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1.
Orthop Surg ; 2020 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-33044764

RESUMO

OBJECTIVE: This study focused on the assessment of paravertebral ossification (PO) after cervical disc arthroplasty (CDA) using computed tomography (CT) images. METHODS: In this retrospective study, 52 patients (from 2004 to 2010) who received CDA at a single center were included (32 males). Preoperative and follow-up X-ray and CT images of all patients who underwent single-level CDA were collected. PO from the C2/3 to C7/T1 in each patient was graded based on a CT grading system. Each segment was divided into operative level, adjacent level, or non-adjacent level. The McAfee' classification system was used to grade PO using X-ray plain film. The range of motion (ROM) and scores of neurological symptoms (Japanese Orthopaedic Association [JOA] score and Neck Disability Index [NDI]) at both preoperative and final follow-up time were acquired. Progression and classification of PO in each group was compared using the chi-square test. ROM between groups were compared using independent t-test. JOA score and NDI between groups were compared using Mann-Whitney U test. RESULTS: The average follow-up time was 81.2 months. In comparison with the preoperative status, the progression of PO development in left and right areas (the Luschka joints areas) in the operative level groups was significantly more severe (area L,χ2 value = 36.612, P < 0.001; area R, χ2 value = 39.172, P < 0.001) than the non-adjacent level groups. In contrast, although the prevalence of PO in all areas of the adjacent level groups was higher than that of the non-adjacent level group in the same segments, there was no significant difference (P > 0.05) in the progression of PO development. The follow-up high-grade (grades III and IV) PO incidence rate using X-ray grading system (3.85%) was significantly lower than that using CT grading system in area L (42.31%) and R (38.46%), but close to that in area A (5.77%) and P (1.92%). The final follow-up ROM was not significantly different with preoperative ROM in patients with low-grade PO (9.47° ± 4.12° vs. 9.76° ± 3.69°, P = 0.794). However, in patients with high-grade PO, the final follow-up ROM was significantly lower than preoperative ROM (5.77° ± 3.32° vs. 9.28° ± 4.15°, P < 0.001). There was no significant difference for JOA score and NDI at follow-up between patients with high-grade and low-grade PO (JOA, 16.2 ± 1.1 vs. 16.8 ± 0.9, P = 0.489; NDI, 8.9 ± 6.1 vs. 8.0 ± 7.3, P = 0.317). CONCLUSION: High-grade PO was observed in the areas of the Luschka joints at the operative level after CDA, which was difficult to observe using X-ray plain film. The PO formation at adjacent segments was not significant.

2.
Artigo em Inglês | MEDLINE | ID: mdl-33019661

RESUMO

Changes in lifestyle behaviors may effectively maintain or improve the health status of individuals with chronic diseases. However, such health behaviors adopted by individuals are unlikely to demonstrate similar patterns. This study analyzed the relationship between the heterogeneous latent classes of health behavior and health statuses among middle-aged and older adults with hypertension, diabetes, or hyperlipidemia in Taiwan. After selecting 2103 individuals from the 2005 and 2009 Taiwan National Health Interview Survey (NHIS), we first identified heterogeneous groups of health behaviors through latent class analysis (LCA). We further explored the relationship between each latent class of health behavior and health status through ordered logit regression. We identified the following five distinct health behavior classes: the all-controlled, exercise and relaxation, healthy diet and reduced smoking or drinking, healthy diet, and least-controlled classes. Regression results indicated that individuals in classes other than the all-controlled class all reported poor health statuses. We also found great magnitude of the coefficient estimates for individuals who reported their health status to be poor or very poor for the least-controlled class. Therefore, health authorities and medical providers may develop targeted policies and interventions that address multiple modifiable health behaviors in each distinct latent class of health behavior.

3.
Sci Rep ; 10(1): 16207, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-33004940

RESUMO

Perilla frutescens (L.) is an important medicinal and edible plant in China with nutritional and medical uses. The extract from leaves of Perilla frutescens contains flavonoids and volatile oils, which are mainly used in traditional Chinese medicine. In this study, we analyzed the transcriptomic and metabolomic data of the leaves of two Perilla frutescens varieties: JIZI 1 and JIZI 2. A total of 9277 differentially expressed genes and 223 flavonoid metabolites were identified in these varieties. Chrysoeriol, apigenin, malvidin, cyanidin, kaempferol, and their derivatives were abundant in the leaves of Perilla frutescens, which were more than 70% of total flavonoid contents. A total of 77 unigenes encoding 15 enzymes were identified as candidate genes involved in flavonoid biosynthesis in the leaves of Perilla frutescens. High expression of the CHS gene enhances the accumulation of flavonoids in the leaves of Perilla frutescens. Our results provide valuable information on the flavonoid metabolites and candidate genes involved in the flavonoid biosynthesis pathways in the leaves of Perilla frutescens.

