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1.
J Appl Microbiol ; 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34470077

RESUMO

AIMS: Pre-eclampsia (PE) affects pregnant patients worldwide, but there is no effective treatment for this condition. We aimed to explore the effect of sodium butyrate (NaB) on PE. METHODS AND RESULTS: In this study, Nω-nitro-L-arginine methyl ester hydrochloride was used to induce PE in pregnant rats. We found that NaB significantly decreased the levels of blood pressure, 24-h protein urine and inflammatory factors (IL-1ß, IL-6 and TGF-ß), increased the foetal and placental weights and intestinal barrier markers (ZO-1, claudin-5 and occludin) expression. In addition, NaB intervention reduced the levels of soluble fms-like tyrosine kinase 1 and soluble endoglin and increased placental growth factor level. Meanwhile, after NaB treatment, the Treg/Th17 ratio of immune cells in the spleen and small intestine of pregnant rats decreased, while the level of pregnancy-related diamine oxidase increased. Notably, the PE rat treatment with NaB improved gut microbiota compositions, especially for the abundances of Firmicutes and Bacteroides, and significantly increased butyric acid and pentanoic acid levels, which might help to alleviate PE in pregnant rats. CONCLUSION: In the PE rat model, exogenous NaB improved intestinal barrier function and reduced adverse outcomes, which might be associated with the gut microbiota and its production of SCFA metabolites. SIGNIFICANCE AND IMPACT OF THE STUDY: NaB might alleviate the adverse outcomes of PE by regulating gut microbiota and its metabolite SCFA, which revealed that NaB might be a potential regulator of gut microbiota and a therapeutic substance for PE.

2.
Brain Lang ; 222: 105013, 2021 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-34520977

RESUMO

Bilingual language representation and cognitive control effects may reflect the dynamic interactions among the complex learning environment, genotype of the individual, and developing cognitive abilities. In this paper we propose a framework considering such interactions. Specifically, we present a nonlinear, developmentally-oriented perspective in which each individual represents a developmental trajectory in multidimensional space. These trajectories focus on the cognitive ecosystem (and how said ecosystem changes over time) and individual expertise (which affects and is affected by the ecosystem). The interactions between ecosystem and expertise lead to the emergence of a system that is built to handle the communicative needs of the individual.

3.
Parasit Vectors ; 14(1): 472, 2021 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-34521449

RESUMO

BACKGROUND: Various stimuli, including Clonorchis sinensis infection, can cause liver fibrosis. Liver fibrosis is characterized by the activation of hepatic stellate cells (HSCs) with massive production of extracellular matrix (ECM). Our previous study showed that the TGF-ß1-induced Smad signaling pathway played a critical role in the activation of HSCs during liver fibrosis induced by worm infection; however, the mechanisms that modulate the TGF-ß/Smad signaling pathway are still poorly understood. Accumulating evidence demonstrates that miRNAs act as an important regulator of activation of HSCs during liver fibrosis. METHODS: The target of miR-497 was determined by bioinformatics analysis combined with a dual-luciferase activity assay. LX-2 cells were transfected with miR-497 inhibitor and then stimulated with TGF-ß1 or excretory/secretory products of C. sinensis (CsESPs), and activation of LX-2 was assessed using qPCR or western blot. In vivo, the mice treated with CCl4 were intravenously injected with a single dose of adeno-associated virus serotype 8 (AAV8) that overexpressed anti-miR-497 sequences or their scramble control for 6 weeks. Liver fibrosis and damage were assessed by hematoxylin and eosin (H&E) staining, Masson staining, and qPCR; the activation of the TGF-ß/Smad signaling pathway was detected by qPCR or western blot. RESULTS: In the present study, the expression of miR-497 was increased in HSCs activated by TGF-ß1 or ESPs of C. sinensis. We identified that Smad7 was the target of miR-497 using combined bioinformatics analysis with luciferase activity assays. Transfection of anti-miR-497 into HSCs upregulated the expression of Smad7, leading to a decrease in the level of p-Smad2/3 and subsequent suppression of the activation of HSCs induced by TGF-ß1 or CsESPs. Furthermore, miR-497 inhibitor delivered by highly-hepatotropic (rAAV8) inhibited TGF-ß/smads signaling pathway by targeting at Smad7 to ameliorate CCL4-induced liver fibrosis. CONCLUSIONS: The present study demonstrates that miR-497 promotes liver fibrogenesis by targeting Smad7 to promote TGF-ß/Smad signaling pathway transduction both in vivo and in vitro, which provides a promising therapeutic strategy using anti-miR-497 against liver fibrosis.

