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1.
Mol Nutr Food Res ; : e2200428, 2023 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-36708241

RESUMO

SCOPE: Changes in the intestinal flora is related to autoimmune hepatitis (AIH) development. The aim of this study was to investigate the synergistic effects of probiotics and prebiotics on liver injury induced by concanavalin A (Con A). METHODS AND RESULTS: C57BL/6 mice were fed probiotics (Pro), prebiotics (Pre), synbiotic (Syn) for 7 day and then Con A was injected via tail veins to induce AIH. Additionally, methylprednisolone (MP) was gavaged 0.5 h after the Con A injection. It was found that both Pro, Pre, Syn and MP decreased the levels of serum transaminase, liver F4/80+ macrophage cells and hepatocellular apoptosis. Pro, Pre and Syn decreased proinflammatory cytokines, elevated levels of anti-inflammatory as well as restored immune imbalance in AIH. Besides, Pro, Pre and Syn not only reshaped the perturbed gut microbiota, but also maintained intestinal barrier integrity, blocked the activation of lipopolysaccharide (LPS)/TLR4/NF-κB pathway in the liver. Interestingly, the effects of Syn were superior to Pro or Pre alone in Con A-induced acute liver injury. CONCLUSIONS: Syn obviously facilitated AIH remission. The combined use of Pro and Pre is effective in improving Pro and Pre efficacy and can be an important tool for preventing and adjuvant treating patients for AIH. This article is protected by copyright. All rights reserved.

3.
Eur J Med Chem ; 247: 115016, 2023 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-36577219

RESUMO

CRBN E3 ligase modulators, also anteriorly called immunomodulatory drugs (IMiDs), exhibit excellent pharmacological activity by degrading cereblon (CRBN) associated multiple substrates and have become an important field for drug development. These modulators such as Thalidomide, Lenalidomide and CC-122 abduct CRBN to adhere to IKZF1/3 and other neosubstrates, and then induce the degradation of these substrates, thus retarding the further development of related diseases. Herein, we reported a series of CC-122 derivatives that inhibit the proliferation of hematological malignant tumor cell lines. Studies further confirmed that several derivatives which exhibit strong anti-proliferation effect induce the significant degradation of IKZF1/3. In addition, we found that the best compound 14 (SIAIS355035) exhibits better degradation activity and better anti-proliferation activities than CC-122, especially in diffuse large B lymphoma cell lines. Moreover, the PK properties of compound 14 are pretty promising with excellent oral bioavailability. These results clarified the SAR of CC-122 derivatives preliminarily and suggested that compound 14 has great value for further studies as an ideal novel CRBN E3 ligase modulation drug.


Assuntos
Peptídeo Hidrolases , Ubiquitina-Proteína Ligases , Ubiquitina-Proteína Ligases/metabolismo , Peptídeo Hidrolases/metabolismo , Talidomida , Lenalidomida , Ubiquitinação , Fatores de Transcrição/metabolismo
4.
Curr Neuropharmacol ; 20(9): 1774-1782, 2022 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-34544343

RESUMO

BACKGROUND: Oxidative stress plays an important role in weight gain induced by antipsychotics in schizophrenia (SCZ). However, little is known about how antioxidant enzymes are involved in weight gain caused by risperidone monotherapy in antipsychotics-naïve first-episode (ANFE) patients with SCZ. Therefore, the main purpose of this study was to investigate the effects of risperidone on several antioxidant enzymes in patients with ANFE SCZ and the relationship between weight gain and changes in antioxidant enzyme activities. OBJECTIVE: The activities of plasma superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx), as well as the levels of malondialdehyde (MDA) were measured in 225 ANFE patients and 125 healthy controls. METHODS: Patients were treated with risperidone monotherapy for 12 weeks. Clinical symptoms, antioxidant enzyme activities, and MDA levels were measured at baseline and during follow-up. RESULTS: Compared with healthy controls, the patients showed higher activities of SOD and CAT but lower MDA levels and GPx activity. At baseline, the CAT activity was associated with body weight or BMI. Further, based on a 7% weight increase from baseline to follow-up, we found 75 patients in the weight gain (WG) group and 150 patients in the non-WG group. Comparing SOD, CAT, GPx activities and MDA levels between the WG group and the non-WG group at baseline and during the 12-week follow-up, it was found that after treatment, the SOD activity in the WG group increased while the MDA level decreased in the non-WG group. Moreover, baseline SOD and GPx activities were predictors of weight gain at 12-week follow-up. CONCLUSION: These results suggest that the antioxidant defense system may have predictive value for the weight gain of ANFE SCZ patients after risperidone treatment.


