatística & dados numéricos , Estudos Transversais , Estados Unidos/epidemiologia , Idoso , Adulto Jovem
8.
Sci Rep ; 14(1): 9533, 2024 04 25.
Artigo em Inglês | MEDLINE | ID: mdl-38664460

RESUMO

Clear cell renal cell carcinoma (ccRCC) represents a highly frequent renal cancer subtype. However, medium-chain acyl-CoA dehydrogenase (ACADM) encodes an important enzyme responsible for fatty acid ß-oxidation (FAO) and its association with prognosis and immunity in cancers has rarely been reported. Therefore, the present work focused on exploring ACADM's expression and role among ccRCC cases. We used multiple public databases and showed the hypo levels of ACADM protein and mRNA within ccRCC. Additionally, we found that ACADM down-regulation showed a remarkable relation to the advanced stage, high histological grade, as well as dismal prognostic outcome. As suggested by Kaplan-Meier curve analysis, cases showing low ACADM levels displayed shorter overall survival (OS) as well as disease-free survival (DFS). Moreover, according to univariate/multivariate Cox regression, ACADM-mRNA independently predicted the prognosis of ccRCC. In addition, this work conducted immunohistochemistry for validating ACADM protein expression and its prognostic role in ccRCC samples. KEGG and GO analyses revealed significantly enriched genes related to ACADM expression during fatty acid metabolism. The low-ACADM group with more regulatory T-cell infiltration showed higher expression of immune negative regulation genes and higher TIDE scores, which might contribute to poor response to immunotherapies. In conclusion, our results confirmed that downregulated ACADM predicted a poor prognosis for ccRCC and a poor response to immunotherapy. Our results provide important data for developing immunotherapy for ccRCC.


Assuntos
Carcinoma de Células Renais , Regulação Neoplásica da Expressão Gênica , Neoplasias Renais , Microambiente Tumoral , Humanos , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/patologia , Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/mortalidade , Microambiente Tumoral/imunologia , Microambiente Tumoral/genética , Neoplasias Renais/genética , Neoplasias Renais/patologia , Neoplasias Renais/metabolismo , Neoplasias Renais/mortalidade , Prognóstico , Feminino , Masculino , Pessoa de Meia-Idade , Biomarcadores Tumorais/metabolismo , Biomarcadores Tumorais/genética , Idoso , Acil-CoA Desidrogenase/genética , Acil-CoA Desidrogenase/metabolismo , Estimativa de Kaplan-Meier
9.
J Prosthet Dent ; 131(5): 904.e1-904.e10, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38472073

RESUMO

STATEMENT OF PROBLEM: Implant placement in the mandibular molar sites plays a crucial role in the restoration of edentulous mandibles. However, the evaluation of bone quantity before implant surgery using cone beam computed tomography (CBCT) is lacking. PURPOSE: The purpose of this clinical study was to evaluate CBCT images of edentulous patients to analyze the feasibility of implant placement in healed mandibular molar sites. MATERIAL AND METHODS: The CBCT data of 138 patients were analyzed in the sagittal plane for measurements of mandibular bone height (MBH), superior bone height (SBH), inferior bone height (IBH), buccal bone width (BBW), lingual bone width (LBW), and alveolar bone widths (ABWs). The edentulous sites were categorized according to the bone quantity and complexity of the implant surgery. Multivariate analysis of variance (MANOVA) was used to analyze the site, sex, and age-related variations. An independent t test was used to compare the difference of bone dimension in different sites and between sexes. One-way ANOVA followed by post hoc tests were used to analyze the difference between different age groups. Categorical variables were presented as number of events and percentages. The chi-squared test was used to compare categorical variables (α=.05). RESULTS: A total of 534 sites of interest were recorded, including 274 hemimandibles. A significant difference in BBW was found between the first and second molar sites. Men had higher MBH, SBH, IBH, and BBW than women. The distribution of implant surgical complexity in the conventional group was 63.5%, while the buccolingual tilted implant group accounted for 17.0%, and the complicated group accounted for 19.5%. Of the 274 hemimandibles, an implant could be placed directly at molar sites in 88% of situations. CONCLUSIONS: The BBW at the mandibular second molar site was greater than that at the first molar site. The amount of available bone in the SBH and BBW was greater in men than in women at the healed molar sites. Age did not significantly affect the complexity of the implant surgery. Implants can be placed directly in healed mandibular molar sites in most patients who require a complete arch mandibular implant-supported restoration.


