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1.
Int J Mol Sci ; 25(11)2024 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-38892474

RESUMO

Diabetic retinopathy (DR) is a very serious diabetes complication. Changes in the O-linked N-acetylglucosamine (O-GlcNAc) modification are associated with many diseases. However, its role in DR is not fully understood. In this research, we explored the effect of O-GlcNAc modification regulation by activating AMP-activated protein kinase (AMPK) in DR, providing some evidence for clinical DR treatment in the future. Bioinformatics was used to make predictions from the database, which were validated using the serum samples of diabetic patients. As an in vivo model, diabetic mice were induced using streptozotocin (STZ) injection with/without an AMPK agonist (metformin) or an AMPK inhibitor (compound C) treatment. Electroretinogram (ERG) and H&E staining were used to evaluate the retinal functional and morphological changes. In vitro, 661 w cells were exposed to high-glucose conditions, with or without metformin treatment. Apoptosis was evaluated using TUNEL staining. The protein expression was detected using Western blot and immunofluorescence staining. The angiogenesis ability was detected using a tube formation assay. The levels of O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA) in the serum changed in the DR patients in the clinic. In the diabetic mice, the ERG wave amplitude and retinal thickness decreased. In vitro, the apoptotic cell percentage and Bax expression were increased, and Bcl2 expression was decreased in the 661 w cells under high-glucose conditions. The O-GlcNAc modification was increased in DR. In addition, the expression of GFAT/TXNIP O-GlcNAc was also increased in the 661 w cells after the high-glucose treatment. Additionally, the Co-immunoprecipitation(CO-IP) results show that TXNIP interacted with the O-GlcNAc modification. However, AMPK activation ameliorated this effect. We also found that silencing the AMPKα1 subunit reversed this process. In addition, the conditioned medium of the 661 w cells may have affected the tube formation in vitro. Taken together, O-GlcNAc modification was increased in DR with photoreceptor cell degeneration and neovascularization; however, it was reversed after activating AMPK. The underlying mechanism is linked to the GFAT/TXNIP-O-GlcNAc modification signaling axis. Therefore, the AMPKα1 subunit plays a vital role in the process.


Assuntos
Proteínas Quinases Ativadas por AMP , Acetilglucosamina , Diabetes Mellitus Experimental , Retinopatia Diabética , N-Acetilglucosaminiltransferases , Retinopatia Diabética/metabolismo , Retinopatia Diabética/tratamento farmacológico , Retinopatia Diabética/patologia , Animais , Camundongos , Acetilglucosamina/metabolismo , N-Acetilglucosaminiltransferases/metabolismo , N-Acetilglucosaminiltransferases/antagonistas & inibidores , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/tratamento farmacológico , Humanos , Proteínas Quinases Ativadas por AMP/metabolismo , Masculino , Apoptose/efeitos dos fármacos , Metformina/farmacologia , beta-N-Acetil-Hexosaminidases/metabolismo , beta-N-Acetil-Hexosaminidases/antagonistas & inibidores , Retina/metabolismo , Retina/patologia , Retina/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Linhagem Celular
2.
Mol Cancer Ther ; : OF1-OF11, 2024 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-38853423

RESUMO

The aberrant activation of FGFR acts as a potent driver of multiple types of human cancers. Despite the development of several conventional small-molecular FGFR inhibitors, their clinical efficacy is largely compromised because of low selectivity and side effects. In this study, we report the selective FGFR1/2-targeting proteolysis-targeting chimera BR-cpd7 that displays significant isoform specificity to FGFR1/2 with half maximal degradation concentration values around 10 nmol/L while sparing FGFR3. The following mechanistic investigation reveals the reduced FGFR signaling, through which BR-cpd7 induces cell-cycle arrest and consequently blocks the proliferation of multiple FGFR1/2-dependent tumor cells. Importantly, BR-cpd7 has almost no antiproliferative activity against cancer cells without FGFR aberrations, furtherly supporting its selectivity. In vivo, BR-cpd7 exhibits robust antitumor effects in FGFR1-dependent lung cancer at well-tolerated dose schedules, accompanied by complete FGFR1 depletion. Overall, we identify BR-cpd7 as a promising candidate for developing a selective FGFR1/2-targeted agent, thereby offering a new therapeutic strategy for human cancers in which FGFR1/2 plays a critical role.

