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1.
Artigo em Inglês | MEDLINE | ID: mdl-34854950

RESUMO

PURPOSE: Pancreatic adenocarcinoma (PAAD) is one of the most common causes of death among solid tumors, and its pathogenesis remains to be clarified. This study aims to elucidate the value of immune/stromal-related genes in the prognosis of PAAD through comprehensive bioinformatics analysis based on the immune microenvironment and validated in Chinese pancreatic cancer patients. METHODS: Gene expression profiles of pancreatic cancer patients were obtained from TCGA database. Differentially expressed genes (DEGs) were identified based on the ESTIMATE algorithm. Gene co-expression networks were constructed using WGCNA. In the key module, survival analysis was used to reveal the prognostic value. Subsequently, we performed functional enrichment analysis to construct a protein-protein interaction (PPI) network. The relationship between tumor immune infiltration and hub genes was analyzed by TIMER and CIBERSORT. Finally, it was validated in the GEO database and in tissues of Chinese pancreatic cancer patients. RESULTS: In the TCGA pancreatic cancer cohort, a low immune/stromal score was associated with a good prognosis. After bioinformatic analysis, 57 genes were identified to be significantly associated with pancreatic cancer prognosis. Among them, up-regulation of four genes (COL6A3, PLAU, MMP11 and MMP14) indicated poor prognosis and was associated with multiple immune cell infiltration. IHC results showed that PLAU protein levels from Chinese pancreatic cancer tissues were significantly higher than those from adjacent non-tumor tissues and were also associated with tumor TNM stage and lymph node metastasis. CONCLUSION: In conclusion, this study demonstrates that PLAU may serve as a new diagnostic and therapeutic target, which is highly expressed in Chinese pancreatic cancer tissues and associated with lymph node metastasis.

2.
Bioorg Med Chem ; 50: 116457, 2021 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-34670167

RESUMO

An aromatic trifluoromethyl ketone moiety was characterized as a new warhead for covalently reversible kinase inhibitor design to target the non-catalytic cysteine residue. Potent and selective covalently reversible inhibitors of FGFR4 kinase were successfully designed and synthesized by utilizing this new warhead. The binding mode of a representative inhibitor was fully characterized by using multiple technologies including MALDI-TOF mass spectrometry, dialysis assay and X-ray crystallographic studies etc. This functional group was also successfully applied to discovery of a new JAK3 inhibitor, suggesting its potential application in designing other kinase inhibitors.

3.
Artigo em Inglês | MEDLINE | ID: mdl-34508564

RESUMO

OBJECTIVES: Dermatomyositis (DM) and clinically amyopathic dermatomyositis (CADM) patients with positive expression of anti-transcription intermediary factor 1-γ (anti-TIF1-γ) antibody (Ab) are characterized by distinct clinicopathological features. We aimed to determine the role of cytokine/chemokine profiles in the classification of anti-TIF1-γ positive DM/CADM patients. METHODS: Serum levels of 24 cytokines/chemokines were measured in 27 anti-TIF1-γ positive DM/CADM patients by a Luminex 200 system. Principal components analysis (PCA) and unsupervised hierarchical clustering were used to reduce variables and establish patient subgroups. Spearman's correlation coefficient was calculated between cytokine/chemokine levels and disease activity markers. RESULTS: Among anti-TIF1-γ positive DM/CADM patients, two distinct patient clusters were identified. The diagnosis of CADM was more common in Cluster 1 than in Cluster 2 (58.3% vs 6.7%, p = 0.008). Skin disease activity was higher in Cluster 2 than in Cluster 1 as measured by CDASI-A (38.6 ± 10.4 vs 25.3 ± 10.0, p = 0.003). Patients within Cluster 2 exhibited significant muscle weakness (MRC ≤ 3, 33.3% vs 0.0%, p = 0.047), higher levels of anti-TIF1-γ Ab (92.4 ± 20.6 vs 66.9 ± 13.9, p = 0.001), and an increased malignancy rate (73.3% vs 25.0%, p = 0.021). Cluster 2 exhibited higher serum levels of CXCL10 (564.2 ± 258.8 vs 122.0 ± 97.8, p < 0.001), CCL2 (1136.6 ± 545.4 vs 441.6 ± 163.3, p < 0.001), Galectin-9 (38879.6 ± 20009.3 vs 12612.4 ± 6640.0, p < 0.001), IL-18 (436.1 ± 188.9 vs 243.0 ± 114.5, p = 0.003), TNF-α (9.3 ± 3.8 vs 5.6 ± 2.4, p = 0.007), and TNFRI (1385.1 ± 338.2 vs 2605.6 ± 928.5, p < 0.001) than Cluster 1. CONCLUSION: In anti-TIF1-γ positive DM/CADM, we identified a "skin-predominant" cluster and a "hyperinflammation" cluster based on the cytokine/chemokine profiles. Cytokine/chemokine profiles in anti-TIF1-γ positive DM/CADM can identify discrete clusters of patients with different disease patterns, organ involvements, and clinical outcomes.

