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1.
Zhongguo Zhen Jiu ; 42(1): 45-8, 2022 Jan 12.
Artigo em Chinês | MEDLINE | ID: mdl-35025157

RESUMO

OBJECTIVE: To observe the effect of electroacupuncture (EA) on postoperative ileus after laparotomy for gastrointestinal cancer. METHODS: A total of 90 patients with postoperative ileus after laparotomy for gastrointestinal cancer were randomized into an EA group and a conventional treatment group, 45 cases in each one. In the conventional treatment group, the postoperative fast track surgical regimen was accepted. In the EA group, on the base of the treatment as the conventional treatment group, acupuncture was applied to Zusanli (ST 36), Shangjuxu (ST 37), Yinlingquan (SP 9) and Taichong (LR 3) and electric stimulation was attached on Zusanli (ST 36) and Yinlingquan (SP 9), with continuous wave, 2 Hz in frequency and 3-5 mA in intensity. Acupuncture was provided once daily till the onset of postoperative exhaust and defecation. The first postoperative exhaust time, the first postoperative defecation time, the postoperative hospital stay and the wound pain under standing on the next morning after entering group were compared in the patients between the two groups. The impact of the EA expectation was analyzed on the first postoperative exhaust time, the first postoperative defecation time and the postoperative hospital stay separately. RESULTS: The first postoperative exhaust time and the first postoperative defecation time in the EA group were earlier than the conventional treatment group (P<0.05), the postoperative hospital stay was shorter than the conventional treatment group (P<0.05), and the rate of wound pain in the postoperative standing was lower than the conventional treatment group (P<0.05). EA expectation had no obvious correlation with the clinical therapeutic effect (P>0.05). CONCLUSION: EA can relieve postoperative ileus symptoms, alleviate pain and shorten hospital stay in the patients after laparotomy for gastrointestinal cancer.


Assuntos
Eletroacupuntura , Neoplasias Gastrointestinais , Íleus , Pontos de Acupuntura , Humanos , Íleus/etiologia , Íleus/terapia , Laparotomia/efeitos adversos
2.
Artigo em Inglês | MEDLINE | ID: mdl-35019259

RESUMO

Nitric oxide (NO) is an endogenous gasotransmitter regulating alternative physiological processes in the cardiovascular system. To achieve translational application of NO, continued efforts are made on the development of orally active NO prodrugs for long-term treatment of chronic cardiovascular diseases. Herein, immobilization of NO-delivery [Fe2(µ-SCH2CH2COOH)2(NO)4] (DNIC-2) onto MIL-88B, a metal-organic framework (MOF) consisting of biocompatible Fe3+ and 1,4-benzenedicarboxylate (BDC), was performed to prepare a DNIC@MOF microrod for enhanced oral delivery of NO. In simulated gastric fluid, protonation of the BDC linker in DNIC@MOF initiates its transformation into a DNIC@tMOF microrod, which consisted of DNIC-2 well dispersed and confined within the BDC-based framework. Moreover, subsequent deprotonation of the BDC-based framework in DNIC@tMOF under simulated intestinal conditions promotes the release of DNIC-2 and NO. Of importance, this discovery of transformer-like DNIC@MOF provides a parallel insight into its stepwise transformation into DNIC@tMOF in the stomach followed by subsequent conversion into molecular DNIC-2 in the small intestine and release of NO in the bloodstream of mice. In comparison with acid-sensitive DNIC-2, oral administration of DNIC@MOF results in a 2.2-fold increase in the oral bioavailability of NO to 65.7% in mice and an effective reduction of systolic blood pressure (SBP) to a ΔSBP of 60.9 ± 4.7 mmHg in spontaneously hypertensive rats for 12 h.

