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1.
J Exp Med ; 218(5)2021 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-33822843

RESUMO

Triple-negative breast cancers (TNBCs) are associated with poor survival mediated by treatment resistance. TNBCs are fibrotic, yet little is known regarding how the extracellular matrix (ECM) evolves following therapy and whether it impacts treatment response. Analysis revealed that while primary untreated TNBCs are surrounded by a rigid stromal microenvironment, chemotherapy-resistant residual tumors inhabit a softer niche. TNBC organoid cultures and xenograft studies showed that organoids interacting with soft ECM exhibit striking resistance to chemotherapy, ionizing radiation, and death receptor ligand TRAIL. A stiff ECM enhanced proapoptotic JNK activity to sensitize cells to treatment, whereas a soft ECM promoted treatment resistance by elevating NF-κB activity and compromising JNK activity. Treatment-resistant residual TNBCs residing within soft stroma had elevated activated NF-κB levels, and disengaging NF-κB activity sensitized tumors in a soft matrix to therapy. Thus, the biophysical properties of the ECM modify treatment response, and agents that modulate stiffness-dependent NF-κB or JNK activity could enhance therapeutic efficacy in patients with TNBC.

2.
Artigo em Inglês | MEDLINE | ID: mdl-33810966

RESUMO

BACKGROUND & AIMS: Sarcopenia is a clinical syndrome that features muscle atrophy and weakness, and has been associated with cardiovascular events and poor clinical outcomes. Recently, the sarcopenia index (SI) was developed as a simple screening tool based upon the serum creatinine to cystatin C (CysC) ratio. We investigated the association between SI and the prevalence of major adverse cardiovascular events (MACE) in patients with obstructive CAD. METHODS & RESULTS: Between January 2010 and December 2018, patients with angina pectoris and obstructive CAD requiring coronary artery intervention were enrolled. Serum levels of CysC and other biomarkers were assessed. Patients were divided into two groups according to the SI ([Cr/CysC] x 100). Demographic characteristics and clinical outcomes of the two groups were evaluated. A total of 427 patients (79.6% men, mean age 69.55 ± 12.04 years) were enrolled. Patients with SI < 120 (n = 214, 28%) were older, more likely to be of the female gender, and to have more hypertension and congestive heart failure (all p < 0.05). The prevalence of major adverse cardiovascular events (MACE) composed of myocardial infarction, stroke, and all-cause mortality was higher in patients with lower SI (p = 0.026). After adjusting for potential confounding factors, multivariate Cox regression (hazard ratio 2.08, p = 0.045) and Kaplan-Meier analyses (log-rank p = 0.0371) revealed that lower SI was significantly associated with a higher prevalence of MACE. CONCLUSIONS: Serum creatinine to cystatin C ratio (SI) may be a useful surrogate marker to predict the future prevalence of MACE in patients with obstructive CAD.

3.
J Mol Cell Cardiol ; 155: 99-110, 2021 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-33713645

RESUMO

Background Diabetes has a pronounced effect on the peripheral vasculature. The accumulation of advanced glycation end products (AGEs) is regarded as the crucial mechanism responsible for vascular damage in diabetes, but it is not easy to be avoided from food. In this study, we aimed to investigate the effects of an oral absorbent, AST-120, on the accumulation of AGEs and changes in blood flow recovery in diabetic mice. Methods The mice were divided into four groups, wild-type (WT) mice without treatment, WT mice treated with 5% AST-120 mixed into pulverized chow, streptozotocin-induced diabetes mellitus (DM) mice, and DM mice treated with 5% AST-120. Six weeks after hind-limb ischemia surgery, blood flow reperfusion, histology, plasma AGE, and cytokine were examined. Bone marrow cells were cultured and derived into macrophages to evaluate the effects of AGEs on macrophage polarization. Results Plasma AGEs were significantly increased in diabetic mice. AST-120 could bind to AGEs and reduced their plasma concentrations. Histological analysis revealed fewer collateral vessels with corresponding impairment of blood flow recovery in diabetic mice. In these mice, AGE-positive and AGE receptor-positive macrophages were numerous in ischemic limbs compared with non- diabetic mice. In diabetic mice, macrophages in ischemic tissues demonstrated greater M1 polarization than M2 polarization; this pattern was reversed in the AST-120 treatment group. The change in macrophage polarization was associated with the corresponding expression of pro-inflammatory cytokines in the ischemic tissues. In cell cultures, AGEs triggered the transformation of bone marrow-derived macrophages into the M1 phenotype. The alterations in the polarization of macrophages were reversed after treatment with AST-120. Conclusions Oral administration of AST-120 decreased the serum levels of AGEs in diabetic mice and improved neovascularization of ischemic limbs. This benefit may be due to, at least partially, the alterations in macrophage polarization and the associated changes in inflammatory cytokines.

