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2.
Life Sci ; : 118786, 2020 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-33221346

RESUMO

AIMS: To assess the effects of three specific exercise training modes, aerobic exercise (A), resistance training (R) and autonomous climbing (AC), aimed at proposing a cross-training method, on improving the physical, molecular and metabolic characteristics of mice without many side effects. MATERIALS AND METHODS: Seven-week-old male mice were randomly divided into four groups: control (C), aerobic exercise (A), resistance training (R), and autonomous climbing (AC) groups. Physical changes in mice were tracked and analysed to explore the similarities and differences of these three exercise modes. Histochemistry, quantitative real-time PCR (RT-PCR), western blot (WB) and metabolomics analysis were performed to identify the underlying relationships among the three training modes. KEY FINDINGS: Mice in the AC group showed better body weight control, glucose and energy homeostasis. Molecular markers of myogenesis, hypertrophy, antidegradation and mitochondrial function were highly expressed in the muscle of mice after autonomous climbing. The serum metabolomics landscape and enriched pathway comparison indicated that the aerobic oxidation pathway (pentose phosphate pathway, galactose metabolism and fatty acid degradation) and amino acid metabolism pathway (tyrosine, arginine and proline metabolism) were significantly enriched in group AC, suggesting an increased muscle mitochondrial function and protein balance ability of mice after autonomous climbing. SIGNIFICANCE: We propose a new exercise mode, autonomous climbing, as a convenient but effective training method that combines the beneficial effects of aerobic exercise and resistance training.

5.
Orthop Surg ; 2020 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-33184974

RESUMO

OBJECTIVE: The aim of the present study was to explore the surgical treatment and prognosis of 27 cases of neurofibromatosis type 1 with severe dystrophic kyphosis. METHODS: We performed surgical treatment for scoliosis and kyphosis caused by dystrophic curves at Peking Union Medical College Hospital, Beijing, China from December 2015 to December 2017. The study included 21 patients with moderate to severe kyphosis, 12 males and 9 females, with an average age of 14.95 ± 6.05 years. All patients had kyphosis angles greater than 70° and had more than four skeletal developmental defects. A total of 6 patients with severe kyphosis, 2 males and 4 females, with an average age of 12.5 years, had more than five skeletal developmental defects with a kyphosis angle greater than 90° or a lumbar kyphosis angle greater than 40°. According to the patient's own situation, we adopted a low-grade surgery scheme (grades 1 or 2) or a high-grade surgery scheme (grades 3-6). The low-grade surgery was mainly lower articular surface resection or pontodestomy, and the high-grade surgery was mainly apical vertebral body or upper discectomy. All patients were followed up to determine their prognosis. RESULTS: Statistical analysis showed that there was a significant difference in preoperative and postoperative scores between the two groups (P < 0.05), and scoliosis correction showed that surgical treatment had a significant effect on scoliosis kyphosis. The mean follow-up time was 66.7 months. Follow-up results showed that 50% of complications after internal fixation were related to high-level surgery. Complications included displacement of the titanium cage, removal of the lamina hook, formation of pseudoarthrosis, and internal fixation failure (with a rate of 7.7%-14.3%). In contrast, there were no associated symptoms for low-grade surgery. In addition, the results showed that gender, age, extent of resection, height, and body mass index had no significant effect on preoperative, postoperative, and prognostic indicators of patients (P > 0.05). CONCLUSION: Early identification of dysplastic scoliosis-related deformities plays an important role in surgical planning and prognosis, and low-level surgical procedures are more favorable for patients' prognosis.

6.
Cell Chem Biol ; 2020 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-33186541

RESUMO

Pioneering microbial genomic surveys have revealed numerous untapped biosynthetic gene clusters, unveiling the great potential of new natural products. Here, using a combination of genome mining, mutasynthesis, and activity screening in an infection model comprising Caenorhabditis elegans and Pseudomonas aeruginosa, we identified candidate virulence-blocking amychelin siderophore compounds from actinomycetes. Subsequently, we developed unreported analogs of these virulence-blocking siderophores with improved potency by exploiting an Amycolatopsis methanolica strain 239T chorismate to salicylate a biosynthetic subpathway for mutasynthesis. This allowed us to generate the fluorinated amychelin, fluoroamychelin I, which rescued C. elegans from P. aeruginosa-mediated killing with an EC50 value of 1.4 µM, outperforming traditional antibiotics including ceftazidime and meropenem. In general, this paper describes an efficient platform for the identification and production of classes of anti-microbial compounds with potential unique modes of action.