3.
J Transl Med ; 22(1): 533, 2024 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-38831470

RESUMO

BACKGROUND: Clear cell renal cell carcinoma (ccRCC) is a common disease in the urinary system, with a high incidence and poor prognosis in advanced stages. Although γ-interferon-inducible protein 16 (IFI16) has been reported to play a role in various tumors, its involvement in ccRCC remains poorly documented, and the molecular mechanisms are not yet clear. METHODS: We conducted bioinformatics analysis to study the expression of IFI16 in ccRCC using public databases. Additionally, we analyzed and validated clinical specimens that we collected. Subsequently, we explored the impact of IFI16 on ccRCC cell proliferation, migration, and invasion through in vitro and in vivo experiments. Furthermore, we predicted downstream molecules and pathways using transcriptome analysis and confirmed them through follow-up experimental validation. RESULTS: IFI16 was significantly upregulated in ccRCC tissue and correlated with poor patient prognosis. In vitro, IFI16 promoted ccRCC cell proliferation, migration, and invasion, while in vivo, it facilitated subcutaneous tumor growth and the formation of lung metastatic foci. Knocking down IFI16 suppressed its oncogenic function. At the molecular level, IFI16 promoted the transcription and translation of IL6, subsequently activating the PI3K/AKT signaling pathway and inducing epithelial-mesenchymal transition (EMT). CONCLUSION: IFI16 induced EMT through the IL6/PI3K/AKT axis, promoting the progression of ccRCC.


Assuntos
Carcinoma de Células Renais , Movimento Celular , Proliferação de Células , Progressão da Doença , Transição Epitelial-Mesenquimal , Interleucina-6 , Neoplasias Renais , Proteínas Nucleares , Fosfatidilinositol 3-Quinases , Fosfoproteínas , Proteínas Proto-Oncogênicas c-akt , Transdução de Sinais , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/patologia , Carcinoma de Células Renais/metabolismo , Humanos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Neoplasias Renais/patologia , Neoplasias Renais/genética , Neoplasias Renais/metabolismo , Linhagem Celular Tumoral , Interleucina-6/metabolismo , Fosfoproteínas/metabolismo , Fosfoproteínas/genética , Proteínas Nucleares/metabolismo , Proteínas Nucleares/genética , Animais , Movimento Celular/genética , Transição Epitelial-Mesenquimal/genética , Regulação Neoplásica da Expressão Gênica , Camundongos Nus , Invasividade Neoplásica , Masculino , Feminino , Prognóstico
4.
Surgery ; 176(1): 137-147, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38734502

RESUMO

BACKGROUND: Despite the Barcelona Clinic Liver Cancer system discouraging hepatectomy for intermediate/advanced hepatocellular carcinoma, the procedure is still performed worldwide, particularly in Asia. This study aimed to develop and validate nomograms for predicting survival and recurrence for these patients. METHODS: We analyzed patients who underwent curative-intent hepatectomy for intermediate/advanced hepatocellular carcinoma between 2010 and 2020 across 3 Chinese hospitals. The Eastern Hepatobiliary Surgery Hospital cohort was used as the training cohort for the nomogram construction, and the Jilin First Hospital and Fujian Mengchao Hepatobiliary Hospital cohorts served as the external validation cohorts. Independent preoperative predictors for survival and recurrence were identified through univariable and multivariable Cox regression analyses. Predictive accuracy was measured using the concordance index and calibration curves. The predictive performance between nomograms and conventional hepatocellular carcinoma staging systems was compared. RESULTS: A total of 1,328 patients met the inclusion criteria. The nomograms for predicting survival and recurrence were developed using 10 and 6 independent variables, respectively. Nomograms' concordance indices in the training cohort were 0.777 (95% confidence interval 0.759-0.800) and 0.719 (95% confidence interval 0.697-0.742) for survival and recurrence, outperforming 4 conventional staging systems (P < .001). Nomograms accurately stratified risk into low, intermediate, and high subgroups. These results were validated well by 2 external validation cohorts. CONCLUSION: We developed and validated nomograms predicting survival and recurrence for patients with intermediate/advanced hepatocellular carcinoma, contradicting Barcelona Clinic Liver Cancer surgical guidelines. These nomograms may facilitate clinicians to formulate personalized surgical decisions, estimate long-term prognosis, and strategize neoadjuvant/adjuvant anti-recurrence therapy.


Assuntos
Carcinoma Hepatocelular , Hepatectomia , Neoplasias Hepáticas , Recidiva Local de Neoplasia , Estadiamento de Neoplasias , Nomogramas , Humanos , Neoplasias Hepáticas/cirurgia , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Carcinoma Hepatocelular/cirurgia , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Masculino , Feminino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/epidemiologia , Estudos Retrospectivos , Idoso , Adulto
5.
Adv Mater ; : e2310731, 2024 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-38805174

RESUMO

As a central metabolic molecule, nicotinamide adenine dinucleotide (NAD+) can potentially treat acute kidney injury (AKI) and chronic kidney disease (CKD); however, its bioavailability is poor due to short half-life, instability, the deficiency of targeting, and difficulties in transmembrane transport. Here a physiologically adaptive gallic acid-NAD+ nanoparticle is designed, which has ultrasmall size and pH-responsiveness, passes through the glomerular filtration membrane to reach injured renal tubules, and efficiently delivers NAD+ into the kidneys. With an effective accumulation in the kidneys, it restores renal function, immune microenvironment homeostasis, and mitochondrial homeostasis of AKI mice via the NAD+-Sirtuin-1 axis, and exerts strong antifibrotic effects on the AKI-to-CKD transition by inhibiting TGF-ß signaling. It also exhibits excellent stability, biodegradable, and biocompatible properties, ensuring its long-term safety, practicality, and clinical translational feasibility. The present study shows a potential modality of mitochondrial repair and immunomodulation through nanoagents for the efficient and safe treatment of AKI and CKD.