3.
Mol Cancer ; 21(1): 8, 2022 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-34980129

RESUMO

BACKGROUND: Approximate 25% HER2-positive (HER2+) breast cancer (BC) patients treated with trastuzumab recurred rapidly. However, the mechanisms underlying trastuzumab resistance remained largely unclear. METHODS: Trastuzumab-resistant associated circRNAs were identified by circRNAs high-throughput screen and qRT-PCR in HER2+ breast cancer tissues with different trastuzumab response. The biological roles of trastuzumab-resistant associated circRNAs were detected by cell vitality assay, colony formation assay, Edu assay, patient-derived xenograft (PDX) models and orthotopic animal models. For mechanisms research, the co-immunoprecipitation, Western blot, immunofluorescence, and pull down assays confirmed the relevant mechanisms of circRNA and binding proteins. RESULTS: We identified a circRNA circCDYL2, which was overexpressed in trastuzumab-resistant patients, which conferred trastuzumab resistance in breast cancer cells in vitro and in vivo. Mechanically, circCDYL2 stabilized GRB7 by preventing its ubiquitination degradation and enhanced its interaction with FAK, which thus sustained the activities of downstream AKT and ERK1/2. Trastuzumab-resistance of HER2+ BC cells with high circCDYL2 could be reversed by FAK or GRB7 inhibitor. Clinically, HER2+ BC patients with high levels of circCDYL2 developed rapid recurrence and had shorter disease-free survival (DFS) and overall survival (OS) following anti-HER2 therapy compared to those with low circCDYL2. CONCLUSIONS: circCDYL2-GRB7-FAK complex plays a critical role in maintaining HER2 signaling, which contributes to trastuzumab resistance and circCDYL2 is a potential biomarker for trastuzumab-resistance in HER2+ BC patients.

4.
BMC Bioinformatics ; 22(Suppl 12): 334, 2022 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-35057729

RESUMO

BACKGROUND: The identification of cancer types is of great significance for early diagnosis and clinical treatment of cancer. Clustering cancer samples is an important means to identify cancer types, which has been paid much attention in the field of bioinformatics. The purpose of cancer clustering is to find expression patterns of different cancer types, so that the samples with similar expression patterns can be gathered into the same type. In order to improve the accuracy and reliability of cancer clustering, many clustering methods begin to focus on the integration analysis of cancer multi-omics data. Obviously, the methods based on multi-omics data have more advantages than those using single omics data. However, the high heterogeneity and noise of cancer multi-omics data pose a great challenge to the multi-omics analysis method. RESULTS: In this study, in order to extract more complementary information from cancer multi-omics data for cancer clustering, we propose a low-rank subspace clustering method called multi-view manifold regularized compact low-rank representation (MmCLRR). In MmCLRR, each omics data are regarded as a view, and it learns a consistent subspace representation by imposing a consistence constraint on the low-rank affinity matrix of each view to balance the agreement between different views. Moreover, the manifold regularization and concept factorization are introduced into our method. Relying on the concept factorization, the dictionary can be updated in the learning, which greatly improves the subspace learning ability of low-rank representation. We adopt linearized alternating direction method with adaptive penalty to solve the optimization problem of MmCLRR method. CONCLUSIONS: Finally, we apply MmCLRR into the clustering of cancer samples based on multi-omics data, and the clustering results show that our method outperforms the existing multi-view methods.

5.
Cell Death Dis ; 13(1): 41, 2022 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-35013118

RESUMO

Despite the great advances in target therapy, lung cancer remains the top cause of cancer-related death worldwide. G protein-coupled receptor neurokinin-1 (NK1R) is shown to play multiple roles in various cancers; however, the pathological roles and clinical implication in lung cancer are unclarified. Here we identified NK1R as a significantly upregulated GPCR in the transcriptome and tissue array of human lung cancer samples, associated with advanced clinical stages and poor prognosis. Notably, NK1R is co-expressed with epidermal growth factor receptor (EGFR) in NSCLC patients' tissues and co-localized in the tumor cells. NK1R can crosstalk with EGFR by interacting with EGFR, transactivating EGFR phosphorylation and regulating the intracellular signaling of ERK1/2 and Akt. Activation of NK1R promotes the proliferation, colony formation, EMT, MMP2/14 expression, and migration of lung cancer cells. The inhibition of NK1R by selective antagonist aprepitant repressed cell proliferation and migration in vitro. Knockdown of NK1R significantly slowed down the tumor growth in nude mice. The sensitivity of lung cancer cells to gefitinib/osimertinib is highly increased in the presence of the selective NK1R antagonist aprepitant. Our data suggest that NK1R plays an important role in lung cancer development through EGFR signaling and the crosstalk between NK1R and EGFR may provide a potential therapeutic target for lung cancer treatment.

