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1.
J Transl Med ; 18(1): 116, 2020 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-32138730

RESUMO

BACKGROUND: Lupus nephritis is one of the most common and severe complications of systemic lupus erythematosus, of which poor prognosis is indicated by aggravated renal hypoxia and tubulointerstitial fibrosis. Cell adhesion molecules play a key role in the progression of lupus nephritis tubulointerstitial lesion, including P-selectin, which mediates the rolling of leukocytes and subsequent adhesion and infiltration and then initiates the inflammatory immune response and ischemia and hypoxia injury. However, the effects and mechanisms of P-selectin in lupus nephritis remain to be investigated, and a noninvasive measurement of lupus nephritis tubulointerstitial hypoxia and fibrosis remains to be explored. METHODS: Thirty-four MRL/lpr mice were randomly divided into the following three groups: MRL/lpr, saline, and anti-P-selectin, which consisted of no treatment, treatment with normal saline, and treatment with anti-P-selectin monoclonal antibody (mAb) from 12 to 16 weeks of age, respectively. Ten male C57BL/6 mice of the same age served as normal controls. 24-h urinary protein, urinary albumin-creatinine ratio, and periodic acid-Schiff were used to assess kidney damage; Western blot or immunohistochemical staining of the hypoxia probe Hypoxyprobe™-1, hypoxia-inducible factor 1α (HIF-1α), and CD31 were used to evaluate hypoxia in renal tissue; and NADPH oxidase subunit gp91phox and p22phox were used to examine renal oxidative stress. The correlation between kidney injury and blood oxygen level-dependent magnetic resonance imaging (BOLD-MRI) was calculated to assess the clinical value of BOLD-MRI. RESULTS: P-selectin is upregulated in lupus nephritis. Blocking P-selectin with mAb alleviated renal tubulointerstitial fibrosis, renal hypoxia, and peritubular capillary loss, without alteration of the levels of lupus activity indicators, anti-dsDNA antibody, or complement C3. BOLD-MRI showed that the reduced R2* values in the renal cortex and medulla of lupus mice were increased when treated with anti-P-selectin mAb as compared with those treated with normal saline, which were negatively correlated with Hypoxyprobe™-1 hypoxia probe and the expression of HIF-1α. CONCLUSIONS: Early intervention of lupus nephritis with anti-P-selectin mAb can significantly improve the hypoxic state of the kidney and reduce the severity of tubulointerstitial lesions. BOLD-MRI techniques are noninvasive and can dynamically evaluate the changes in renal lesions and intrarenal oxygenation levels before and after treatment in lupus nephritis.

2.
Oxid Med Cell Longev ; 2020: 9349762, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32184919

RESUMO

Although endogenous nucleus pulposus-derived mesenchymal stem cell- (NPMSC-) based regenerative medicine has provided promising repair strategy for intervertebral disc (IVD) degeneration, the hostile microenvironments in IVD, including oxidative stress, can negatively affect the survival and function of the NPMSCs and severely hinder the endogenous repair process. Therefore, it is of great importance to reveal the mechanisms of the endogenous repair failure caused by the adverse microenvironments in IVD. The aim of this study was to investigate the effect of oxidative stress on the rat NPMSCs and its underlying mechanism. Our results demonstrated that oxidative stress inhibited cell viability, induced apoptosis, and increased the production of reactive oxygen species (ROS) in NPMSCs. In addition, the results showed that the expression level of heme oxygenase-1 (HO-1) increased at an early stage but decreased at a late stage when NPMSCs were exposed to oxidative stress, and the oxidative damages of NPMSCs could be partially reversed by promoting the expression of HO-1. Further mechanistic analysis indicated that the protective effect of HO-1 against oxidative damage in NPMSCs was mediated by the activation of autophagy. Taken together, our study revealed that oxidative stress could inhibit cell viability, induce apoptosis, and increase ROS production in NPMSCs, and HO-1-mediated autophagy might act as a protective response to the oxidative damage. These findings might enhance our understanding on the mechanism of the endogenous repair failure during IVD degeneration and provide novel research direction for the endogenous repair of IVD degeneration.