7.
Mol Med Rep ; 22(6): 5262-5270, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33174032

RESUMO

Tissue damage in diabetes is at least partly due to elevated reactive oxygen species production by the mitochondrial respiratory chain during hyperglycemia. Sustained hyperglycemia results in mitochondrial dysfunction and the abnormal expression of mitochondrial genes, such as NADH: Ubiquinone oxidoreductase subunit A13 (NDUFA13). Metformin, an AMP­activated protein kinase (AMPK) activator, protects cardiomyocytes from oxidative stress by improving mitochondrial function; however, the exact underlying mechanisms are not completely understood. The aim of the present study was to investigated the molecular changes and related regulatory mechanisms in the response of H9C2 cardiomyocytes to metformin under high glucose conditions. H9C2 cells were subjected to CCK­8 assay to assess cell viability. Reactive oxygen species generation was measured with DCFH­DA assay. Western blotting was used to analyze the expression levels of NDUFA13, AMPK, p­AMPK and GAPDH. Reverse transcription­quantitative PCR was used to evaluate the expression levels of mitochondrial genes and transcription factors. It was observed that metformin protected H9C2 cardiomyocytes by suppressing high glucose (HG)­induced elevated oxidative stress. In addition, metformin stimulated mitochondrial biogenesis, as indicated by increased expression levels of mitochondrial genes (NDUFA1, NDUFA2, NDUFA13 and manganese superoxide dismutase) and mitochondrial biogenesis­related transcription factors [peroxisome proliferator­activated receptor­gamma coactivator­1α, nuclear respiratory factor (NRF)­1, and NRF­2] in the metformin + HG group compared with the HG group. Moreover, metformin promoted mitochondrial NDUFA13 protein expression via the AMPK signaling pathway, which was abolished by pretreatment with the AMPK inhibitor, Compound C. The results suggested that metformin protected cardiomyocytes against HG­induced oxidative stress via a mechanism involving AMPK, NDUFA13 and mitochondrial biogenesis.

8.
Colorectal Dis ; 2020 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-33191594

RESUMO

AIM: To evaluate the physiologic variation in rectoanal inhibitory reflex (RAIR) after laparoscopic intersphincteric resection (Lap-ISR) for ultralow rectal cancer. METHOD: This was a retrospective study that included 56 patients who underwent Lap-ISR from a prospectively collected database. The RAIR was examined preoperatively and up to 12-months after ileostomy closure. The primary outcome included physiologic variation in RAIR and its difference between partial, subtotal, and total ISR. The secondary outcome was its correlation with functional outcome. RESULTS: The reflex was present in 95% (53/56) of patients preoperatively, in 36% (20/56) before ileostomy closure, in 48% (27/56) at 3-6 months, and in 61% (34/56) at 12-months after ileostomy closure. The elicited volume of RAIR was significantly increased at 12-months after ileostomy closure than that at baseline (P = 0.005), but its duration and amplitude did not differ significantly. There was no significant difference in the reflex recovery between the ISR groups (partial vs subtotal vs total: 65% vs 63% vs 44%, P = 0.61). At 12-months after ileostomy closure, the RAIR-present group had favorable functional results and patient satisfaction (P < 0.05). Major fecal incontinence was found in 82% of patients in the RAIR-absent group. CONCLUSION: The RAIR is abolished in the majority of patients after Lap-ISR, but a time-dependent recovery could be observed in more than half of the patients. The reflex recovery is not be influenced by the resection grade of the internal sphincter. However, persistent loss of the RAIR correlates with worse continence.

9.
Langmuir ; 36(45): 13708-13715, 2020 11 17.
Artigo em Inglês | MEDLINE | ID: mdl-33161721

RESUMO

Finding DNA sequences that can adsorb strongly on nanomaterials is critical for bioconjugate and biointerface chemistry. In most previous work, unmodified DNA with a phosphodiester backbone (PO DNA) were screened or selected for adsorption on inorganic surfaces. In this work, the adsorption of phosphorothioate (PS)-modified DNA (PS DNA) on graphene oxide (GO) is studied. By use of fluorescently labeled oligonucleotides as probes, all the tested PS DNA strands are adsorbed more strongly on GO compared to the PO DNA of the same sequence. The adsorption mechanism is probed by washing the adsorbed DNA with proteins, surfactants, and urea. Molecular dynamics simulations show that van der Waals forces are responsible for the tighter adsorption of PS DNA. Polycytosine (poly-C) DNA, in general, has a high affinity for the GO surface, and PS poly-C DNA can adsorb even stronger, making it an ideal anchoring sequence on GO. With this knowledge, noncovalent functionalization of GO with a diblock DNA is demonstrated, where a PS poly-C block is used to anchor on the surface. This conjugate achieves better hybridization than the PO DNA of the same sequence for hybridization with the complementary DNA.