4.
Anesth Analg ; 2021 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-34524124

RESUMO

BACKGROUND: The maternal pain threshold gradually increases during pregnancy, especially in late pregnancy. A series of mechanisms underlying pregnancy-induced analgesia have been reported. However, these mechanisms are still not completely clear, and the underlying molecular mechanisms need further investigation. We examined the relationship between the antinociceptive effect and the expression level of programmed cell death ligand-1 (PD-L1) during pregnancy and further observed the changes in pain thresholds and expression levels of cytokines in late-pregnant mice before and after blockade of PD-L1 or programmed cell death-1 (PD-1). METHODS: Part 1: Female mice were assigned to 3 groups (nonpregnant, late-pregnant, and postpartum). Part 2: Late-pregnant mice were assigned to 3 treatment groups (control [phosphate buffer solution], RMP1-14 [mouse anti-PD-1 antibody], and soluble PD-1 [sPD-1]). Behavioral testing (mechanical and thermal) and tissue (serum and spinal cord) analysis were performed on all groups. PD-L1, interleukin (IL)-10, tumor necrosis factor-α (TNF-α), and IL-6 expression levels in tissue were examined via reverse transcription-polymerase chain reaction (RT-PCR), enzyme-linked immunosorbent assay (ELISA), and Western blot analysis. RESULTS: The mechanical and thermal pain thresholds were significantly increased in late pregnancy and decreased after delivery. PD-L1 expression was also elevated in late pregnancy and decreased after delivery. In addition, in the late stage of gestation, the maternal inflammatory microenvironment was dominated by anti-inflammatory factors. After administration of RMP1-14 or sPD-1, the pain thresholds of late-pregnant mice were significantly reduced. In late-pregnant mice, the high level of IL-10 was obviously reduced, and the low levels of TNF-α and IL-6 were elevated. CONCLUSIONS: The PD-L1/PD-1 pathway mediates pregnancy-induced analgesia, partially via the regulation of cytokines.

5.
Phys Chem Chem Phys ; 23(35): 19673-19679, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34524289

RESUMO

The quantum anomalous Hall (QAH) effect has been experimentally observed in magnetically-doped topological insulators. However, the QAH effect is only seen at extremely low temperatures due to the weak magnetic coupling, small band gap and low carrier mobility. Here, based on first-principles density functional theory, we predict that the Janus Mn2X3Y3 (X, Y) = F, Cl, Br, I are high Curie temperature ferromagnets. Furthermore, we find that they are Dirac half-metals characterized by a Dirac cone in one spin channel with carrier mobilities comparable to freestanding germanene and a large band gap in the other spin channel except for Mn2F3I3. Simultaneously, when the spin-orbital coupling interaction is considered, the Janus Mn2F3Cl3, Mn2Cl3Br3, and Mn2Br3I3 exhibit a nontrivial band gap, indicating that they host a QAH phase. More interestingly, both the Chern number sign and the chiral edge current are tuned by changing the direction of magnetization. Moreover, we find that topological properties are related to the lattice constant and magnetocrystalline anisotropy. Our findings would suggest the possibility of not only realizing the QAH effect but also designing the flow direction of the edge current.