4.
Sci Rep ; 11(1): 5853, 2021 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-33712706

RESUMO

Bacterial cancer therapy was developed using probiotic Escherichia coli Nissle 1917 (EcN) for medical intervention of colorectal cancer. EcN was armed with HlyE, a small cytotoxic protein, under the control of the araBAD promoter (PBAD). The intrinsic limitation of PBAD for the gene expression is known to be negated by glucose and afflicted with all-or-nothing induction in host bacteria. This issue was addressed by metabolic engineering of EcN to uncouple the glucose-mediated control circuit and the L-arabinose transport-induction loop and to block L-arabinose catabolism. As a result, the reprogrammed strain (designated EcNe) enabled efficient expression of HlyE in a temporal control manner. The HlyE production was insensitive to glucose and reached a saturated level in response to L-arabinose at 30-50 µM. Moreover, the administrated EcNe exhibited tumor-specific colonization with the tumor-to-organ ratio of 106:1. Equipped with HlyE, EcNe significantly caused tumor regression in mice xenografted with human colorectal cancer cells. Overall, this study proposes a new strategy for the bacteria-mediated delivery of therapeutic proteins to tumors.

5.
Ann Palliat Med ; 10(3): 2958-2970, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33691439

RESUMO

BACKGROUND: The present study aimed to explore the effectiveness of electro-acupuncture (EA) in combination with a local anesthetic used in Western medicine in preventing the side effects of gastroscopy. METHODS: A sample group of 150 patients were divided into three groups based on treatment methods: an EA group, a dyclonine hydrochloride mucilage group, and a combined treatment group. In the EA group, EA stimulation was given at the Hegu, Neiguan, and Zusanli acupoints; in the dyclonine hydrochloride mucilage group, patients took 10 mL of dyclonine hydrochloride mucilage orally; in the combined treatment group, prevention of side effects was attempted by administration of both acupuncture and oral local anesthetic. The incidences of nausea, emesis, salivation, cough, restlessness, and breath holding during gastroscopy were observed and recorded for the three groups. Mean arterial pressure, heart rate, and oxygen saturation were recorded before the examination, and changes in these measures were recorded as the gastroscope passed through the pylorus and after the examination. The visual analogue scale (VAS) values of nausea and emesis, the rate of successful first-pass intubation, and the time of gastroscopy were also recorded. Statistical analysis was performed using R-3.5.3 software. RESULTS: Incidences of side effects (e.g., nausea, emesis, salivation, restlessness, and breath holding) during the examination were lower in the combined treatment group than in the EA group and the dyclonine hydrochloride mucilage group (P<0.05 and P<0.01, respectively). Furthermore, the changes in heart rate and oxygen saturation when the gastroscope passed through the pylorus and after the examination were better in the combined treatment group than in the EA group and dyclonine hydrochloride mucilage group (P<0.01). The VAS values of nausea and emesis, the first-pass success rate, and examination duration were also better for the combined treatment group than for the other two groups (P<0.05 and P<0.01). CONCLUSIONS: EA combined with local anesthesia with dyclonine hydrochloride mucilage can alleviate side effects during gastroscopy, reduce patient pain, and improve the efficiency of the procedure.

7.
Aesthet Surg J ; 2021 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-33649752

RESUMO

BACKGROUND: Since 2007, when the anatomy of facial fat compartment was described, an increasing number of studies on the aging process of the compartment of cadavers has emerged. OBJECTIVES: The authors evaluated the aging changes of lateral facial fat compartments on the same person. METHODS: Sixty-three patients were included in this retrospective study. All patients had magnetic resonance imaging scans with at least 4 years apart. The authors targeted the fat compartments of the superficial temporal, subcutaneous temporal, and buccal fat pad, comparing the data on different time points. RESULTS: The thickness of the subcutaneous temporal fat did not change significantly. The 3 diameters of the superficial temporal fat compartment all became thinner on the axial view (P < 0.05). On the sagittal view, the superficial temporal fat elongated from 38.89 mm to 43.74 mm (P < 0.05). The buccal fat compartment also lengthened from 68.73 mm to 74.39 mm (P < 0.05) and had a positive correlation with follow-up duration only. CONCLUSIONS: The study revealed the fat compartment change on the same person with time. The temporal hollow mainly originates from the thinner part of the superficial temporal fat. The descending of the buccal fat pad aggravates the labiomandibular fold. By understanding the aging process more fully, we can rejuvenate our patients more naturally.