6.
Artigo em Inglês | MEDLINE | ID: mdl-35001883

RESUMO

OBJECTIVES: To establish and evaluate a machine learning radiomics model based on grayscale and Sonazoid contrast enhanced ultrasound images for the preoperative prediction of microvascular invasion (MVI) in hepatocellular carcinoma (HCC) patients. METHODS: 100 cases of histopathological confirmed HCC lesions were prospectively included. Regions of interest were segmented on both grayscale and Kupffer phase of Sonazoid contrast enhanced (CEUS) images. Radiomic features were extracted from tumor region and region containing 5 mm of peritumoral liver tissues. Maximum relevance minimum redundancy (MRMR) and Least Absolute Shrinkage and Selection Operator (LASSO) were used for feature selection and Support Vector Machine (SVM) classifier was trained for radiomic signature calculation. Radiomic signatures were incorporated with clinical variables using univariate-multivariate logistic regression for the final prediction of MVI. Receiver operating characteristic curves, calibration curves and decision curve analysis were used to evaluate model's predictive performance of MVI. RESULTS: Age were the only clinical variable significantly associated with MVI. Radiomic signature derived from Kupffer phase images of peritumoral liver tissues (kupfferPT) displayed a significantly better performance with an area under the receiver operating characteristic curve (AUROC) of 0.800 (95% confidence interval: 0.667, 0.834), the final prediction model using Age and kupfferPT achieved an AUROC of 0.804 (95% CI: 0.723, 0.878), accuracy of 75.0%, sensitivity of 87.5% and specificity of 69.1%. CONCLUSIONS: Radiomic model based on Kupffer phase ultrasound images of tissue adjacent to HCC lesions showed an observable better predictive value compared to grayscale images and has potential value to facilitate preoperative identification of HCC patients at higher risk of MVI.

7.
J Phys Chem Lett ; : 792-800, 2022 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-35044179

RESUMO

Nonspecific binding of crowder proteins with functional proteins is likely prevalent in vivo, yet direct quantitative evidence, let alone residue-specific information, is scarce. Here we present nuclear magnetic resonance (NMR) characterization showing that bovine serum albumin weakly but preferentially interacts with the histidine carrier protein (HPr). Notably, the binding interface overlaps with that for HPr's specific partner protein, EIN, leading to competition. The crowder protein thus decreases the EIN-HPr binding affinity and accelerates the dissociation of the native complex. In contrast, Ficoll-70 stabilizes the native complex and slows its dissociation, as one would expect from excluded-volume and microviscosity effects. Our atomistic modeling of macromolecular crowding rationalizes the experimental data and provides quantitative insights into the energetics of protein-crowder interactions. The integrated NMR and modeling study yields benchmarks for the effects of crowded cellular environments on protein-protein specific interactions, with implications for evolution regarding how nonspecific binding can be minimized or exploited.