Assuntos
Tomografia Computadorizada de Feixe Cônico , Implantação Dentária Endóssea , Estudos de Viabilidade , Mandíbula , Dente Molar , Humanos , Tomografia Computadorizada de Feixe Cônico/métodos , Masculino , Feminino , Mandíbula/diagnóstico por imagem , Mandíbula/cirurgia , Estudos Retrospectivos , Dente Molar/diagnóstico por imagem , Pessoa de Meia-Idade , Adulto , Idoso , Implantação Dentária Endóssea/métodos , Arcada Edêntula/diagnóstico por imagem , Arcada Edêntula/cirurgia , Implantes Dentários
10.
J Craniofac Surg ; 35(1): e58-e60, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-37955447

RESUMO

Bone defect caused by jaw cystectomy has always been the main factor affecting postoperative wound healing and is also the common cause of maxillofacial bone defect, which brings challenges to the subsequent restoration of missing teeth. In this paper, the authors report a 22-year-old young woman who had a mandibular cyst in the left lower posterior tooth area. She underwent mandibular bone cyst excision and simultaneous extraction of teeth 36 and 37. One and two months after the removal of the mandibular bone cyst, autologous tooth transplantation was performed in stages from tooth 28 to tooth 36 and from tooth 18 to tooth 37. The case shows that tooth autotransplantation is a viable option for the restoration of dentition defects after the excision of jaw cysts, which can promote the healing of the bone defect after the operation.


Assuntos
Cistos Ósseos , Cistos Maxilomandibulares , Feminino , Humanos , Adulto Jovem , Adulto , Dentição , Transplante Autólogo , Cistos Maxilomandibulares/diagnóstico por imagem , Cistos Maxilomandibulares/cirurgia , Dente Pré-Molar
11.
Phys Med Biol ; 69(2)2024 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-38064745

RESUMO

The FLASH effect of carbon ion therapy has recently attracted significant attention from the scientific community. However, the radiobiological mechanism of the effect and the exact therapeutic conditions are still under investigation. Therefore, the dosimetry accuracy is critical for testing hypotheses about the effect and quantifying FLASH Radiotherapy. In this paper, the FLASH ionization chamber at low-pressure was designed, and its dose rate dependence was verified with the Faraday cup. In addition, the dose response was tested under the air pressure of the ionization chamber of 10 mbar, 80 mbar and 845 mbar, respectively. The results showed that when the pressure was 10 mbar, the dose linearity was verified and calibrated at the dose rate of ∼50 Gy s-1, and the residuals were less than 2%. In conclusion, the FLASH ionization chamber is a promising instrument for online dose monitoring.


Assuntos
Radioterapia com Íons Pesados , Radiometria , Dosagem Radioterapêutica , Radiometria/métodos
12.
Mol Cell Endocrinol ; 582: 112143, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38158148

RESUMO

Elevated circulating level of branched-chain amino acids (BCAAs) is closely related to the development of type 2 diabetes. However, the role of BCAA catabolism in various tissues in maintaining glucose homeostasis remains largely unknown. Pancreatic α-cells have been regarded as amino acid sensors in recent years. Therefore, we generated α-cell specific branched-chain alpha-ketoacid dehydrogenase E1α subunit (BCKDHA) knockout (BCKDHA-αKO) mice to decipher the effects of BCAA catabolism in α-cells on whole-body energy metabolism. BCKDHA-αKO mice showed normal body weight, body fat, and energy expenditure. Plasma glucagon level and glucose metabolism also remained unchanged in BCKDHA-αKO mice. Whereas, the deletion of BCKDHA led to increased α-cell number due to elevated cell proliferation in neonatal mice. In vitro, only leucine among BCAAs promoted aTC1-6 cell proliferation, which was blocked by the agonist of BCAA catabolism BT2 and the inhibitor of mTOR Rapamycin. Like Rapamycin, BT2 attenuated leucine-stimulated phosphorylation of S6 in αTC1-6 cells. Elevated phosphorylation level of S6 protein in pancreatic α-cells was also observed in BCKDHA-αKO mice. These results suggest that local accumulated leucine due to defective BCAA catabolism promotes α-cell proliferation through mTOR signaling, which is insufficient to affect glucagon secretion and whole-body glucose homeostasis.