Assuntos
Antipsicóticos , Esquizofrenia , Antioxidantes/uso terapêutico , Antipsicóticos/uso terapêutico , Estudos de Casos e Controles , Humanos , Estudos Longitudinais , Estresse Oxidativo , Estudos Prospectivos , Risperidona/uso terapêutico , Esquizofrenia/tratamento farmacológico , Superóxido Dismutase/metabolismo , Superóxido Dismutase/uso terapêutico , Aumento de Peso
5.
BMC Pregnancy Childbirth ; 22(1): 889, 2022 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-36456970

RESUMO

BACKGROUND: Gestational diabetes mellitus (GDM) can lead to adverse maternal and fetal outcomes, and early prevention is particularly important for their health, but there is no widely accepted approach to predict it in the early pregnancy. The aim of the present study is to build and evaluate predictive models for GDM using routine indexes, including maternal clinical characteristics and laboratory biomarkers, before 16 gestational weeks. METHODS: A total of 2895 pregnant women were recruited and maternal clinical characteristics and laboratory biomarkers before 16 weeks of gestation were collected from two hospitals. All participants were randomly stratified into the training cohort and the internal validation cohort by the ratio of 7:3. Using multivariable logistic regression analysis, two nomogram models, including a basic model and an extended model, were built. The discrimination, calibration, and clinical validity were used to evaluate the models in the internal validation cohort. RESULTS: The area under the receiver operating characteristic curve of the basic and the extended model was 0.736 and 0.756 in the training cohort, and was 0.736 and 0.763 in the validation cohort, respectively. The calibration curve analysis showed that the predicted values of the two models were not significantly different from the actual observations (p = 0.289 and 0.636 in the training cohort, p = 0.684 and 0.635 in the internal validation cohort, respectively). The decision-curve analysis showed a good clinical application value of the models. CONCLUSIONS: The present study built simple and effective models, indicating that routine clinical and laboratory parameters can be used to predict the risk of GDM in the early pregnancy, and providing a novel reference for studying the prediction of GDM.


Assuntos
Diabetes Gestacional , Gravidez , Feminino , Humanos , Diabetes Gestacional/diagnóstico , Diabetes Gestacional/epidemiologia , Feto , Cuidado Pré-Natal , Família , Biomarcadores
6.
Front Oncol ; 12: 992171, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36465350

RESUMO

Protein-protein interactions (PPIs) play vital roles in normal cellular processes. Dysregulated PPIs are involved in the process of various diseases, including cancer. Thus, these PPIs may serve as potential therapeutic targets in cancer treatment. However, despite rapid advances in small-molecule drugs and biologics, it is still hard to target PPIs, especially for those intracellular PPIs. Macrocyclic peptides have gained growing attention for their therapeutic properties in targeting dysregulated PPIs. Macrocyclic peptides have some unique features, such as moderate sizes, high selectivity, and high binding affinities, which make them good drug candidates. In addition, some oncology macrocyclic peptide drugs have been approved by the US Food and Drug Administration (FDA) for clinical use. Here, we reviewed the recent development of macrocyclic peptides in cancer treatment. The opportunities and challenges were also discussed to inspire new perspectives.

