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1.
Neural Regen Res ; 18(1): 141-149, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-35799534

RESUMO

Neuroinflammation and the NACHT, LRR, and PYD domains-containing protein 3 inflammasome play crucial roles in secondary tissue damage following an initial insult in patients with traumatic brain injury (TBI). Maraviroc, a C-C chemokine receptor type 5 antagonist, has been viewed as a new therapeutic strategy for many neuroinflammatory diseases. We studied the effect of maraviroc on TBI-induced neuroinflammation. A moderate-TBI mouse model was subjected to a controlled cortical impact device. Maraviroc or vehicle was injected intraperitoneally 1 hour after TBI and then once per day for 3 consecutive days. Western blot, immunohistochemistry, and TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling) analyses were performed to evaluate the molecular mechanisms of maraviroc at 3 days post-TBI. Our results suggest that maraviroc administration reduced NACHT, LRR, and PYD domains-containing protein 3 inflammasome activation, modulated microglial polarization from M1 to M2, decreased neutrophil and macrophage infiltration, and inhibited the release of inflammatory factors after TBI. Moreover, maraviroc treatment decreased the activation of neurotoxic reactive astrocytes, which, in turn, exacerbated neuronal cell death. Additionally, we confirmed the neuroprotective effect of maraviroc using the modified neurological severity score, rotarod test, Morris water maze test, and lesion volume measurements. In summary, our findings indicate that maraviroc might be a desirable pharmacotherapeutic strategy for TBI, and C-C chemokine receptor type 5 might be a promising pharmacotherapeutic target to improve recovery after TBI.

2.
Med Gas Res ; 13(1): 15-22, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-35946218

RESUMO

Postherpetic neuralgia (PHN) is a devastating disease with extraordinarily poor treatment outcomes. Both pulsed radiofrequency (PRF) and ozone have good effects on the treatment of the disease. However, whether PRF and ozone have a synergistic effect on PHN remains unclear. Therefore, this study aimed to assess the therapeutic effects of ozone alone and in combination with PRF in the treatment of PHN. Ninety-one patients with PHN were assigned into two groups: PRF combined with ozone (PRF + ozone group, n = 44) and ozone therapy alone (ozone group, n = 47). In PRF + ozone group, the high-voltage, long-duration PRF was applied to the target dorsal root ganglions. Then ozonated water (11.5 µg/mL) was injected through the inner cannula. In the ozone group, all other processes were the same as those in the PRF + ozone group apart from the electrical stimulation. The therapeutic efficacy was evaluated by visual analog scale and tactile sensation at pre-treatment and post-treatment 3, 6, and 12 months. Compared with pre-treatment data, the visual analog scale score was significantly decreased in both groups after treatment. Compared with the ozone group, the visual analog scale score was significantly decreased in the PRF + ozone group at 3, 6, and 12 months. Similarly, the tactile sensation was also significantly decreased at post-treatment when compared to pre-treatment. However, there were no statistical differences between the two groups. Regression analysis results showed that the history of diabetes mellitus and age had significant negative and positive effects, respectively, on the treatment results. To conclude, the administration of PRF + ozone and ozone therapy alone could both improve pain symptoms. Moreover, treatment effects and total efficacy rates tended to be higher for the combination of PRF and ozone than ozone alone. This conclusion was especially true for long-term therapeutic effects.


Assuntos
Neuralgia Pós-Herpética , Ozônio , Tratamento por Radiofrequência Pulsada , Gânglios Espinais , Humanos , Neuralgia Pós-Herpética/tratamento farmacológico , Ozônio/uso terapêutico , Tratamento por Radiofrequência Pulsada/métodos , Estudos Retrospectivos
3.
Neural Regen Res ; 18(3): 626-633, 2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-36018187

