Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 355
Filtrar
1.
J Ethnopharmacol ; 282: 114583, 2022 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-34487850

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Herb-derived anti-tumor agents, such as paclitaxel and vincristine, exert significant but varied effectivenesses towards different cancer types. Similarly, Centipeda minima (CM) is a well-known traditional Chinese medicine that has been used to treat rhinitis, relieve pain and reduce swelling, and recently found to exert overwhelming anti-tumor effects against breast cancer, colon cancer, and nasopharyngeal carcinoma with different response rates. However, what is the optimizing cancer model that benefits most from CM, and what is the specific target underlying still require more exclusive and profound investigations. AIMS OF THE STUDY: This study aimed to explore the dominant tumor model and specific target of CM by integrative pharmacology and biological experiments. MATERIALS AND METHODS: The most predominant and specific cancer types that are sensitive to CM were screened and identified based on a combination network pharmacology and bioinformatics analysis. Compound-target network and protein-protein interaction of CM-related cancer targets were carried out to determine the most abundant active compound. Simultaneously, the priority target responsible for CM-related anti-tumor efficacy was further validated by molecular docking and in vitro experiments. RESULTS: In total, approximately 42% (8/19) of the targets were enriched in prostate cancer (p = 1.25E-09), suggesting prostate cancer would be the most sensitive tumor response to CM-related efficacy. Furthermore, we found that arnicolide D (ARD), the most abundant and representative active compound of CM, could directly bind to Src with binding energy of -7.3 kcal/mol, implying Src would be the priority target responsible for CM-related anti-tumor efficacy. Meanwhile, the results were further validated by solvent-induced protein precipitation (SIP) assay. In addition, PCR and WB results also revealed that either CM or ARD could not influence the gene expression of Src, while significantly decreased its protein expression instead, which further suggested that ARD might markedly shortene the Src protein half-life to promote Src protein degradation, thereby achieving significant anti-prostate cancer efficacy. CONCLUSION: Our findings not only suggest CM as a promising Src-targeting candidate for prostate cancer treatment, but also bring up a strategy for understanding the personalization of herbal medicines by using integrative pharmacology.

2.
Spectrochim Acta A Mol Biomol Spectrosc ; 266: 120417, 2022 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-34600324

RESUMO

Taking formamide (FA) as a model compound of protein, the water structure in the ternary mixtures of dimethyl sulfoxide (DMSO)-water-FA was studied by near-infrared (NIR) spectroscopy. The interaction of DMSO and water, and the effect of FA on the interaction, were analyzed with the help of chemometric methods. Continuous wavelet transform (CWT) was used to enhance the resolution of the spectra. A peak at 6437 cm-1 depicting the interaction of DMSO and water through hydrogen bonding (SO…HO) was observed in the transformed spectra. When FA exists in the mixture, the intensity of the peak decreases with the increase of formamide content, showing that FA may replace the water to form the hydrogen bond of SO and HN. In addition, temperature-dependent NIR spectroscopy was used to analyze the effect of the three components on the spectral variation with temperature. Analyzing the spectral data by alternating trilinear decomposition (ATLD) and multiple linear regression, two varying spectral features were obtained that are related to water and DMSO, but no spectral feature was found that significantly varies with the content of FA. The result implies that DMSO is still the key component to prevent the water from icing, although FA may reduce slightly the anti-freezing effect.


Assuntos
Espectroscopia de Luz Próxima ao Infravermelho , Água , Dimetil Sulfóxido , Ligação de Hidrogênio , Proteínas
3.
Ann Transl Med ; 9(18): 1416, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34733968