6.
Mol Metab ; 84: 101953, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38710444

RESUMO

OBJECTIVE: Lipid metabolism plays an important role in early pregnancy, but its effects on decidualization are poorly understood. Fatty acids (FAs) must be esterified by fatty acyl-CoA synthetases to form biologically active acyl-CoA in order to enter the anabolic and/or catabolic pathway. Long-chain acyl-CoA synthetase 4 (ACSL4) is associated with female reproduction. However, whether it is involved in decidualization is unknown. METHODS: The expression of ACSL4 in human and mouse endometrium was detected by immunohistochemistry. ACSL4 levels were regulated by the overexpression of ACSL4 plasmid or ACSL4 siRNA, and the effects of ACSL4 on decidualization markers and morphology of endometrial stromal cells (ESCs) were clarified. A pregnant mouse model was established to determine the effect of ACSL4 on the implantation efficiency of mouse embryos. Modulation of ACSL4 detects lipid anabolism and catabolism. RESULTS: Through examining the expression level of ACSL4 in human endometrial tissues during proliferative and secretory phases, we found that ACSL4 was highly expressed during the secretory phase. Knockdown of ACSL4 suppressed decidualization and inhibited the mesenchymal-to-epithelial transition induced by MPA and db-cAMP in ESCs. Further, the knockdown of ACSL4 reduced the efficiency of embryo implantation in pregnant mice. Downregulation of ACSL4 inhibited FA ß-oxidation and lipid droplet accumulation during decidualization. Interestingly, pharmacological and genetic inhibition of lipid droplet synthesis did not affect FA ß-oxidation and decidualization, while the pharmacological and genetic inhibition of FA ß-oxidation increased lipid droplet accumulation and inhibited decidualization. In addition, inhibition of ß-oxidation was found to attenuate the promotion of decidualization by the upregulation of ACSL4. The decidualization damage caused by ACSL4 knockdown could be reversed by activating ß-oxidation. CONCLUSIONS: Our findings suggest that ACSL4 promotes endometrial decidualization by activating the ß-oxidation pathway. This study provides interesting insights into our understanding of the mechanisms regulating lipid metabolism during decidualization.


Assuntos
Coenzima A Ligases , Endométrio , Ácidos Graxos , Gotículas Lipídicas , Oxirredução , Feminino , Coenzima A Ligases/metabolismo , Coenzima A Ligases/genética , Animais , Camundongos , Humanos , Endométrio/metabolismo , Ácidos Graxos/metabolismo , Gravidez , Gotículas Lipídicas/metabolismo , Decídua/metabolismo , Adulto , Metabolismo dos Lipídeos , Implantação do Embrião , Células Estromais/metabolismo
7.
Front Endocrinol (Lausanne) ; 15: 1357580, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38706699

RESUMO

Background and objective: Type 2 Diabetes Mellitus (T2DM) with insulin resistance (IR) is prone to damage the vascular endothelial, leading to the formation of vulnerable carotid plaques and increasing ischemic stroke (IS) risk. The purpose of this study is to develop a nomogram model based on carotid ultrasound radiomics for predicting IS risk in T2DM patients. Methods: 198 T2DM patients were enrolled and separated into study and control groups based on IS history. After manually delineating carotid plaque region of interest (ROI) from images, radiomics features were identified and selected using the least absolute shrinkage and selection operator (LASSO) regression to calculate the radiomics score (RS). A combinatorial logistic machine learning model and nomograms were created using RS and clinical features like the triglyceride-glucose index. The three models were assessed using area under curve (AUC) and decision curve analysis (DCA). Results: Patients were divided into the training set and the testing set by the ratio of 0.7. 4 radiomics features were selected. RS and clinical variables were all statically significant in the training set and were used to create a combination model and a prediction nomogram. The combination model (radiomics + clinical nomogram) had the largest AUC in both the training set and the testing set (0.898 and 0.857), and DCA analysis showed that it had a higher overall net benefit compared to the other models. Conclusions: This study created a carotid ultrasound radiomics machine-learning-based IS risk nomogram for T2DM patients with carotid plaques. Its diagnostic performance and clinical prediction capabilities enable accurate, convenient, and customized medical care.