6.
Molecules ; 26(17)2021 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-34500792

RESUMO

Identification of drug-target interactions (DTIs) is vital for drug discovery. However, traditional biological approaches have some unavoidable shortcomings, such as being time consuming and expensive. Therefore, there is an urgent need to develop novel and effective computational methods to predict DTIs in order to shorten the development cycles of new drugs. In this study, we present a novel computational approach to identify DTIs, which uses protein sequence information and the dual-tree complex wavelet transform (DTCWT). More specifically, a position-specific scoring matrix (PSSM) was performed on the target protein sequence to obtain its evolutionary information. Then, DTCWT was used to extract representative features from the PSSM, which were then combined with the drug fingerprint features to form the feature descriptors. Finally, these descriptors were sent to the Rotation Forest (RoF) model for classification. A 5-fold cross validation (CV) was adopted on four datasets (Enzyme, Ion Channel, GPCRs (G-protein-coupled receptors), and NRs (Nuclear Receptors)) to validate the proposed model; our method yielded high average accuracies of 89.21%, 85.49%, 81.02%, and 74.44%, respectively. To further verify the performance of our model, we compared the RoF classifier with two state-of-the-art algorithms: the support vector machine (SVM) and the k-nearest neighbor (KNN) classifier. We also compared it with some other published methods. Moreover, the prediction results for the independent dataset further indicated that our method is effective for predicting potential DTIs. Thus, we believe that our method is suitable for facilitating drug discovery and development.

7.
Front Immunol ; 12: 741839, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34512673

RESUMO

The dysregulation of NLRP3 inflammasome plays a critical role in pathogenesis of various human inflammatory diseases, thus NLRP3 inflammasome activation must be tightly controlled at multiple levels. However, the underlying mechanism regulating NLRP3 inflammasome activation remains unclear. Herein, the effects of Tripartite motif-containing protein 65 (TRIM65) on NLRP3 inflammasome activation and the underlying molecular mechanism were investigated in vitro and in vivo. Inhibition or deletion of Trim65 could significantly strengthen agonist induced NLRP3 inflammasome activation in THP-1 cells and BMDMs, indicated by increased caspase-1 activation and interleukin-1ß secretion. However, TRIM65 had no effect on poly (dA: dT)-induced AIM2 inflammasome activation or flagellin-induced IPAF inflammasome activation. Mechanistically, immunoprecipitation assays demonstrated that TRIM65 binds to NACHT domain of NLRP3, promotes lys48- and lys63- linked ubiquitination of NLRP3 and restrains the NEK7-NLRP3 interaction, thereby inhibiting NLRP3 inflammasome assembly, caspase-1 activation, and IL-1ß secretion. In vivo, three models of inflammatory diseases were used to confirm the suppression role of TRIM65 in NLRP3 inflammasome activation. TRIM65-deficient mice had a higher production of IL-1ß induced by lipopolysaccharide in sera, and more IL-1ß secretion and neutrophil migration in the ascites, and more severity of joint swelling and associated IL-1ß production induced by monosodium urate, suggesting that TRIM65 deficiency was susceptible to inflammation. Therefore, the data elucidate a TRIM65-dependent negative regulation mechanism of NLRP3 inflammasome activation and provide potential therapeutic strategies for the treatment of NLRP3 inflammasome-related diseases.

8.
Bioengineered ; 12(1): 5583-5594, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34515620

RESUMO

Alleviating cardiac dysfunction improves the prognosis of heart failure patients. Lycorine is an alkaloid with several beneficial biological properties. Here, we used mice to evaluate the effect of lycorine on cardiac dysfunction elicited by isoproterenol. Mice were divided into four groups: control, lycorine, isoproterenol, and isoproterenol + lycorine. Mice in the combined group were treated daily with 10 mg/kg isoproterenol intraperitoneally for 2 weeks and 5 mg/kg lycorine was given simultaneously intraperitoneally for 4 weeks. Cardiac structure and function were assessed by echocardiography, hematoxylin and eosin staining, and Masson's trichrome staining. Isoproterenol-induced cardiac dysfunction and histopathological injury that was significantly improved by treatment with lycorine. Western blotting and the quantitative real-time polymerase chain reaction were used to explore the molecular mechanisms of these effects. Levels of the inflammatory cytokines, interleukin (IL)-1ß, IL-6, and tumor necrosis factor-α, were increased by treatment with isoproterenol; these increases were significantly reduced by lycorine, with involvement of the NF-κB signaling pathway. The fibrotic factors, collagen I and collagen III, were increased by isoproterenol and decreased by treatment with lycorine through inhibiting activation of the Smad signaling pathway. In addition, lycorine alleviated oxidative stress as evidenced by a reduction in total reactive oxygen species in the isoproterenol + lycorine group compared to the isoproterenol group. Lycorine exerted an anti-apoptotic effect as evidenced by upregulating Bcl-2 and downregulating Bax. Overall, our findings demonstrate that lycorine protects against cardiac dysfunction induced by isoproterenol by inhibiting inflammation, fibrosis, oxidative stress, and apoptosis.