7.
Artigo em Inglês | MEDLINE | ID: mdl-36456838

RESUMO

Alcoholic liver disease (ALD) is a worldwide health threaten lack of effective treatment. Gut dysbiosis and concomitant augmented intestinal permeability are strongly implicated in the pathogenesis and progression of ALD. Research on the protective effect of probiotics on ALD is limited, and more effective intestinal microecological regulators and the related mechanisms still need to be further explored. In the present study, the protective effects and mechanisms of a compound probiotic against acute alcohol-induced liver injury in vivo were explod. It was showed that the compound probiotic ameliorated liver injury in acute ALD mice and stabilized the levels of ALT, AST, and TG in serum. The compound probiotic reversed acute alcohol-induced gut dysbiosis and maintained the intestinal barrier integrity by upregulating the production of mucus and the expression of tight junction (TJ) proteins and thus reduced LPS level in liver. Meanwhile, the compound probiotic reduced inflammation level by inhibiting TLR4/NF-κB signaling pathway and suppressed oxidative stress level in liver. Furthermore, the compound probiotic alleviated liver lipid accumulation by regulating fatty acid metabolism-associated genes and AMPK-PPARα signaling pathway. Noteworthy, fecal microbiota transplantation (FMT) realized comparable protective effect with that of compound probiotic. In conclusion, present study demonstrates the beneficial effects and underlying mechanism of the compound probiotic against acute alcohol-induced liver injury. It provides clues for development of novel strategy for treatment of ALD.

8.
J Biochem Mol Toxicol ; : e23271, 2022 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-36510830

RESUMO

Atherosclerosis (AS) is one of the principal causes of cardiovascular disorder. Reportedly, vascular smooth muscle cells (VSMCs) and human umbilical vein endothelial cells (HUVECs) play key roles in AS development, and microRNAs (miRNAs) regulate their functions. The function of miR-216b-5p in AS remains unknown. Human VSMCs and human HUVECs were treated with ox-LDL to establish the in vitro model of AS. MiR-216b-5p and IGF2 expressions in VSMCs and HUVECs were probed by qRT-PCR and western blot. The viability, cell cycle progression, and apoptosis of VSMCs and HUVECs were evaluated by Cell Counting Kit-8 (CCK-8), 5-ethynyl-2'-deoxyuridine, and flow cytometry assays, respectively. The binding sites between IGF2 3'UTR and miR-216b-5p were validated by dual-luciferase reporter assay. miR-216b-5p expression was declined in ox-LDL-induced VSMCs and HUVECs. In VSMCs, miR-216b-5p overexpression inhibited excessive proliferation and induced apoptosis. MiR-216b-5p could markedly restrain the viabiblity of VSMCs induced by ox-LDL and enhanced the viability of HUVECs. Additionally, IGF2 was confirmed as the direct target of miR-216b-5p and transfection of IGF2 overexpression plasmids rescued the effects of miR-216b-5p on VSMCs and HUVECs. miR-216b-5p alleviates the dysfunction of VSMCs and HUVECs caused by ox-LDL via repressing IGF2, and exerts protective functions to block the development of AS.

9.
Opt Express ; 30(24): 43728-43740, 2022 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-36523065

RESUMO

In this paper, by elaborately splicing multiple transmissive metasurfaces (MSs) featuring polarization isolation, multiple linear polarized (LP) vortex beams are generated simultaneously and independently in different directions. Specifically, by carefully optimizing the radius of the array and the distance between the MS and array, each MS generates a well-performed deflection vortex beam with a low side-lobe level and little diffraction, resulting in a minor effect on other deflection vortex beams. Subsequently, four transmissive MSs are elaborately spliced, showing the polarization isolation characteristic between the adjacent MS, and thereby each MS is only illuminated by the respective antenna array. In addition, each MS only generates the desired LP vortex beam, and the corresponding cross-polarization is suppressed. Finally, the simulation and measurement results show that multiple LP vortex beams carrying different orbital angular momentum (OAM) modes are generated simultaneously and independently in different directions, verifying the effectiveness of the proposed method.