Assuntos
Diabetes Mellitus Tipo 2 , AVC Isquêmico , Nomogramas , Ultrassonografia , Humanos , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/diagnóstico por imagem , Masculino , Feminino , Pessoa de Meia-Idade , AVC Isquêmico/diagnóstico por imagem , AVC Isquêmico/etiologia , AVC Isquêmico/epidemiologia , Idoso , Ultrassonografia/métodos , Fatores de Risco , Aprendizado de Máquina , Artérias Carótidas/diagnóstico por imagem , Artérias Carótidas/patologia , Medição de Risco/métodos , Ultrassonografia das Artérias Carótidas , Radiômica
8.
J Agric Food Chem ; 72(19): 10814-10827, 2024 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-38710027

RESUMO

Foxtail millet is an important cereal crop that is relatively sensitive to salt stress, with its yield significantly affected by such stress. Alternative splicing (AS) widely affects plant growth, development, and adaptability to stressful environments. Through RNA-seq analysis of foxtail millet under different salt treatment periods, 2078 AS events were identified, and analyses were conducted on differential gene (DEG), differential alternative splicing gene (DASG), and overlapping gene. To investigate the regulatory mechanism of AS in response to salt stress in foxtail millet, the foxtail millet AS genes SiCYP19, with two AS variants (SiCYP19-a and SiCYP19-b), were identified and cloned. Yeast overexpression experiments indicated that SiCYP19 may be linked to the response to salt stress. Subsequently, we conducted overexpression experiments of both alternative splicing variants in foxtail millet roots to validate them experimentally. The results showed that, under salt stress, both SiCYP19-a and SiCYP19-b jointly regulated the salt tolerance of foxtail millet. Specifically, overexpression of SiCYP19-b significantly increased the proline content and reduced the accumulation of reactive oxygen species (ROS) in foxtail millet, compared to that in SiCYP19-a. This shows that SiCYP19-b plays an important role in increasing the content of proline and promoting the clearance of ROS, thus improving the salt tolerance of foxtail millet.


Assuntos
Processamento Alternativo , Regulação da Expressão Gênica de Plantas , Proteínas de Plantas , Tolerância ao Sal , Setaria (Planta) , Setaria (Planta)/genética , Setaria (Planta)/metabolismo , Setaria (Planta)/efeitos dos fármacos , Tolerância ao Sal/genética , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Espécies Reativas de Oxigênio/metabolismo
9.
Genes (Basel) ; 15(4)2024 04 11.
Artigo em Inglês | MEDLINE | ID: mdl-38674418

RESUMO

Gliomas are the most prevalent primary malignant tumors affecting the brain, with high recurrence and mortality rates. Accurate diagnoses and effective treatment challenges persist, emphasizing the need for identifying new biomarkers to guide clinical decisions. Long noncoding RNAs (lncRNAs) hold potential as diagnostic and therapeutic biomarkers in cancer. However, only a limited subset of lncRNAs in gliomas have been explored. Therefore, this study aims to identify lncRNA signatures applicable to patients with gliomas across all grades and explore their clinical significance and potential biological mechanisms. Data used in this study were obtained from TCGA, CGGA, and GEO datasets to identify key lncRNA signatures in gliomas through differential and survival analyses and machine learning algorithms. We examined their associations with the clinical characteristics, gene mutations, diagnosis, and prognosis of gliomas. Functional enrichment analysis was employed to elucidate the potential biological mechanisms associated with these significant lncRNA signatures. We explored competing endogenous RNA (ceRNA) regulatory networks. We found that NDUFA6-DT emerged as a significant lncRNA signature in gliomas, with reduced NDUFA6-DT expression associated with a worse prognosis in gliomas. Nomogram analysis incorporating NDUFA6-DT expression levels exhibited excellent prognostic and predictive capabilities. Functional annotation suggested that NDUFA6-DT might influence immunological responses and synaptic transmission, potentially modifying glioma initiation and progression. The associated ceRNA network revealed the possible presence of the NDUFA6-DT-miR-455-3p-YWHAH/YWHAG axis in low-grade glioma (LGG) and glioblastoma multiforme (GBM), regulating the PI3K-AKT signaling pathway and influencing glioma cell survival and apoptosis. We believe that NDUFA6-DT is a novel lncRNA linked to glioma diagnosis and prognosis, potentially becoming a pivotal biomarker for glioma.