RESUMO

Background: The human leukocyte antigen G5 subtype (HLA-G5) is a major histocompatibility complex (MHC) molecule that is selectively expressed at the maternal-foetal tissue interface and is required for the successful implantation of the in vitro fertilized embryo. It is critical to detect HLA-G5, especially HLA-G5 expression in embryo fluid, during in vitro embryo incubation and culture. However, the specificity and sensitivity of traditional ELISA methods to detect sHLA-G5 are insufficient. This work aimed to explore novel nucleic acid aptamer gold (Au)-nanoparticles to detect soluble HLA-G5 in liquid samples. Methods: Soluble HLA-G5 was obtained using a prokaryotic expression system, and two novel aptamers (HLA-G5-Apt1 and HLA-G5-Apt2) detecting HLA-G5 were screened by the Systematic Evolution of Ligands by Exponential Enrichment (SELEX) method. Small (10 nm) gold nanoparticles (AuNPs) were incubated with AptHLAs to form two novel nucleic acid aptamers: Au-nanoparticles (AuNPs-AptHLA-G5-1 and AuNPs-AptHLA-G5-2). Results: The results showed that AptHLA-G5-1 and AptHLA-G5-2 have a high affinity for HLA-G5 and can detect its presence in liquid samples. Using the colorimetric sensing method, AuNPs-AptHLA-G1 had a detection limit as low as 20 ng/mL (recovery range between 98.7% to 102.0%), while AuNPs-AptHLA-G2 had a detection limit as low as 20 ng/mL (recovery range between 98.9% to 103.6%). Conclusions: Our work demonstrates that novel AuNPs are efficient detectors for HLA-G5 and are useful for diagnosis and treatment in the field of obstetrics-gynaecology.

4.
Mitochondrial DNA B Resour ; 6(12): 3343-3345, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34746409

RESUMO

Myricaria elegans, an endemic species to the Himalayas, is a distinctive deciduous shrubbery plant-primarily distributed in the Qinghai-Tibet Plateau and adjacent regions in China. It is a kind of fuelwood, medicinal, and ecology-protecting woody plant species. In this study, the whole chloroplast (cp) genome sequence of M. elegans was assembled and characterized by high-throughput sequencing data. The complete cp genome of M. elegans was 155,245 bp in length with a GC content of 37.4%. It contained a large single-copy region (LSC) of 84,846 bp, and a small single-copy region (SSC) of 18,290 bp, which were separated by a pair of 26,053 bp inverted repeat regions (IRs). The cp genome of M. elegans was composed of 130 genes, including 85 protein-coding genes, 37 transfer RNA (tRNA) genes, and eight ribosomal RNA (rRNA) genes. Phylogenetic analysis revealed that M. elegans formed a clade with Myricaria, and it showed a close relationship with Myricaria prostrata.

5.
Diabetes Res Clin Pract ; 182: 109130, 2021 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-34774643

RESUMO

AIMS: To explore trajectories of gestational weight gain (GWG) before diagnosis and its association with risk of gestational diabetes mellitus (GDM). METHODS: A population-based retrospective cohort study including 37,060 women with live singleton was conducted between 2013 and 2019 in China. Latent class trajectory model (LCTM) was used to identify GWG trajectories, and Poisson regression with robust error estimates was used to estimate risk ratio (RR) of GDM. RESULTS: Among total 37,060 participants, 25.47% of women were developed with GDM. Two trajectories of GWG were identified as non-excessive weight gain (94.31%) and excessive weight gain (5.69%) before diagnosis of GDM. Women with excessive GWG trajectory before diagnosis had significantly 32.8% (aRR = 1.328, 95 %CI: 1.252 âˆ¼ 1.409, P < 0.001) increased risk of developing GDM compared with non-excessive GWG trajectory. Women with excessive GWG trajectory also had higher risk of macrosomia (aRR = 1.476, 95 %CI: 1.307 âˆ¼ 1.666, P < 0.001) and cesarean delivery (aRR = 1.126, 95 %CI: 1.081 âˆ¼ 1.174, P < 0.001). The impact of excessive GWG trajectory on GDM was greater among pre-pregnancy normal weight women compared with overweight/obese or underweight women. CONCLUSION: Women with excessive GWG trajectory before diagnosis had significantly higher risk of GDM and GDM-related adverse outcomes, and pre-pregnancy normal weight women with excessive GWG trajectory should also be concerned.