3.
Biomed Res Int ; 2020: 9707238, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32190693

RESUMO

Numerous grading scales have been proposed to predict the outcome of aneurysmal subarachnoid hemorrhage (SAH); however, these have not been validated in angiogram-negative SAH patients. In this study, we aim to validate and compare the aneurysmal SAH grading scales in angiogram-negative SAH patients. There were 190 angiogram-negative SAH patients analyzed from January 2014 to December 2015. The outcomes were measured by delayed cerebral ischemia (DCI) and poor outcome (defined as modified Rankin Scale (mRS) 3-6 or 4-6). The predictive performance of the grading scales was assessed via evaluation of distribution, trend, association, and discrimination. In regard to the distribution, none of the patients were categorized as HAIR 8 and SAH score 8. Both grading scales indicated a significant trend between scores and outcome (P < 0.05), and association with the outcome (OR > 1). The modified Fisher Scale (mFS), World Federation of Neurosurgical Societies scale (WFNS), and combined scores VASOGRADE and HAIR showed good predictive accuracy (area under the curve (AUC) > 0.750) for DCI. The predictive accuracy in each scale performed well in predicting poor outcome, with the exception of mFS and the Subarachnoid hemorrhage Early Brain Edema Score (SEBES). However, the mFS performed with increased accuracy when predicting mRS 4-6. The VASOGRADE, HAIR, and WFNS may be valuable prognostic tools for predicting both DCI and poor outcome. The mFS can be applicable for predicting DCI and mRS 4-6. The SAH score and the Hunt-Hess were also optimal for predicting poor outcome. The predictive performance of SEBES was relatively poor compared to the other scales.

4.
Phytother Res ; 2020 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-32185829

RESUMO

Gemcitabine (GEM) resistance in pancreatic adenocarcinoma mediated by the receptor for advanced glycation end products (RAGE) has been demonstrated. Therefore, investigating the safety and the potential of new auxiliary methods for pancreatic cancer treatment is urgent. Ursolic acid (UA), a natural pentacyclic triterpenoid found in apple peels, rosemary, and thyme, has been reported to have anticancer capacity. This study aimed to reveal the underlying mechanisms of UA in cell death and drug enhancement, especially in GEM-resistant pancreatic cancer cells. First, GEM-resistant cells (MIA Paca-2GEMR cells) were established by incrementally increasing GEM culture concentrations. UA treatment reduced cell viability through cell cycle arrest and endoplasmic reticulum (ER) stress, resulting in apoptosis and autophagy in a dose-dependent manner in MIA Paca-2 and MIA Paca-2GEMR cells. High RAGE expression in MIA Paca-2GEMR cells was suppressed by UA treatment. Interestingly, knocking down RAGE expression showed similar UA-induced effects in both cell lines. Remarkably, UA had a drug-enhancing effect by decreasing cell viability and increasing cell cytotoxicity when combined with GEM treatment. In conclusions, UA triggered ER stress, subsequently regulating apoptosis- and autophagy-related pathways and increasing GEM chemosensitivity in pancreatic cancer cells by inhibiting the expression of RAGE.

5.
Biochemistry ; 2020 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-32207963

RESUMO

Over 80 loss-of-function (LOF) mutations in the SLC6A8 creatine transporter (hCRT1) are responsible for cerebral creatine deficiency syndrome (CCDS), which gives rise to a spectrum of neurological defects including intellectual disability, epilepsy, and autism spectrum disorder. To gain insight into the nature of the molecular defects caused by these mutations, we quantitatively profiled the cellular processing, trafficking, expression, and function of eight pathogenic CCDS variants in relation to wild-type and one neutral isoform. All eight CCDS variants exhibit measurable proteostatic deficiencies that likely contribute to the observed LOF. However, the magnitude of their specific effects on expression and trafficking of hCRT1 vary considerably, and we find that the LOF associated with two of these variants primarily arises from the disruption of the substrate-binding pocket. In conjunction with an analysis of structural models of the transporter, we use these data to suggest mechanistic classifications for these variants. To evaluate potential avenues for therapeutic intervention, we assessed the sensitivity of these variants to temperature and measured their response to the proteostasis regulator 4-phenylbutyrate (4-PBA). Only one of the tested variants (G132V) is temperature-sensitive, though its response to 4-PBA is negligible. Nevertheless, 4-PBA significantly enhances the activity of WT hCRT1 in HEK293T cells, which suggests it may be worth evaluating as a therapeutic for female intellectual disability patients carrying a single CCDS mutation. Together, these findings reveal that pathogenic SLC6A8 mutations cause a spectrum of molecular defects that should be taken into consideration in future efforts to develop CCDS therapeutics.