Assuntos
Diabetes Mellitus Tipo 2 , Camundongos , Animais , Leucina , Glucagon , Aminoácidos de Cadeia Ramificada/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Glucose , Proliferação de Células , Sirolimo
13.
BMC Microbiol ; 23(1): 353, 2023 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-37978430

RESUMO

BACKGROUND: The dinucleotide alarmone diadenosine tetraphosphate (Ap4A), which is found in cells, has been shown to affect the survival of bacteria under stress. RESULTS: Here, we labeled Ap4A with biotin and incubated the labeled Ap4A with the total proteins extracted from kanamycin-treated Escherichia coli to identify the Ap4A binding protein in bacteria treated with kanamycin. Liquid chromatography‒mass spectrometry (LCMS) and bioinformatics were used to identify novel proteins that Ap4A interacts with that are involved in biofilm formation, quorum sensing, and lipopolysaccharide biosynthesis pathways. Then, we used the apaH knockout strain of E. coli K12-MG1655, which had increased intracellular Ap4A, to demonstrate that Ap4A affected the expression of genes in these three pathways. We also found that the swarming motility of the apaH mutant strain was reduced compared with that of the wild-type strain, and under kanamycin treatment, the biofilm formation of the mutant strain decreased. CONCLUSIONS: These results showed that Ap4A can reduce the survival rate of bacteria treated with kanamycin by regulating quorum sensing (QS). These effects can expand the application of kanamycin combinations in the treatment of multidrug-resistant bacteria.


Assuntos
Escherichia coli , Canamicina , Canamicina/farmacologia , Escherichia coli/genética , Escherichia coli/metabolismo , Percepção de Quorum
14.
J Mol Evol ; 91(6): 780-792, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-37924420

RESUMO

Hypoxia-inducible factor 1 (HIF-1) is a crucial transcriptional factor that can restore oxygen balance in the body by regulating multiple vital activities. Two HIF-1α copies were retained in cyprinid fish after experiencing a teleost-specific genome duplication. How the "divergent collaboration" of HIF-1αA and HIF-1αB proceeds in regulating mitophagy and apoptosis under hypoxic stress in cells of cyprinid fish remains unclear. In this study, zebrafish HIF-1αA/B expression plasmids were constructed and transfected into the epithelioma papulosum cyprini cells and were subjected to hypoxic stress. HIF-1αA induced apoptosis through promoting ROS generation and mitochondrial depolarization when cells were subjected to oxygen deficiency. Conversely, HIF-1αB was primarily responsible for mitophagy induction, prompting ATP production to mitigate apoptosis. HIF-1αA did not induce mitophagy in the mitochondria and lysosomes co-localization assay but it was involved in the regulation of different mitophagy pathways. Over-expression of HIF-1αA increased the expression of bnip3, fundc1, Beclin1, and foxo3, suggesting it has a dual role in mitochondrial autophagy and cell death. Each duplicated copy also experienced functional divergence and target shifting in the regulation of complexes in the mitochondrial electron transport chain (ETC). Our findings shed light on the post-subfunctionalization function of HIF-1αA and HIF-1αB in zebrafish to fine-tune regulation of mitophagy and apoptosis following hypoxia exposure.


Assuntos
Cyprinidae , Peixe-Zebra , Animais , Peixe-Zebra/genética , Peixe-Zebra/metabolismo , Mitofagia/genética , Hipóxia/genética , Cyprinidae/genética , Apoptose/genética
15.
J Bone Miner Res ; 38(12): 1885-1899, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-37850815

RESUMO

CREB-binding protein (CBP) (CREBBP) and p300 (EP300) are multifunctional histone acetyltransferases (HATs) with extensive homology. Germline mutations of CBP or p300 cause skeletal abnormalities in humans and mice. However, the precise roles of CBP/p300 in bone homeostasis remain elusive. Here, we report that conditional knockout of CBP or p300 in osteoblasts results in reduced bone mass and strength due to suppressed bone formation. The HAT activity is further confirmed to be responsible for CBP/p300-mediated osteogenesis using A-485, a selective inhibitor of CBP/p300 HAT. Mechanistically, CBP/p300 HAT governs osteogenic gene expression in part through transcriptional activation of ß-catenin and inhibition of Stat1. Furthermore, acetylation of histone H3K27 and the transcription factor Foxo1 are demonstrated to be involved in CBP/p300 HAT-regulated ß-catenin and Stat1 transcription, respectively. Taken together, these data identify acetyltransferases CBP/p300 as critical regulators that promote osteoblast differentiation and reveal an epigenetic mechanism responsible for maintaining bone homeostasis. © 2023 American Society for Bone and Mineral Research (ASBMR).