6.
Front Mol Neurosci ; 14: 720984, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34720871

RESUMO

Objective: The objective of this study is to explore the role of GRIN2A gene in idiopathic generalized epilepsies and the potential underlying mechanism for phenotypic variation. Methods: Whole-exome sequencing was performed in a cohort of 88 patients with idiopathic generalized epilepsies. Electro-physiological alterations of the recombinant N-methyl-D-aspartate receptors (NMDARs) containing GluN2A mutants were examined using two-electrode voltage-clamp recordings. The alterations of protein expression were detected by immunofluorescence staining and biotinylation. Previous studies reported that epilepsy related GRIN2A missense mutations were reviewed. The correlation among phenotypes, functional alterations, and molecular locations was analyzed. Results: Three novel heterozygous missense GRIN2A mutations (c.1770A > C/p.K590N, c.2636A > G/p.K879R, and c.3199C > T/p.R1067W) were identified in three unrelated cases. Electrophysiological analysis demonstrated R1067W significantly increased the current density of GluN1/GluN2A NMDARs. Immunofluorescence staining indicated GluN2A mutants had abundant distribution in the membrane and cytoplasm. Western blotting showed the ratios of surface and total expression of the three GluN2A-mutants were significantly increased comparing to the wild type. Further analysis on the reported missense mutations demonstrated that mutations with severe gain-of-function were associated with epileptic encephalopathy, while mutations with mild gain of function were associated with mild phenotypes, suggesting a quantitative correlation between gain-of-function and phenotypic severity. The mutations located around transmembrane domains were more frequently associated with severe phenotypes and absence seizure-related mutations were mostly located in carboxyl-terminal domain, suggesting molecular sub-regional effects. Significance: This study revealed GRIN2A gene was potentially a candidate pathogenic gene of idiopathic generalized epilepsies. The functional quantitative correlation and the molecular sub-regional implication of mutations helped in explaining the relatively mild clinical phenotypes and incomplete penetrance associated with GRIN2A variants.

7.
Front Surg ; 8: 655692, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34778351

RESUMO

Objective: This study aims to explore the effectiveness and safety of tranexamic acid (TXA) in reducing the bleeding amount of surgical patients with degenerative spinal disease in the perioperative period. Methods: A total of 80 cases of patients, who underwent elective posterior lumbar interbody fusion surgeries under general anesthesia, were enrolled in this study. The age of these patients ranged within 41-69 years old, and the surgical vertebral body segments were ≥2. The ASA classification was Level I or Level II. These patients were divided into two groups using the random number table (n = 40): TXA group and control group (S group). In the TXA group, the skin was incised after the anesthesia induction, and 20 mg/kg of TXA was immediately injected into the vein. The injection continued at a rate of 10 mg·kg-1·h-1 during the surgery, until the surgery was finished. In the S group, IV and pump injection with an equal amount of normal saline (NS) were performed. Then, the RBC, Hb, HCT, AST, ALT, BUN, Cr, PT, TT, APTT, FIB, and D-dimer were measured before the surgery and at 1 day after the surgery, and the SSFQ, intraoperative bleeding amount, homologous transfusion volume, urine volume, infusion quantity, surgical duration, drainage volume at 24 h after the surgery, total bleeding amount and adverse event occurrence at 1 week after the surgery were recorded. Results: The RBC, Hb and HCT at 1 day after the surgery were higher in TXA group than in the S group (average P < 0.05). Intraoperative bleeding, drainage volume at 24 h after surgery, and total blood loss were lower in the TXA group than in the S group (average P < 0.05). The SSFQ score and length of stay were lesser in the TXA group than in the S group (average P < 0.05). The differences in AST, ALT, BUN, Cr, PT, TT, APTT, FIB, and D-dimer at 1 day after the surgery for these two groups of patients had no statistical significance (average P > 0.05). Conclusion: TXA can reduce the bleeding amount of surgical patients with degenerative spinal disease in the perioperative period and decrease the length of stay, but does not increase the occurrence rate of adverse events, thereby promoting postoperative rehabilitation. Clinical Trial Registration: www.chictr.org.cn/index.aspx, identifier: ChiCTR2000033597.