9.
J Vis Exp ; (174)2021 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-34515686

RESUMO

The loss of function of melanocytes leads to vitiligo, which seriously affects the physical and mental health of the affected individuals. Presently, there is no effective long-term treatment for vitiligo. Therefore, it is imperative to develop a convenient and effective treatment for vitiligo. Regenerative medicine technology for direct reprogramming of skin cells into melanocytes seems to be a promising novel treatment of vitiligo. This involves the direct reprogramming of the patient's skin cells into functional melanocytes to help ameliorate the loss of melanocytes in patients with vitiligo. However, this method needs to be first tested on mice. Although direct reprogramming is widely used, there is no clear protocol for direct reprogramming into melanocytes. Moreover, the number of available transcription factors is overwhelming. Here, a concentrated lentivirus packaging system protocol is presented to produce transcription factors selected for reprogramming skin cells to melanocytes, including Sox10, Mitf, Pax3, Sox2, Sox9, and Snai2. Mouse embryonic fibroblasts (MEFs) were infected with the concentrated lentivirus for all these transcription factors for the direct reprogramming of the MEFs into induced melanocytes (iMels) in vitro. Furthermore, these transcription factors were screened, and the system was optimized for direct reprogramming to melanocytes. The expression of the characteristic markers of melanin in iMels at the gene or protein level was significantly increased. These results suggest that direct reprogramming of fibroblasts to melanocytes could be a successful new therapeutic strategy for vitiligo and confirm the mechanism of melanocyte development, which will provide the basis for further direct reprogramming of fibroblasts into melanocytes in vivo.

10.
Oncologist ; 2021 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-34516729

RESUMO

BACKGROUND: PD-1/PD-L1 blockade immunotherapies have changed the landscape of cancer therapy. However, the main limitation of these therapies is the lack of definitively predictive biomarkers to predict treatment response. Whether PD-L1 expression on circulating tumor cells (CTCs) is associated with the clinical outcomes of immunotherapy remains to be extensively investigated. METHODS: 155 patients with different advanced cancers were enrolled in this study and treated with anti-PD-1/PD-L1 monoclonal antibodies (mAbs). Using the Pep@MNPs method, CTCs were isolated and enumerated. The PD-L1 expression levels were analyzed by an immunofluorescence assay for semiquantitative assessment with four categories (negative, low, medium and high). RESULTS: Prior to immunotherapy, 81.93% (127/155) of patients had PD-L1-positive CTCs, and 71.61% (111/155) had at least one PD-L1-high CTC. The group with PD-L1-positive CTCs had a higher disease control rate (DCR) (71.56%, 91/127), with a DCR of only 39.29% (11/28) for the remaining individuals (P=0.001). The objective response rate (ORR) and DCR in PD-L1-high patients were higher than those in the other patients (32.44% vs 13.64%, P=0.018 and 75.68% vs 40.91%, P<0.0001, respectively). The reduction in the counts and ratios of PD-L1-positive CTCs and PD-L1-high CTCs reflected a beneficial response to PD-1/PD-L1 inhibitors. Furthermore, patients with PD-L1-high CTCs had significantly longer progression-free survival (PFS) (4.9 vs 2.2 months, P<0.0001) and overall survival (OS) (16.1 vs 9.0 months, P=0.0235) than those without PD-L1-high CTCs.Conclusions The PD-L1 level on CTCs may serve as a clinically actionable biomarker for immunotherapy, and its dynamic changes could predict the therapeutic response. IMPLICATIONS FOR PRACTICE: This study was designed to investigate the role of PD-L1 expression on circulating tumor cells in predicting and monitoring response to PD-1/PD-L1 blockade immunotherapies in patients with advanced cancer. The results of the study showed that PD-L1-high expression CTCs were both a predictive biomarker and a prognostic factor in patients with advanced cancer treated with anti-PD-1/PD-L1 mAbs. These observations suggest that PD-L1 level on CTCs is a potential clinical biomarker for immunotherapy.