RESUMO

Ferroptosis plays a key role in aggravating the progression of spinal cord injury (SCI), but the specific mechanism remains unknown. In this study, we constructed a rat model of T10 SCI using a modified Allen method. We identified 48, 44, and 27 ferroptosis genes that were differentially expressed at 1, 3, and 7 days after SCI induction. Compared with the sham group and other SCI subgroups, the subgroup at 1 day after SCI showed increased expression of the ferroptosis marker acyl-CoA synthetase long-chain family member 4 and the oxidative stress marker malondialdehyde in the injured spinal cord while glutathione in the injured spinal cord was lower. These findings with our bioinformatics results suggested that 1 day after SCI was the important period of ferroptosis progression. Bioinformatics analysis identified the following top ten hub ferroptosis genes in the subgroup at 1 day after SCI: STAT3, JUN, TLR4, ATF3, HMOX1, MAPK1, MAPK9, PTGS2, VEGFA, and RELA. Real-time polymerase chain reaction on rat spinal cord tissue confirmed that STAT3, JUN, TLR4, ATF3, HMOX1, PTGS2, and RELA mRNA levels were up-regulated and VEGFA, MAPK1 and MAPK9 mRNA levels were down-regulated. Ten potential compounds were predicted using the DSigDB database as potential drugs or molecules targeting ferroptosis to repair SCI. We also constructed a ferroptosis-related mRNA-miRNA-lncRNA network in SCI that included 66 lncRNAs, 10 miRNAs, and 12 genes. Our results help further the understanding of the mechanism underlying ferroptosis in SCI.

4.
Comput Math Methods Med ; 2022: 2935992, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35341003

RESUMO

Background: To evaluate the clinical effects and safety of glucocorticoids for patients with nonarteritic anterior ischemic optic neuropathy (NAION). Methods: The databases MEDLINE, Embase, PubMed, Cochrane Database, and Web of Science were used to search for the relevant studies, and full-text articles that reported on the evaluation of glucocorticoids vs. no-treatment or placebo for patients with NAION. Review Manager 5.4 was used to estimate the pooled effects of the results among selected studies. Forest plots, funnel plots, and Begg's rank correlation were also performed on the included articles. Results: A total of 983 patients were contained in the 9 studies that satisfied the eligibility criteria. The meta-analysis showed that, compared with the control group, the glucocorticoid group had significantly improved the VA (MD: -0.25, 95% CI [-0.45, -0.05], P = 0.02), VF (MD: -0.50, 95% CI [-0.94, -0.07], P = 0.02), and RNFL (MD: -14.10, 95% CI [-26.41, -1.79], P = 0.02) in NAION patients and had a high improvement rate of VA (RR 1.31, 95% CI [1.12, 1.52], P = 0.0005). No significant publication bias was observed in our study. Discussion. Our research preliminarily confirmed the effectiveness of glucocorticoids for NAION treatment, but more high-quality RCTs focusing on the hormone adverse reactions should be performed to verify our conclusions.


Assuntos
Glucocorticoides , Neuropatia Óptica Isquêmica , Glucocorticoides/uso terapêutico , Humanos , Neuropatia Óptica Isquêmica/tratamento farmacológico
5.
Digit Health ; 8: 20552076221123705, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36090673

RESUMO

Background: Major depressive disorder and bipolar disorder in adolescents are prevalent and are associated with cognitive impairment, executive dysfunction, and increased mortality. Early intervention in the initial stages of major depressive disorder and bipolar disorder can significantly improve personal health. Methods: We collected 309 samples from the Adolescent Brain Cognitive Development study, including 116 adolescents with bipolar disorder, 64 adolescents with major depressive disorder, and 129 healthy adolescents, and employed a support vector machine to develop classification models for identification. We developed a multimodal model, which combined functional connectivity of resting-state functional magnetic resonance imaging and four anatomical measures of structural magnetic resonance imaging (cortical thickness, area, volume, and sulcal depth). We measured the performances of both multimodal and single modality classifiers. Results: The multimodal classifiers showed outstanding performance compared with all five single modalities, and they are 100% for major depressive disorder versus healthy controls, 100% for bipolar disorder versus healthy control, 98.5% (95% CI: 95.4-100%) for major depressive disorder versus bipolar disorder, 100% for major depressive disorder versus depressed bipolar disorder and the leave-one-site-out analysis results are 77.4%, 63.3%, 79.4%, and 81.7%, separately. Conclusions: The study shows that multimodal classifiers show high classification performances. Moreover, cuneus may be a potential biomarker to differentiate major depressive disorder, bipolar disorder, and healthy adolescents. Overall, this study can form multimodal diagnostic prediction workflows for clinically feasible to make more precise diagnose at the early stage and potentially reduce loss of personal pain and public society.