10.
Fish Physiol Biochem ; 2022 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-36525144

RESUMO

Melanocortin 3 and 4 receptors are two important neural G protein-coupled receptors that regulate energy homeostasis in vertebrates. Melanocortin receptor accessory protein 2 (MRAP2) is also involved in the regulation of food intake and body weight as a variable regulator of melanocortin receptors. Rainbow trout (Oncorhynchus mykiss) is a valuable cold-water fish cultured worldwide. In the rainbow trout model, we cloned and identified mrap2a, a paralog of mrap2. Rainbow trout mrap2a consisted of a 690 bp ORF and was expected to encode a putative protein of 229 amino acids. The qPCR results showed that rainbow trout mrap2a was expressed at high levels in brain tissue similar to mc3r and mc4r. In addition, co-immunoprecipitation verified that MRAP2a interacts with MC3R and MC4R in vitro and that MRAP2a is involved in and regulates the constitutive activity and signaling of MC3R and MC4R. MRAP2a reduced constitutive and agonist-stimulated cAMP levels of MC3R; furthermore, MRAP2a increased constitutive ERK1/2 activation but reduced ligand-induced stimulation at high levels of expression. For MC4R, MRAP2a showed decreased cAMP basal activity but increased agonist-stimulated cAMP signaling and increased ACTH ligand sensitivity. However, MRAP2a failed to affect MC4R constitutive activity and agonist-induced ERK1/2 signaling. Undoubtedly, our study will have great significance for revealing the conserved role of MC4R and MC3R signaling in teleost fish, especially in cold-water fish growth and energy homeostasis.

11.
Fish Physiol Biochem ; 2022 Dec 22.
Artigo em Inglês | MEDLINE | ID: mdl-36547499

RESUMO

The melanocortin-3-receptor (MC3R) plays an important role in mammals' food intake and energy homeostasis. However, its physiological role in bony fishes, such as grass carp, has not been well understood. This study reports the molecular cloning, tissue distribution, and pharmacological characterization of grass carp melanocortin-3-receptor (ciMC3R). Phylogenetic and chromosomal synteny analyses indicated that ciMC3R was closest to cyprinid fishes in evolution. Quantitative PCR experiments revealed that the mRNA of ciMC3R was highly expressed in the brain of grass carp. The cytological function of ciMC3R was investigated by the co-transfection of pcDNA3.1-ciMC3R and the signal-pathway-specific luciferase into the HEK293T cells. Results revealed that the four agonists, α-MSH, ß-MSH, ACTH, and NDP-MSH, potentiate the activation of ciMC3R and further increase the production of cAMP and upregulate the MAPK/ERK signaling, respectively. Our study will provide basic data for exploring the physiological functions of grass carp MC3R, especially in energy homeostasis and food intake.