4.
Redox Biol ; 37: 101741, 2020 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-33035815

RESUMO

BACKGROUND: Inherited methylmalonic acidemia is characterized by mitochondrial dysfunction, oxidative stress, and damage of mitochondria-rich organs in children. It is unclear whether methylmalonic acid (MMA) is related to poor prognosis in adults. The study aims to investigate the associations of MMA with all-cause and cause-specific mortality in the general population. METHODS: Overall, 23,437 adults from the US National Health and Nutrition Examination Survey (NHANES) were enrolled. NHANES 1999-2004 and 2011-2014 were separately used as primary and validation subsets (median follow-up 13.5 and 2.8 years, respectively). Circulating MMA was measured with gas chromatography/mass spectrophotometry. Hazard ratios (HR) were estimated using weighted Cox regression models. RESULTS: During 163,632 person-years of follow-up in NHANES 1999-2004, 3019 deaths occurred. Compared with participants with MMA <120 nmol/L, those with MMA≥250 nmol/L had increased all-cause and cardiovascular mortality in the multivariable-adjusted model [HR(95%CI), 1.62 (1.43-1.84) and 1.66 (1.22-2.27), respectively]. The association was especially significant among participants with normal cobalamin. MMA remained an independent predictor of all-cause mortality occurring whether within 5-year, 5-10 years, or beyond 10-year of follow-up (each p for trend≤0.007). That association was repeatable in NHANES 2011-2014. Moreover, baseline MMA improved reclassification for 10-year mortality in patients with cardiovascular disease (net reclassification index 0.239, integrated discrimination improvement 0.022), overmatched established cardiovascular biomarkers C-reactive protein or homocysteine. CONCLUSIONS: Circulating level of mitochondrial-derived MMA is strongly associated with elevated all-cause and cardiovascular mortality. Our results support MMA as a surrogate biomarker of mitochondrial dysfunction to predict poor prognosis in adults. The biological mechanisms under cardiovascular disease warrant further investigation.

5.
Mol Med Rep ; 22(5): 3962-3968, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32901836

RESUMO

Previous studies have demonstrated that calycosin is a natural phytoestrogen with a similar structure to estrogen, which can inhibit cell proliferation and induce apoptosis in a variety of tumors. Calycosin exerts potential pharmacological effects on osteosarcoma cells by inducing apoptosis. The aim of the present study was to elucidate the specific molecular mechanism of calycosin­induced apoptosis in osteosarcoma cells. Cell proliferation was determined by an MTT assay. Annexin V/PI and JC­1 staining were used to detect apoptosis and mitochondrial dysfunction, respectively, by flow cytometry. Western blot analysis was used to detect the expression of caspases or mitochondrial proteins. The results revealed that calycosin reduced the cell viability of human osteosarcoma 143B cells, induced apoptosis and increased the loss of mitochondrial membrane potential (MMP). In addition, calycosin increased the expression of the proapoptotic antiapoptotic proteins cleaved caspase­3, cleaved caspase­9, cleaved poly(ADP­ribose) polymerase and Bcl­2­associated X protein (Bax), and decreased the expression of the antiapoptotic proapoptotic protein B­cell lymphoma­2 (Bcl­2), thus altering the Bax/Bcl­2 ratio. In addition, the expression levels of cytochrome c were markedly decreased in the mitochondria and increased in the cytoplasm following calycosin treatment. Furthermore, calycosin treatment induced p38­mitogen­activated protein kinase (MAPK) phosphorylation, whereas the p38­MAPK inhibitor BIRB 796 markedly reversed cell viability, apoptosis and loss of MMP in 143B cells. These results suggested that calycosin inhibited osteosarcoma 143B cell growth via p38­MAPK regulation of mitochondrial­dependent intrinsic apoptotic pathways.