6.
Front Pharmacol ; 13: 927083, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36091807

RESUMO

U0126, as an inhibitor of the MAPK signaling pathway, is closely related to various biological processes, such as differentiation, cell growth, autophagy, apoptosis, and stress responses. It makes U0126 play an essential role in balancing cellular homeostasis. Although U0126 has been suggested to inhibit various cancers, its complete mechanisms have not been clarified in cancers. This review summarized the most recent and relevant research on the many applications of U0126 and described its role and mechanisms in different cancer cell types. Moreover, some acknowledged functions of U0126 researched in the laboratory were listed in our review. We discussed the probability of using U0126 to restain cancers or suppress the MAPK pathway as a novel way of cancer treatment.

7.
Oxid Med Cell Longev ; 2022: 6248779, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36092156

RESUMO

Background: Inflammation plays important roles during myocardial infarction (MI). Macrophage polarization is a major factor that drives the inflammatory process. Our previous study found that RNA polymerase II subunit 5-mediating protein (RMP) knockout in cardiomyocytes caused heart failure by impairing mitochondrial structure and function. However, whether macrophage RMP plays a role in MI has not been investigated. Methods: Macrophage RMP-knockout in combination with a mouse model of MI was used to study the function of macrophage RMP in MI. Next, we modified bone marrow-derived macrophages (BMDMs) by plasmid transfection, and the BMDMs were administered to LysM-Cre/DTR mice by tail vein injection. Immunoblotting and immunofluorescence were used to detect macrophage polarization, fibrosis, angiogenesis, and the p38 signaling pathway in each group. Results: Macrophage RMP deficiency aggravates cardiac dysfunction, promotes M1 polarization, and inhibits angiogenesis after MI. However, RMP overexpression in macrophages promotes M2 polarization and angiogenesis after MI. Mechanistically, we found that RMP regulates macrophage polarization through the heat shock protein 90- (HSP90-) p38 signaling pathway. Conclusions: Macrophage RMP plays a significant role in MI, likely by regulating macrophage polarization via the HSP90-p38 signaling pathway.


Assuntos
Ativação de Macrófagos , Infarto do Miocárdio , Animais , Inflamação/metabolismo , Macrófagos/metabolismo , Camundongos , Infarto do Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo
8.
ACS Omega ; 7(35): 30816-30822, 2022 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-36092571

RESUMO

Heavy crude oil exhibits very complex viscoelastic behaviors due to its complex composition of resins, asphaltenes, saturates, and aromatics. It has a great influence on oil production and transportation. In this work, the viscoelastic behaviors of three different heavy crude oils were measured using a rotational rheometer. In conclusion, all of these heavy crude oils display linear viscoelastic behaviors in the experimental range. The loss modulus (E″) of the three crude oils decreased as the experimental temperature increased, and the variation trends of the three crude oils were basically the same. However, the experimental temperature has almost no effect on the storage modulus (E'), which always retained a constant value of 0.4 Pa. Furthermore, the storage modulus (E') and loss modulus (E″) increase as the angular frequency increases. To describe the physical deformation characteristics of viscoelastic materials, the generalized Maxwell model and the fractional derivative Maxwell model are used to establish the constitutive relation of heavy crude oil. In conclusion, the generalized Maxwell model and the fractional derivative Maxwell model can predict the experimental results very well. All of the square of the correlation coefficient (R 2) values are greater than 0.95. However, the number of fitting parameters for the fractional derivative Maxwell model is less than that for the fourth-order generalized Maxwell model which can save the calculating time. Therefore, the fractional derivative Maxwell model is suggested to describe the viscoelastic behavior of heavy crude oil in industrial applications.