8.
Am J Med Sci ; 2021 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-34687616

RESUMO

BACKGROUND: Polycythemia vera (PV) is a common type of Philadelphia chromosome-negative chronic myeloproliferative disorder. PV-associated kidney disease is rarely reported and remains poorly understood. It has been observed that chronic kidney disease could be a risk factor for poor prognosis in PV. METHODS: We retrospectively analyzed the clinicopathological features of renal presentations in eight patients with confirmed PV-associated kidney disease. RESULTS: The eight patients were 6 males and 2 females, with a mean age of 46.4±16.8 years. Six patients had a history of PV, with a duration range 0.5-16 years. The other two patients were newly diagnosed with PV simultaneously with glomerular disease. Seven patients conducted a JAK2 V617F mutation test, with a positive result in five. Proteinuria and renal dysfunction were the patients' main complaints, with only one having nephrotic syndrome and three having microscopic hematuria. The level of proteinuria ranged from 0.52-10.96 g/day. Three patients had advanced chronic kidney disease (CKD), two in stage 3b and one in stage 4, but only one patient had anemia. Three patients had monoclonal immunoglobulinemia, one patient with immunoglobulin (Ig) G kappa plus light chain lambda, one patient with IgG kappa, and one patient with IgG lambda. Five patients underwent a renal biopsy. The pathological diagnosis was IgA nephropathy in three, non-IgA mesangial proliferative glomerulopathy in one, and glomerular hypertrophy with ischemic renal injury in one patient. Glomerular ischemia, ischemic shrinkage, focal segmental sclerosis, and glomerulomegaly were common pathological features. Glomerular crescents and endocapillary proliferation were also observed. All patients were administered hydroxyurea, and seven were administered renin-angiotensin system inhibitors. During follow-up, one patient with uncontrolled PV developed secondary myelofibrosis and died, three patients were lost to follow-up, and four patients remained alive with CKD. CONCLUSIONS: Patients with untreated or uncontrolled PV could have massive proteinuria and advanced CKD, pathologically showing ischemic, sclerosing glomerular lesions with hypercellurity, glomerular crescents and endocapillary proliferation. IgA nephropathy was most commonly diagnosed. These findings deserve attention because early screening and effective control of PV may benefit the long-term kidney prognosis.

9.
Natl Sci Rev ; 8(1): nwaa091, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34691550

RESUMO

The often-used phrase 'the uplift of the Tibetan Plateau' implies a flat-surfaced Tibet rose as a coherent entity, and that uplift was driven entirely by the collision and northward movement of India. Here, we argue that these are misconceptions derived in large part from simplistic geodynamic and climate modeling, as well as proxy misinterpretation. The growth of Tibet was a complex process involving mostly Mesozoic collisions of several Gondwanan terranes with Asia, thickening the crust and generating complex relief before the arrival of India. In this review, Earth system modeling, paleoaltimetry proxies and fossil finds contribute to a new synthetic view of the topographic evolution of Tibet. A notable feature overlooked in previous models of plateau formation was the persistence through much of the Cenozoic of a wide east-west orientated deep central valley, and the formation of a plateau occurred only in the late Neogene through compression and internal sedimentation.

10.
Front Med (Lausanne) ; 8: 736098, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34692728

RESUMO

Background: Immunoglobulin G4-related disease (IgG4-RD) is a systemic immunoreactivity-based fibro-inflammatory disease. Immunoglobulin G4-related kidney disease (IgG4-RKD) is a frequently overlooked diagnosis. This study aimed to describe IgG4-RKD and examine the factors relevant to the renal outcomes of IgG4-RD. Methods: We studied a prospective IgG4-RKD cohort between January 2012 and December 2020 with close follow-up. Clinicopathologic data at kidney biopsy were collected and analyzed. We aimed to explore independent risk factors for long-term renal outcome and disease relapse. Patients with an eGFR<45 ml/min per 1.73m2 at 12 months were defined as having poor outcomes. Results: The included 42 patients with IgG4-RKD had a mean age of 58.5 ± 8.7 years (male-to-female ratio = 5:1). The IgG4-RD responder index (RI) was 12.2 ± 3.3. A total of 66.7% of the patients presented with acute on kidney disease or acute on chronic kidney disease. Eight patients (19.0%) showed nephrotic-range proteinuria, and nine (21.4%) had high-titer IgG4-autoantibodies, including antineutrophil cytoplasmic antibody and anti-phospholipase A2 receptor. A kidney biopsy was conducted in 40 patients. Thirty-seven (90.0%) patients were diagnosed with IgG4-related tubulointerstitial nephritis, and 19 (47.5%) of them had concurrent glomerular diseases (membranous nephropathy [MN], n = 3; crescentic glomerulonephritis [CrGN], n = 11; diabetic kidney disease, n = 3; and both MN and CrGN, n = 2). IgG4-RD RI had a close relationship with serum C3 (R = -0.509, P = 0.001), C4 (R = -0.314, P = 0.049) levels, and peripheral blood eosinophil count (PBEC; R = 0.377, P = 0.024), factors that were not included in RI scores. Correlation analysis disclosed that IgG4-RD RI (R = 0.422, P = 0.007), organs involved (R = 0.452, P = 0.003), and C3 (R = -0.487, R = 0.002) were correlated with the percentage decrease of serum creatinine at 1 month. However, multivariate regression analysis failed to identify any clinicopathological parameters that could predict short-term renal restoration and IgG4-RKD relapse. Ten out of 29 variables, of most importance, were identified by the least absolute shrinkage and selection operator (LASSO) regression analysis. By multivariate logistic regression a higher serum IgG4 (OR = 0.671, P = 0.010), IgG1 (OR = 1.396, P = 0.049), IgG3 (OR = 19.154, P = 0.039), and erythrocyte sedimentation rate (ESR; OR = 1.042, P = 0.032) were found to be independent factors for poor long-term outcome. Conventional immunosuppressive medications and/or rituximab were prescribed, and in 83.3% of the patients, the kidney function improved. Repeat kidney biopsies confirmed the remission of interstitial inflammation in two patients under immunosuppressive therapy. However, the disease relapse rate was as high as 31.0%. Conclusions: We strongly recommend a kidney biopsy in active IgG4-RD, especially when there is proteinuria and renal dysfunction, because concurrent glomerular involvement and active interstitial inflammation should be assessed. A higher serum IgG1, IgG3, and ESR were independent factors for the poor long-term renal outcome; however, elevated IgG4 predicted a good renal prognosis, and appropriate and timely immunosuppressive therapy can help achieve a better prognosis.