11.
Bioengineered ; 12(1): 5504-5515, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34514952

RESUMO

The present study was aimed to evaluate the expression profile of Zinc finger C3H1 domain-containing protein (ZFC3H1) using bioinformatic analysis of public datasets from The Cancer Genome Atlas database (TCGA). The results showed that the expression levels of ZFC3H1 were notably lower than the corresponding non-cancerous tissues in prostate adenocarcinoma (PRAD), and patients in the high ZFC3H1-expression group showed poor survival. We hypothesized that the low expression of ZFC3H1 in tumor tissue might have be an inhibitory effect on the autoimmune system. We predicted the regulatory target and protein interaction partner network of ZFC3H1, and identified a PPI network composed of 26 node genes in PRAD. Furthermore, we found that the expression levels of MPHOSPH6 (encoding M-phase phosphoprotein 6) and MRPS31 (encoding mitochondrial ribosomal protein S31) were lower in PRAD tissues than in non-cancerous tissues, and the survival time of patients with high MPHOSPH6 and MRPS31 expression was poor. To further demonstrate the role of ZC3H1 in PRAD, we knocked-down the ZFC3H1 expression and found that the inhibition of ZFC3H1 significantly inhibited PRAD cell migration and invasion. Furthermore, ZFC3H1 siRNA treatment could reduce cell viability and increase the number of apoptotic cells in PRAD cells. Taken together, ZFC3H1 could represent a new marker for PRAD prognosis and provide a reference for the development of new therapies to treat PRAD.

12.
Proteomics ; : e2100007, 2021 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-34482643

RESUMO

Methionine (Met) and cystine (CySS) are key sulfur donors in cell metabolism and are important nutrients for sustaining tumor growth; however, the molecular effects associated with their deprivation remain to be characterized. Here, we devised a xenograft mouse model to assess the impact of their deprivation on A549 xenografts and the xenograft-bearing animal. Results show that Met and CySS deprivation inhibits A549 growth in vitro, not in vivo. Deprivation was detrimental to the xenograft-bearing mouse, as demonstrated by weight loss and renal dysfunction. Differentially expressed proteins in A549 xenograft and mouse kidneys were characterized using quantitative proteomics. Functional annotation and protein-protein interaction network analysis revealed the enriched signaling pathways, including focal adhesion (Fn1) in the A549 xenograft, and xenobiotic metabolism (Cyp2e1) and glutathione metabolism (Ggt1) in the mouse kidney. Met and CySS deprivation inhibits the migratory and invasive properties of cancer cells, as evidenced by reduced expression of the epithelial to mesenchymal transition marker N-cadherin in A549 cells in vitro. Moreover, IGFBP1 protein expression was inhibited in both A549 xenograft and mouse kidneys. This study provides the first insights into changes within the proteome profile and biological processes upon Met and CySS deprivation in a A549 xenograft mouse model. This article is protected by copyright. All rights reserved.

13.
Chem Commun (Camb) ; 2021 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-34486623

RESUMO

We describe a catalytic asymmetric iminium ion cyclization reaction of simple 2-alkenylbenzaldimines using a BINOL-derived chiral N-triflyl phosphoramide. The corresponding 1-aminoindenes and tetracyclic 1-aminoindanes are formed in good yields and high enantioselectivities. Further, the chemical utility of the obtained enantiopure 1-aminoindene is demonstrated for the asymmetric synthesis of (S)-rasagiline.