6.
Artigo em Inglês | MEDLINE | ID: mdl-32150960

RESUMO

In the drinking water reservoir ecosystem, phytoplankton and bacteria play important roles in shaping freshwater health and function. In this work, the associated bacterial community functional diversity during degradation of phytoplankton was determined using the substrate utilization profiling (BIOLOG) technique, meanwhile, the composition and concentration of phytoplankton were examined using a microscope. The results indicated that Euglena decreased 58.33% from 0 to 38 d, while the smallest degradation of Bacillariophyta was 20.19%. Average well color development (AWCD590nm) increased during the static periods from 0 to 38 d; however, the AWCD590nm of 18 and 38 d had no significant difference (p < 0.05). The Simpson's index (D) was in accordance with Shannon's diversity (H) and species richness(S); it was measured to be18 > 38 > 5 > 0d. There were significant differences in the pattern and level of carbon sources used by the phytoplankton-associated bacteria. In addition, the principle component analyses (PCA) suggested that the first principle component (PC1) and the second principle component (PC2) explained 46.76% and 21.49% of the total variation for bacterial community, respectively. Redundancy analysis (RDA) revealed that cell abundance of phytoplankton was negatively correlated with the AWCD590nm, amino acids and other functional indexes. Therefore, the data suggest that there are differences in the phytoplankton-associated bacterial community functional diversity during different static stages of water samples collected from the drinking water reservoir.

7.
Proc Natl Acad Sci U S A ; 117(12): 6762-6770, 2020 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-32161129

RESUMO

Nematode-trapping fungi (NTF) are a group of specialized microbial predators that consume nematodes when food sources are limited. Predation is initiated when conserved nematode ascaroside pheromones are sensed, followed by the development of complex trapping devices. To gain insights into the coevolution of this interkingdom predator-prey relationship, we investigated natural populations of nematodes and NTF that we found to be ubiquitous in soils. Arthrobotrys species were sympatric with various nematode species and behaved as generalist predators. The ability to sense prey among wild isolates of Arthrobotrys oligospora varied greatly, as determined by the number of traps after exposure to Caenorhabditis elegans While some strains were highly sensitive to C. elegans and the nematode pheromone ascarosides, others responded only weakly. Furthermore, strains that were highly sensitive to the nematode prey also developed traps faster. The polymorphic nature of trap formation correlated with competency in prey killing, as well as with the phylogeny of A. oligospora natural strains, calculated after assembly and annotation of the genomes of 20 isolates. A chromosome-level genome assembly and annotation were established for one of the most sensitive wild isolates, and deletion of the only G-protein ß-subunit-encoding gene of A. oligospora nearly abolished trap formation. In summary, our study establishes a highly responsive A. oligospora wild isolate as a model strain for the study of fungus-nematode interactions and demonstrates that trap formation is a fitness character in generalist predators of the nematode-trapping fungus family.