4.
Nucleic Acids Res ; 49(18): 10235-10249, 2021 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-34551426

RESUMO

Forkhead box (FOX) proteins are an evolutionarily conserved family of transcription factors that play numerous regulatory roles in eukaryotes during developmental and adult life. Dysfunction of FOX proteins has been implicated in a variety of human diseases, including cancer, neurodevelopment disorders and genetic diseases. The FOX family members share a highly conserved DNA-binding domain (DBD), which is essential for DNA recognition, binding and function. Since the first FOX structure was resolved in 1993, >30 FOX structures have been reported to date. It is clear now that the structure and DNA recognition mechanisms vary among FOX members; however, a systematic review on this aspect is lacking. In this manuscript, we present an overview of the mechanisms by which FOX transcription factors bind DNA, including protein structures, DNA binding properties and disease-causing mutations. This review should enable a better understanding of FOX family transcription factors for basic researchers and clinicians.

5.
Biochem Biophys Res Commun ; 579: 1-7, 2021 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-34571387

RESUMO

Chronic myeloid leukemia (CML) is a hematologic malignancy originating from BCR-ABL oncogene-transformed hematopoietic stem cells (HSCs) known as leukemia stem cells (LSCs). Therefore, targeting LSCs is of primary importance to eradicate CML. The present study demonstrates that picropodophyllin (PPP) effectively induces apoptosis and inhibits colony formation in CML stem/progenitor cells as well as quiescent CML progenitors resistant to imatinib therapy, while sparing normal hematopoietic cells in vitro. Administration of PPP in vivo markedly diminishes CML stem/progenitor cells in a transgenic mouse model of CML by inhibition of cell proliferation and enhancement of apoptosis in LSK cells, and significantly improves survival of CML mice. Furthermore, PPP treatment preferentially leads to transcriptional activation of p53 in CML but not normal CD34+ cells, upregulation of p53 protein in LSCs-enriched Sca-1+ cells from CML mice, and increased phosphorylation of p53 and upregulation of Bax protein in Ku812 cells. These results suggest that the inhibitory effects of PPP on CML stem/progenitor cells are associated with selective activation of p53 pathway and propose that PPP is a potent agent that selectively targets CML LSCs, and may be of value in the CML therapy.

6.
Genet Test Mol Biomarkers ; 25(6): 434-444, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34152845

RESUMO

Aims: Many studies and researchers have reported on the genetic association between lipoprotein lipase (LPL) gene polymorphisms and myocardial infarction (MI). The results, however, have been inconclusive. Therefore, we assessed the relationship of LPL gene polymorphisms and MI risk by performing a meta-analysis. Methods: Literature was retrieved through PubMed, Web of Science, the Cochrane Library, Chinese National Knowledge Infrastructure (CNKI), and Embase databases. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were used to evaluate the genetic associations between LPL gene polymorphisms and MI risk. A total of nine studies, with 10 individual groups, comprising 2785 cases and 4317 controls were used for this meta-analysis. Results: The allelic (p = 0.0003, OR [95% CI] = 0.86 [0.79-0.93]) and dominant models (p = 0.001, OR [95% CI] = 0.83 [0.73-0.93]), but not the recessive model (p > 0.05) of LPL gene showed that the HindIII variant significantly decreased the risk of MI. In addition, the allelic model (p = 0.04, OR [95% CI] = 0.71 [0.50-0.99]) for the S447X variant showed a significant decrease in the risk of MI. No association was observed between the PvuII variant and MI (p > 0.05). A subgroup analysis based on ethnicity revealed that all of the genetic models (allelic model: p < 0.00001, OR [95% CI] = 0.62 [0.51-0.77]; dominant model: p = 0.003, OR [95% CI] = 0.66 [0.50-0.87]; recessive model (p = 0.02, OR [95% CI] = 0.47 [0.25-0.88]) found an association of the HindIII polymorphism with MI in the Asian, but not in the Caucasian population (p > 0.05). Under the dominant model the HindIII SNP was also shown to be associated with MI risk in the Caucasian population (p = 0.03, OR [95% CI] = 0.87 [0.76-0.99]). In addition, the allelic (p = 0.02, OR [95% CI] = 0.75 [0.59-0.95]) and dominant models (p = 0.02, OR [95% CI] = 0.51 [0.29-0.90]) for S447X demonstrated a significantly decreased MI risk in the Caucasian, but not in the Asian population (p > 0.05). Conclusions: LPL HindIII and S447X polymorphisms, but not PvuII might be the protective factors for MI. To confirm these results, case-control studies with larger numbers of subjects need to be conducted.