6.
Mater Sci Eng C Mater Biol Appl ; 114: 110977, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32993996

RESUMO

Cell infiltration and proliferation are prerequisites for tissue regeneration and repair. The aim of the present study was to evaluate the motility and function of vascular smooth muscle cells (SMCs) in a silk-based small-caliber artificial blood vessel (SFTS) following implantation to replace the common carotid artery in rabbits. Hematoxylin and eosin (HE) staining showed a number of SMCs clearly distributed in the scaffold at 1 month, which gradually increased up to 80-90% of autologous blood vessels at 3 months and was 100% at 12 months. Smooth muscle myosin heavy chain (SM-MHC) and α-smooth muscle actin (α-SMA) are specific markers of SMCs. Real-time PCR results showed that the gene expression level of α-SMA in SFTSs was significantly down-regulated within 6 months, except in the early stage of implantation. The relative expression level of α-SMA at 12 months was five times higher than that at 3 months, indicating that SMCs phenotype transformed from synthetic to contractile. The SM-MHC+ and α-SMA+ SMCs were disorderly distributed in the scaffolds at 1 month, but became ordered along the circumference 6 months after grafting as shown by immunohistochemistry. Results indicated that the bionic SFTSs were able to induce in situ angiogenesis in defects.

7.
Int J Oncol ; 57(4): 939-955, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32945394

RESUMO

Lung cancer has the highest incidence and mortality rates among the malignant tumor types worldwide. Platinum­based chemotherapy is the main treatment for advanced non­small­cell lung cancer (NSCLC), and epidermal growth factor receptor­tyrosine kinase inhibitors (EGFR­TKIs) have greatly improved the survival of patients with EGFR­sensitive mutations. However, there is no standard therapy for treating patients who are EGFR­TKI resistant. Combining EGFR­TKIs and platinum­based chemotherapy is the most popular strategy in the clinical practice. However, the synergistic mechanism between EGFR­TKIs and platinum remains unknown. Therefore, the aim of the present study was to determine the synergistic mechanism of gefitinib (an EGFR­TKI) and cisplatin (a main platinum­based drug). MTT assay, apoptosis analysis, tumorsphere formation and an orthotropic xenograft mouse model were used to examine the combination effects of gefitinib and cisplatin on NSCLC. Co­immunoprecipitation and immunofluorescence were used to identify the underlying mechanism. It was found that gefitinib could selectively inhibit EGFR from entering the nucleus, decrease DNA­PK activity and enhance the cytotoxicity of cisplatin on NSCLC. Collectively, the results suggested that inhibition of DNA­dependent protein kinase by gefitinib may be due to the synergistic mechanism between gefitinib and cisplatin. Thus, the present study provides a novel insight into potential biomarkers for the selection of combination therapy of gefitinib and cisplatin.

8.
Eur J Pharmacol ; 886: 173526, 2020 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-32890460

RESUMO

Ovarian cancer is the leading cause of death among gynecologic cancer patients. Although platinum-based chemotherapy as a frontline treatment for ovarian cancer has been widely used in clinical settings, its clinical efficacy is not satisfactory due to the resistance of ovarian cancer cells to apoptosis. Therefore, it is of great significance to induce non-apoptotic programed cell death patterns, such as paraptosis, in ovarian cancer. In this study, we aimed to explore the potential anticancer mechanisms of novel rhein derivative 4a, which was modified with rhein as a lead compound. The results showed that a wide range of vacuoles from the endoplasmic reticulum and mitochondria appeared in ovarian SKOV3, SKOV3-PM4, and A2780 cells treated with derivative 4a, and the cell death caused by derivative 4a is a type of non-apoptotic and non-autophagic death, which is caused by expansion and damage of the endoplasmic reticulum or mitochondria, showing the characteristics of para-apoptotic death. Furthermore, derivative 4a stimulated the unfolded protein reaction of ovarian cancer cells by upregulating the expression of Bip78 and activating the PERK-eIF2α-ATF4 pathways. Notably, rhein derivative 4a-induced cell death was positively correlated with activation of p38, ERK, and JNK, and negatively correlated with Alix, a known protein that inhibits paraptosis. In addition, derivative 4a treatment also induced G2/M phase arrest in ovarian cancer cells. Taken together, our study reveals that derivative 4a induces paraptosis, and this finding can serve as a basis in developing a new strategy for the treatment of antiapoptotic ovarian cancer.