Assuntos
Proteína de Ligação a CREB , Fatores de Transcrição de p300-CBP , Animais , Humanos , Camundongos , Acetilação , beta Catenina/metabolismo , Proteína de Ligação a CREB/genética , Proteína de Ligação a CREB/metabolismo , Histona Acetiltransferases/genética , Histona Acetiltransferases/metabolismo , Osteogênese/genética , Fatores de Transcrição de p300-CBP/genética , Fatores de Transcrição de p300-CBP/metabolismo , Fator de Transcrição STAT1/metabolismo
16.
J Med Chem ; 66(17): 12586-12601, 2023 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-37650525

RESUMO

Here, we present the discovery of a novel class of benzimidazole-based allosteric modulators of nicotinic acetylcholine receptors (nAChRs). The modulators were developed based on a compound (1) exhibiting positive modulatory activity at α4ß2 nAChR in a compound library screening by functional characterization of 100 analogues of 1 at nAChRs. Two distinct series of positive and negative allosteric modulators (PAMs and NAMs, respectively) comprising benzimidazole as a shared structural moiety emerged from this SAR study. The PAMs mediated weak modulation of α4ß2 and α6ß2ß3, whereas the NAMs exhibited essentially equipotent inhibition of α4ß2, α6ß2ß3, α6ß4ß3, and α3ß4 nAChRs, with analogue 9j [2-(2,4-dichlorophenoxy)-1,3-dimethyl-1-H-benzo[d]imidazole-3-ium] displaying high-nanomolar and low-micromolar IC50 values at the ß2- and ß4-containing receptor subtypes, respectively. We propose that the PAMs and NAMs act through overlapping sites in the nAChR, and these findings thus underline the heterogenous modes of modulation that can arise from a shared allosteric site in the receptor.


Assuntos
Benzimidazóis , Receptores Nicotínicos , Sítio Alostérico , Benzimidazóis/farmacologia , Membrana Celular
17.
J Med Chem ; 66(16): 11536-11554, 2023 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-37566000

RESUMO

The recombination of natural product (NP) fragments in unprecedented ways has emerged as an important strategy for bioactive compound discovery. In this context, we propose that privileged primary fragments predicted to be enriched in activity against a specific target class can be coupled to diverse secondary fragments to engineer selectivity among closely related targets. Here, we report the synthesis of an alkaloid-inspired compound library enriched in spirocyclic ring fusions, comprising 58 compounds from 12 tropane- or quinuclidine-containing scaffolds, all of which can be considered pseudo-NPs. The library displays excellent predicted drug-like properties including high Fsp3 content and Lipinski's rule-of-five compliance. Targeted screening against selected members of the serotonin and dopamine G protein-coupled receptor family led to the identification of several hits that displayed significant agonist or antagonist activity against 5-HT2A and/or 5-HT2C, and subsequent optimization of one of these delivered a lead dual 5-HT2B/C antagonist with a highly promising selectivity profile.


Assuntos
Alcaloides , Quinuclidinas , Serotonina , Alcaloides/farmacologia , Receptor 5-HT2A de Serotonina , Receptor 5-HT2C de Serotonina , Receptores de Serotonina , Agonistas do Receptor 5-HT2 de Serotonina/farmacologia , Antagonistas do Receptor 5-HT2 de Serotonina/farmacologia , Tropanos , Quinuclidinas/química , Quinuclidinas/farmacologia
18.
Brain Res ; 1819: 148545, 2023 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-37619853