11.
J Gen Appl Microbiol ; 2021 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-34483223

RESUMO

Corynebacterium glutamicum is an important industrial strain for amino acids and a key model organism for human pathogens. The study of C. glutamicum oxidoreductases, such as mycoredoxin 1 (Mrx1), dithiol-disulfide isomerase DsbA, and DsbA-like Mrx1, is helpful for understanding the survival, pathogenic infection, and stress resistance of its homologous species. However, the action mode and enzymatic function of C. glutamicum NCgl0018 preserving the Cys-Pro-Phe-Cys motif, annotated as a putative DsbA, have remained enigmatic. Here, we report that the NCgl0018-deleted strain increased sensitivity to various oxidative stresses. The ncgl0018 expression was induced in the stress-responsive extracytoplasmic function-sigma (ECF-σ) factor SigH- and organic peroxide- and antibiotic-sensing regulator (OasR)-dependent manner by stress. NCgl0018 reduced S-mycothiolated mixed disulfides and intramolecular disulfides via a monothiol-disulfide mechanism preferentially linking the mycothiol/mycothione reductase/NADPH electron pathway. Site-directed mutagenesis confirmed Cys107 was the resolving Cys residue, while Cys104 was the nucleophilic cysteine that was oxidized to a sulfenic acid and then could form an intramolecular disulfide bond with Cys107 or a mixed disulfide with mycothiol under stress. Biochemical analyses indicated that NCgl0018 lacked oxidase properties like the classical DsbA. Further, enzymatic rates and substrate preferences of NCgl0018 were highly similar to those of DsbA-like Mrx1. Collectively, our study presented the first evidence that NCgl0018 protected against stresses by functioning as a novel DsbA-like Mrx1 but not DsbA and Mrx1.

12.
Materials (Basel) ; 14(17)2021 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-34501142

RESUMO

A polarization-insensitive diffusion metasurface using a period-changed unit cell is presented for reducing the radar cross-section (RCS) of metallic objects in ultrawideband. Two metallic Minkowski loops are proposed as coding elements, different from traditional designs. The "0" element is constructed by period-changed unit cells to achieve a 180 ± 30° phase difference with the same reflection amplitude of nearly -0.9 dB in an ultrawideband from 7.1 to 29.2 GHz. Multilayer geometry with a thickness of 4.5 mm (about 0.105λ0 at the lowest operating frequency) and rotational symmetry loops are used to realize the ultrawideband characteristic and polarization-insensitive behavior. For verification, a polarization-insensitive diffusion metasurface is designed, fabricated, and measured. The simulated and measured results of the diffusion metasurface are in good consistency and the results both show that the metasurface enables a 10 dB backscattering reduction over an amazing ultrawideband ranging from 7.1 to 29.2 GHz (BW of 122%).