9.
Zhen Ci Yan Jiu ; 45(1): 46-50, 2020 Jan 25.
Artigo em Chinês | MEDLINE | ID: mdl-32144908

RESUMO

OBJECTIVE: To observe the clinical effect of herbal cake-partitioned moxibustion combined with Rhinocort spray in the treatment of symptoms, sleep quality and daily life quality of patients with moderate-severe allergic rhinitis(AR).. METHODS: A total of 67 patients with persistent moderate-severe AR were recruited in the present study and randomized into a treatment group (n=35) and a control group (n=32). The patients in the treatment group were treated by herbal cake-partitioned moxibustion (applied to Dazhui [GV14], and bilateral Feishu [BL13], Shenshu [BL23] and Zhiyang [GV9], 3 moxa-cones/time, once every other day) plus Rhinocort spray (once in the morning and evening separately, 256 µg/d), and patients in the control group treated by Rhinocort spray alone (the same to that mentioned above). All the treatments were given for 4 weeks. The therapeutic effect was evaluated with reference to the "Principles and Recommended Schemes for Diagnosis and Treatment of AR" formulated by Otolaryngology Branch of Chinese Medical Association before and after the treatment. The severity of symptoms of AR was assessed by using visual analogue scale (VAS), the life quality of nasal conjunctivitis assessed using "Rhino-conjunctivitis Quality of Life Questionnaire (RQLQ)", and the sleep quality assessed using "Pittsburgh Sleep Quality Index (PSQI)" before and after the treatment, followed by 3 months' follow-up survey. RESULTS: After the treatment, the VAS and RQLQ scores in both groups and PSQI of the treatment group were significantly decreased in comparison with their own base-line levels of pre-treatment in each group (P<0.05). The RQLQ and PSQI in the treatment group were substantially lower than those in the control group (P<0.05). No marked difference was found between the two groups in VAS(P>0.05). Follow-up survey showed that the VAS and RQLQ scores in both groups and PSQI of the treatment group were still significantly lower than those of pre-treatment in each group(P<0.05), and the VAS, RQLQ and PSQI scores of the treatment group were significantly lower than those of the control group(P<0.05). After 4 weeks' treatment, of the 32 and 35 AR patients in the control and treatment groups, 7 and 16 experienced marked improvement, 16 and 14 were effective, and 9 and 5 failed, with the effective rate being 71.9% and 85.7%, respectively. The effective rate of the treatment group was significantly superior to that of the control group (P<0.05). CONCLUSION: Herbal cake-partitioned moxibustion combined with Rhinocort spray has a good therapeutic effect in improving symptoms, sleep and quality of life in patients with persistent moderate-severe AR, which is obviously superior to that of Rhinocort spray alone in improving sleep and quality of life.


Assuntos
Moxibustão , Rinite Alérgica , Pontos de Acupuntura , Budesonida , Humanos , Qualidade de Vida , Rinite Alérgica/terapia
10.
Chin J Integr Med ; 2020 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-32170521

RESUMO

With reference to international guidelines for the development of tools-Grading of Recommendations Assessment, Development and Evaluation (GRADE) system approach and reasoning, this practice guideline has been drafted reflecting the characteristics of acupuncture to improve effectiveness and safety of acupuncture treatment for allergic rhinitis. This guideline includes outlining the acupuncture diagnosis and treatment principles for allergic rhinitis, suggesting recommendations and related evidence for the acupuncture treatment of allergic rhinitis, and defining operating methods and precautions for the acupuncture treatment of allergic rhinitis.

11.
J Med Chem ; 2020 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-32097000

RESUMO

Increased usage of daptomycin to treat infections caused by Gram-positive bacterial pathogens has resulted in emergence of resistant mutants. In a search for more effective daptomycin analogues through medicinal chemistry studies, we found that methylation at the nonproteinogenic amino acid kynurenine in daptomycin could result in significant enhancement of antibacterial activity. Termed "kynomycin," this new antibiotic exhibits higher antibacterial activity than daptomycin and is able to eradicate methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE) strains, including daptomycin-resistant strains. The improved antimicrobial activity of kynomycin was demonstrated in in vitro time-killing assay, in vivo wax worm model, and different mouse infection models. The increased antibacterial activity, improved pharmacokinetics, and lower cytotoxicity of kynomycin, compared to daptomycin, showed the promise of the future design and development of next-generation daptomycin-based antibiotics.