8.
Lab Invest ; 2022 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-35013531

RESUMO

Exosomes, one of three main types of extracellular vesicles, are ~30-100 nm in diameter and have a lipid bilayer membrane. They are widely distributed in almost all body fluids. Exosomes have the potential to regulate unknown cellular and molecular mechanisms in intercellular communication, organ homeostasis, and diseases. They are critical signal carriers that transfer nucleic acids, proteins, lipids, and other substances into recipient cells, participating in cellular signal transduction and material exchange. ncRNAs are non-protein-coding genes that account for over 90% of the genome and include microRNAs (miRNAs), long ncRNAs (lncRNAs), and circular RNAs (circRNAs). ncRNAs are crucial for physiological and pathological activities in the liver by participating in gene transcription, posttranscriptional epigenetic regulation, and cellular processes through interacting with DNA, RNA, or proteins. Recent evidence from both clinical and preclinical studies indicates that exosome-derived noncoding RNAs (ncRNAs) are highly involved in the progression of acute and chronic liver diseases by regulating hepatic lipid metabolism, innate immunity, viral infection, fibrosis, and cancer. Therefore, exosome-derived ncRNAs have promising potential and clinical implications for the early diagnosis, targeted therapy, and prognosis of liver diseases.

9.
Environ Sci Technol ; 56(2): 1041-1052, 2022 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-34964603

RESUMO

The hybrid of l-cysteine and agarose can reduce HAuCl4 and support the rapid growth of plasmonic gold nanoparticles (Au NPs) in the hydrogel phase. The l-cysteine-doped agarose hydrogel (C-AGH) not only offers the substrate the capacity to reduce Au(III) ions but also stabilizes and precisely modulates the in situ grown Au NPs with high repeatability, easy operation, and anti-interference performance. Herein, before the incubation of HAuCl4, the improved hydrogel is preincubated in the aqueous solution containing mercury ions, and the cysteine can specifically conjugate with mercury via the thiol groups. Subsequently, the responsive allochroic bands from dark blue to red can be identified in the solid hydrogel after the incubation of HAuCl4, which is attributed to the formation of regulated Au-Hg nanoamalgams. As a proof-of-concept, toxic Hg2+ ions are exploited as targets for constructing novel sensing assays based on the improved C-AGH protocol. Based on naked-eye recognition, Hg2+ could be rapidly and simply measured. Additionally, the high-throughput and trace analysis with a low limit of detection (3.7 nM) is performed using a microplate reader. On the basis of the filtering technique and remodeling of hydrogels, C-AGH working as the filtering membrane can even achieve the integration of enrichment and measurement with enhanced sensitivity. Significantly, the strategy of using an allochroic hydrogel with the staining of Au NPs can promote the rapid and primary assessment of water quality in environmental analysis.

10.
Aging Clin Exp Res ; 2021 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-34855152

RESUMO

BACKGROUND AND AIMS: Stroke is currently the leading cause of death in China; however, the past decade has produced no new epidemiological studies of stroke. Therefore, the current study aimed to compare the prevalence and risk factors of stroke between 2010 and 2019. METHODS: A comparative study was used to analyze the prevalence of risk factors for stroke in a population aged 65 years or older between 2010 and 2019. Demographic characteristics, risk factors, medical history, and other clinical characteristics were collected for all participants via door-to-door interviews and inpatient hospital records. RESULTS: The standardized prevalence of stroke was 7.9% in 2010 and 14.2% in 2019 (p < 0.001). The prevalence of stroke was significantly higher in men than in women (p < 0.05) for all age groups. The risk factors of stroke were being male, hypertension, and diabetes mellitus in both 2010 and 2019. When comparing the risk factors between 2010 and 2019, these risk factors were statistically significantly more strongly associated with stroke in 2019 than in 2010. CONCLUSION: The current study suggests that the prevalence of stroke increased nearly by twofold in a population aged 65 years or older within the past 10 years. Hypertension, diabetes mellitus, and being male were the primary risk factors. In addition, these factors were more significantly associated with stroke in 2019 compared to 2010.