9.
BMC Endocr Disord ; 20(1): 141, 2020 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-32928178

RESUMO

BACKGROUND: Studies have shown that the response of bone mineral density (BMD) to parathyroidectomy for symptomatic primary hyperparathyroidism (PHPT) is heterogeneous and difficult to predict. However, the independent factors affecting BMD in PHPT patients after parathyroidectomy remains limited and inconclusive. This study aimed to explore the independent factors affecting BMD changes in symptomatic PHPT patients after parathyroidectomy. METHODS: This study retrospectively analyzed 105 patients with symptomatic PHPT treated at Beijing Jishuitan Hospital between January 2010 and December 2015. The primary outcome was a > 10% increase in BMD at 3 years after parathyroidectomy compared with the preoperative value, whereas the secondary outcomes were BMD changes at various measurement sites. RESULTS: A total of 105 patients with a mean age of 46.37 years were included in this study. Univariate logistic regression analysis indicated that hypertension (odds ratio [OR[: 0.032; 95% confidence interval [CI]: 0.001-0.475; P = 0.012), and parathyroid hormone level (OR: 1.006; 95% CI: 1.004-1.009; P = 0.044) were associated with the > 10% BMD increase. However, these results were not significant after adjustments for potential confounders. Moreover, the BMD values at the lumbar spine, femoral neck, femoral trochanter, Ward's triangle, and whole body after parathyroidectomy were significantly greater than those before the operation (P < 0.05). CONCLUSIONS: This study suggests that patient characteristics were not associated with the > 10% BMD increase. However, the BMD values of the femur and lumbar spine were significantly increased in symptomatic PHPT patients after parathyroidectomy.

10.
J Fluoresc ; 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32935195

RESUMO

We evaluated the ability of different fluorescent indicators by various analytical instruments, including a laser scanning confocal microscope (LSCM), fluorescence plate reader, and flow cytometer (FCM), to measure the mitochondrial membrane potential (ΔΨm) of cardiac H9c2 cells during oxidative stress-induced mitochondrial injury. The mitochondrial oxygen consumption rate and a transmission electron microscope were used to detect changes in mitochondrial functions and morphology, respectively. Cardiac H9c2 cells were exposed to H2O2 (500, 750, 1000, and 1250 µM) to induce mitochondrial oxidative stress injury, and fluorescent indicators including tetramethyl rhodamine ethyl ester (TMRE), 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolocarbocyanine iodide (JC-1), and rhodamine 123 (R123) were used to detect changes in ΔΨm using an LSCM, fluorescence plate reader, and FCM. The decrease in ΔΨm caused by H2O2 was determined by endpoint and dynamic analyses after staining with JC-1 or TMRE. With the R123 probe, the LSCM could only detect the change in ΔΨm caused by 1000 µM H2O2. Moreover, R123 was less effective than JC-1 and TMRE for measurement of ΔΨm by the LSCM. Our data indicated that an LSCM is the most suitable instrument to detect dynamic changes in ΔΨm, whereas all three instruments can detect ΔΨm at the endpoint.

12.
Cancer Cytopathol ; 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32931158

RESUMO

BACKGROUND: Urinary cytology is a noninvasive and cost-effective diagnostic and surveillance test in the clinical management of urothelial carcinoma (UC). The Paris System for Reporting Urinary Cytology (TPS), published in 2016, introduced definite diagnostic criteria aimed at improving performance in detecting high-grade UC (HGUC) and decreasing the indeterminate (atypical) diagnosis. METHODS: The authors retrospectively reviewed and compared urinary cytology diagnoses reported between January 2013 and December 2014 (pre-TPS, 7658 cases) and between May 2016 and April 2018 (post-TPS, 20,026 cases) to assess the influence of TPS in their practice. The time in between was used as a learning period. Follow-up information and correlation with the UroVysion fluorescence in situ hybridization test were obtained when available. RESULTS: Urinary cytology diagnoses pre-TPS included negative for UC (NUC) (n = 5293; 69.2%), atypical urothelial cells (AUC) (n = 2227; 29%), and suspicious/positive for HGUC (SHGUC/HGUC) (n = 138; 1.8%). Diagnoses post-TPS included negative for HGUC (NHGUC) (n = 18,507; 92.4%), AUC (n = 1237; 6.2%), and SHGUC/HGUC (n = 282; 1.4%). Comparing the pre-TPS and post-TPS periods, AUC diagnoses decreased from 29% to 6.2% (P < .00001), and the specificity and positive predictive value of AUC to detect HGUC significantly improved from 49% to 86% (P < .00001) and from 9% to 39% (P = .002), respectively. The correlation of an AUC diagnosis with a positive UroVysion test improved from 17% to 38% (P < .00001), whereas overall use of the UroVysion test was decreased. CONCLUSIONS: Implementation of TPS resulted in a significant reduction in AUC diagnoses that had a superior correlation with a subsequent biopsy and a UroVysion test, resulting in potential reductions in test use and medical cost.