7.
Front Cell Dev Biol ; 9: 621810, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34178975

RESUMO

Distant metastasis is a major cause of treatment failure in nasopharyngeal carcinoma (NPC) patients. Cell surface proteins represent attractive targets for cancer diagnosis or therapy. However, the cell surface proteins associated with NPC metastasis are poorly understood. To identify potential therapeutic targets for NPC metastasis, we isolated cell surface proteins from two isogenic NPC cell lines, 6-10B (low metastatic) and 5-8F (highly metastatic), through cell surface biotinylation. Stable isotope labeling by amino acids in cell culture (SILAC) based proteomics was applied to comprehensively characterize the cell surface proteins related with the metastatic phenotype. We identified 294 differentially expressed cell surface proteins, including the most upregulated protein myoferlin (MYOF), two receptor tyrosine kinases(RTKs) epidermal growth factor receptor (EGFR) and ephrin type-A receptor 2 (EPHA2) and several integrin family molecules. These differentially expressed proteins are enriched in multiple biological pathways such as the FAK-PI3K-mTOR pathway, focal adhesions, and integrin-mediated cell adhesion. The knockdown of MYOF effectively suppresses the proliferation, migration and invasion of NPC cells. Immunohistochemistry analysis also showed that MYOF is associated with NPC metastasis. We experimentally confirmed, for the first time, that MYOF can interact with EGFR and EPHA2. Moreover, MYOF knockdown could influence not only EGFR activity and its downstream epithelial-mesenchymal transition (EMT), but also EPHA2 ligand-independent activity. These findings suggest that MYOF might be an attractive potential therapeutic target that has double effects of simultaneously influencing EGFR and EPHA2 signaling pathway. In conclusion, this is the first study to profile the cell surface proteins associated with NPC metastasis and provide valuable resource for future researches.

8.
J Hematol Oncol ; 14(1): 85, 2021 05 31.
Artigo em Inglês | MEDLINE | ID: mdl-34059100

RESUMO

Cancer is a disease with complex pathological process. Current chemotherapy faces problems such as lack of specificity, cytotoxicity, induction of multi-drug resistance and stem-like cells growth. Nanomaterials are materials in the nanorange 1-100 nm which possess unique optical, magnetic, and electrical properties. Nanomaterials used in cancer therapy can be classified into several main categories. Targeting cancer cells, tumor microenvironment, and immune system, these nanomaterials have been modified for a wide range of cancer therapies to overcome toxicity and lack of specificity, enhance drug capacity as well as bioavailability. Although the number of studies has been increasing, the number of approved nano-drugs has not increased much over the years. To better improve clinical translation, further research is needed for targeted drug delivery by nano-carriers to reduce toxicity, enhance permeability and retention effects, and minimize the shielding effect of protein corona. This review summarizes novel nanomaterials fabricated in research and clinical use, discusses current limitations and obstacles that hinder the translation from research to clinical use, and provides suggestions for more efficient adoption of nanomaterials in cancer therapy.


Assuntos
Nanomedicina , Nanoestruturas/uso terapêutico , Neoplasias/terapia , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , Sistemas de Liberação de Medicamentos , Humanos , Neoplasias/patologia , Microambiente Tumoral
9.
Comput Struct Biotechnol J ; 19: 2148-2159, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33995909

RESUMO

Farnesoid X receptor (FXR) is a bile acid activated nuclear receptor (BAR) and is mainly expressed in the liver and intestine. Upon ligand binding, FXR regulates key genes involved in the metabolic process of bile acid synthesis, transport and reabsorption and is also involved in the metabolism of carbohydrates and lipids. Because of its important functions, FXR is considered as a promising drug target for the therapy of bile acid-related liver diseases. With the approval of obeticholic acid (OCA) as the first small molecule to target FXR, many other small molecules are being evaluated in clinical trials. This review summarizes the structures of FXR, especially its ligand binding domain, and the development of small molecules (including agonists and antagonists) targeting FXR.