11.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 29(6): 1858-1863, 2021 Dec.
Artigo em Chinês | MEDLINE | ID: mdl-34893123

RESUMO

OBJECTIVE: To investigate the effect of U2AF1 gene mutation to inflammatory cytokine in SKM-1 cell of human myelodysplastic syndromes (MDS), and whether the above effects were mediated by FOXO3a-Bim signaling pathway. METHODS: Wide-type U2AF1 and mutant U2AF1 (the serine residue 34 was replaced by phenylalanine, and named as S34F) recombinant expression plasmids were constructed. Lentiviruses were packaged and transfected into SKM-1 cells. The expression of FOXO3a was up-regulated by lentiviruses, and its transfection rate was investigated. The cell proliferation was detected by CCK-8 method. Flow cytometry was used to detect the apoptosis and cycle of the cells. The expression pro-inflammatory cytokine IL-1ß, IL-6, TNF-α and anti-inflammatory cytokine IL-4 were detected by qRT-PCR. FOXO3a, Bim, Bcl-2 and Bax protein expression levels were detected by Western blot. RESULTS: Compared with the control group, the cell apoptosis rate, pro-inflammatory cytokine IL-1ß and TNF-α transcription levels were significantly increased in the S34F group (P<0.05); cell cycle was blocked at the G2 phase; cell proliferation and the anti-inflammatory cytokine IL-4 transcription level were significantly decreased; the expression levels of FOXO3a, Bim and Bax protein were significantly increased (P<0.05); while the expression level of Bcl-2 protein was significantly decreased (P<0.05). The up-regulation of FOXO3a could significantly inhibited the proliferation and increased cell apoptosis of SKM-1 cells with U2AF1 S34F mutation; cell cycle was blocked at the S and G2 phases; the pro-inflammatory cytokine IL-1ß and TNF-α transcription levels were significantly decreased (P<0.05), and the transcription level of anti-inflammatory cytokine IL-4 showed no statistically significant as compared with control group (P>0.05). CONCLUSION: U2AF1 S34F mutation can regulate inflammatory phenotype in SKM-1 cells, which may be mediated through FOXO3a-Bim signaling pathway.

12.
Mol Biol Evol ; 2021 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-34893856

RESUMO

Domestic sheep and their wild relatives harbor substantial genetic variants that can form the backbone of molecular breeding, but their genome landscapes remain understudied. Here, we present a comprehensive genome resource for wild ovine species, landraces and improved breeds of domestic sheep, comprising high-coverage (∼16.10×) whole-genomes of 810 samples from 7 wild species and 158 diverse domestic populations. We detected, in total, ∼121.2 million single nucleotide polymorphisms (SNPs), ∼61 million of which are novel. Some display significant (P < 0.001) differences in frequency between wild and domestic species, or are private to continent-wide or individual sheep populations. Retained or introgressed wild gene variants in domestic populations have contributed to local adaptation, such as the variation in the HBB associated with plateau adaptation. We identified novel and previously reported targets of selection on morphological and agronomic traits such as stature, horn, tail configuration and wool fineness. We explored the genetic basis of wool fineness and unveiled a novel mutation (chr25: T7068586C) in the 3'-UTR of IRF2BP2 as plausible causal variant for fleece fiber diameter. We reconstructed pre-historical migrations from the Near Eastern domestication center to South-and-Southeast Asia, and found two main waves of migrations across the Eurasian Steppe and the Iranian Plateau in the Early and Late Bronze Ages. Our findings refine our understanding of genome variation as shaped by continental migrations, introgression, adaptation and selection of sheep.

13.
J Psychiatr Res ; 145: 111-117, 2021 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-34894520

RESUMO

The prevalence of dementia has been widely reported, and its potential risk and protective factors are well-characterized. However, there is a scarcity of related information regarding mild cognitive impairment (MCI). Thus this population-based study aimed to determine the prevalences of MCI and its subtypes, as well as to identify the risk and protective factors for MCI in the Chinese elderly population of Singapore. Results showed that the overall prevalence of MCI was 12.5%, while the gender-adjusted prevalence of MCI was 12.3%. Gender was found to be significantly associated with the subtypes of MCI, with males more likely to have amnestic MCI and females more likely to have non-amnestic MCI. Older age, lower educational levels, lower social activity levels, depression, hypertension, hyperlipidemia, diabetes and stroke were found to be risk factors for MCI in univariate analysis. However, multivariable analysis showed that only hypertension and stroke were the significant risk factors for MCI. Higher educational levels and active social engagements were significant protective factors for MCI in multivariable analysis. Age and depression had boundary significant associations with the prevalence of MCI. After adjusting for gender, the influence of hypertension, stroke, social engagement, age and depression on MCI remained unchanged, except that education became a boundary significant lower risk factor of MCI development. In conclusion, this study presented the prevalence, risk and protective factors for MCI among Singaporean Chinese older adults, which facilitates the screening of vulnerable groups for MCI.