8.
Adv Mater ; : e2008611, 2021 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-33754374

RESUMO

The control of the optoelectronic properties of 2D organic-inorganic hybrid perovskite (2D-OIHP) lead halides is an increasingly prevalent topic. Herein, the observation of the circular photogalvanic effect (CPGE) in new enantiomorphic 2D-OIHP lead iodides is reported, which are synthesized as a first OIHP-related system belonging to a chiral space group by incorporating organic chiral cations into the inorganic layers of lead iodides. The CPGE is an optoelectronic phenomenon associated with the spin-orbit coupling of heavy atoms in noncentrosymmetric systems. Owing to the CPGE, light-helicity-dependent steady photocurrents are generated without an external bias voltage under the irradiation of circularly polarized light. Furthermore, the sign reversal of the CPGE photocurrent depending on the chirality of the designed 2D-OIHP lead iodides is observed. This result indicates formation of the theoretically predicted radial spin-polarized texture in k-space of chiral systems owing to spin-momentum locking. Hence, chiral 2D-OIHP lead halides can be a promising platform for engineering opto-spintronic functionalities.

9.
Environ Pollut ; 278: 116799, 2021 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-33743268

RESUMO

The mediating influence of thyroid function on the association of phthalate exposure with glucose metabolism, including insulin resistance, remains unclear. We explored the mediating influence of thyroid hormone levels on the phthalate exposure-insulin resistance association. This cross-sectional study of 217 Taiwanese adults assessed insulin resistance (Homeostatic Model Assessment for Insulin Resistance, HOMA-IR scores) and the levels of 11 urinary phthalate metabolites and 5 thyroid hormones. Multiple regression models were used to analyze the associations among serum thyroid hormone levels, urinary phthalate metabolite levels, and HOMA-IR scores. The mediation analysis assessed the influence of thyroid function on the phthalate exposure-HOMA-IR association. Our data indicated urinary mono-ethylhexyl phthalate (MEHP) levels was negatively associated with free thyroxine (T4) (ß = -0.018; 95% confidence interval [CI]: -0.031, -0.005) and positively associated with HOMA-IR scores (ß = 0.051, 95% CI: 0.012, 0.090). The study also revealed urinary mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP) levels was negatively associated with free T4 (ß = -0.036, 95% CI: -0.056, -0.017) and HOMA-IR (ß = 0.070, 95% CI: 0.013, 0.126). Free T4 and HOMA-IR had a negative association (ß = -0.757, 95% CI: -1.122, -0.392). In the mediation analysis, free T4 mediated 24% and 35% of the associations of urinary MEHP and MEOHP with HOMA-IR, respectively. Our findings revealed the mediating role of thyroid function in the phthalate exposure-glucose metabolism association in adults.

10.
Ann Palliat Med ; 10(3): 2458-2468, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33549012

RESUMO

BACKGROUND: Parkinson's disease (PD) is a central nervous system degenerative disease. The progressive death of dopaminergic neurons is closely correlated to mitochondrial dysfunction. Resveratrol contains three hydroxyl groups, and has a strong neuroprotective effect. This study aimed to investigate the protective effect of resveratrol liposome on mitochondria of substantia nigra cells in Parkinsonized rats through experiment. METHODS: The investigators used 6-hydroxydopamine to establish the Parkinsonized rat model, and used resveratrol liposome from Polygonum cuspidatum (20 mg·kg-1) for gavage, up to a total volume of 1 mL, once-daily, for two weeks. After treatment, the levels of mitochondrial membrane potential, mitochondrial complexes I-IV, mitochondrial cytochrome C, apoptosis-inducing factor (AIF), PTEN-induced putative kinase 1 (PINK1), tumor necrosis factor-receptor-associated protein 1 (TRAP1) and phosphorylated TRAP1 in rat mesencephalic cells were detected according to the operation instructions of the kits. RESULTS: After two weeks of treatment, resveratrol liposomes could significantly enhance the activity of mitochondrial electron transfer chain complex I in the substantia nigra cells of Parkinsonized model rats, promote the expression of complex I subcomponent MT-ND1-37kD, improve mitochondrial membrane potential, inhibit the release of mitochondrial cytochrome C and apoptotic inducible factor, enhance the expression of mitochondrial functional protein PINK1, increase the phosphorylated TRAP1 level, and elevate the phosphorylated TRAP1/TRAP1 ratio. CONCLUSIONS: Resveratrol liposome has positive effects on mitochondria in substantia nigra cells of Parkinsonized rats, and may be one of its pharmacological mechanisms.