10.
Nat Commun ; 12(1): 2280, 2021 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-33863900

RESUMO

The tumor suppressor p53 is mutated in approximately half of all human cancers. p53 can induce apoptosis through mitochondrial membrane permeabilization by interacting with and antagonizing the anti-apoptotic proteins BCL-xL and BCL-2. However, the mechanisms by which p53 induces mitochondrial apoptosis remain elusive. Here, we report a 2.5 Å crystal structure of human p53/BCL-xL complex. In this structure, two p53 molecules interact as a homodimer, and bind one BCL-xL molecule to form a ternary complex with a 2:1 stoichiometry. Mutations at the p53 dimer interface or p53/BCL-xL interface disrupt p53/BCL-xL interaction and p53-mediated apoptosis. Overall, our current findings of the bona fide structure of p53/BCL-xL complex reveal the molecular basis of the interaction between p53 and BCL-xL, and provide insight into p53-mediated mitochondrial apoptosis.


Assuntos
Apoptose/genética , Mitocôndrias/fisiologia , Proteína Supressora de Tumor p53/ultraestrutura , Proteína bcl-X/ultraestrutura , Linhagem Celular Tumoral , Cristalografia por Raios X , Humanos , Simulação de Acoplamento Molecular , Mutação , Ligação Proteica/genética , Multimerização Proteica/genética , Proteínas Recombinantes/genética , Proteínas Recombinantes/isolamento & purificação , Proteínas Recombinantes/metabolismo , Proteínas Recombinantes/ultraestrutura , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/isolamento & purificação , Proteína Supressora de Tumor p53/metabolismo , Proteína bcl-X/genética , Proteína bcl-X/isolamento & purificação , Proteína bcl-X/metabolismo
11.
ACS Med Chem Lett ; 12(4): 647-652, 2021 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-33859803

RESUMO

Covalent kinase inhibitors are rapidly emerging as a class of therapeutics with clinical benefits. Herein we report a series of selective 2-aminopyrimidine-based fibroblast growth factor receptor 4 (FGFR4) inhibitors exploring different types of cysteine-targeting warheads. The structure-activity relationship study revealed that the chemically tuned warheads α-fluoro acrylamide, vinylsulfonamide, and acetaldehyde amine were suitable as covalent warheads for the design of selective FGFR4 inhibitors. Compounds 6a, 6h, and 6i selectively suppressed FGFR4 enzymatic activity with IC50 values of 53 ± 18, 45 ± 11, and 16 ± 4 nM, respectively, while sparing FGFR1/2/3. X-ray crystal structure and MALDI-TOF studies demonstrated that compound 6h bearing the α-fluoro acrylamide binds to FGFR4 with an irreversible binding mode, whereas compound 6i with an acetaldehyde amine binds to FGFR4 with a reversible covalent mode. 6h and 6i might provide some fundamental structural information for the rational design of new selective FGFR4 inhibitors.

12.
J Hematol Oncol ; 14(1): 67, 2021 04 21.
Artigo em Inglês | MEDLINE | ID: mdl-33883020

RESUMO

Myeloid leukemia 1 (MCL-1) is an antiapoptotic protein of the BCL-2 family that prevents apoptosis by binding to the pro-apoptotic BCL-2 proteins. Overexpression of MCL-1 is frequently observed in many tumor types and is closely associated with tumorigenesis, poor prognosis and drug resistance. The central role of MCL-1 in regulating the mitochondrial apoptotic pathway makes it an attractive target for cancer therapy. Significant progress has been made with regard to MCL-1 inhibitors, some of which have entered clinical trials. Here, we discuss the mechanism by which MCL-1 regulates cancer cell apoptosis and review the progress related to MCL-1 small molecule inhibitors and their role in cancer therapy.