14.
Neurosci Bull ; 2021 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-34487324

RESUMO

Human genetic prion diseases (gPrDs) are directly associated with mutations and insertions in the PRNP (Prion Protein) gene. We collected and analyzed the data of 218 Chinese gPrD patients identified between Jan 2006 and June 2020. Nineteen different subtypes were identified and gPrDs accounted for 10.9% of all diagnosed PrDs within the same period. Some subtypes of gPrDs showed a degree of geographic association. The age at onset of Chinese gPrDs peaked in the 50-59 year group. Gerstmann-Sträussler-Scheinker syndrome (GSS) and fatal familial insomnia (FFI) cases usually displayed clinical symptoms earlier than genetic Creutzfeldt-Jakob disease (gCJD) patients with point mutations. A family history was more frequently recalled in P105L GSS and D178N FFI patients than T188K and E200K patients. None of the E196A gCJD patients reported a family history. The gCJD cases with point mutations always developed clinical manifestations typical of sporadic CJD (sCJD). EEG examination was not sensitive for gPrDs. sCJD-associated abnormalities on MRI were found in high proportions of GSS and gCJD patients. CSF 14-3-3 positivity was frequently detected in gCJD patients. Increased CSF tau was found in more than half of FFI and T188K gCJD cases, and an even higher proportion of E196A and E200K gCJD patients. 63.6% of P105L GSS cases showed a positive reaction in cerebrospinal fluid RT-QuIC. GSS and FFI cases had longer durations than most subtypes of gCJD. This is one of the largest studies of gPrDs in East Asians, and the illness profile of Chinese gPrDs is clearly distinct. Extremely high proportions of T188K and E196A occur among Chinese gPrDs; these mutations are rarely reported in Caucasians and Japanese.

15.
Zhongguo Zhong Yao Za Zhi ; 46(16): 4061-4068, 2021 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-34467715

RESUMO

Reverse prediction and molecular docking techniques were employed to evaluate the feasibility of reniformin A(RA) as an anti-tumor leading compound. Based on the reverse prediction, network pharmacology was used to construct a "disease-compound-target-pathway" network. Thirty-nine tumor-related targets of RA were predicted, which participated in the regulation of multiple cellular activities such as apoptosis, cell cycle, and tumor metastasis, and regulated estrogen signal transduction and inflammatory response. Discovery Studio 2020 was adopted for molecular docking and toxicity prediction(TOPKAT). As revealed by the results, the binding affinity of RA with the tumor-related targets ABL1, ESR1, SRC and BCL-XL was stronger than that of oridonin(OD), while its mutagenicity, rodent carcinogenesis, and oral LD_(50) in rats were all inferior to that of OD. Furthermore, in vitro experiments were performed to confirm the anti-tumor activity of RA, and the mechanism was preliminarily discussed. The results demonstrated that RA was superior to OD in cytotoxicity, inhibition of cell colony formation, and induction of apoptosis. RA, possessing potent anti-tumor activity, is expected to be a new anti-tumor leading compound.


Assuntos
Medicamentos de Ervas Chinesas , Neoplasias , Animais , Medicamentos de Ervas Chinesas/farmacologia , Chumbo , Simulação de Acoplamento Molecular , Neoplasias/tratamento farmacológico , Neoplasias/genética , Ratos , Transdução de Sinais
16.
Wound Manag Prev ; 67(9): 34-46, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34473642