9.
Chem Sci ; 13(32): 9321-9328, 2022 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-36093003

RESUMO

Near-infrared (NIR)-emitting materials have been extensively studied due to their important applications in biosensing and bioimaging. Luminescent metal-organic frameworks (LMOFs) are a new class of highly emissive materials with strong potential for utilization in biomedical related fields because of their nearly unlimited structural and compositional tunability. However, very little work has been reported on organic linker-based NIR-MOFs and their emission properties. In the present work, a series of yttrium-tetracarboxylate-based LMOFs (HIAM-390X) are prepared via judicious linker design to achieve NIR emission with diverse structures. The introduction of an amino group not only offers the remarkable emission bathochromic shift from 521 nm, 665 nm to 689 nm for the resultant MOFs, but also influences the linker conformations, leading to the topology evolution from (4,12)-c ftw, (4,8)-c scu, which is rarely reported in rare earth element-based MOFs, to an unprecedented topology hlx for HIAM-3901 (without an amino group), HIAM-3905 (with one amino group) and HIAM-3906 (with two amino groups). Among these MOFs, HIAM-3907 shows an emission maximum at ∼790 nm, with the emission tail close to 1000 nm. The NIR emission may be attributed to the combination of the strongly electron-donating amino group and the strongly electron-withdrawing acceptor naphtho[2,3-c][1,2,5]selenadiazole. This work sheds light on the rational design of organic linker-based LMOFs with controlled structures and NIR emission, and inspires future interest in biosensing and bioimaging related applications of NIR-MOFs.

10.
iScience ; 25(9): 104918, 2022 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-36093059

RESUMO

Microenvironment cells (MCs) play a critical role in tumor proliferation, progression, and metastasis. However, it has not been adequately addressed whether MCs could be used as a reliable prognostic marker in glioblastoma (GBM). In the current study, the cell pair (CP) score was constructed in 1137 GBM samples based on the cell pair algorithm and Gaussian finite mixture model (GMM) and was verified in 73 GBM samples from the Xiangya cohort. CP score predicted GBM patients' survival and response to anti-PD-1 treatment with high sensitivity. Macrophage markers CD68 and CD163 were co-expressed with pericyte markers MCAM and MG2. Pericyte could mediate the infiltration, migration, and M2 type polarization of macrophages by MCAM. The CP score was a valuable tool for predicting survival outcomes and guiding immunotherapy for GBM patients. Cell pair pericyte/macrophage and gene pair CD163/MCAM were biologically significant in the tumor microenvironment of GBM.

11.
Circulation ; : 101161CIRCULATIONAHA122059755, 2022 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-36098051

RESUMO

BACKGROUND: Women and men with heart failure (HF) and preserved ejection fraction may differ in their clinical characteristics and their response to therapy. The aim of this study was to evaluate the influence of sex on the effects of empagliflozin in patients with HF and preserved ejection fraction enrolled in the EMPEROR-Preserved trial (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction). METHODS: The effects of empagliflozin on the primary outcome of cardiovascular death or hospitalization for HF and on secondary outcomes (including total HF hospitalization, cardiovascular and all-cause mortality, and Kansas City Cardiomyopathy Questionnaire scores) were compared in women and men in the overall cohort and in subgroups defined by left ventricular ejection fraction (41%-49%, 50%-59%, and ≥60%). The effects of empagliflozin on physiological measures, including changes in systolic blood pressure, uric acid, hemoglobin, body weight, and natriuretic peptide levels, were also assessed. RESULTS: Of the 5988 patients randomized, 2676 (44.7%) were women. In the placebo arm, women tended to have lower risk for adverse outcomes, including a lower risk of all-cause mortality (hazard ratio, 0.69 [95% CI, 0.56, 0.84]). Compared with placebo, empagliflozin reduced the risk of cardiovascular death or hospitalization for HF to a similar degree in both sexes (hazard ratio, 0.81 [95% CI, 0.69, 0.96] for men; and hazard ratio, 0.75 [95% CI, 0.61, 0.92] for women; Pinteraction=0.54). Sex did not modify the relationship between empagliflozin and outcomes across ejection fraction groups. Similar results were seen for secondary outcomes and physiological measures. Compared with placebo, empagliflozin improved the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score to a similar extent in both sexes (1.38 for men versus 1.63 for women at 52 weeks; Pinteraction=0.77); the results were similar for Kansas City Cardiomyopathy Questionnaire overall summary score and total summary score. CONCLUSIONS: Empagliflozin produced similar benefits on outcomes and health status in women and men with HF and preserved ejection fraction. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03057951.