13.
Oncol Lett ; 22(3): 646, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34386068

RESUMO

Lung cancer is the leading cause of cancer-related mortality worldwide. Non-small cell lung cancer (NSCLC) accounts for ~85% of all lung cancer cases. Patients harboring epidermal growth factor receptor (EGFR) mutations usually develop resistance to treatment with frontline EGFR-tyrosine kinase inhibitors (EGFR-TKIs). The present review summarizes the current findings and delineates the molecular mechanism of action for the therapeutic effects of herbal extracts and phytochemicals in overcoming EGFR-TKI resistance in NSCLC. Novel molecular targets underlying EGFR-TKI resistance in NSCLC are also discussed. This review provides valuable information for the development of herbal bioactive compounds as alternative treatments for EGFR-TKI-resistant NSCLC.

14.
Front Pharmacol ; 12: 630319, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34434104

RESUMO

Siegesbeckia orientalis L. (SO) is a commonly used Chinese medicinal herb. It has long been used as a remedy in traditional Chinese medicine (TCM) for symptoms that resemble inflammatory joint disorders. However, it is slightly toxic. According to the TCM theory, processing can reduce the toxicity of the herbs. Here, we performed metabolomics to determine whether processing with rice wine reduces the toxicity of raw SO, and to explore the mechanisms underlying the raw SO-induced toxicity and the toxicity-reducing effect of processing. Our results showed that raw SO has long-term toxicity in rats. It significantly elevated the serum level of LDH and caused histopathological damages in the lung tissues. It is worth noting that the LDH level in the PSO group was lower than that in the raw SO group, and the damages in lung tissues were relatively mild in PSO-treated rats, suggesting that processing reduces the pulmonary toxicity of the raw. Moreover, a total of 32 significantly changed metabolites were identified. Based on the MetaboAnalyst pathway analysis, we found that two characteristic metabolic pathways including alanine, aspartate and glutamate metabolism and glycerophospholipid metabolism were only changed in the raw SO group, while histidine metabolism was only changed in the PSO group, which suggests that induction of oxidative stress contributes to raw SO-induced pulmonary toxicity, and free radical scavenging might be responsible for the toxicity-reducing effect of processing. Our data shed new light on how raw SO induces pulmonary toxicity and how the toxicity can be reduced by processing. This study not only provides scientific justifications for the traditional processing theory of SO, but also helps to optimize the processing protocol and the clinical drug combination of SO.

15.
Cell Death Dis ; 12(8): 791, 2021 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-34385421

RESUMO

Although high-fat diet (HFD) has been implicated in the development of colorectal cancer (CRC), the critical signaling molecule that mediates the cancer growth is not well-defined. Identifying the master regulator that controls CRC growth under HFD can facilitate the development of effective therapeutics for the cancer treatment. In this study, the global lipidomics and RNA sequencing data show that, in the tumor tissues of CRC-bearing mouse models, HFD not only increases tumor weight, but also the palmitic acid level and TLR4 expression, which are reduced when HFD is replaced by control diet. These concomitant changes suggest the roles of palmitic acid and TLR4 in CRC growth. Subsequent studies show that palmitic acid regulates TLR4 expression in PU.1-dependent manner. Knockdown of PU.1 or mutations of PU.1-binding site on TLR4 promoter abolish the palmitic acid-increased TLR4 expression. The role of palmitic acid/PU.1/TLR4 axis in CRC growth is further examined in cell model and animal models that are fed either HFD or palmitic acid-rich diet. More importantly, iTRAQ proteomics data show that knockdown of TLR4 changes the metabolic enzyme profiles in the tumor tissues, which completely abolish the HFD-enhanced ATP production and cancer growth. Our data clearly demonstrate that TLR4 is a master regulator for CRC growth under HFD by programming cancer metabolism.