12.
Artigo em Inglês | MEDLINE | ID: mdl-36573083

RESUMO

Aims: Abnormal changes in cardiac function have been reported in menopausal women, but there are few clinical studies on this topic. Erxian decoction (EXD) is a classic prescription that is widely used in the treatment of female menopausal diseases. The purpose of this study was to investigate the dynamic evolution of cardiac function and glucose and lipid metabolism in ovariectomized (OVX) rats and the intervention effect of EXD. Materials and Methods: The OVX climacteric rat model was established by bilateral ovariectomy. After successful modeling, the rats were randomly divided into four groups: the sham operation (SHAM) group (equal volumes of purified water), OVX group (equal volumes of purified water), estradiol (E2) group (1.8 × 10-4 g/kg), and EXD group (9 g/kg). Each group of rats was treated for 16 weeks. At the 4th, 8th, 12th, and 16th weeks after treatment, the cardiac function of the rats in each group was evaluated by ultrasound. The coaxial method was used to measure blood pressure (BP). Serum endothelin-1 (ET-1) and angiotensin-2 (Ang II) levels were determined by the enzyme-linked immunosorbent assay (ELISA). The strip method was used to measure fasting blood glucose (FBG). The serum total cholesterol (TC) and triglyceride (TG) levels of rats were measured with the oxidase method. Direct methods were used to measure serum high-density lipoprotein (HDL-C) and low-density lipoprotein (LDL-C) levels. At week 16 of dosing, serum E2 levels were determined by E2 radioimmunoassay. The myocardium and uterus of the rats in each group were stained with HE (hematoxylin-eosin). The ultrastructure of the rat myocardium was observed by electron microscopy. Results: After the 16th week of treatment, the serum E2 level decreased (P < 0.05), and the uterus was atrophied in OVX rats. The cardiac ejection fraction (EF%) decreased at 4 weeks after treatment, and systolic and diastolic function decreased after 12 weeks. After the 16th week, the EF%, which reflects the "pump" function of the heart, decreased significantly (P < 0.05 or P < 0.01). At the 4th, 8th, 12th, and 16th weeks of treatment, the systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean pressure (MBP) of the rats in the OVX group increased with time (P < 0.05 or P < 0.01). The serum ET-1 and Ang II levels of rats in the OVX group increased (P < 0.05 or P < 0.01). In the OVX group, FBG was increased (P < 0.05 or P < 0.01), and blood lipids, especially LDL-C, were significantly increased (P < 0.05 or P < 0.01). After the 16th week of treatment, the myocardial tissue of OVX rats showed obvious pathological changes. EXD significantly increased serum E2 levels (P < 0.01), decreased ET-1 and Ang II levels (P < 0.01), reduced the cardiac function risk factors BP, FBG, and blood lipids, and significantly improved cardiac function and structural changes in OVX rats (P < 0.05 or P < 0.01). Conclusions: EXD can improve abnormal cardiac structure and function in OVX rats.

13.
Artigo em Inglês | MEDLINE | ID: mdl-36401011

RESUMO

Dioxins and dioxin-like polychlorinated biphenyls (DL-PCBs) are mainly released as by-products of human activities, often in the form of mixtures, and the potential harm on human health deserves attention. Therefore, our study aimed to analyze the combined effect of dioxins and DL-PCB exposures on hypertension (HTN) among US adults. Data of eligible participants were acquired from the National Health and Nutrition Examination Survey (NHANES). Multiple logistic regression models with adjustment for covariates were applied to explore the associations between 13 persistent organic pollutants (POPs) and HTN. Stratified analyses and interaction analyses were then conducted by age and gender. Finally, the combined effects of dioxins and DL-PCBs on HTN were assessed by the weighted quantile sum (WQS) model and the Bayesian kernel machine regression (BKMR) model. A total of 976 adults were included in our study, of whom 397 had HTN. Spearman correlations indicated positive correlations among 13 POPs. And most of them (except PCB28, PCB66, and 1,2,3,4,7,8,9-hpcdf) had significant effects on HTN. The result of WQS revealed that mixed exposure to dioxins and DL-PCBs was significantly associated with increased risk of HTN (OR: 2.205; 95% CIs: 1.555, 3.127). The BKMR model also presented a positive trend of HTN risk with exposure to multiple dioxins and DL-PCBs. And 1,2,3,4,6,7,8,9-ocdd may be the main factor for this positive association. Considering the limitations of our cross-sectional study with the small sample, further prospective studies are necessary to validate our findings.