Assuntos
Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Neoplasias/genética , Humanos , Proteína de Sequência 1 de Leucemia de Células Mieloides/genética , Neoplasias/patologia
13.
mBio ; 12(2)2021 03 30.
Artigo em Inglês | MEDLINE | ID: mdl-33785613

RESUMO

Retinoic acid-inducible gene I (RIG-I) is a sensor that recognizes cytosolic double-stranded RNA derived from microbes to induce host immune response. Viruses, such as herpesviruses, deploy diverse mechanisms to derail RIG-I-dependent innate immune defense. In this study, we discovered that mouse RIG-I is intrinsically resistant to deamidation and evasion by herpes simplex virus 1 (HSV-1). Comparative studies involving human and mouse RIG-I indicate that N495 of human RIG-I dictates species-specific deamidation by HSV-1 UL37. Remarkably, deamidation of the other site, N549, hinges on that of N495, and it is catalyzed by cellular phosphoribosylpyrophosphate amidotransferase (PPAT). Specifically, deamidation of N495 enables RIG-I to interact with PPAT, leading to subsequent deamidation of N549. Collaboration between UL37 and PPAT is required for HSV-1 to evade RIG-I-mediated antiviral immune response. This work identifies an immune regulatory role of PPAT in innate host defense and establishes a sequential deamidation event catalyzed by distinct deamidases in immune evasion.IMPORTANCE Herpesviruses are ubiquitous pathogens in human and establish lifelong persistence despite host immunity. The ability to evade host immune response is pivotal for viral persistence and pathogenesis. In this study, we investigated the evasion, mediated by deamidation, of species-specific RIG-I by herpes simplex virus 1 (HSV-1). Our findings uncovered a collaborative and sequential action between viral deamidase UL37 and a cellular glutamine amidotransferase, phosphoribosylpyrophosphate amidotransferase (PPAT), to inactivate RIG-I and mute antiviral gene expression. PPAT catalyzes the rate-limiting step of the de novo purine synthesis pathway. This work describes a new function of cellular metabolic enzymes in host defense and viral immune evasion.


Assuntos
Amidofosforribosiltransferase/metabolismo , Proteína DEAD-box 58/metabolismo , Herpes Simples/enzimologia , Herpesvirus Humano 1/enzimologia , Proteínas Estruturais Virais/metabolismo , Replicação Viral , Amidofosforribosiltransferase/genética , Motivos de Aminoácidos , Animais , Proteína DEAD-box 58/química , Proteína DEAD-box 58/genética , Herpes Simples/genética , Herpes Simples/virologia , Herpesvirus Humano 1/genética , Herpesvirus Humano 1/fisiologia , Interações Hospedeiro-Patógeno , Humanos , Camundongos , Ligação Proteica , Especificidade da Espécie , Proteínas Estruturais Virais/genética
14.
Nucleic Acids Res ; 49(6): 3573-3583, 2021 04 06.
Artigo em Inglês | MEDLINE | ID: mdl-33577686

RESUMO

Forkhead transcription factors bind a canonical consensus DNA motif, RYAAAYA (R = A/G, Y = C/T), as a monomer. However, the molecular mechanisms by which forkhead transcription factors bind DNA as a dimer are not well understood. In this study, we show that FOXO1 recognizes a palindromic DNA element DIV2, and mediates transcriptional regulation. The crystal structure of FOXO1/DIV2 reveals that the FOXO1 DNA binding domain (DBD) binds the DIV2 site as a homodimer. The wing1 region of FOXO1 mediates the dimerization, which enhances FOXO1 DNA binding affinity and complex stability. Further biochemical assays show that FOXO3, FOXM1 and FOXI1 also bind the DIV2 site as homodimer, while FOXC2 can only bind this site as a monomer. Our structural, biochemical and bioinformatics analyses not only provide a novel mechanism by which FOXO1 binds DNA as a homodimer, but also shed light on the target selection of forkhead transcription factors.


Assuntos
DNA/metabolismo , Proteína Forkhead Box O1/química , Proteína Forkhead Box O1/metabolismo , DNA/química , Fatores de Transcrição Forkhead/química , Fatores de Transcrição Forkhead/metabolismo , Células HEK293 , Humanos , Sequências Repetidas Invertidas , Modelos Moleculares , Ligação Proteica , Multimerização Proteica , Transcrição Genética
15.
Eur J Med Chem ; 214: 113219, 2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33618175

RESUMO

Fibroblast growth factor receptor 4 (FGFR4) is a member of the fibroblast growth factor receptor family, which is closely related to the occurrence and development of hepatocellular carcinoma (HCC). In this article, a series of indazole derivatives were designed and synthesized by using computer-aided drug design (CADD) and structure-based design strategies, and then they were evaluated for their inhibition of FGFR4 kinase and antitumor activity. F-30 was subtly selective for FGFR4 compared to FGFR1; it affected cell growth and migration by inhibiting FGFR4 pathways in HCC cell lines in a dose-dependent manner.