Assuntos
Biomarcadores Tumorais , Neoplasias Encefálicas , Regulação Neoplásica da Expressão Gênica , Glioma , RNA Longo não Codificante , Humanos , RNA Longo não Codificante/genética , Glioma/genética , Glioma/patologia , Biomarcadores Tumorais/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Prognóstico , Redes Reguladoras de Genes
10.
World J Surg ; 48(1): 86-96, 2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-38686746

RESUMO

BACKGROUND: Low-grade appendiceal mucinous neoplasms (LAMN) are very rare, accounting for approximately 0.2%-0.5% of gastrointestinal tumors. We conducted a multicenter retrospective study to explore the impact of different surgical procedures combined with HIPEC on the short-term outcomes and long-term survival of patients. METHODS: We retrospectively analyzed the clinicopathological data of 91 LAMN perforation patients from 9 teaching hospitals over a 10-year period, and divided them into HIPEC group and non-HIPEC group based on whether or not underwent HIPEC. RESULTS: Of the 91 patients with LAMN, 52 were in the HIPEC group and 39 in the non-HIPEC group. The Kaplan-Meier method predicted that 52 patients in the HIPEC group had 5- and 10-year overall survival rates of 82.7% and 76.9%, respectively, compared with predicted survival rates of 51.3% and 46.2% for the 39 patients in the non-HIPEC group, with a statistically significant difference between the two groups (χ2 = 10.622, p = 0.001; χ2 = 10.995, p = 0.001). Compared to the 5-year and 10-year relapse-free survival rates of 75.0% and 65.4% in the HIPEC group, respectively, the 5-year and 10-year relapse-free survival rates of 48.7% and 46.2% in the non-HIPEC group were significant different between the two outcomes (χ2 = 8.063, p = 0.005; χ2 = 6.775, p = 0.009). The incidence of postoperative electrolyte disturbances and hypoalbuminemia was significantly higher in the HIPEC group than in the non-HIPEC group (p = 0.023; p = 0.044). CONCLUSIONS: This study shows that surgery combined with HIPEC can significantly improve 5-year and 10-year overall survival rates and relapse-free survival rates of LAMN perforation patients, without affecting their short-term clinical outcomes.


Assuntos
Adenocarcinoma Mucinoso , Neoplasias do Apêndice , Quimioterapia Intraperitoneal Hipertérmica , Humanos , Estudos Retrospectivos , Masculino , Feminino , Neoplasias do Apêndice/terapia , Neoplasias do Apêndice/mortalidade , Neoplasias do Apêndice/patologia , Pessoa de Meia-Idade , Adulto , Adenocarcinoma Mucinoso/terapia , Adenocarcinoma Mucinoso/mortalidade , Adenocarcinoma Mucinoso/patologia , Idoso , Terapia Combinada , Resultado do Tratamento , Taxa de Sobrevida , Gradação de Tumores , Perfuração Intestinal/etiologia , Neoplasias Peritoneais/terapia , Neoplasias Peritoneais/mortalidade
12.
Int J Mol Sci ; 25(7)2024 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-38612838

RESUMO

Petal blotch is a specific flower color pattern commonly found in angiosperm families. In particular, Rosa persica is characterized by dark red blotches at the base of yellow petals. Modern rose cultivars with blotches inherited the blotch trait from R. persica. Therefore, understanding the mechanism for blotch formation is crucial for breeding rose cultivars with various color patterns. In this study, the metabolites and genes responsible for the blotch formation in R. persica were identified for the first time through metabolomic and transcriptomic analyses using LC-MS/MS and RNA-seq. A total of 157 flavonoids were identified, with 7 anthocyanins as the major flavonoids, namely, cyanidin 3-O-(6″-O-malonyl) glucoside 5-O-glucoside, cyanidin-3-O-glucoside, cyanidin 3-O-galactoside, cyanidin O-rutinoside-O-malonylglucoside, pelargonidin 3-O-glucoside, pelargonidin 3,5-O-diglucoside, and peonidin O-rutinoside-O-malonylglucoside, contributing to pigmentation and color darkening in the blotch parts of R. persica, whereas carotenoids predominantly influenced the color formation of non-blotch parts. Zeaxanthin and antheraxanthin mainly contributed to the yellow color formation of petals at the semi-open and full bloom stages. The expression levels of two 4-coumarate: CoA ligase genes (Rbe014123 and Rbe028518), the dihydroflavonol 4-reductase gene (Rbe013916), the anthocyanidin synthase gene (Rbe016466), and UDP-flavonoid glucosyltransferase gene (Rbe026328) indicated that they might be the key structural genes affecting the formation and color of petal blotch. Correlation analysis combined with weighted gene co-expression network analysis (WGCNA) further characterized 10 transcription factors (TFs). These TFs might participate in the regulation of anthocyanin accumulation in the blotch parts of petals by modulating one or more structural genes. Our results elucidate the compounds and molecular mechanisms underlying petal blotch formation in R. persica and provide valuable candidate genes for the future genetic improvement of rose cultivars with novel flower color patterns.