14.
PLoS One ; 17(11): e0277871, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36395187

RESUMO

Osteoclasts are the only multinucleated cells in vivo responsible for bone resorption and are vital for regulating bone remodeling and maintaining bone mass. The RAW264.7 cell line is widely used to study osteoclastic differentiation and biological molecular mechanism. However, protocols for inducing osteoclast formation in RAW264.7 cells vary considerably between laboratories, hindering the replication of results. Therefore, we tested the influence of culture conditions on osteoclast differentiation, including cell density and receptor activator of nuclear factor kappa-B ligand (RANKL) concentrations with or without macrophage colony-stimulating factors (M-CSF). Tartrate-resistant acid phosphatase (TRAP) staining was used to detect the morphology of osteoclasts. qPCR was used to detect gene expression of osteoclast-specific gene marker cathepsin K (CTSK), osteoclast transcription factors c-Fos and nuclear factor of activated T cells, cytoplasmic 1 (NFATc1). The bone resorption function was evaluated by a scanning electron microscope (SEM). RANKL treatment increased multinucleated osteoclasts formation and increased CTSK, c-Fos and NFATc1 gene expression. Compared with RANKL treatment, M-CSF significantly decreased multinucleated osteoclasts formation, reduced CTSK gene expression and had little effect on c-Fos and NFATc1 gene expression. Concerning bone resorption activity, RANKL treatment increased bone resorption pits on bovine bone slices. Significantly higher levels of osteoclastogenesis were observed with RAW264.7-cell density of 2×104 cells/well in 24-well plates. Our results suggest that the addition of 50 ng/ml M-CSF has no positive effect on osteoclastogenesis. RANKL treatment and cell density contribute to osteoclast formation, and the optimal conditions are beneficial when exploring osteoclast function and mechanism.


Assuntos
Reabsorção Óssea , Osteogênese , Animais , Bovinos , Fator Estimulador de Colônias de Macrófagos/farmacologia , Fatores de Transcrição NFATC/genética , Fatores de Transcrição NFATC/metabolismo , Diferenciação Celular , Reabsorção Óssea/genética , Reabsorção Óssea/metabolismo , Proteínas Proto-Oncogênicas c-fos/genética
15.
Eur J Clin Pharmacol ; 2022 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-36334108

RESUMO

PURPOSE: Aspirin has been suggested to reduce the risk of cancer. However, previous studies have been inconsistent regarding the relationship between aspirin use and the risk of occurrence of hepatocellular carcinoma (HCC). The purpose of this study was to assess the effect of aspirin on clinical outcomes in patients with HCC in a meta-analysis and to explore the possible dose-response relationship. METHODS: A systematic literature search was conducted in 10 electronic databases and 4 registries. The combined hazard ratios (HRs) were calculated using a random-effects model with 95% confidence interval (CIs) to assess the effect of aspirin on the risk of HCC. Relevant subgroup analyses and sensitivity analyses were performed. RESULTS: The results show that aspirin use correlated with lower incidence of HCC (HR: 0.75, 95% CI: 0.71-0.80), decreased risk of HCC recurrence (HR: 0.79, 95% CI: 0.65-0.96), and reduced mortality (HR: 0.72, 95% CI: 0.60-0.87). The results of the subgroup analysis showed that aspirin use was consistently associated with reduced incidence of HCC across different regions, study designs, and populations. A linear relationship was found for both dosage and duration of aspirin use. An increased of bleeding with aspirin use among patients was also observed (HR 1.10, 95% CI: 1.02-1.20). CONCLUSIONS: This meta-analysis found that aspirin use was independently associated with a reduced risk of HCC incidence, recurrence, and death. Furthermore, aspirin use influenced HCC occurrence in a dose-dependent and duration-dependent manner. However, an increased risk of bleeding with aspirin use was noted.