14.
Plant Biotechnol J ; 2021 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-34861095

RESUMO

Humans have domesticated diverse species from across the plant kingdom; however, our current understanding of plant domestication is largely founded on major cereal crops. Here, we examine the evolutionary processes and genetic basis underlying the domestication of water caltrop (Trapa spp., Lythraceae), a traditional, yet presently underutilized non-cereal crop that sustained early Chinese agriculturalists. We generated a chromosome-level genome assembly of tetraploid T. natans, and then divided the allotetraploid genome into two subgenomes. Based on resequencing data from 57 accessions, representing cultivated diploid T. natans, wild T. natans (2x and 4x) and diploid T. incisa, we showed that water caltrop was likely first domesticated in the Yangtze River Valley as early as 6300 yr BP, and experienced a second improvement c. 800 years ago. We also provided strong support for an allotetraploid origin of T. natans within the past 230 000-310 000 years. By integrating selective sweep and transcriptome profiling analyses, we identified a number of genes potentially selected and/or differentially expressed during domestication, some of which likely contributed not only to larger fruit sizes but also to a more vigorous root system, facilitating nutrient uptake, environmental stress response and underwater photosynthesis. Our results shed light on the evolutionary and domestication history of water caltrop, one of the earliest domesticated crops in China. This study has implications for genomic-assisted breeding of this presently underutilized aquatic plant, and improves our general understanding of plant domestication.

16.
Front Immunol ; 12: 770744, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34899720

RESUMO

Mounting evidence has suggested that modulating microglia polarization from pro-inflammatory M1 phenotype to anti-inflammatory M2 state might be a potential therapeutic approach in the treatment of subarachnoid hemorrhage (SAH) injury. Our previous study has indicated that sirtuin 1 (SIRT1) could ameliorate early brain injury (EBI) in SAH by reducing oxidative damage and neuroinflammation. However, the effects of SIRT1 on microglial polarization and the underlying molecular mechanisms after SAH have not been fully illustrated. In the present study, we first observed that EX527, a potent selective SIRT1 inhibitor, enhanced microglial M1 polarization and nod-like receptor pyrin domain-containing 3 (NLRP3) inflammasome activation in microglia after SAH. Administration of SRT1720, an agonist of SIRT1, significantly enhanced SIRT1 expression, improved functional recovery, and ameliorated brain edema and neuronal death after SAH. Moreover, SRT1720 modulated the microglia polarization shift from the M1 phenotype and skewed toward the M2 phenotype. Additionally, SRT1720 significantly decreased acetylation of forkhead box protein O1, inhibited the overproduction of reactive oxygen species (ROS) and suppressed NLRP3 inflammasome signaling. In contrast, EX527 abated the upregulation of SIRT1 and reversed the inhibitory effects of SRT1720 on ROS-NLRP3 inflammasome activation and EBI. Similarly, in vitro, SRT1720 suppressed inflammatory response, oxidative damage, and neuronal degeneration, and improved cell viability in neurons and microglia co-culture system. These effects were associated with the suppression of ROS-NLRP3 inflammasome and stimulation of SIRT1 signaling, which could be abated by EX527. Altogether, these findings indicate that SRT1720, an SIRT1 agonist, can ameliorate EBI after SAH by shifting the microglial phenotype toward M2 via modulation of ROS-mediated NLRP3 inflammasome signaling.