12.
Hepatology ; 2022 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-36098707

RESUMO

BACKGROUND & AIMS: Monocyte-derived macrophages (MoMFs), a dominant population of hepatic macrophages under inflammation, play a crucial role in liver fibrosis progression. Spleen serves as an extra monocyte reservoir in inflammatory conditions; however, the precise mechanisms of involvement of spleen in the pathogenesis of liver fibrosis remain unclear. APPROACH & RESULTS: By splenectomy and splenocyte transfusion, it was observed that splenic CD11b+ cells accumulated intrahepatically as Ly6Clo MoMFs to exacerbate CCl4 -induced liver fibrosis. The splenocyte migration into the fibrotic liver was further directly visualized by spleen-specific photo-convertion with KikGR mice and confirmed by CD45.1+ /CD45.2+ spleen transplantation. Spleen-derived CD11b+ cells purified from fibrotic livers were then annotated by scRNA-seq and a subtype of CD11b+ CD43hi Ly6Clo splenic monocytes (sM-1s) was identified, which was markedly expanded in both spleens and livers of mice with liver fibrosis. sM-1s exhibited mature feature with high expressions of F4/80, produced much ROS, and manifested preferential migration into livers. Once recruited, sM-1s underwent sequential transformation to sM-2s (highly expressed Mif, Msr1, Clec4d, and Cstb), and then to sMφs with macrophage features of higher expressions of CX3 CR1, F4/80, MHC II and CD64 in the fibrotic hepatic milieu. Further, sM-2s and sMφs were demonstrated capable of activating hepatic stellate cells and thus exacerbating liver fibrosis. CONCLUSIONS: CD11b+ CD43hi Ly6Clo splenic monocytes migrate into liver and shift to macrophages, which account for the exacerbation of liver fibrosis. These findings reveal precise mechanisms of spleen-liver axis in hepatic pathogeneisis, and shed light on the potential of sM-1 as candidate target for controlling liver diseases.

13.
J Hazard Mater ; 439: 129690, 2022 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-36104924

RESUMO

The trophodynamics of toxic trace metals is significant for assessing the threat of toxic trace metals to the aquatic ecosystem and human safety. However, due to the difficulty of accurately calculating the trophic positions of freshwater aquatic organisms in the food web, the comprehensive process of trophodynamics of toxic trace metals in freshwater ecosystems was still rarely known. By integrating the compound-specific nitrogen stable isotopic analysis of amino acids (CSIA-AAs) and the Bayesian stable isotope mixing model (SIMM) as a novel approach, the present study investigated the trophodynamics of five toxic trace metals (Zn, As, Cr, Cu, and Hg) in the food web of the YangZong Lake, a plateau freshwater lake that was once heavily polluted by arsenic in Yunnan Province, China. The results revealed that Hg tended to be efficiently biomagnified in the food web with a trophic magnification factor of 1.75; As, Cr, and Cu were biodiluted significantly, while Zn showed no biomagnification or biodilution trends. The dietary health risk assessment indicated the potential health risk of toxic trace metals for the local residents of long-term fish consumption. The present work highlights the accuracy and reliability of the novel CSIA-AAS+SIMM approach in the calculation of the trophic positions of freshwater organisms.


Assuntos
Mercúrio , Oligoelementos , Poluentes Químicos da Água , Animais , Organismos Aquáticos/metabolismo , Teorema de Bayes , China , Ecossistema , Monitoramento Ambiental/métodos , Cadeia Alimentar , Humanos , Lagos/química , Mercúrio/metabolismo , Reprodutibilidade dos Testes , Medição de Risco , Oligoelementos/metabolismo , Poluentes Químicos da Água/análise
14.
Chin Med ; 17(1): 109, 2022 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-36109750