10.
Clin Chim Acta ; 2020 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-33181148

RESUMO

Atherosclerosis is one of the chronic progressive diseases, which is caused by vascular injury and promoted by the interaction of various inflammatory factors and inflammatory cells. In recent years, kruppel-like factor 4 (KLF4), a significant transcription factor that participated in cell growth, differentiation and proliferation, has been proved to cause substantial impacts on regulating cardiovascular disease. This paper will give a comprehensive summary to highlight KLF4 as a crucial regulator of foam cell formation, vascular smooth muscle cells (VSMCs) phenotypic transformation, macrophage polarization, endothelial cells inflammation, lymphocyte differentiation and cell proliferation in the process of atherosclerosis. Recent studies show that KLF4 may be an important "molecular switch" in the process of improving vascular injury and inflammation under harmful stimulation, suggesting that KLF4 is a latent disease biomarker for the therapeutic target of atherosclerosis and vascular disease.

11.
Med Chem ; 2020 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-33222676

RESUMO

BACKGROUND: Podophyllotoxin is a natural lignan which possesses anticancer and antiviral activities. Etoposide and teniposide are semisynthetic glycoside derivatives of podophyllotoxin and are increasingly used in cancer medicine. OBJECTIVE: The present work was aimed to design and synthesize a series of 2, 4, 5-trideoxyhexopyranosides derivatives of 4'-demethylepipodophyllotoxin as novel anticancer agents. METHODS: A divergent de novo synthesis of 2, 4, 5-trideoxyhexopyranosides derivatives of 4'-demethylepipodophyllotoxin has been established via palladium-catalyzed glycosylation. The abilities of synthesized glycosides to inhibit the growth of A549, HepG2, SH-SY5Y, KB/VCR and HeLa cancer cells were investigated by MTT assay. Flow cytometric analysis of cell cycle with propidium iodide DNA staining was employed to observe the effect of compound 5b on cancer cell cycle. RESULTS: Twelve D and L monosaccharides derivatives 5a-5l have been efficiently synthesized in three steps from various pyranone building blocks employing de novo glycosylation strategy. D-monosaccharide 5b showed highest cytotoxicity on five cancer cell lines with the IC50 values from 0.9 to 6.7 mM. It caused HepG2 cycle arrest at G2/M phase in a concentration-dependent manner. CONCLUSION: The present work leads to the development of novel 2, 4, 5-trideoxyhexopyranosides derivatives of 4'- demethylepipodophyllotoxin. The biological results suggested that the replacement of the glucosyl moiety of etoposide with 2, 4, 5-trideoxyhexopyranosyl is favorable to their cytotoxicity. D-monosaccharide 5b caused HepG2 cycle arrest at G2/M phase in a concentration-dependent manner.

12.
J Org Chem ; 85(22): 14744-14752, 2020 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-33136392

RESUMO

A metal-free and base-free procedure for the phosphorylation of imidazo[1,2-a]pyridines with phosphine oxides under the irradiation of visible light at room temperature in green solvent was reported, featuring mild and sustainable conditions, convenient operation, as well as good functional group compatibility.

13.
J Cell Mol Med ; 2020 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-33150736

RESUMO

It remains unclear whether the necessity of calcified mellitus induced by high inorganic phosphate (Pi) is required and the roles of autophagy plays in aldosterone (Aldo)-enhanced vascular calcification (VC) and vascular smooth muscle cell (VSMC) osteogenic differentiation. In the present study, we found that Aldo enhanced VC both in vivo and in vitro only in the presence of high Pi, alongside with increased expression of VSMC osteogenic proteins (BMP2, Runx2 and OCN) and decreased expression of VSMC contractile proteins (α-SMA, SM22α and smoothelin). However, these effects were blocked by mineralocorticoid receptor inhibitor, spironolactone. In addition, the stimulatory effects of Aldo on VSMC calcification were further accelerated by the autophagy inhibitor, 3-MA, and were counteracted by the autophagy inducer, rapamycin. Moreover, inhibiting adenosine monophosphate-activated protein kinase (AMPK) by Compound C attenuated Aldo/MR-enhanced VC. These results suggested that Aldo facilitates high Pi-induced VSMC osteogenic phenotypic switch and calcification through MR-mediated signalling pathways that involve AMPK-dependent autophagy, which provided new insights into Aldo excess-associated VC in various settings.