17.
Front Pharmacol ; 12: 754527, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34925014

RESUMO

Vasodilatory therapy plays an important role in the treatment of cardiovascular diseases, especially hypertension and coronary heart disease. Previous research found that Guanxinning tablet (GXNT), a traditional Chinese compound preparation composed of Salvia miltiorrhiza (Danshen) and Ligusticum chuanxiong (Chuanxiong), increase blood flow in the arteries, but whether vasodilation plays a role in this effect remains unclear. Here, we found that GXNT significantly alleviated the vasoconstriction of isolated rabbit thoracic aorta induced by phenylephrine (PE), norepinephrine (NE), and KCl in a dose-dependent manner with or without endothelial cells (ECs). Changes in calcium ion levels in vascular smooth muscle cells (VSMCs) showed that both intracellular calcium release and extracellular calcium influx through receptor-dependent calcium channel (ROC) declined with GXNT treatment. Experiments to examine potassium channels suggested that endothelium-denuded vessels were also regulated by calcium-activated potassium channels (Kca) and ATP-related potassium channels (KATP) but not voltage-gated potassium channels (kv) and inward rectifying potassium channels (KIR). For endothelium-intact vessels, the nitric oxide (NO) and cyclic guanosine monophosphate (cGMP) contents in vascular tissue obviously increased after GXNT treatment, and pretreatment with the NO synthase inhibitor Nw-nitro-L-arginine methyl ester (L-NAME) or guanylyl cyclase inhibitor methylthionine chloride (MB) significantly inhibited vasodilation. An assessment of NO-related pathway protein expression revealed that GXNT enhanced the expression of phosphorylated endothelial NO synthase (eNOS) in a dose-dependent manner but had no effect on total eNOS, p-Akt, Akt, or PI3K levels in human umbilical vein ECs (HUVECs). In addition to PI3K/AKT signaling, Ca2+/calmodulin (CaM)-Ca2+/CaM-dependent protein kinase II (CaMKII) signaling is a major signal transduction pathway involved in eNOS activation in ECs. Further results showed that free calcium ion levels were decreased in HUVECs with GXNT treatment, accompanied by an increase in p-CaMKII expression, implying an increase in the Ca2+/CaM-Ca2+/CaMKII cascade. Taken together, these findings suggest that the GXNT may have exerted their vasodilative effect by activating the endothelial CaMKII/eNOS signaling pathway in endothelium-intact rings and calcium-related ion channels in endothelium-denuded vessels.

18.
Front Pharmacol ; 12: 783104, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34955853

RESUMO

Background: Given their changing pathophysiology, elderly patients carry a high risk of embolism and bleeding events; hence, use of appropriate anticoagulants is very important. Low molecular weight heparin (LMWH) is one of the most widely used anticoagulants although LMWHs differ in their anti-Xa, antithrombin, and anticoagulant activities. To date, no study has directly compared the safety and efficacy of different LMWHs in the elderly. We aimed to compare such differences by conducting a network meta-analysis. Methods: We searched the Pubmed, Embase, and Cochrane databases for randomized controlled trials (RCTs) of LMWHs that included patients ≥60 years old up to July 22, 2020. Safety outcomes included venous thromboembolism (VTE) or VTE-related death, deep thrombus embolism, and pulmonary embolism. Safety outcomes were clinically relevant bleeding, major bleeding, minor bleeding, and all-cause death. We calculated relative ratios (RR) and 95% confidence intervals (CI) for all outcomes. The cumulative ranking probabilities (SUCRA) were conducted to rank the comparative effects and safety of all LMWHs. Results: We included 27 RCTs (30,441 elderly), comprising five LMWHs. LMWH was more effective than placebo in preventing VTE or VTE-related death (RR 0.36, 95% CI 0.25-0.53) but less effective than a novel oral anticoagulant (RR 1.59, 95% CI 1.33-1.91) and safer than acenocoumarol regarding risk of clinically relevant bleeding (RR 0.67, 95% CI 0.49-0.90). However, indirect comparison of efficacy and safety of the five LMWHs showed no significant difference in our network analysis, and the subgroup analyses (such as in patients with deep venous thrombosis, cardiac disease, or age >65 years old) supported the results. The SUCRA showed that tinzaparin performed best in preventing VTE or VTE-related death (SUCRA 68.8%, cumulative probability 42.3%) and all-cause death (SUCRA 84.2%, cumulative probability 40.7%), whereas nadroparin was predominant in decreasing the risk of clinically relevant bleeding (SUCRA 84.8%, cumulative probability 77.0%). Conclusions: On present evidence, there are no significant differences in the efficacy and safety of different LMWHs for the elderly. According to the rank probability analysis, nadroparin seems to be safer for the elderly with a high risk of bleeding, whereas tinzaparin is more effective for those with low bleeding risk.