11.
Sci Rep ; 11(1): 4593, 2021 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-33633282

RESUMO

Sacubitril/valsartan is a combined neprilysin inhibitor/angiotensin II receptor blocker designed for treatment of heart failure (HF). Nonetheless, its renal protective effect remained an issue of debate. This retrospective cohort study investigated the renal protective effect of sacubitril/valsartan in HF patients. HF patients on sacubitril/valsartan or valsartan for > 30 days were matched for gender, age, estimated glomerular filtration rate (eGFR), and left ventricular ejection fraction (LVEF) to be enrolled into analysis. The follow-up period was 18 months. The outcomes included end eGFR, renal function decline defined as 20% reduction of eGFR, mortality, and HF-related hospitalization. Each group had 137 patients after matching. The mean age was 72.7 years and 65.7% were male. Mean eGFR was 70.9 mL/min/1.73 m2 and LVEF was 54.0% at baseline. Overall, the eGFR of sacubitril/valsartan groups was significantly higher than valsartan group at the end (P < 0.01). Subgroup analysis showed that the difference in eGFR was significant in subgroups with LVEF ≥ 40% or eGFR ≥ 60 mL/min/1.73 m2. Multivariate Cox regression model showed that sacubitril/valsartan group had significantly reduced risk for renal function decline (hazard ratio: 0.5, 95% confidence interval: 0.3-0.9). Kaplan-Meier curve showed no difference in the risk for cardiovascular mortality, all-cause mortality or HF-related hospitalization. We showed renal protective effect of neprilysin inhibition in HF patients and specified that subgroups with LVEF ≥ 40% or eGFR ≥ 60 mL/min/1.73 m2 were sensitive to this effect, suggesting an optimal subgroup of this treatment.

12.
Endocrinology ; 2021 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-33640969

RESUMO

PURPOSE: Arteriovenous fistula (AVF) maturation failure remains a clinical dilemma and its pathobiology is largely unclear. Secondary hyperparathyroidism is a complication of chronic renal failure that associated with cardiovascular disease. While parathyroid hormone (PTH) has prosclerotic effect on vascular smooth muscle cells, its role on AVF maturation failure was unknown. METHODS: Patients receiving AVF creation were enrolled retrospectively to investigate the association between plasma PTH and AVF maturation. A mouse model of secondary hyperparathyroidism and aortocaval AVF was used to investigate the effect of PTH on AVF lesion. A cell model of vascular smooth muscle cell treated with PTH in pressurized culture system was used to disclose the signaling pathway underlying the effect of PTH on AVF lesion. RESULTS: In patients receiving AVF creation, higher PTH was associated with increased risk for maturation failure. In mouse model, vascular wall thickness and myofibroblasts of AVF significantly increased with higher PTH. When the same mice was treated by cinacalcet, AVF lesions were attenuated by suppression of PTH. Cell model showed that PTH increased the marker of myofibroblasts, integrin ß6 subunit (ITGB6) via the phospho-Akt pathway. Finally, in the same model of mice AVF, higher PTH also increased the expression of ITGB6 in the smooth muscle layer of AVF, suggesting the transition to myofibroblast. CONCLUSIONS: Overall, our results suggest that higher PTH increased the risk of AVF maturation failure through increasing the transition of vascular smooth muscle cells to myofibroblasts. Lowering PTH may be a strategy to enhance AVF maturation.