16.
Environ Sci Pollut Res Int ; 29(59): 88461-88487, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36329245

RESUMO

The association between allergic respiratory diseases, such as asthma and allergic rhinitis (AR), and green space (GS) remains controversial. Our study aimed to summarize and synthesize the association between individual GS exposure and the incidence of asthma/AR. We systematically summarized the qualitative relationship between GS exposure and asthma and AR. The pooled odds ratio (OR) with 95% confidence intervals (CIs) was used to estimate the effect of the Normalized Difference Vegetation Index (NDVI) on asthma and AR. A total of 21 studies were included for systematic review, and 8 of them underwent meta-analysis. In the meta-analysis of current asthma, the 0 < radius ≤ 100 m group, 100 < radius ≤ 300 m group, and 500 < radius ≤ 1000 m group presented weak negative associations between the NDVI and current asthma. For ever asthma, slight positive associations existed in the 0 < radius ≤ 100 m group and 300 < radius ≤ 500 m group. In addition, the NDVI might slightly reduce the risk of AR in radius of 100 m and 500 m. Our findings suggest that the effects of GS exposure on asthma and AR were not significant. Differences in GS measurements, disease diagnoses and adjusted confounders across studies may have an impact on the results. Subsequent studies should consider potential confounding factors and use more accurate GS exposure measurements to better understand the impact of GS exposure on respiratory disease in the population.


Assuntos
Asma , Rinite Alérgica , Humanos , Incidência , Parques Recreativos , Rinite Alérgica/epidemiologia , Asma/epidemiologia , Razão de Chances
17.
Cell Chem Biol ; 29(11): 1616-1629.e12, 2022 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-36323324

RESUMO

Aberrant overexpression of nicotinamide phosphoribosyltransferase (NAMPT) has been reported in a variety of tumor cells and is a poor prognosis factor for patient survival. It plays an important role in tumor cell proliferation, acting concurrently as an nicotinamide adenine dinucleotide (NAD+) synthase and, unexpectedly, as an extracellular signaling molecule for several tumor-promoting pathways. Although previous efforts to modulate NAMPT activity were limited to enzymatic inhibitors with low success in clinical studies, protein degradation offers the possibility to simultaneously disrupt NAMPT's enzyme activity and ligand capabilities. Here we report the development of two highly selective proteolysis-targeting chimeras (PROTACs) that promote NAMPT degradation in a cereblon-dependent manner. Both PROTAC degraders outperform a clinical candidate, FK866, in killing effect on hematological tumor cells. These results emphasize the importance and feasibility of applying PROTACs as a superior strategy for targeting proteins with multiple tumor-promoting functions like NAMPT, which is not easily achieved by conventional enzymatic inhibitors.


Assuntos
Neoplasias , Nicotinamida Fosforribosiltransferase , Humanos , Proliferação de Células , NAD , Neoplasias/tratamento farmacológico , Proteólise
18.
Dis Markers ; 2022: 4882375, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36438895

RESUMO

Purpose: This present study is aimed at exploring the FGB expression in breast cancer (BC) and the role of FGB in BC. Methods: A total of 150 pairs of BC tissues and adjacent tissues from BC surgery patients were collected. RT-qPCR was utilized to evaluate the mRNA expression of FGB and miR-877-5p. Immunohistochemistry was applied to evaluate the protein expression of FGB. Chi-square test was performed to evaluate the relationship between FGB expression level and clinical characteristics. Cell proliferation was examined using CCK-8 assay. Cell invasion was evaluated by transwell assay. Flow cytometry assay was applied to measure cell apoptosis. The protein expression was evaluated by western blot. BALB/C nude mice were used to establish the xenograft tumor model. Results: FGB was more highly expressed in BC tumor, and the expression of FGB was relevant to TNM stage and lymph node metastasis and showed a positive correlation. FGB was proved to be directly regulated via miR-877-5p and enhanced proliferation and invasion of BC cells. FGB downregulation markedly inhibited the tumor growth, including tumor weight and volume. In addition, the Ki-67 expression was observably declined in the sh-FGB group. The protein expression of E-cadherin was markedly raised in the sh-FGB group while the protein expression of N-cadherin and vimentin was markedly declined in the sh-FGB group. Conclusion: In conclusion, miR-877-5p inhibits epithelial mesenchymal transformation, cell proliferation, and invasion of BC cells via downregulating FGB.