12.
Eur J Dermatol ; 2020 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-32031529

RESUMO

BACKGROUND: Cutaneous adverse drug reactions (CADRs) are drug-induced skin reactions with or without systemic involvement, ranging from mild maculopapular exanthema (MPE) to life-threatening severe CADRs (S-CADRs). Due to their unpredictability and severity, early recognition of suspected causative drugs is highly recommended. However, the profile of CADRs remains unknown in China. OBJECTIVES: To assess the clinical profile, predominant causative drugs, and cost associated with CADRs in Shanghai, China. MATERIALS AND METHODS: Clinical records of inpatients admitted with a diagnosis of CADRs to the dermatology ward of Huashan Hospital from January 2007 to December 2016 were retrospectively studied. RESULTS: A total of 1,883 patients (1,231 female and 652 male), admitted with a diagnosis of CADR, were investigated. S-CADRs made up 21.99% of all cases (n=414), and urticaria (27.19%) was the most frequent reaction. Of the patients, 53.43% suffered from multiple drug-induced drug eruptions and the rest (45.83%) from single drug-induced drug eruptions. Overall, antimicrobials (28.85%) was the main drug group involved, and for S-CADRs, this was antiepileptic drugs (36.15%). The total cost for CADRs was RMB23,718,788.83 ($3,588,319.04). Both age and sex were related to admission cost (p=0.005 and p=7.84E-8, respectively). Antimicrobials were the most common treatment causing CADRs. CONCLUSION: The management of CADRs requires considerable medical cost. CADRs are not only a health problem but also a significant financial burden for affected individuals.

13.
J Clin Neurosci ; 73: 245-251, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32067828

RESUMO

Fragile X syndrome (FXS) is a common mental retardation syndrome. Anxiety and abnormal social behaviors are prominent features of FXS in humans. To better understand the effects of hyperbaric oxygen therapy (HBOT) on these behaviors, we analyzed anxiety-related and social behaviors in Fmr1 knockout mice treated by HBOT. In the open field test, HBOT group mice preferred the periphery to central areas and tended to run or walk along the wall. The results suggested that thigmotaxis was significantly increased in the HBOT group compared with the control group. In the elevated plus maze test, the percentage of distance traveled was significantly increased in the open arm and significantly decreased in the closed arm for HBOT group mice compared with control group mice. These results suggested that HBOT group mice displayed enhanced motor activity in the open arm and exhibited fewer anxiety-related behaviors. In the three-chambered social approach test, the HBOT group mice made more approaches to the wire cup containing an acquaintance mouse than control group mice in the sociability test and made more approaches to the wire cup containing a stranger mouse than control group mice in the social novelty preference test. The results suggested that HBOT group mice showed increased levels of social interaction and decreased "social anxiety" than the control group to partner mice in this test. Our findings indicated that HBOT resulted in altered anxiety and social behavior in Fmr1 knockout mice and could possibly be used as a treatment for FXS.

14.
Proc Natl Acad Sci U S A ; 117(10): 5260-5268, 2020 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-32094196

RESUMO

A critical problem in the fight against bacterial infection is the rising rates of resistance and the lack of new antibiotics. The discovery of new targets or new antibacterial mechanisms is a potential solution but is becoming more difficult. Here we report an antibacterial mechanism that safeguards intestine cells from enteropathogenic Escherichia coli (EPEC) by shutting down an infection-responsive signal of the host intestine cell. A key step in EPEC infection of intestinal cells involves Tir-induced actin reorganization. Nck mediates this event by binding with Tir through its SH2 domain (Nck-SH2) and with WIP through its second SH3 domain (Nck-SH3.2). Here we report the design of a synthetic peptide that reacts precisely with a unique cysteine of the Nck-SH3.2 domain, blocks the binding site of the Nck protein, and prevents EPEC infection of Caco-2 cells. Oral update of this nontoxic peptide before EPEC administration safeguards mice from EPEC infection and diarrhea. This study demonstrates domain-specific blockage of an SH3 domain of a multidomain adaptor protein inside cells and the inhibition of Tir-induced rearrangement of the host actin cytoskeleton as a previously unknown antibacterial mechanism.