19.
Curr HIV Res ; 2021 Dec 27.
Artigo em Inglês | MEDLINE | ID: mdl-34961450

RESUMO

BACKGROUND: The efficacy of highly active antiretroviral therapy (HAART) therapy can be estimated by immunological response and the incidence of opportunistic infections. OBJECTIVE: To evaluate the effectiveness of different durations of HAART in terms of immunological response markers (CD4 count and CD4/CD8 ratio) along with disease progression markers (incidence of oral lesions) in Chinese patients with HIV. METHODS: This single-center, retrospective, real-world study included patients with HIV, grouped into treatment group and treatment-naïve group of which the former was further divided into (6, 12, and 18 months) based on the treatment duration. The CD4 and CD8 cell counts were analyzed by the FACSCalibur flow cytometry. Kruskal-Wallis test was applied to determine the outcome of different duration of HAART. Oral examination was carried out according to the WHO type IV examination. RESULTS: In 246 patients with HIV, CD4 counts increased significantly post-HAART compared with pre-HAART in all three treatment groups (P<.001), while CD8 count decreased significantly (P<.05) in all three treated group. A significant association of HAART with CD4/CD8 ratio was observed (P<.001). A significant increase in CD4 count was observed between 12-month and 18-month treatment group (P<.05). The occurrence of oral lesions reduced significantly in the treatment group. CONCLUSION: We observed a better response of HAART regimen with 18 months of duration than 12-months and 6-months therapies and reduction in oral lesions.

20.
Front Plant Sci ; 12: 758785, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34938306

RESUMO

The adjustment of stomatal density and clustered ratio on the epidermis is the important strategy for plants to respond to drought, because the stoma-based water loss is directly related to plant growth and survival under drought conditions. But the relevant adjustment mechanism still needs to be explored. 1-Aminocyclopropane-1-carboxylate (ACC) is disclosed to promote stomatal development, while in vivo ACC levels depend on activation of ACC synthase (ACS) family members. Based on the findings of ACS expression involving in drought response and several ACS activity inhibitors reducing stomatal density and cluster in drought response, here we examined how ACS activation is involved in the establishment of stomatal density and cluster on the epidermis under drought conditions. Preliminary data indicated that activation of ACS2 and/or ACS6 (ACS2/6) increased stomatal density and clustered ratio on the Arabidopsis leaf epidermis by accumulating ACC under moderate drought, and raised the survival risk of seedlings under escalated drought. Further exploration indicated that, in Arabidopsis seedlings stressed by drought, the transcription factor SPEECHLESS (SPCH), the initiator of stomatal development, activates ACS2/6 expression and ACC production; and that ACC accumulation induces Ca2+ deficiency in stomatal lineage; this deficiency inactivates a subtilisin-like protease STOMATAL DENSITY AND DISTRIBUTION 1 (SDD1) by stabilizing the inhibition of the transcription factor GT-2 Like 1 (GTL1) on SDD1 expression, resulting in an increases of stomatal density and cluster ratio on the leaf epidermis. This work provides a novel evidence that ACS2/6 activation plays a key role in the establishment of stomatal density and cluster on the leaf epidermis of Arabidopsis in response to drought.

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