RESUMO

BACKGROUND: Ulcerative colitis (UC) is a common inflammatory intestinal disease. Astragali Radix (AR) is one of the traditional Chinese medicines used in clinic for UC treatment. In our previous study, the whole ingredient extract (WIE) from AR have been proved to possess better immunomodulatory effects on immunosuppressed mice compared with the conventional water extraction (WAE). In the present study, we further evaluated the therapeutic effects of WIE against dextran sodium sulfate (DSS)-induced UC in mice through systemic immune regulation. METHODS: Gradient solvent extraction has been used to prepare the WIE of AR. The HPLC-MS analysis approach has been employed to analyze and compare the chemical differences between WAE and WIE. UC model was reproduced in 3% DSS-induced C57BL/6 mice for 6 days. Flow cytometric analysis for splenic lymphocyte subset. ELISA kits were used to determine the cytokines in the serum and colon tissues. The histopathological characteristics of colon were evaluated by hematoxylin-eosin staining and immunohistochemistry. RESULTS: The chemical compositions and the contents of main active ingredients were more abundant and higher in WIE than those in WAE. The WIE treatment altered a better action on reducing colitis disease activity index (DAI) and histological scores, as well as the recovered body weight and increased colon length in mice compared to the WAE group. Additionally, WIE showed better effects in recovering the levels of peripheral white blood cells in blood and cytokines (IL-2, IL-6 and MCP-1) in serum or colon tissues, improving the percentage of CD3+ and the ratio of CD4+/CD8+ in the spleen, and inhibiting the spleen enlargement in DSS-induced UC mice. CONCLUSIONS: WIE has a more complete chemical composition than WAE. Meanwhile, WIE possesses better therapeutic effects on UC through resuming dysfunctional immunity in mice.

15.
Eur J Cancer ; 175: 125-135, 2022 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-36113242

RESUMO

BACKGROUND: A phase 1a first-in-human study evaluated the safety/tolerability, preliminary antitumour activity and pharmacokinetics of the oral MEK1/2 inhibitor FCN-159 in Chinese patients with advanced, NRAS-mutant melanoma. PATIENTS AND METHODS: Patients received a single FCN-159 dose at assigned levels, proceeding to continuous dosing (once daily [QD] for 28-day cycles) if no dose-limiting toxicities (DLTs) occurred within the next 3 days. Dose escalation was initiated after review of data for the previous dose level. The primary end-point was incidence of DLTs after the first dose. RESULTS: Thirty-three patients were enrolled across nine FCN-159 dose groups (0.2-15 mg QD). One DLT occurred: grade 3 folliculitis in the 15-mg group. There was one grade >3 treatment-emergent adverse event (TEAE), death of unknown aetiology (not FCN-159 related). The most common FCN-159-related TEAE was rash (36.4%), and the incidence of grade ≥3 FCN-159-related TEAEs was 15.2%. Antitumour activity at QD doses <6 mg was limited; therefore, efficacy data are presented only for doses ≥6 mg (n = 21). The objective response and clinical benefit rates were 19.0% (four partial responses) and 52.4%, respectively. Median (95% confidence interval) duration of response and progression-free survival were 4.8 months (2.8-not reached) and 3.8 months (1.8-5.6), respectively. FCN-159 exposure increased dose-proportionately; geometric mean terminal half-life was 29.9-56.9 h. CONCLUSIONS: FCN-159 was well tolerated and demonstrated promising antitumour activity at doses ≥6 mg QD in patients with advanced, NRAS-mutant melanoma. The recommended phase 2 dose was 12 mg QD. GOV IDENTIFIER: NCT03932253. https://clinicaltrials.gov/ct2/show/NCT03932253.

16.
J Agric Food Chem ; 2022 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-36120893

RESUMO

Dietary saponins have the potential to ameliorate atherosclerosis (AS). Gypenosides of Gynostemma pentaphyllum (GPs) have been used as functional foods to exhibit antiatherosclerotic activity. The present study aimed to explore the protective effect, underlying mechanism and active substances of GPs on AS in vivo and in vitro. Results demonstrated GPs administration reduced the serum concentrations of TC and LDL-C, upregulated the plasma HDL-C content, inhibited the secretion of ICAM-1, VCAM-1, and MCP-1, and alleviated vascular lesions in VitD3 plus high cholesterol diet-induced AS rats as well as reduced adhesion factors levels in ox-LDL-stimulated HUVECs, which was potentially associated with suppressing PCSK9/LOX-1 pathway. Further activity-guided phytochemical investigation of GPs led to the identification of five new dammarane-type glycosides (1-5) and ten known analogs (6-15). Bioassay evaluation showed compounds 1, 6, 7, 12, 13, and 14 observably reduced the expressions of PCSK9 and LOX-1, as well as the secretion of adhesion factors in injured HUVECs. Molecular docking experiments suggested that the active saponins of GPs might bind to the allosteric pocket of PCSK9 located at the catalytic and C-terminal domains, and 2α-OH-protopanaxadiol-type gypenosides might exert a higher affinity for an allosteric binding site on PCSK9 by hydrogen-bond interaction with ARG-458. These findings provide new insights into the potential nutraceutical application of GPs and their bioactive compounds in the prevention and discovery of novel therapeutic strategies for AS.