15.
Sci Rep ; 10(1): 1957, 2020 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-32029755

RESUMO

Escherichia coli is an important pathogenic indicator in drinking water. Viable but non-culturable (VBNC) E. coli induced by low level chlorination was found to have higher antibiotic tolerance. The emerging of VBNC bacteria in drinking water systems is posing challenges to the control of bio-safety. It is necessary to study the underlying mechanisms of VBNC state E. coli under actual residual chlorine condition of drinking water pipe network. In this study, we investigated the changes of morphology and gene expressions that might present such state. The results indicated that the size of VBNC E. coli was not remarkably changed or recovered culturability under favorable environmental conditions. Results from transcriptomic analysis revealed that the regulated genes related to fimbrial-like adhesin protein, putative periplasmic pilin chaperone, regulators of the transcriptional regulation, antibiotic resistance genes and stress-induced genes, rendering VBNC cells more tolerant to adverse environmental conditions. In total of 16 genes were significantly up-regulated under the VBNC state, including three genes encoding toxic protein (ygeG, ibsD, shoB), indicating that VBNC E. coil was still a threat to human. The work is of great relevance in the context of better understanding this poorly understood physiological state.

16.
Artigo em Inglês | MEDLINE | ID: mdl-32065690

RESUMO

RATIONALE: Paris polyphylla var. yunnanensis (Franch) Hand Mazz (PPY) is a traditional Chinese medicine (TCM) with antitumor, antibacterial, hemostatic, and anthelmintic activities. Identification of chemical constituents from PPY is helpful to discover the potential active ingredients and can be used to control its quality. METHODS: The composition of PPY was identified with using ultra-high-performance liquid chromatography combined with quadrupole time-of-flight mass spectrometry (UPLC/QTOF-MS/MS) coupled with a molecular networking strategy. First, the UPLC/QTOF-MS/MS approach was optimized for chemical compound profiling. Then, the MS data were processed using PeakView™ combined with an in-house database to quickly characterize the secondary metabolites. Lastly, molecular networking excavates new molecular weights to discover unknown or trace natural products based on the characteristics of each cluster. RESULTS: A total of 222 compounds, including 77 Isospirostanols, 2 spirostanols, 19 furostanols, 10 pseudospirostanols, 6 cholesterols, 10 C21 steroids, 5 insect metamorphosis hormones, 3 plant sterols, 6 five-ring triterpenoids, 4 flavonoids, 8 fatty acids, 2 phenylpropanoids, and 8 other compounds were characterized in PPY by comparing their main fragmentation characteristics and pathways with literature data, and 62 of them, including 54 steroidals and 8 phenylpropanoids, were discovered or tentatively identified for the first time. CONCLUSIONS: This study extended the application of molecular networking strategy to traditional herbal medicine and developed a molecular networking-based screening approach with a significant increase of efficiency for the discovery and identification of trace novel natural products.

17.
Artigo em Inglês | MEDLINE | ID: mdl-32083767

RESUMO

Peptides have important biological functions. However, peptides' susceptibility to proteolysis is a big hurdle to their application. We demonstrated, for the first time, that poly(2-oxazoline) can work as functional mimics of peptides. Using host defense peptide as a model, we showed poly(2-oxazoline) based glycine pseudopeptides can mimic host defense peptide and have potent in vitro and in vivo activities against methicillin-resistant Staphylococcus aureus that cause formidable infections. The poly(2-oxazoline) showed potent activity against persister cells that are highly resistant to antibiotics. S taphylococcus aureus were unable to acquire resistance upon poly(2-oxazoline), owning to the reactive oxygen species related antimicrobial mechanism. Poly(2-oxazoline) treated Staphylococcus aureus were still sensitive to common antibiotics, demonstrating no observable antimicrobial pressure or cross-resistance in using antimicrobial poly(2-oxazoline). Our study highlighted poly(2-oxazoline) as a new type of functional mimics of peptides and opened up new avenues in designing and exploring peptide mimetics for biological functions and applications.