Assuntos
Antocianinas , Rosa , Humanos , Rosa/genética , Cromatografia Líquida , Espectrometria de Massas em Tandem , Melhoramento Vegetal , Perfilação da Expressão Gênica , Flavonoides , Glucosídeos
14.
Mol Cancer Ther ; 2024 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-38647531

RESUMO

The aberrant activation of fibroblast growth factor receptor (FGFR) acts as a potent driver of multiple types of human cancers. Despite the development of several conventional small-molecular FGFR inhibitors, their clinical efficacy is largely compromised due to low selectivity and side effects. Here, we report the selective FGFR1/2-targeting proteolysis targeting chimeric (PROTAC), BR-cpd7 that displays significant isoform specificity to FGFR1/2 with DC50 values around 10 nM, while sparing FGFR3. The following mechanistic investigation reveals the reduced FGFR signaling, through which BR-cpd7 induces cell cycle arrest and consequently blocks the proliferation of multiple FGFR1/2-dependent tumor cells. Importantly, BR-cpd7 has almost no anti-proliferative activity against cancer cells without FGFR aberrations, furtherly supporting its selectivity. In vivo, BR-cpd7 exhibits robust antitumor effects in FGFR1-dependent lung cancer at well-tolerated dose schedules, accompanied by complete FGFR1 depletion. Overall, we identify BR-cpd7 as a promising candidate for developing a selective FGFR1/2-targeted agent, thereby offering a new therapeutic strategy for human cancers in which FGFR1/2 plays a critical role.

15.
Small ; : e2301074, 2024 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-38659180

RESUMO

The coating of filter media with silver is typically achieved by chemical deposition and aerosol processes. Whilst useful, such approaches struggle to provide uniform coating and are prone to blockage. To address these issues, an in situ method for coating glass fibers is presented via the dopamine-mediated electroless metallization method, yielding filters with low air resistance and excellent antibacterial performance. It is found that the filtration efficiency of the filters is between 94 and 97% and much higher than that of silver-coated filters produced using conventional dipping methods (85%). Additionally, measured pressure drops ranged between 100 and 150 Pa, which are lower than those associated with dipped filters (171.1 Pa). Survival rates of Escherichia coli and Bacillus subtilis bacteria exposed to the filters decreased to 0 and 15.7%±1.49, respectively after 2 h, with no bacteria surviving after 6 h. In contrast, survival rates of E. coli and B. subtilis bacteria on the uncoated filters are 92.5% and 89.5% after 6 h. Taken together, these results confirm that the in situ deposition of silver onto fiber surfaces effectively reduces pore clogging, yielding low air resistance filters that can be applied for microbial filtration and inhibition in a range of environments.

16.
PLoS One ; 19(4): e0301931, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38683829

RESUMO

OBJECTIVE: Immune checkpoint inhibitor pneumonitis (CIP) is a prevalent form of immunotherapy-induced pulmonary toxicity, ranking among the leading causes of mortality associated with immune checkpoint inhibitors (ICIs). Despite its significance, the risk stratification of CIP in advanced non-small cell lung cancer (NSCLC) remains uncertain. In this study, we conducted a comprehensive analysis, comparing various factors such as histological types, treatment regimens, PD-L1 expression levels, and EGFR/ALK negativity in advanced NSCLC. Our investigation extends to evaluating the relative risk of developing CIP based on previous treatment history. This analysis aims to provide valuable insights for the identification of specific patient subgroups at higher risk, facilitating more effective risk management and precision therapy approaches. METHODS: PubMed, Embase, and Cochrane databases were systematically searched up to February 16, 2023. We conducted a screening of randomized controlled trials (RCTs) that compared ICI monotherapy or its combination with chemotherapy in advanced NSCLC. The trials were categorized based on histological type, treatment regimen, PD-L1 expression level, EGFR/ALK-negative status, and prior treatment history. Subsequently, the data were stratified into five subgroups, and the occurrences of all-grades (1-5) and high-grades (3-5) pneumonia events were extracted. Odds ratios (OR) and corresponding 95% confidence intervals (CI) were then calculated for further analysis. RESULTS: Twenty-two RCTs, encompassing 13,725 patients with advanced NSCLC, were included in this analysis. Regardless of histology (OR = 2.47, 95% CI 1.41-4.33, P = 0.002; OR = 1.84, 95% CI 1.10-3.09, P = 0.02), treatment regimen (OR = 3.27, 95% CI 2.00-5.35, P < 0.00001; OR = 2.91, 95% CI 1.98-4.27, P < 0.00001), PD-L1 expression level (OR = 5.11, 95% CI 2.58-10.12, P < 0.00001; OR = 5.15, 95% CI 2.48-10.70, P < 0.0001), negative EGFR/ALK expression (OR = 4.32, 95% CI 2.22-8.41, P < 0.0001; OR = 3.6, 95% CI 1.56-8.28, P = 0.003), whether there is a history of treatment (OR = 3.27, 95% CI 2.00-5.35, P < 0.00001; OR = 2.74, 95% CI 1.75-4.29, P < 0.0001), ICI use was associated with a higher risk of all-grade (1-5) and high-grade (3-5) pneumonia compared to chemotherapy. Subgroup analysis revealed that the squamous group, the ICI vs. combination chemotherapy (CT) group, the PD-L1 > 50% group, and the previously untreated group had a higher risk of developing all-grade and grade 3-5 CIP (P < 0.05). CONCLUSIONS: In advanced NSCLC, ICI treatment was linked to an elevated risk of pneumonitis across all grades (1-5) as well as high-grade occurrences (3-5) compared to chemotherapy. Notably, individuals with squamous histology and high PD-L1 expression, along with those lacking a history of prior treatment, demonstrated a heightened susceptibility to developing immune-related pneumonitis of all grades (1-5) and high grades (3-5). These observations provide valuable insights for clinicians seeking to enhance the management of pulmonary toxicity associated with immunotherapy.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Inibidores de Checkpoint Imunológico , Neoplasias Pulmonares , Pneumonia , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/imunologia , Inibidores de Checkpoint Imunológico/efeitos adversos , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Pneumonia/induzido quimicamente , Ensaios Clínicos Controlados Aleatórios como Assunto , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/metabolismo
17.
Anal Chem ; 96(19): 7566-7576, 2024 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-38684118