13.
Anal Bioanal Chem ; 412(27): 7615-7625, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32856110

RESUMO

An integrated aflatoxin B1 (AFB1) detection platform with quantum dot (QD)-based electrochemical immunosensor and an automated magneto-controlled pretreatment system was successfully developed. The automated pretreatment system adopts the immunoaffinity magnetic beads (IMB) as the capture probe of AFB1 and QD-labeled AFB1 complete antigen (AFB1-BSA-QDs) as the signal probe. AFB1-BSA-QDs can be easily converted into corresponding metallic cations through acidic treatment, which can be detected electrochemically via anode stripping voltammetry (ASV). Moreover, a disposable screen-printed electrode (SPE) without requiring any further modification is used in the novel electrochemical immunosensor' making routine testing feasible. Under optimal conditions, the detectable concentration range of AFB1 was 0.08-800 µg/kg. The metal ion signal associated linearly with the logarithm of AFB1 concentration within the range of 5-240 µg/kg, with a detection limit of 0.05 µg/kg. The spiked recoveries of three different concentrations in four different matrixes ranged from 83.9 to 118.0%, and inter-day relative standard deviations were below 10%. Furthermore, the methodology was validated by analyzing naturally contaminated samples, and results of the novel immunosensor were in good agreement with those of LC-MS/MS, demonstrating the potentiality of the developed method for the monitor of AFB1 in cereals and oils.

14.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 28(4): 1245-1250, 2020 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-32798406

RESUMO

OBJECTIVE: To evaluate the value of serum free light chain (sFLC) κ/λ ratio (sFLCR) on the diagnosis and prognosis of patients with newly diagnosed multiple myeloma(MM), and explore the effect of sFLCR normalization on the prognosis of patients after 4 courses of induction therapy. METHODS: The clinical data of 43 newly diagnosed MM patients from January 2014 to January 2019 were analyzed retrospectively. Immunoturbidimetry was used to detect the expression levels of sFLC κ and λ. According to the ratio of involved and uninvolved sFLC, using 100 as a boundary, the MM patients were divided into the high ratio group (sFLCR≥100 or ≤0.01) and the low ratio group (0.010.05). CONCLUSION: Patients in the high ratio group at the initial diagnosis have worse renal function, later stage of disease, lower deep remission rate, earlier disease progression, shorter survival time, and worse clinical prognosis.


Assuntos
Mieloma Múltiplo/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica , Humanos , Cadeias Leves de Imunoglobulina , Prognóstico , Estudos Retrospectivos
15.
Carbohydr Polym ; 246: 116654, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32747286

RESUMO

Although some drug-based supramolecular systems have been constructed to overcome multidrug resistance and enhance the bioavailability of chemical drugs, strengthening the specific stimuli-responsive and active targeting ability of these systems is still a major challenge. In this paper, the synthesis and self-assembly behaviour of supramolecular self-assemblies with active targeting ß-cyclodextrin-modified hyaluronic acid (HA-CD) and drug-drug conjugates (curcumin-oxoplatin, Cur-Pt) as building moieties were carefully investigated. Notably, the curcumin was chosen not only as the chemical anti-cancer drug, but also acted as the guest molecule which could be included into CD cavity to form host-guest interaction-based supramolecular assemblies. The obtained self-assemblies exhibited pH- and esterase-responsive drug release behaviours. Furthermore, basic cell experiments were performed to prove their effective cellular toxicity based on A549 cells and PC3 cells with high expression of CD44 receptor but they showed no toxicity to normal LO-2 cells with low expression of CD44 receptor, which suggests their potential application in the targeted drug release field.