Assuntos
Neoplasias da Mama , MicroRNAs , Camundongos , Animais , Humanos , Feminino , Transição Epitelial-Mesenquimal/genética , Invasividade Neoplásica/genética , MicroRNAs/genética , MicroRNAs/metabolismo , Regulação Neoplásica da Expressão Gênica , Movimento Celular/genética , Camundongos Nus , Linhagem Celular Tumoral , Camundongos Endogâmicos BALB C , Neoplasias da Mama/patologia , Fibrinogênio/metabolismo
19.
Eur J Med Chem ; 244: 114810, 2022 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-36306539

RESUMO

The oncogenic fusion protein BCR-ABL is the driving force of leukemogenesis in chronic myeloid leukemia (CML). Despite the great advance in CML treatment through the application of tyrosine kinase inhibitors (TKIs) against BCR-ABL, disease recurrence after TKI discontinuation and clinical resistance mainly due to BCR-ABL mutations continue to be an issue. Herein we report our efforts to synthesize a novel series of CRBN-recruiting proteolysis-targeting chimeras (PROTACs) targeting BCR-ABL based on the allosteric inhibitor asciminib. Our efforts have led to the discovery of compound 30 (SIAIS100) through extensive SAR studies by the optimization of linker parameters as well as linker attachment points of both target-binding warhead and CRBN ligands, which exhibited the most potent degradative activity with a DC50 value of 2.7 nM and Dmax of 91.2% against BCR-ABL and has an IC50 value of 12 nM in BCR-ABL + K562 cells. The binding model and the stability evaluation of 30-induced ternary complex formation were also elucidated through computational simulations. Furthermore, 30 induced sustained and robust BCR-ABL degradation and maintained the efficacy for 96 h post-washout. Moreover, the proteomics analysis showed that 30 degraded BCR-ABL and three CRBN's neo-substrates, including IKZF1, IKZF3, and ZFP91. Additionally, 30 also exerted degradative activity against a panel of clinically relevant resistance-conferring mutations of BCR-ABL, including gatekeeper mutation T315I, several single mutations associated with TKI resistance, and certain highly resistant compound mutations. Our study provided a deeper understanding of the development of PROTACs targeting BCR-ABL and novel potential therapeutic agents for CML treatment.


Assuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva , Inibidores de Proteínas Quinases , Humanos , Inibidores de Proteínas Quinases/química , Resistencia a Medicamentos Antineoplásicos , Proteínas de Fusão bcr-abl , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Células K562 , Mutação , Ubiquitina-Proteína Ligases
20.
Iran J Public Health ; 51(8): 1790-1797, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-36249109

RESUMO

Background: Dietary factors play an important role in gastric cancer risk. They have not been investigated extensively in Hanzhong area, China. Methods: We conducted a population-based case-control study of gastric cancer in Hanzhong area, China in 2018-2020. A total of 121 patients with historically confirmed gastric adenocarcinomas were interviewed. Controls were an age-stratified random sample of residents of Hanzhong area. The dietary questionnaire was a 70-item semiquantitative food frequency adapted for the Hanzhong diet. Odds ratios were calculated for quartiles of consumption of food groups and were adjusted for age, gender, calories, chili pepper intake, cigarette smoking, socioeconomic status, added salt, and history of peptic ulcer disease. Results: There was approximately a threefold increased risk of gastric cancer for frequent consumption (highest quartile) of both fresh meat (odds ratio (OR) = 3.0) and processed meat (OR = 3.3). Odds ratios were also significantly elevated for frequent consumption of dairy products (OR = 3.1) and fish (OR = 3.1). The authors observed a decreasing gradient of risk with increasing frequency of vegetable consumption due to a significant inverse trend for the yellow and orange vegetables. Conclusion: High intake of citrus fruits showed a slight inverse association. These findings are consistent with many studies around the world that indicate important roles for salt, processed meats, and vegetable consumption in gastric cancer risk.

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