16.
Indian J Cancer ; 58(3): 349-354, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34380842

RESUMO

Background: High risk of post-surgery complications have always been related with uncontrolled blood glucose, while the relationship between blood glucose and analgesia has not been compared on radical resection of colon cancer. The aim of this study is to investigate the effects of multimodal analgesia on perioperative insulin resistance in patients undergoing radical resection of colon cancer. Methods: Sixty patients with colon cancer scheduled for radical resection surgery were equally divided into two groups randomly, the control group (TAP group) received general anesthesia and the transversus abdominis plane block analgesia, and the experimental group (GEA group) received extra epidural anesthesia. The analgesic efficacy was evaluated with visual analog scale (VAS). Insulin resistance indicators like fasting plasma glucose (FPG), resistin (RESIS), fasting insulin (FINS), homeostasis model assessment (HOMA) levels, and inflammation indicator interleukin-6 (IL-6) were evaluated during the surgery. Results: IL-6 increase was significant in the TAP group than that in GEA group (P < 0.01). The insulin resistance increased significantly in TAP group than that in GEA group including HOMA (P < 0.05) and FPG (P < 0.05). There was no significant difference in RESIS levels and VAS scores in the two groups. Conclusion: Epidural anesthesia leads to less inflammation in radical resection of colon cancer and the insulin level and insulin resistance increased after the surgeries based on FINS and HOMA..

17.
3 Biotech ; 11(8): 372, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34290951

RESUMO

ncgl2478 gene from Corynebacterium glutamicum encodes a thiol-disulfide oxidoreductase enzyme annotated as dithiol-disulfide isomerase DsbA. It preserves a Cys-Pro-Phe-Cys active-site motif, which is presumed to be an exclusive characteristic of the novel DsbA-mycoredoxin 1 (Mrx1) cluster. However, the real mode of action, the nature of the electron donor pathway and biological functions of NCgl2478 in C. glutamicum have remained enigmatic so far. Herein, we report that NCgl2478 plays an important role in stress resistance. Deletion of the ncgl2478 gene increases the size of growth inhibition zones. The ncgl2478 expression is induced in the stress-responsive extra-cytoplasmic function-sigma (ECF-σ) factor SigH-dependent manner by stress. It receives electrons preferentially from the mycothiol (MSH)/mycothione reductase (Mtr)/NADPH pathway. Further, NCgl2478 reduces S-mycothiolated mixed disulfides and intramolecular disulfides via a monothiol-disulfide and a dithiol-disulfide exchange mechanism, respectively. NCgl2478 lacks oxidase activity; kinetic properties of its demycothiolation are different from those of Mrx1. Site-directed mutagenesis confirms Cys24 is the resolving Cys residue, while Cys21 is the nucleophilic cysteine that is oxidized to a sulfenic acid and then forms an intramolecular disulfide bond with Cys24 or a mixed disulfide with MSH under oxidative stress. In conclusion, our study presents the first evidence that NCgl2478 protects against various stresses by acting as an MSH-dependent thiol-disulfide reductase, belonging to a novel DsbA-Mrx1 cluster.

18.
CNS Neurosci Ther ; 27(10): 1146-1156, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34109749

RESUMO

AIMS: CHD4 gene, encoding chromodomain helicase DNA-binding protein 4, is a vital gene for fetal development. In this study, we aimed to explore the association between CHD4 variants and idiopathic epilepsy. METHODS: Trios-based whole-exome sequencing was performed in a cohort of 482 patients with childhood idiopathic epilepsy. The Clinical Validity Framework of ClinGen and an evaluating method from five clinical-genetic aspects were used to determine the association between CHD4 variants and epilepsy. RESULTS: Four novel heterozygous missense mutations in CHD4, including two de novo mutations (c.1597A>G/p.K533E and c.4936G>A/p.E1646K) and two inherited mutations with co-segregation (c.856C>G/p.P286A and c.4977C>G/p.D1659E), were identified in four unrelated families with eight individuals affected. Seven affected individuals had sinus arrhythmia. From the molecular sub-regional point of view, the missense mutations located in the central regions from SNF2-like region to DUF1087 domain were associated with multisystem developmental disorders, while idiopathic epilepsy-related mutations were outside this region. Strong evidence from ClinGen Clinical Validity Framework and evidences from four of the five clinical-genetic aspects suggested an association between CHD4 variants and epilepsy. CONCLUSIONS: CHD4 was potentially a candidate pathogenic gene of childhood idiopathic epilepsy with arrhythmia. The molecular sub-regional effect of CHD4 mutations helped explaining the mechanisms underlying phenotypic variations.