16.
Medicine (Baltimore) ; 99(30): e20652, 2020 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-32791662

RESUMO

The aim of this study is to explore the clinical outcome and indications in treating anterior ring injury of Tile C pelvic fracture with minimally invasive internal fixation.We retrospectively reviewed 18 patients (aged 25-62, 34.2 ±â€Š7.4) with 26 pelvic anterior ring injuries of Tile C pelvic fracture treated with minimally invasive internal fixation in our hospital were from January 2012 to August 2016. Two cases were pubic symphysis diastasis, 15 were anterior ring fracture (7 were bilateral), and 1 was vertical displacement of pubic symphysis associated with pubic ramus fracture. According to Tile classification, 8, 4, and 6 cases were types C1, C2, and C3, respectively. All patients accepted the operation of pelvic fractures on both rings, while the anterior ring injuries were treated with minimally invasive internal fixation. The period from injury to operation was 5 to 32 days (11.2 ±â€Š3.7). Four patients had pubic symphysis diastasis or pelvic anterior ring fracture medial obturator foramen reduced with modified Pfannenstiel incision and fixed with cannulated screws, 14 patients (22 fractures) had a fractured lateral obturator foramen reduced with modified Pfannenstiel incision associated with small iliac crest incision and fixed with locking reconstruction plates. Clinical data, such as operation time, intraoperative bleeding, Matta standard to assess the reduction quality of fracture, and complications, were collected and analyzed.The operation time ranged from 30 to 65 minutes (42.8 ±â€Š18.7), and the intraoperative bleeding volume was 30 to 150 mL (66.5 ±â€Š22.8). All cases were continuously followed-up for 16 to 42 months (30.2 ±â€Š4.6). All fractures were healed between 3 and 9 months postoperatively (4.9 ±â€Š2.7 months). According to the Matta standard assessment, 18, 7, and 1 cases were excellent, good, and fair, respectively, with a 96.2% (25/26) rate of satisfaction. Neither reduction loss, fixation failure, nor infection occurred; complications included 1 patient with fatal liquefaction, 1 patient had lateral femoral cutaneous nerve injury, and 1 patient complained of discomfort in the inguinal area due to fixation stimulation.Minimally invasive internal fixation for pelvic anterior ring injury in Tile C pelvic fracture has the advantages of less damage, safer manipulation, less complications, and good prognosis.


Assuntos
Fixação Interna de Fraturas/estatística & dados numéricos , Fraturas Ósseas/cirurgia , Ossos Pélvicos/lesões , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Procedimentos Cirúrgicos Minimamente Invasivos , Ossos Pélvicos/cirurgia , Estudos Retrospectivos
17.
Int J Biol Sci ; 16(14): 2595-2611, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32792859

RESUMO

Introduction: Crizotinib is a kinase inhibitor targeting c-MET/ALK/ROS1 used as the first-line chemical for the treatment of non-small cell lung cancer (NSCLC) with ALK mutations. Although c-MET is frequently overexpressed in 35-72% of NSCLC, most NSCLCs are primarily resistant to crizotinib treatment. Method: A set of NSCLC cell lines were used to test the effect of chidamide on the primary crizotinib resistance in vitro and in vivo. Relationships between the synergistic effect of chidamide and c-MET expression and RNA methylation were systemically studied with a battery of molecular biological assays. Results: We found for the first time that chidamide could sensitize the effect of crizotinib in a set of ALK mutation-free NSCLC cell lines, especially those with high levels of c-MET expression. Notably, chidamide could not increase the sensitivity of NSCLC cells to crizotinib cultured in serum-free medium without hepatocyte growth factor (HGF; a c-MET ligand). In contrast, the addition of HGF into the serum-/HGF-free medium could restore the synergistic effect of chidamide. Moreover, the synergistic effect of chidamide could also be abolished either by treatment with c-MET antibody or siRNA-knockdown of c-MET expression. While cells with low or no c-MET expression were primarily resistant to chidamide-crizotinib cotreatment, enforced c-MET overexpression could increase the sensitivity of these cells to chidamide-crizotinib cotreatment. Furthermore, chidamide could decrease c-MET expression by inhibiting mRNA N6-methyladenosine (m6A) modification through the downregulation of METTL3 and WTAP expression. Chidamide-crizotinib cotreatment significantly suppressed the activity of c-MET downstream molecules. Conclusion: Chidamide downregulated c-MET expression by decreasing its mRNA m6A methylation, subsequently increasing the crizotinib sensitivity of NSCLC cells in a c-MET-/HGF-dependent manner.