14.
Artigo em Inglês | MEDLINE | ID: mdl-33211468

RESUMO

Mussel-inspired poly(catecholamine) coatings from polydopamine (PDA) have been widely studied to design functional coatings for various materials. The chemical precursor of dopamine (DA), levodopa (l-DOPA, 3,4-dihydroxyphenyl-l-alanine), is known as the main element of mussel adhesive foot protein, but it is relatively hard to be constructed into a desirable coating on a given material surface under the same conditions as those for DA. Herein, we report a codeposition strategy to achieve the rapid fabrication of mussel-inspired coatings by l-DOPAwith polyethyleneimine (PEI) and to deeply understand the formation mechanism of those aggregates and coatings from l-DOPA/PEI. DFT calculations, fluorescence spectra, nuclear magnetic resonance analysis, and liquid chromatography-tandem mass spectrometry identification demonstrate that the formation of l-DOPA/PEI aggregates is effectively accelerated by PEI crosslinking with those intermediates of oxidized l-DOPA, including l-DOPAquinone and 5,6-dihydroxyindole-2-carboxylic acid as well as 5,6-dihydroxyindole, through Michael-addition and Schiff-base reactions. Therefore, we can facilely control the growth rate and the particle size of the l-DOPA/PEI aggregates in the deposition solution by adjusting the concentration of PEI. The coating formation rate of l-DOPA/PEI is four times faster than that of PDA and DA/PEI within 12 h. These l-DOPA/PEI coatings are demonstrated to display potential as structure colors, superhydrophilic surfaces, and antibacterial materials.

15.
PLoS One ; 15(11): e0242700, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33211772

RESUMO

Mitochondrial fusion and fission are dynamic processes regulated by the cellular microenvironment. Under nutrient starvation conditions, mitochondrial fusion is strengthened for energy conservation. We have previously shown that newborns of Ubl4A-deficient mice were more sensitive to starvation stress with a higher rate of mortality than their wild-type littermates. Ubl4A binds with the actin-related protein Arp2/3 complex to synergize the actin branching process. Here, we showed that deficiency in Ubl4A resulted in mitochondrial fragmentation and apoptosis. A defect in the fusion process was the main cause of the mitochondrial fragmentation and resulted from a shortage of primed Arp2/3 complex pool around the mitochondria in the Ubl4A-deficient cells compared to the wild-type cells. As a result, the mitochondrial fusion process was not undertaken quickly enough to sustain starvation stress-induced cell death. Consequently, fragmented mitochondria lost their membrane integrity and ROS was accumulated to trigger caspase 9-dependent apoptosis before autophagic rescue. Furthermore, the wild-type Ubl4A, but not the Arp2/3-binding deficient mutant, could rescue the starvation-induced mitochondrial fragmentation phenotype. These results suggest that Ubl4A promotes the mitochondrial fusion process via Arp2/3 complex during the initial response to nutrient deprivation for cell survival.

16.
Bioorg Med Chem Lett ; 30(24): 127652, 2020 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-33130293

RESUMO

Hypoxia-inducible factor 1α (HIF-1α) is a known regulator of tumor cell proliferation, migration, and angiogenesis. The presence of a high concentration of HIF-1α is positively correlated with the severity of cancer. Therefore, the inhibition of this pathway represents an important therapeutic target for the treatment of various types of cancer. Here, we designed and synthesized 30 panaxadiol (PD) derivatives and evaluated their inhibitory activities against HIF-1α transcription. Of these, compound 3l exhibited the most promising inhibitory activity (IC50 = 3.7 µM) and showed significantly decreased cytotoxicity compared with PD. Compound 9e exhibited the strongest cytotoxic effect and may be considered for further preclinical development.

17.
Neurosci Lett ; 740: 135441, 2020 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-33184037

RESUMO

BACKGROUND: A recent study on early onset Parkinson's disease (PD) revealed that NUS1 is a risk gene for PD. Clinically, essential tremor (ET) is closely related to PD. In this study, we aimed to detect NUS1 variants and assess the effect of those variants on patients with ET. METHODS: The 5 coding regions and the exon-intron boundaries of NUS1 were directly sequenced in 395 patients with ET and an equal number of healthy controls, matched for age and sex. The function of variants was assessed by pathogenic predictive software programs. Genetic analysis of variants was used to evaluate susceptibility to ET. RESULTS: A total of 6 exonic variants were identified, including 3 synonymous and 3 missense variants. The non-synonymous variants were predicted to be tolerable. No variants had significant association with ET (none of the p-values were less than 0.05, using Fisher's exact test). CONCLUSION: Our study suggested that NUS1 variants may not contribute to the risk of ET.