RESUMO

Genetically encoding proximal-reactive unnatural amino acids (PrUaas), such as fluorosulfate-l-tyrosine (FSY), into natural proteins of interest (POI) confer the POI with the ability to covalently bind to its interacting proteins (IPs). The PrUaa-incorporated POIs hold promise for blocking undesirable POI-IP interactions. Selecting appropriate PrUaa anchor sites is crucial, but it remains challenging with the current methodology, which heavily relies on crystallography to identify the proximal residues between the POIs and the IPs for the PrUaa anchorage. To address the challenge, here, we propose a footprinting-directed genetically encoded covalent binder (footprinting-GECB) approach. This approach employs carbene footprinting, a structural mass spectrometry (MS) technique that quantifies the extent of labeling of the POI following the addition of its IP, and thus identifies the responsive residues. By genetically encoding PrUaa into these responsive sites, POI variants with covalent bonding ability to its IP can be produced without the need for crystallography. Using the POI-IP model, KRAS/RAF1, we showed that engineering FSY at the footprint-assigned KRAS residue resulted in a KRAS variant that can bind irreversibly to RAF1. Additionally, we inserted FSY at the responsive residue in RAF1 upon footprinting the oncogenic KRASG12D/RAF1, which lacks crystal structure, and generated a covalent binder to KRASG12D. Together, we demonstrated that by adopting carbene footprinting to direct PrUaa anchorage, we can greatly expand the opportunities for designing covalent protein binders for PPIs without relying on crystallography. This holds promise for creating effective PPI inhibitors and supports both fundamental research and biotherapeutics development.


Assuntos
Metano , Metano/análogos & derivados , Metano/química , Humanos , Pegadas de Proteínas/métodos , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/química , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Ligação Proteica , Espectrometria de Massas
18.
Front Immunol ; 15: 1308543, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38433845

RESUMO

Background: This study evaluates the efficacy of alpha-fetoprotein (AFP) response as a surrogate marker for determining recurrence-free survival (RFS) in patients with unresectable hepatocellular carcinoma (uHCC) who undergo salvage hepatectomy following conversion therapy with tyrosine kinase inhibitor (TKI) and anti-PD-1 antibody-based regimen. Methods: This multicenter retrospective study included 74 patients with uHCC and positive AFP (>20 ng/mL) at diagnosis, who underwent salvage hepatectomy after treatment with TKIs and anti-PD-1 antibody-based regimens. The association between AFP response-defined as a ≥ 80% decrease in final AFP levels before salvage hepatectomy from diagnosis-and RFS post-hepatectomy was investigated. Results: AFP responders demonstrated significantly better postoperative RFS compared to non-responders (P<0.001). The median RFS was not reached for AFP responders, with 1-year and 2-year RFS rates of 81.3% and 70.8%, respectively. In contrast, AFP non-responders had a median RFS of 7.43 months, with 1-year and 2-year RFS rates at 37.1% and 37.1%, respectively. Multivariate Cox regression analysis identified AFP response as an independent predictor of RFS. Integrating AFP response with radiologic tumor response facilitated further stratification of patients into distinct risk categories: those with radiologic remission experienced the most favorable RFS, followed by patients with partial response/stable disease and AFP response, and the least favorable RFS among patients with partial response/stable disease but without AFP response. Sensitivity analyses further confirmed the association between AFP response and improved RFS across various cutoff values and in patients with AFP ≥ 200 ng/mL at diagnosis (all P<0.05). Conclusion: The "20-80" rule based on AFP response could be helpful for clinicians to preoperatively stratify the risk of patients undergoing salvage hepatectomy, enabling identification and management of those unlikely to benefit from this procedure.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Prognóstico , Carcinoma Hepatocelular/cirurgia , Estudos Retrospectivos , alfa-Fetoproteínas , Hepatectomia , Neoplasias Hepáticas/cirurgia
19.
Int J Biol Macromol ; 266(Pt 1): 130818, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38479659