18.
Carbohydr Res ; 495: 108088, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32807356

RESUMO

We report the preparation of multivalent amide-sialoside-decorated human serum albumin (HSA) and bovine serum albumin (BSA) as mimics of natural mucin and bioshields against influenza virus infection. Free sialic acid with an amine on C-2 was covalently attached to the protein scaffolds using di-(N-succinimidyl) adipate. Dynamic light scattering (DLS) showed that the synthetic neomucins were able to act as bioshields and aggregate the influenza virion particles. The dissociation constants (KD) of the interactions between the prepared glycoconjugates and three different viral strains were measured by isothermal titration calorimetry (ITC) indicating the multivalent presentation of sialyl ligands on the HSA and BSA backbones can dramatically enhance the adsorbent capability compared to the corresponding monomeric sialoside. Hemagglutinin inhibition (HAI) and neuraminidase inhibition (NAI) assays showed that the glycoconjugates acted as moderate HA and NA inhibitors, thus impeding viral infection. Moreover, the different binding affinities of the glycoproteins to HA and NA proteins from different influenza viruses demonstrated the importance of HA/NA balance in viral replication and evolution. These findings provide a foundation for the development of antiviral drugs and viral adsorbent materials based on mimicking the structure of mucin.

19.
Clin Nutr ; 2020 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-32768317

RESUMO

BACKGROUND & AIMS: There has been controversial evidence regarding the relationship between isomers of circulating trans-fatty acids (TFAs) and mortality. This study aimed to ascertain the relationships between plasma TFAs and overall or cause-specific mortality of the general population in two independent subsets from the US National Health and Nutrition Examination Survey (1999-2000 and 2009-2010 cycles). METHODS AND RESULTS: Plasma TFA isomers (C16:1n-7t, C18:1n-7t, C18:1n-9t and C18:2n-6,9t) in 3439 adults free of cancer or severe cardiovascular disease were analyzed by gas chromatography/mass spectrometry. Overall, 259 died among 1376 individuals over a median follow-up of 15.6 years in the 1999-2000 cycle, and 105 died in the latter subset of 2063 subjects during a median of 5.9 years. Cox proportional hazards regression was conducted to estimate the hazard ratios of mortality. The main isomer of industrially derived TFAs, elaidic acid (C18:1n-9t) was considerably associated with long-term total mortality in the 1999-2000 cycle after adjusting for confounders, with a 54% increase in the top tertile compared with the bottom one. However, the association disappeared with halving C18:1n-9t by 2009-2010. In contrast, neither of the ruminant-derived TFAs (C16:1n-7t and C18:1n-7t) suggested any inverse correlations with all-cause death, mortality due to heart disease, cancer or other causes. CONCLUSION: The major isomer of industrial TFAs, the higher circulating C18:1n-9t might be associated with increased long-term mortality. The associations with death risk turned slight with the reduction of TFAs consumption by half. However, dietary guidelines should rigorously identify the healthy effect of animal TFAs consumption.

20.
BMC Plant Biol ; 20(1): 349, 2020 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-32703155

RESUMO

BACKGROUND: The objectives of this study were to reveal the anthocyanin biosynthesis metabolic pathway in white and purple flowers of Salvia miltiorrhiza using metabolomics and transcriptomics, to identify different anthocyanin metabolites, and to analyze the differentially expressed genes involved in anthocyanin biosynthesis. RESULTS: We analyzed the metabolomics and transcriptomics data of S. miltiorrhiza flowers. A total of 1994 differentially expressed genes and 84 flavonoid metabolites were identified between the white and purple flowers of S. miltiorrhiza. Integrated analysis of transcriptomics and metabolomics showed that cyanidin 3,5-O-diglucoside, malvidin 3,5-diglucoside, and cyanidin 3-O-galactoside were mainly responsible for the purple flower color of S. miltiorrhiza. A total of 100 unigenes encoding 10 enzymes were identified as candidate genes involved in anthocyanin biosynthesis in S. miltiorrhiza flowers. Low expression of the ANS gene decreased the anthocyanin content but enhanced the accumulation of flavonoids in S. miltiorrhiza flowers. CONCLUSIONS: Our results provide valuable information on the anthocyanin metabolites and the candidate genes involved in the anthocyanin biosynthesis pathways in S. miltiorrhiza.

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