18.
BMC Musculoskelet Disord ; 21(1): 717, 2020 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-33143667

RESUMO

BACKGROUND: Percutaneous endoscopic decompression (PED) is considered a minimally invasive and safe procedure in lumbar degenerative disease. Few authors report the success of PED for thoracic spinal stenosis (TSS) with thoracic myelopathy. The objective of this study was to compare the outcome of PED versus posterior decompressive laminectomy (PDL) for TSS. METHODS: We retrospectively reviewed 30 consecutive patients who underwent surgery for single-level TSS from January 1, 2015 to May 1, 2019.These patients were divided into PED (n = 16) and PDL(n = 14) group. Preoperative demographic characteristics and perioperative outcomes were reviewed. Pre- and postoperative neurological status was evaluated using the modified Japanese Orthopaedic Association (mJOA) score and the recovery rate (RR). RESULTS: The patients' mean age was 57.3 years (27-76) in PED group and 58.8 years (34-77) in PDL group. No statistical difference was found between two groups with regards to neurological status at pre-operative and final follow-up. The RR in PED group achieved the same improvement as PDL group (87.5% vs 85.7%, P > 0.05), while the PED brought advantages in operative time(m) (86.4 vs 132.1, p < 0.05), blood loss (mL) (18.21 vs 228.57, p < 0.05),drainage volume(mL) (15.5 vs 601.4, p < 0.05), and hospital stay (d) (3.6 vs 5.6, p < 0.05). CONCLUSIONS: Both PED and PDL showed favorable outcome in the treatment of TSS. Besides, PED had advantages in reducing traumatization. In terms of perioperative quality of life, PED could be an efficient supplement to traditional posterior decompressive laminectomy in patients with TSS.

19.
Macromol Rapid Commun ; : e2000507, 2020 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-33210416

RESUMO

As a kind of temperature-responsive hydrogel, polystyrene-co-poly(N-isopropylacrylamide)/poly(N-isopropylacrylamide) (PS-co-PNIPAM/PNIPAM) core-shell nanoparticles prepared by two-step copolymerization are widely studied and used because of their specific structures and properties. Unlike most reports about the steady stability of PS-co-PNIPAM/PNIPAM core-shell nanoparticle hydrogel emulsion, in this work, the PS-co-PNIPAM/PNIPAM core-shell nanoparticle hydrogel emulsion (symbolized as PS/PNIPAM hydrogel emulsion), which is prepared after the second step of synthesis and without washing out a large number of PNIPAM polymer segments, shows a reversible temperature-dependent sol-gel transition characteristic during the temperature range of 34-80 °C. The PS/PNIPAM hydrogel emulsion is a normal solution at room temperature, and it changes from a sol to a gel statue when the temperature approaches up to low critical solution temperature (LCST). As the temperature continues to increase, the gel (core-shell nanoparticles as the crosslinkers and the linear PNIPAM chain as the 3D gel network) of the PS/PNIPAM hydrogel emulsion gradually shrinks and drains linearly. Compared with most crosslinked hydrogels, the hydrogel here can be arbitrarily changed in shape according to use needs, which is convenient for use, transportation, and storage. Here a new route is provided for the preparation of a PS/PNIPAM core-shell hydrogel nanoparticle system, as well as a new supramolecular crosslinking sol-gel system for application in biomedical materials, sensors, biological separation, drug release, macromolecular adsorption, and purification.

20.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 36(11): 1021-1025, 2020 Nov.
Artigo em Chinês | MEDLINE | ID: mdl-33210597

RESUMO

Objective To investigate the regulation and clinical significance of T cell immunoglobulin and mucin domain-containing molecule 3 (TIM-3)/galectin-9 signaling pathway in regulatory T cells (Tregs) and Th17 cells in patients with chronic lymphocytic leukemia (CLL). Methods The study enrolled 36 healthy individuals and 40 newly diagnosed CLL patients. The Tregs, Th17 cells, TIM-3+ Tregs and TIM-3+ Th17 cells were detected by the flow cytometry in their peripheral blood. Concentrations of IL-10, IL-17 and galectin-9 in serum were measured by the ELISA. Results Compared with the healthy controls, the CLL group had the higher levels of TIM-3+ Tregs, Tregs/Th17 cell ratio, TIM-3+ Tregs/TIM-3+ Th17 cell ratio, IL-10, galectin-9, and IL-10/IL-17 ratio. The level of TIM-3 expression on T cells, galectin-9 and the IL-10/IL-17 ratio in the CLL patients increased with the advance of Binet stage. Conclusion The TIM-3/galectin-9 signaling pathway is involved in the negative regulation of T cells in patients with CLL.

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