RESUMO

OBJECTIVE: Glucose metabolism plays a crucial role in the progression of Alzheimer's disease (AD). The purpose of this study is to identify genes related to glucose metabolism in AD by bioinformatics, construct an early AD prediction model from the perspective of glucose metabolism, and analyze the characteristics of immune cell infiltration. METHODS: AD-related modules and genes were screened by weighted gene co-expression network analysis (WGCNA). The GO and KEEG enrichment analysis were used to explore the potential biological functions of glucose metabolism related genes (GMRGs) in AD. The Least Absolute Shrinkage Selection Operator (LASSO) method was used to construct an early AD prediction model based on GMRGs. Then, the receiver operating characteristic curve (ROC) and nomogram were introduced to evaluate the effectiveness of this model. Finally, CIBERSORT and single-cell analysis were applied for illustrating the immune characteristics in AD patients. RESULTS: A total of 462 differential expressed genes (DEGs) were obtained between Non-Alzheimer's disease (ND,) and AD groups. The genes in the blue module had the highest correlation with AD by WGCNA analysis. We found 18 intersected genes among DEGs, blue model genes and GMRGs according to the Venn diagram. The GO and KEEG enrichment analysis showed that these 18 genes were mainly involved in the production of metabolites and energy, glycolysis, amino acid biosynthesis and so on. The early AD prediction model including ENO2, TPI1, AEBP1, HERC1, PCSK1, PREPL, SLC25A4, UQCRC2, CHST6, DDIT4, ACSS1 and SUCLA2 was constructed by LASSO analysis. The area under the curve (AUC) of this model in brain tissues was 0.942. Then, we draw the nomogram of this model and the C-index was 0.942. The model was further validated in blood samples and the AUC was 0.644. Immune cell infiltration analysis showed that the proportion of plasma cells, T cells follicular helper and activated NK cells in AD group were significantly lower than ND group, while the proportion of M1 macrophages, neutrophils, T cells CD4 naive and γ-δ T cells was significantly increased when compared with the ND group. Additionally, the specific GMRGs such as ENO2, DDIT4, and SUCLA2 are significantly correlated with certain immune cells such as plasma cells, follicular helper T cells, and M1 macrophages. Single-cell analysis results suggested that the increased macrophages in AD was associated with the up-regulation of AEBP1, DDIT4 and ACSS1. CONCLUSIONS: The diagnosis model based on the twelve GMRGs has strong predictive ability and can be used as early diagnosis biomarkers for AD. In addition, these GMRGs closely associate with AD development by influencing the glucose metabolism of immune cells.


Assuntos
Doença de Alzheimer , Humanos , Doença de Alzheimer/genética , Metabolismo dos Carboidratos , Glicólise , Área Sob a Curva , Glucose , Carboxipeptidases , Proteínas Repressoras
19.
J Craniofac Surg ; 34(8): e810-e812, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37602478

RESUMO

Maxillofacial radiotherapy has a significant negative impact on oral health and impacted teeth often lead to diseases such as jaw cysts and periapical periodontitis. This article reports a case of jaw osteomyelitis (with both impacted teeth and periodontitis) occurring 10 years after radiotherapy for nasopharyngeal carcinoma. There is no systematic treatment plan for patients with both pathogenic factors in clinical practice, so it is important to develop a systematic and complete treatment plan before radiotherapy and chemotherapy. The periodontal treatment of patients receiving radiotherapy and the timing of extraction of impacted teeth are mainly discussed.


Assuntos
Cistos Maxilomandibulares , Osteomielite , Dente Impactado , Humanos , Cistos Maxilomandibulares/diagnóstico , Osteomielite/diagnóstico , Periodontite , Extração Dentária , Dente Impactado/radioterapia , Radioterapia/efeitos adversos
20.
Life Sci Space Res (Amst) ; 38: 87-100, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-37481313

RESUMO

The response of plants to radiation is an essential topic in both space plant cultivation and mutation breeding by radiation. In this study, heavy ion beams (HIB) generated by the ground accelerator and X-rays (XR) were used as models of high linear energy transfer (LET) and low LET radiation to study the molecular response mechanism of Platycodon grandiflorus (P. grandiflorus) seedlings after irradiation. The gene and protein expression profiles of P. grandiflorus after 15 Gy HIB and 20 Gy XR radiation were analyzed by transcriptome and proteome. The results showed that the number of differentially expressed genes (DEGs) induced by HIB radiation was less than that of XR group, but HIB radiation induced more differentially expressed proteins (DEPs). Both HIB and XR radiation activated genes of RNA silencing, double-strand break repair and cell catabolic process. DNA replication and cell cycle related genes were down-regulated. The genes of cell wall and external encapsulating structure were up-regulated after HIB radiation. The gene expression of protein folding and glucan biosynthesis increased after XR radiation. Protein enrichment analysis indicated that HIB radiation resulted in differential protein enriched in photosynthesis and secondary metabolite biosynthesis pathways, while XR radiation induced differential protein of glyoxylate and dicarboxylate metabolism and carbon metabolism. After HIB and XR radiation, the genes of antioxidant system and terpenoid and polyketide metabolic pathways presented different expression patterns. HIB radiation led to the enrichment of non-homologous end-joining pathway. The results will contribute to understanding the biological effects of plants under space radiation.


Assuntos
Íons Pesados , Platycodon , Raios X , Antioxidantes , Carbono
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