19.
Microb Cell Fact ; 20(1): 110, 2021 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-34082775

RESUMO

BACKGROUND: CssR, the product of the Corynebacterium glutamicum ncgl1578 gene cotranscribed with ncgl1579, is a TetR (tetracycline regulator) family repressor. Although many TetR-type regulators in C. glutamicum have been extensively described, members of the TetR family involved in the stress response remain unidentified. RESULTS: In this study, we found that CssR regulated the transcription of its own gene and the ncgl1576-ncgl1577 operon. The ncgl1576-ncgl1577 operon, which is located upstream of cssR in the orientation opposite that of the cssR operon, encodes an ATP-binding cassette (ABC), some of which are involved in the export of a wide range of antimicrobial compounds. The cssR-deletion (ΔcssR) mutant displayed increased resistance to various stresses. An imperfect palindromic motif (5'-TAA(G)TGN13CA(G)TTA-3'; 25 bp) located at the intergenic region between cssR and ncgl1577 was identified as the sole binding site for CssR. Expression of cssR and ncgl1577 was induced by antibiotics and heavy metals but not H2O2 or diamide, and the DNA-binding activity of CssR was impaired by antibiotics and heavy metals but not H2O2. Antibiotics and heavy metals caused CssR dissociation from target gene promoters, thus derepressing their transcription. Oxidant treatment neither altered the conformation of CssR nor modified its cysteine residues, indicating that the cysteine residues in CssR have no redox activity. In the ΔcssR mutant strain, genes involved in redox homeostasis also showed increased transcription levels, and the NADPH/NADP+ ratio was higher than that of the parental strain. CONCLUSION: The stress response mechanism of CssR in C. glutamicum is realized via ligand-induced conformational changes of the protein, not via cysteine oxidation-based thiol modification. Moreover, the crucial role of CssR in the stress response was demonstrated by negatively controlling the expression of the ncgl1576-ncgl1577 operon, its structural gene, and/or redox homeostasis-related genes.


Assuntos
Corynebacterium glutamicum/genética , Corynebacterium glutamicum/metabolismo , Estresse Fisiológico , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Antibacterianos/farmacologia , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Sítios de Ligação , Corynebacterium glutamicum/efeitos dos fármacos , DNA Bacteriano , Regulação Bacteriana da Expressão Gênica , Homeostase , Metais Pesados/farmacologia , Óperon , Oxirredução , Regiões Promotoras Genéticas , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Deleção de Sequência
20.
J Magn Reson Imaging ; 2021 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-34184356

RESUMO

BACKGROUND: Renal hypoxia, which caused by a mismatch between oxygen delivery and oxygen demand, may be the primary pathophysiological pathway driving diabetic kidney disease (DKD). Blood oxygenation level-dependent (BOLD) magnetic resonance imaging (MRI) could detect hypoxia, but can be limited in distinguishing increased oxygen consumption or decreased blood supply. PURPOSE: To explore multiparametric functional MRI in evaluating mechanism of the hypoxia changes in early stage of DKD. STUDY TYPE: Prospective. ANIMAL MODEL: Thirty-five New Zealand White rabbits were divided into control group (n = 5) and alloxan-induced diabetes mellitus (DM) groups (DM3 group: n = 15, DM7 group: n = 15). FIELD STRENGTH/SEQUENCE: 3 T MRI/BOLD, arterial spin labeling (ASL), and asymmetric spin-echo (ASE). ASSESSMENT: The renal oxygenation level (R2*), renal blood flow (RBF), and oxygen extraction fraction (OEF) were evaluated by BOLD, ASL, and ASE MRI, respectively. The regions of interest were manually drawn including cortex, outer stripes of outer medulla (OS), and inner stripes of outer medulla (IS). STATISTICAL TESTS: Analysis of variance, independent-sample t-test, and paired-sample t-test were applied for comparisons among groups, between groups, and within the same group. P < 0.05 was considered statistically significant. RESULTS: All renal regions of DM3 group at Day 3 after DM induction showed significantly higher R2* and OEF values compared to baseline. The RBF values showed no statistically significant difference (P = 0.62, 0.76, 0.09 in cortex, OS, and IS, respectively). For DM7 group at Day 7, R2*, OEF, and RBF values showed no statistically significant difference compared to baseline (P = 0.06, 0.05, 0.06 of R2*; 0.70, 0.64, 0.68 of OEF; and 0.33, 0.58, 0.48 of RBF in cortex, OS, and IS, respectively). DATA CONCLUSION: BOLD MRI could detect renal hypoxia in early stage of DKD rabbit model, which was mainly revealed by increased oxygen consumption, but not affected by renal blood flow change. LEVEL OF EVIDENCE: 2 Technical Efficacy Stage: 1.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...