18.
J Recept Signal Transduct Res ; : 1-7, 2020 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-32098557

RESUMO

Fibroblast growth factor receptor-like-1 (FGFRL1) is important to cell motility and links with tumorigenic potential in various types of cancers. To investigate the biological function and underlying mechanism of FGFRL1 in rectal adenocarcinoma, we conducted this study. TCGA and Oncomine databases were used to analyze FGFRL1 expression and its association with clinical characteristics or overall survival (OS) in rectal adenocarcinoma patients. siRNA strategy was implemented to knockdown FGFRL1 expression in rectal adenocarcinoma cells. CCK8, colony formation, wound healing, and transwell assays were implemented to measure cell behaviors. qRT-PCR and western blot were utilized to identify mRNA and protein expression levels. FGFRL1 was significantly increased in rectal adenocarcinoma tissue samples, either colon or rectum. High-regulation of FGFRL1 expression induced poorer outcome of rectal adenocarcinoma patients. Downregulation of FGFRL1 inhibited the proliferation, colony formation, migration, and invasion of SW837 cells. The MAPK pathway-related proteins, phosphorylation of MEK and ERK, were also decreased after si-FGFRL1 transfection. These findings demonstrated that FGFRL1, acting as a potential inducator, may promote the progression of rectal adenocarcinoma via activating the MAPK signaling pathway.

19.
Artigo em Inglês | MEDLINE | ID: mdl-32061180

RESUMO

Biocompatible and proteolysis-resistant poly-ß-peptides have broad applications and are dominantly synthesized via the harsh and water-sensitive ring-opening polymerization of ß-lactams in a glovebox or using a Schlenk line, catalyzed by the strong base LiN(SiMe3 )2 . We have developed a controllable and water-insensitive ring-opening polymerization of ß-amino acid N-thiocarboxyanhydrides (ß-NTAs) that can be operated in open vessels to prepare poly-ß-peptides in high yields, with diverse functional groups, variable chain length, narrow dispersity and defined architecture. These merits imply wide applications of ß-NTA polymerization and resulting poly-ß-peptides, which is validated by the finding of a HDP-mimicking poly-ß-peptide with potent antimicrobial activities. The living ß-NTA polymerization enables the controllable synthesis of random, block copolymers and easy tuning of both terminal groups of polypeptides, which facilitated the unravelling of the antibacterial mechanism using the fluorophore-labelled poly-ß-peptide.

20.
Ann Clin Transl Neurol ; 7(2): 200-209, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32023010

RESUMO

OBJECTIVE: To describe the clinical and genetic features of two patients with different phenotypes due to various Dynactin 1 (DCTN1) gene mutations and further explore the phenotype-genotype relationship. METHODS: Patient 1 is a 23-year-old man with congenital foot deformity and life-long distal muscle weakness and atrophy. Patient 2 is a 48-year-old woman with adult-onset progressive weakness, lower limbs atrophy, and pyramid bundle signs. Electrophysiology test showed normal nerve conduction velocity of both patients and neurogenic changes in needle electromyography. Open sural nerve biopsy for Patient 1 showed slight loss of myelinated nerve fibers. Both patients were performed with whole-exome sequencing followed by functional study of identified variants. RESULTS: Two mutations in DCTN1 gene were identified in Patient 1 (c.626dupC) and Patient 2 (c.3823C>T), respectively. In vitro, the wild type mostly located in cytoplasm and colocalized with α-tubulin. However, c.626dupC tended to be trapped into nuclear and the c.3823C>T formed cytoplasmic aggregates, both losing colocalization with α-tubulin. Western blotting showed a truncated mutant with less molecular weight of c.626dupC was expressed. INTERPRETATION: We identify two novel DCTN1 mutations causing different phenotypes: (1) early-onset distal hereditary motor neuropathy plus congenital foot malformation and (2) amyotrophic lateral sclerosis, respectively. We provide the initial evidence that foot developmental deficiency probably arises from subcellular localizing abnormality of Dynactin 1, revealing DCTN1-related spectrum is still expanding.

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