RESUMO

BACKGROUND: Smoking is a risk factor for many diseases. PURPOSE: This study explored the relationship between current or past smoking and pressure injury (PI) risk through a systematic review and meta-analysis. METHODS: The databases PubMed, Web of Science, and China National Knowledge Infrastructure were searched for the years between 2001 and 2020. Quality of evidence was estimated by the Newcastle-Ottawa Scale. The random effects model was applied to assess the odds ratios (OR) and 95% confidence intervals (CI); pooled adjusted OR and 95% CI, subgroup analysis, publication bias, sensitivity analyses, and meta-regression analysis were performed. RESULTS: Fifteen (15) studies (12 retrospective and 3 prospective) comprising data on 11 304 patients were eligible for inclusion in the review. The meta-analysis demonstrated that smoking increased the risk of PI (OR = 1.498; 95% CI, 1.058-2.122), and the pooled adjusted OR (1.969) and 95% CI (1.406-2.757) confirmed this finding. Publication bias was not detected by funnel plot, Begg's test (P = .322), or Egger's test (P = .666). Subgroup analyses yielded the same observations in both retrospective (OR = 1.607; 95% CI, 1.043-2.475) and prospective (OR = 1.218; 95% CI, 0.735-2.017) studies. The results were consistent across sensitivity analyses (OR = 1.07; 95% CI, 1.043- 2.475). Relevant heterogeneity moderators were not identified by meta-regression analysis with PI incidence (P = .466), years of patient data included (P = .637), mean patient age (P = .650), and diabetes mellitus diagnosis (P = .509). CONCLUSION: This study found that individuals who are current or formers smokers have an almost 1.5 times higher risk of PI development than do those who do not smoke.

17.
J Biol Chem ; : 101149, 2021 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-34473994

RESUMO

Metabolic flexibility is the capacity of cells to alter fuel metabolism in response to changes in metabolic demand or nutrient availability. It is critical for maintaining cellular bioenergetics and is involved in the pathogenesis of cardiovascular disease and metabolic disorders. However, the regulation and function of metabolic flexibility in lymphatic endothelial cells (LECs) remain unclear. We have previously shown that glycolysis is the predominant metabolic pathway to generate ATP in LECs and that fibroblast growth factor receptor (FGFR) signaling controls lymphatic vessel formation by promoting glycolysis. Here we found that chemical inhibition of FGFR activity or knockdown of FGFR1 induces substantial upregulation of fatty acid ß-oxidation (FAO) while reducing glycolysis and cellular ATP generation in LECs. Interestingly, such compensatory elevation was not observed in glucose oxidation and glutamine oxidation. Mechanistic studies show that FGFR blockade promotes the expression of CPT1A, a rate-limiting enzyme of FAO; this is achieved by dampened ERK activation, which in turn upregulates the expression of the peroxisome proliferator activated receptor α (PPARα). Metabolic analysis further demonstrates that CPT1A depletion decreases total cellular ATP levels in FGFR1-deficient rather than wild-type LECs. This result suggests that FAO, which makes a negligible contribution to cellular energy under normal conditions, can partially compensate for energy deficiency caused by FGFR inhibition. Consequently, CPT1A silencing potentiates the effect of FGFR1 knockdown on impeding LEC proliferation and migration. Collectively, our study identified a key role of metabolic flexibility in modulating the effect of FGFR signaling on LEC growth.

18.
Zhongguo Zhong Yao Za Zhi ; 46(15): 3814-3823, 2021 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-34472254

RESUMO

Volatile oil is the main effective component and an important quality indicator of Artemisia argyi leaves. In this study, 100 germplasm resources of A. argyi were collected from all the related habitats in China. The total volatile oils in A. argyi leaves were extracted by steam distillation and the content was determined by GC-MS. The result demonstrated that the content of total volatile oils was in the range of 0.53%-2.55%, with the average of 1.43%. A total of 39 chemical constituents were identified from the volatile oils, including 13 shared by the 100 germplasm resources. Clustering analysis of the 39 constituents showed that the 100 A. argyi samples were categorized into groups Ⅰ(9), Ⅱ(2), Ⅲ(66) and Ⅳ(23), and group Ⅲ had the most volatile medicinal components, with the highest content. Five principal components(PCs) were extracted from 13 shared constituents, which explained 73.454% of the total variance. PC1, PC2, and PC3 mainly reflected the pharmacological activity of volatile oils and the rest two the aroma information. The volatile oils identified in this study lay a foundation for variety breeding of and rational utilization of volatile oils in A. argyi leaves.