17.
Front Cardiovasc Med ; 9: 971414, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36119741

RESUMO

Background: Soluble programmed cell death-ligand 1 (sPD-L1) has been well documented to activate immunosuppression and is considered an essential predictor of negative clinical outcomes for several malignances and inflammatory conditions. However, the clinical significance of sPD-L1 in the peripheral blood of patients with coronary artery disease (CAD) remains unclear. The aim of this study was to assess the correlations of sPD-L1 with clinical features in CAD patients and evaluate the diagnostic value of this protein in CAD. Methods: A total of 111 CAD patients and 97 healthy volunteers who served as healthy controls (HCs) were consecutively enrolled. Plasma levels of sPD-L1 were measured with an amplified enzyme-linked immunosorbent assay (ELISA), and hs-CRP was measured with a C-reactive protein assay kit. The levels of other inflammatory cytokines were assessed in 88 CAD patients and 47 HCs by a multiparameter immunoluminescence flow cytometry detection technique. A logistic regression model was used to assess the independent association of sPD-L1 with acute coronary syndrome (ACS). The correlation between sPD-L1 and inflammatory cytokines in ACS was also assessed. Results: Plasma levels of sPD-L1 were significantly increased in CAD patients, especially those with ACS. Univariate logistic regression analysis revealed that sPD-L1 (OR: 3.382, 95% CI: 2.249-5.084, p < 0.001), BMI, hypertension, diabetes, dyslipidemia, previous MI, and the levels of HDL-C, LDL-C and hs-CRP were significantly associated with ACS. sPD-L1 (OR: 3.336, 95% CI: 1.084-6.167, p = 0.001) was found to be independently and significantly associated with ACS in the subsequent multivariable logistic regression analysis. Additionally, elevated plasma sPD-L1 levels were associated with increased interleukin-6 and interleukin-8 levels in ACS patients. Receiver operating characteristic (ROC) analysis showed that the AUC of sPD-L1 for diagnosing ACS was 0.778, with a sensitivity of 73.9% and a specificity of 73.4%, which was comparable with that of the inflammatory biomarker hs-CRP. Conclusion: The plasma sPD-L1 level reflects the severity of CAD, is associated with inflammatory responses and is a potential new biomarker for the diagnosis of ACS.

18.
BMC Med Genomics ; 15(1): 191, 2022 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-36076209

RESUMO

PURPOSE: Patient-derived xenograft (PDX) models were established to reproduce the clinical situation of original cancers and have increasingly been applied to preclinical cancer research. Our study was designed to establish and genetically characterize cervical cancer PDX models. METHODS: A total of 91 fresh fragments obtained from 22 surgically resected cervical cancer tissues were subcutaneously engrafted into female NOD-SCID mice. Hematoxylin and eosin (H&E) staining was performed to assess whether the established PDX models conserved the histological features of original patient cervical cancer tissues. Moreover, a Venn diagram was applied to display the overlap of all mutations detected in whole-genome sequencing (WGS) data from patient original cervical cancer (F0) and F2-, F3-PDX models. The whole exome sequencing (WES) and the "maftools" package were applied to determine the somatic mutations among primary cervical cancers and the established PDX models. RESULTS: Our study successfully developed a panel of cervical cancer PDX models and the latency time of cervical cancer PDX model establishment was variable with a progressive decrease as the passage number increased, with a mean time to initial growth of 94.71 days in F1 engraftment to 40.65 days in F3 engraftment. Moreover, the cervical cancer PDX models preserved the histological features of their original cervical cancer. WGS revealed that the genome of original cervical cancer was preserved with high fidelity in cervical cancer PDX models throughout the xenografting and passaging process. Furthermore, WES demonstrated that the cervical cancer PDX models maintained the majority somatic mutations of original cervical cancer, of which the KMT2D, LRP1B, NAV3, TP53, FAT1, MKI67 and PKHD1L1 genes were identified as the most frequently mutated genes. CONCLUSIONS: The cervical cancer PDX models preserved the histologic and genetic characteristics of their original cervical cancer, which helped to gain a deeper insight into the genetic alterations and lay a foundation for further investigation of the molecular targeted therapy of cervical cancer.