13.
Spine J ; 2021 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-33545371

RESUMO

BACKGROUND CONTEXT: Accurately predicting the survival of patients with spinal metastases is important for guiding surgical intervention. The SORG machine-learning (ML) algorithm for the 90-day and 1-year mortality of patients with metastatic cancer to the spine has been multiply validated, with a high degree of accuracy in both internal and external validation studies. However, prior external validations were conducted using patient groups located on the east coast of the United States, representing a generally homogeneous population. The aim of this study was to externally validate the SORG algorithms with a Taiwanese population. STUDY DESIGN/SETTING: Retrospective study at a single tertiary care center in Taiwan PATIENT SAMPLE: Four hundred and twenty-seven patients who underwent surgery for metastatic spine disease from November 1, 2010 to December 31, 2018 OUTCOME MEASURES: 90-Day and 1-Year Mortality METHODS: The baseline characteristics of our validation cohort were compared with those of the previously published developmental and external validation cohorts. Discrimination (c-statistic and receiver operating curve), calibration (calibration plot, intercept, and slope), overall performance (Brier score), and decision curve analysis were used to assess the performance of the SORG ML algorithms in this cohort. RESULTS: Ninety-day and 1-year mortality rates were 110 of 427 (26%) and 256 of 427 (60%), respectively. The external validation cohort and the developmental cohort differed in body mass index (BMI), preoperative performance status, American Spinal Injury Association impairment scale, primary tumor histology and in several laboratory measurements. The SORG ML algorithm for 90-day and 1-year mortality demonstrated a high level of discriminative ability (c-statistics of 0.73 [95% confidence interval [CI], 0.67-0.78] and 0.74 [95% CI, 0.69-0.79]), overall performance, and had a positive net benefit throughout the range of threshold probabilities in decision curve analysis. The algorithm for 1-year mortality had a calibration intercept of 0.08, representing a good calibration. However, the 90-day mortality algorithm underestimated mortality for the lowest predicted probabilities, with an overall intercept of 0.81. CONCLUSIONS: The SORG algorithms for predicting 90-day and 1-year mortality in patients with spinal metastatic disease generally performed well on international external validation in a predominately Taiwanese population. However, 90-day mortality was underestimated in this group. Whether this inconsistency was due to different primary tumor characteristics, body mass index, selection bias or other factors remains unclear, and may be better understood with further validative works that utilize international and/or diverse populations.

14.
Nat Chem Biol ; 2021 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-33603247

RESUMO

Precision tools for spatiotemporal control of cytoskeletal motor function are needed to dissect fundamental biological processes ranging from intracellular transport to cell migration and division. Direct optical control of motor speed and direction is one promising approach, but it remains a challenge to engineer controllable motors with desirable properties such as the speed and processivity required for transport applications in living cells. Here, we develop engineered myosin motors that combine large optical modulation depths with high velocities, and create processive myosin motors with optically controllable directionality. We characterize the performance of the motors using in vitro motility assays, single-molecule tracking and live-cell imaging. Bidirectional processive motors move efficiently toward the tips of cellular protrusions in the presence of blue light, and can transport molecular cargo in cells. Robust gearshifting myosins will further enable programmable transport in contexts ranging from in vitro active matter reconstitutions to microfabricated systems that harness molecular propulsion.

15.
J Orthop Surg (Hong Kong) ; 29(1): 2309499020988179, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33550932

RESUMO

PURPOSE: Tension band wiring technique has been widely used for treating patellar fracture. Conventional techniques are associated with some complications and several modifications have been introduced to increase stabilization. The purpose of this study was to compare two different fixation techniques, the one-end and both-ends Kirschner wire bending fixation methods. METHODS: We retrospectively reviewed patient data from 2013 to 2017, including the age, sex, body height, body weight, BMI, lesion of injury, trauma mechanism, fracture displacement and classification, type of fixation, fracture healing duration, length of follow-up, clinical results and complications. The surgical outcome was assessed using the pain score (VAS), Lysholm knee score, and knee joint ROM. Plain radiographs were used to evaluate radiographic outcomes and assess the fracture union duration and hardware complications. We performed statistical analysis to compare these two different fixation techniques. RESULTS: There were no significant differences between the two groups in terms of demographic data, fracture healing duration, level of the K-wires, distance between the K-wires, or length of the K-wires over the patella length (all p > 0.05). There were significant differences in the VAS score, K-wire migration, flexion degree, ROM, and Lysholm score (all p < 0.001) between the two different fixation methods. CONCLUSION: The both-ends K-wire bending fixation method has a lower complication rate and results in a better clinical outcome than the one-end K-wire bending fixation method. This revised technique can effectively control both ends of the K-wires, thus eliminating the possibility of K-wire migration and improving the fixation stability.