RESUMO

Alkaline protease AprE, produced by Bacillus licheniformis 2709 is an important edible hydrolase, which has potential applications in nutrient acquisition and medicine. The expression of AprE is finely regulated by a complex transcriptional regulation system. However, there is little study on transcriptional regulation mechanism of AprE biosynthesis in Bacillus licheniformis, which limits system engineering and further enhancement of AprE. Here, the severely depressed expression of aprE in degU and degS deletion mutants illustrated that the regulator DegU and its phosphorylation played a crucial part in AprE biosynthesis. Further electrophoretic mobility shift assay (EMSA) in vitro indicated that phosphorylated DegU can directly bind to the regulatory region though the DNase I foot-printing experiments failed to observe protected region. The plasmid-mediated overexpression of degU32 (Hy) obviously improved the yield of AprE by 41.6 % compared with the control strain, which demonstrated the importance of phosphorylation state of DegU on the transcription of aprE in vivo. In this study, the putative binding sequence of aprE (5'-TAAAT……AAAAT…….AACAT…TAAAA-3') located upstream -91 to -87 bp, -101 to -97 bp, -195 to -191 bp, -215 to -211 bp of the transcription start site (TSS) in B. licheniformis was computationally identified based on the DNA-binding sites of DegU in Bacillus subtilis. Overall, we systematically investigated the influence of the interplay between phosphorylated DegU and its cognate DNA sequence on expression of aprE, which not only contributes to the further AprE high-production in a genetically modified host in the future, but also significantly increases our understanding of the aprE transcription mechanism.


Assuntos
Bacillus licheniformis , Proteínas de Bactérias , Endopeptidases , Regulação Bacteriana da Expressão Gênica , Proteínas de Membrana Transportadoras , Bacillus licheniformis/genética , Bacillus licheniformis/enzimologia , Bacillus licheniformis/metabolismo , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Endopeptidases/genética , Endopeptidases/metabolismo , Fosforilação , Regiões Promotoras Genéticas
20.
Apoptosis ; 29(5-6): 785-798, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38517601

RESUMO

Osteoarthritis (OA) is a common disease in middle-aged and elderly people. An imbalance in calcium ion homeostasis will contribute to chondrocyte apoptosis and ultimately lead to the progression of OA. Transient receptor potential channel 4 (TRPV4) is involved in the regulation of intracellular calcium homeostasis. TRPV4 is expressed in primary cilia, which can sense mechanical stimuli from outside the cell, and its abnormal expression is closely related to the development of OA. Low-intensity pulsed ultrasound (LIPUS) can alleviate chondrocyte apoptosis while the exact mechanism is unclear. In this project, with the aim of revealing the mechanism of action of LIPUS, we proposed to use OA chondrocytes and animal models, LIPUS intervention, inhibition of primary cilia, use TRPV4 inhibitors or TRPV4 agonist, and use Immunofluorescence (IF), Immunohistochemistry (IHC), Western Blot (WB), Quantitative Real-time PCR (QP) to detect the expression of cartilage synthetic matrix and endoplasmic reticulum stress markers. The results revealed that LIPUS altered primary cilia expression, promoted synthetic matrix metabolism in articular chondrocytes and was associated with primary cilia. In addition, LIPUS exerted a active effect on OA by activating TRPV4, inducing calcium inward flow, and facilitating the entry of NF-κB into the nucleus to regulate synthetic matrix gene transcription. Inhibition of TRPV4 altered primary cilia expression in response to LIPUS stimulation, and knockdown of primary cilia similarly inhibited TRPV4 function. These results suggest that LIPUS mediates TRPV4 channels through primary cilia to regulate the process of knee osteoarthritis in mice.


Assuntos
Condrócitos , Cílios , Osteoartrite do Joelho , Canais de Cátion TRPV , Animais , Canais de Cátion TRPV/metabolismo , Canais de Cátion TRPV/genética , Cílios/metabolismo , Cílios/patologia , Camundongos , Condrócitos/metabolismo , Condrócitos/patologia , Osteoartrite do Joelho/metabolismo , Osteoartrite do Joelho/patologia , Osteoartrite do Joelho/genética , Osteoartrite do Joelho/terapia , Apoptose/genética , Progressão da Doença , Camundongos Endogâmicos C57BL , Masculino , Cartilagem Articular/metabolismo , Cartilagem Articular/patologia , Modelos Animais de Doenças , Cálcio/metabolismo , Estresse do Retículo Endoplasmático , Humanos
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