Assuntos
Antineoplásicos/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Desenho de Fármacos , Indazóis/farmacologia , Neoplasias Hepáticas/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Indazóis/síntese química , Indazóis/química , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Receptor Tipo 4 de Fator de Crescimento de Fibroblastos , Relação Estrutura-Atividade
16.
Aging (Albany NY) ; 13(5): 6982-6998, 2021 02 17.
Artigo em Inglês | MEDLINE | ID: mdl-33621955

RESUMO

Androgen receptor (AR) and histone deacetylase 6 (HDAC6) are important targets for cancer therapy. Given that both AR antagonists and HDAC6 inhibitors modulate AR signaling, a novel AR/HDAC6 dual inhibitor is investigated for its anticancer effects in castration-resistant prostate cancer (CRPC). Zeta55 inhibits nuclear translocation of AR and suppresses androgen-induced PSA and TMPRSS2 expression. Meanwhile, Zeta55 selectively inhibits HDAC6 activity, leading to AR degradation. Zeta55 reduces the growth of AR-overexpressing VCaP prostate cancer cells both in vitro and in a CRPC xenograft model. These results provide preclinical proof of principle for Zeta55 as a promising therapeutic in prostate cancer treatment.


Assuntos
Antagonistas de Receptores de Andrógenos/farmacologia , Desacetilase 6 de Histona/antagonistas & inibidores , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Transporte Ativo do Núcleo Celular/efeitos dos fármacos , Antagonistas de Receptores de Andrógenos/química , Animais , Masculino , Camundongos SCID , Antígeno Prostático Específico/efeitos dos fármacos , Serina Endopeptidases/efeitos dos fármacos
17.
J Hematol Oncol ; 14(1): 23, 2021 02 10.
Artigo em Inglês | MEDLINE | ID: mdl-33568192

RESUMO

Fibroblast growth factor receptors (FGFRs) play key roles in promoting the proliferation, differentiation, and migration of cancer cell. Inactivation of FGFRs by tyrosine kinase inhibitors (TKI) has achieved great success in tumor-targeted therapy. However, resistance to FGFR-TKI has become a concern. Here, we review the mechanisms of FGFR-TKI resistance in cancer, including gatekeeper mutations, alternative signaling pathway activation, lysosome-mediated TKI sequestration, and gene fusion. In addition, we summarize strategies to overcome resistance, including developing covalent inhibitors, developing dual-target inhibitors, adopting combination therapy, and targeting lysosomes, which will facilitate the transition to precision medicine and individualized treatment.


Assuntos
Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Receptores de Fatores de Crescimento de Fibroblastos/antagonistas & inibidores , Animais , Antineoplásicos/uso terapêutico , Humanos , Terapia de Alvo Molecular , Mutação/efeitos dos fármacos , Neoplasias/genética , Neoplasias/metabolismo , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Tirosina Quinases/antagonistas & inibidores , Receptores de Fatores de Crescimento de Fibroblastos/genética , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo , Transdução de Sinais/efeitos dos fármacos
18.
Biochem Biophys Res Commun ; 534: 1047-1052, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-33121679

RESUMO

Farnesoid X receptor (FXR) is considered as a potential target for the treatment of several liver disorders such as primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). Tropifexor is a highly potent and non-steroidal FXR agonist that has progressed into phase II clinical trials in patients with PBC. The clinical trials demonstrate that tropifexor improved serum markers of patients with liver diseases and lower side effect such as pruritus that might be implicated with TGR5 activation. However, the molecular mechanism of the potency and selectivity of tropifexor remains unclear. In this study, the binding affinity of FXR and tropifexor is measured by isothermal titration calorimetry (ITC) assays. The crystal structure of the FXR/tropifexor complex is determined at 2.7 Å resolution to explain the molecular mechanism of tropifexor bound to FXR-LBD. Structural comparison with other FXR/agonists structures reveals the conformational change in the FXR/tropifexor structure. Moreover the structural superposition of TGR5/tropifexor indicates that the steric hindrance between tropifexor and TGR5 might be a possible explanation for the impotency arises of tropifexor to TGR5. Overall, our analyses might provide an insight into the molecular mechanism of tropifexor binding to FXR-LBD and account for the high selectivity of tropifexor for FXR versus TGR5.