Assuntos
Artemisia , Óleos Voláteis , Destilação , Melhoramento Vegetal , Folhas de Planta
19.
J Infect Dis ; 2021 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-34480575

RESUMO

BACKGROUND: We have previously reported the safety and immunogenicity four weeks after two doses of the Clover COVID-19 vaccine candidate, SCB-2019, a stabilized pre-fusion form of the SARS-CoV-2 S-protein (S-trimer). We now report persistence of antibodies up to 6 months after vaccination, and cross-neutralization titers against three Variants of Concern (VoC). METHODS: In a phase 1 study adult (18-54 years) and elderly (55-75 years) volunteers received two vaccinations 21 days apart with 3, 9 or 30µg doses of SCB-2019 adjuvanted with CpG-1018/alum or placebo. We measured IgG antibodies against SCB-2019, ACE2-competitive-binding antibodies, and neutralizing antibodies against wild type SARS-CoV-2 (Wuhan-Hu-1) at Days 101 and 184, and neutralizing antibodies against three VoC, Alpha (B.1.1.7), Beta (B.1.351) and Gamma (P.1) in Day 36 sera. RESULTS: Titers waned from their peak at Days 36-50, but SCB-2019 IgG antibodies, ACE2-competitive binding antibodies and neutralizing antibodies against wild type SARS-CoV-2 persisted at 25-35% of their observed peak levels at Day 184. Day 36 sera also demonstrated dose-dependent increases in neutralizing titers against the three VoC. CONCLUSIONS: SCB-2019 dose-dependently induced immune responses against wild-type SARS-CoV-2 which persisted up to Day 184. Neutralizing antibodies were cross-reactive against three of the most prevalent VoC.

20.
Signal Transduct Target Ther ; 6(1): 329, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34471087

RESUMO

It's a challenge for detecting the therapeutic targets of a polypharmacological drug from variations in the responsed networks in the differentiated populations with complex diseases, as stable coronary heart disease. Here, in an adaptive, 31-center, randomized, double-blind trial involving 920 patients with moderate symptomatic stable angina treated by 14-day Danhong injection(DHI), a kind of polypharmacological drug with high quality control, or placebo (0.9% saline), with 76-day following-up, we firstly confirmed that DHI could increase the proportion of patients with clinically significant changes on angina-frequency assessed by Seattle Angina Questionnaire (ΔSAQ-AF ≥ 20) (12.78% at Day 30, 95% confidence interval [CI] 5.86-19.71%, P = 0.0003, 13.82% at Day 60, 95% CI 6.82-20.82%, P = 0.0001 and 8.95% at Day 90, 95% CI 2.06-15.85%, P = 0.01). We also found that there were no significant differences in new-onset major vascular events (P = 0.8502) and serious adverse events (P = 0.9105) between DHI and placebo. After performing the RNA sequencing in 62 selected patients, we developed a systemic modular approach to identify differentially expressed modules (DEMs) of DHI with the Zsummary value less than 0 compared with the control group, calculated by weighted gene co-expression network analysis (WGCNA), and sketched out the basic framework on a modular map with 25 functional modules targeted by DHI. Furthermore, the effective therapeutic module (ETM), defined as the highest correlation value with the phenotype alteration (ΔSAQ-AF, the change in SAQ-AF at Day 30 from baseline) calculated by WGCNA, was identified in the population with the best effect (ΔSAQ-AF ≥ 40), which is related to anticoagulation and regulation of cholesterol metabolism. We assessed the modular flexibility of this ETM using the global topological D value based on Euclidean distance, which is correlated with phenotype alteration (r2: 0.8204, P = 0.019) by linear regression. Our study identified the anti-angina therapeutic module in the effective population treated by the multi-target drug. Modular methods facilitate the discovery of network pharmacological mechanisms and the advancement of precision medicine. (ClinicalTrials.gov identifier: NCT01681316).

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