16.
Sci Rep ; 11(1): 1159, 2021 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-33441969

RESUMO

Endothelial progenitor cells (EPCs) improve endothelial impairment, which in turn restores endothelial function in patients with heart failure (HF). In the present study, we tested whether fenofibrate, with its anti-inflammatory and vasoprotective effects, could improve myocardial function by activating EPCs through the eNOS pathway in a doxorubicin (DOX)-induced cardiomyopathy mouse model. Wild-type mice were divided into 4 groups and treated with vehicle, DOX + saline, DOX + fenofibrate, and DOX + fenofibrate + L-NAME (N(ω)-nitro-L-arginine methyl ester). DOX-induced cardiac atrophy, myocardial dysfunction, the number of circulating EPCs and tissue inflammation were analyzed. Mice in the DOX + fenofibrate group had more circulating EPCs than those in the DOX + saline group (2% versus 0.5% of total events, respectively) after 4 weeks of treatment with fenofibrate. In addition, the inhibition of eNOS by L-NAME in vivo further abolished the fenofibrate-induced suppression of DOX-induced cardiotoxic effects. Protein assays revealed that, after DOX treatment, the differential expression of MMP-2 (matrix metalloproteinase-2), MMP-9 (matrix metalloproteinase-9), TNF-α (tumor necrosis factor-α), and NT-pro-BNP (N-terminal pro-B-type natriuretic peptide) between saline- and DOX-treated mice was involved in the progression of HF. Mechanistically, fenofibrate promotes Akt/eNOS and VEGF (vascular endothelial growth factor), which results in the activation of EPC pathways, thereby ameliorating DOX-induced cardiac toxicity.

17.
Gastric Cancer ; 2021 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-33515163

RESUMO

BACKGROUND: Gastric cancer (GC) is the third leading cause of cancer mortality globally and a molecularly heterogeneous disease. Identifying the driver pathways in GC progression is crucial to improving the clinical outcome. Recent studies identified ASPM (abnormal spindle-like microcephaly-associated) and FOXM1 (Forkhead box protein M1) as novel Wnt and cancer stem cell (CSC) regulators; their pathogenetic roles and potential crosstalks in GC remain unclarified. METHODS: The expression patterns of ASPM isoforms and FOXM1 were profiled in normal gastric epithelial and GC tissues. The functional roles of ASPM and FOXM1 in Wnt activity, cancer stemness and GC progression, and the underlying signaling processes were investigated. RESULTS: Approximately one third of GC cells upregulate the expression of ASPM isoform I (ASPMiI) in their cytoplasm; the tumors with a high ASPMiI positive score (≥ 10%) are associated with a poor prognosis of the patients. Mechanistically, the molecular interplay among FOXM1, ASPMiI and DVL3 was found to converge on ß-catenin to control the Wnt activity and the stemness property of GC cells. This multi-mode Wnt-regulatory module serves to reinforce Wnt signals in CSCs by transcriptional regulation (FOXM1-ASPM), protein-protein interactions (ASPMiI-DVL3-ß-catenin), and nuclear translocation (FOXM1-ß-catenin). CONCLUSIONS: This study illuminates a novel Wnt- and stemness-regulatory mechanism in GC cells and identifies a novel subset of FOXM1highASPMiIhigh GC with potential to guide Wnt- and stemness-related diagnostics and therapies.