Assuntos
Benzotiazóis/química , Benzotiazóis/farmacologia , Isoxazóis/química , Isoxazóis/farmacologia , Receptores Citoplasmáticos e Nucleares/agonistas , Cristalografia por Raios X , Humanos , Modelos Moleculares , Ligação Proteica , Conformação Proteica/efeitos dos fármacos , Receptores Citoplasmáticos e Nucleares/química , Receptores Citoplasmáticos e Nucleares/metabolismo
19.
Herz ; 46(Suppl 2): 253-264, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33095272

RESUMO

BACKGROUND: Endothelial nitric oxide synthase (eNOS) has been reported to be involved in the atherosclerotic process. A number of studies have investigated the association between eNOS gene polymorphisms and the risk of carotid atherosclerosis (CAS). However, the results are conflicting and inconclusive. The aim of this study was to evaluate precisely the association between the eNOS T786C, G894T, and 4a/4b polymorphisms and CAS risk. MATERIAL AND METHODS: A meta-analysis was carried out by retrieving relevant studies from PubMed, Embase, China National Knowledge Infrastructure (CNKI), and Cochrane databases without a restriction on publication year. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were used to describe the strength of the association with CAS. RESULTS: Data were obtained from eight case-control studies comprising 2975 cases and 2624 controls. Significant associations were detected between the allelic and recessive models of the eNOS T786C polymorphism (allelic: p = 0.04; OR, 95% CI = 1.57 [1.01, 2.44]; recessive: p = 0.03; OR, 95% CI = 1.53 [1.04, 2.24]), as well as the allelic and dominant models of the eNOS 4a/4b polymorphism, and CAS risk in an Asian subgroup (allelic: p = 0.02; OR, 95% CI = 1.49 [1.07, 2.07]; dominant: p = 0.01; OR, 95% CI = 1.50 [1.09, 2.05]), but not in a Caucasian subgroup (p > 0.05). No association was observed between the eNOS G894T polymorphism and CAS risk (p > 0.05). CONCLUSION: Our study provides evidence that the allelic and recessive models of the eNOS T786C polymorphism and the allelic and dominant models of the eNOS 4a/4b polymorphism may increase the risk of CAS in Asian populations.


Assuntos
Doenças das Artérias Carótidas , Óxido Nítrico Sintase Tipo III , Doenças das Artérias Carótidas/diagnóstico por imagem , Doenças das Artérias Carótidas/genética , Predisposição Genética para Doença/genética , Humanos , Óxido Nítrico Sintase Tipo III/genética , Razão de Chances , Polimorfismo Genético , Polimorfismo de Nucleotídeo Único/genética
20.
J Hazard Mater ; 402: 123800, 2021 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-33254803

RESUMO

Thallium (Tl) and uranium (U) contaminants pose serious threats to the ecological environment and human health. In this research, a cost-effective feroxyhite (δ-FeOOH) dispersed with sodium dodecyl sulfonate (SDS) was prepared and a series of experiments were optimized to explore the removal mechanism of Tl+ and UO22+ from the effluent. The SDS/δ-FeOOH exhibited highly dispersed colloidal particles and showed significantly enhanced adsorption performance on the removal of Tl and U in the presence of H2O2 and pH of 7.0. Equilibrium uptakes of 99.5% and 99.7% were rapidly achieved for Tl+ and UO22+ within 10 min, respectively. The Freundlich isotherm model fitted well with the adsorption data of Tl and U. The maximum isotherm sorption capacity of SDS/δ-FeOOH for Tl+ and UO22+ was 182.9 and 359.6 mg/g, respectively. The sorption of Tl followed the pseudo-second-order kinetic model, whereas the sorption of U followed the pseudo-first-order kinetic model. The uptake of Tl and U by SDS/δ-FeOOH was notably inhibited at Na+, K+ concentrations over 5.0 mM, and a high content of dissolved organic matter (over 0.5 mg/L). The mechanistic study revealed that ion exchange, precipitation, and surface complexation were main mechanisms for the removal of Tl and U. The findings of this study indicate that stabilizer dispersion may serve as an effective strategy to facilitate the treatment of wastewater containing Tl and U by using δ-FeOOH.

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