18.
J Med Chem ; 64(3): 1435-1453, 2021 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-33492141

RESUMO

In this paper, we present a copper(I)-catalyzed nitrile-addition/N-arylation ring-closure cascade for the synthesis of 5,11-dihydro-6H-indolo[3,2-c]quinolin-6-ones from 2-(2-bromophenyl)-N-(2-cyanophenyl)acetamides. Using CuBr and t-BuONa in dimethylformamide (DMF) as the optimal reaction conditions, the cascade reaction gave the target products, in high yields, with a good substrate scope. Application of the cascade reaction was demonstrated on the concise total syntheses of alkaloid isocryptolepine. Further optimization of the products from the cascade reaction led to 3-chloro-5,12-bis[2-(dimethylamino)ethyl]-5,12-dihydro-6H-[1,3]dioxolo[4',5':5,6]indolo[3,2-c]quinolin-6-one (2k), which exhibited the characteristic DNA topoisomerase-I inhibitory mechanism of action with potent in vitro anticancer activity. Compound 2k actively inhibited ARC-111- and SN-38-resistant HCT-116 cells and showed in vivo activity in mice bearing human HCT-116 and SJCRH30 xenografts. The interaction of 2k with the Top-DNA cleavable complex was revealed by docking simulations to guide the future optimization of 5,11-dihydro-6H-indolo[3,2-c]quinolin-6-ones as topoisomerase-I inhibitors.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Cobre/química , Nitrilos/química , Quinolonas/síntese química , Quinolonas/farmacologia , Inibidores da Topoisomerase I/síntese química , Inibidores da Topoisomerase I/farmacologia , Animais , Catálise , DNA Topoisomerases Tipo I/química , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Masculino , Camundongos , Camundongos Nus , Modelos Moleculares , Simulação de Acoplamento Molecular , Quinolonas/farmacocinética , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Inibidores da Topoisomerase I/farmacocinética , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Ultrason Sonochem ; 70: 105305, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33126185

RESUMO

The binary nanomaterials and graphitic carbon based hybrid has been developed as an important porous nanomaterial for fabricating electrode with applications in non-enzymatic (bio) sensors. We report a fast synthesis of bimetal oxide particles of nano-sized manganese ferrite (MnFe2O4) decorated on graphitic carbon nitride (GCN) via a high-intensity ultrasonic irradiation method for C (30 kHz and 70 W/cm2). The nanocomposites were analyzed by powder X-ray diffraction, XPS, EDS, TEM to ascertain the effects of synthesis parameters on structure, and morphology. The MnFe2O4/GCN modified electrode demonstrated superior electrocatalytic activity toward the neurotransmitter (5-hydroxytryptamine) detection with a high peak intensity at +0.21 V. The appealing application of the MnFe2O4/GCN/GCE as neurotransmitter sensors is presented and a possible sensing mechanism is analyzed. The constructed electrochemical sensor for the detection of 5-hydroxytryptamine (STN) showed a wide working range (0.1-522.6 µM), high sensitivity (19.377 µA µM-1 cm-2), and nano-molar detection limit (3.1 nM). Moreover, it is worth noting that the MnFe2O4/GCN not only enhanced activity and also promoted the electron transfer rate towards STN detection. The proposed sensor was analyzed for its real-time applications to the detection of STN in rat brain serum, and human blood serum in good satisfactory results was obtained. The results showed promising reproducibility, repeatability, and high stability for neurotransmitter detection in biological samples.

20.
ACS Chem Biol ; 16(1): 58-66, 2021 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-33307682

RESUMO

The glucagon-like peptide 1 receptor (GLP-1R) is a class B G-protein coupled receptor (GPCR) and diabetes drug target expressed mainly in pancreatic ß-cells that, when activated by its agonist glucagon-like peptide 1 (GLP-1) after a meal, stimulates insulin secretion and ß-cell survival and proliferation. The N-terminal region of GLP-1 interacts with membrane-proximal residues of GLP-1R, stabilizing its active conformation to trigger intracellular signaling. The best-studied agonist peptides, GLP-1 and exendin-4, share sequence homology at their N-terminal region; however, modifications that can be tolerated here are not fully understood. In this work, a functional screen of GLP-1 variants with randomized N-terminal domains reveals new GLP-1R agonists and uncovers a pattern whereby a negative charge is preferred at the third position in various sequence contexts. We further tested this sequence-structure-activity principle by synthesizing peptide analogues where this position was mutated to both canonical and noncanonical amino acids. We discovered a highly active GLP-1 analogue in which the native glutamate residue three positions from the N-terminus was replaced with the sulfo-containing amino acid cysteic acid (GLP-1-CYA). The receptor binding and downstream signaling properties elicited by GLP-1-CYA were similar to the wild type GLP-1 peptide. Computational modeling identified a likely mode of interaction of the negatively charged side chain in GLP-1-CYA with an arginine on GLP-1R. This work highlights a strategy of combinatorial peptide screening coupled with chemical exploration that could be used to generate novel agonists for other receptors with peptide ligands.

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