Assuntos
Neoplasias do Colo do Útero , Animais , Modelos Animais de Doenças , Feminino , Xenoenxertos , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Exp Cell Res ; 420(1): 113332, 2022 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-36084668

RESUMO

Acute renal damage presents a significant danger to kidney health. Previous research has found that acute kidney injury shows high levels of oxidative stress and inflammation caused by sepsis. Although mesenchymal stem cells (MSCs) can repair acute kidney injury. However, involvement of MSCs exosomes generated from adipose tissue and bone marrow in lipopolysaccharide-induced acute kidney damage is not clear. LPS (7.5 mg/kg) intraperitoneal injection was used to produce AKI, and 30 min before the LPS administration, adipose-derived MSCs (ADSCs) exosomes (1 × 105 and 5 × 105) and bone marrow-derived MSCs(BMSCs) exosomes (1 × 105 and 5 × 105) were delivered individually. The function of the rat kidney was explored. Inflammation, oxidative stress, and autophagy levels were further investigated. Both adipose-derived and bone marrow-derived MSCs can enhance renal function and structural damage, such as BUN, Creatinine, and cystatin C levels, as well as tubular damage scores. These findings indicate that both adipose-derived MSCs exosomes and bone marrow-derived MSCs exosomes decrease oxidative stress and inflammation, as well as make a substantial influence on kidney tissue in autophagy levels. Furthermore, compared to bone marrow-derived MSCs exosomes, adipose-derived MSCs exosomes improved kidney function and structure more significantly. We discovered that adipose-derived MSCs exosomes protect against LPS-induced AKI by inhibiting oxidative stress and inflammation.

20.
Front Immunol ; 13: 949356, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36105822

RESUMO

Background: Behçet's disease (BD) is a unique autoimmune chronic systemic vasculitis that affects veins and arteries of all sizes. BD can lead to recurrent vascular events, especially venous thrombosis, with an incidence rate of 40%, or pseudoaneurysms formed under long-term inflammatory reaction or iatrogenic stimulation. BD-related risk factors promote endothelial dysfunction, platelet activation and overactivation of tissue factors leading to mural inflammatory thrombi. Thrombosis may be the first clinical manifestation of BD. Case presentation: A 32-year-old man complaining of progressive swelling and pain in the right lower extremity for 30 days was initially diagnosed with "venous thrombosis of the right lower extremity," using color Doppler ultrasonography. Patient underwent inferior vena cava filter placement combined with deep vein angioplasty of the right lower extremity and catheter-directed urokinase thrombolysis. Postoperative oral anticoagulant therapy was administered. However, the patient was readmitted 20 days later for pulsatile pain in the right groin. Prior medical history included 4 years of repeated oral and perineal ulcers, and 2 months of blurred vision. Abdominal computed tomography angiography (CTA) revealed rupture of the right common iliac artery (CIA) and left internal iliac artery (IIA), complicated by a pseudoaneurysm. Based on the clinical manifestations and other auxiliary examination results, the patient was re-diagnosed with "BD combined with deep venous thrombosis of the right lower extremity and an iliac artery pseudoaneurysm." Stent implantation was performed for iliac artery pseudoaneurysm after symptoms were controlled with timely immunosuppressive therapy. After endovascular treatment, the patient underwent continued immunosuppressive therapy and dynamic reexaminations of abdominal CTA, which revealed that a small amount of contrast agent at the stent in the right CIA continued to flow into the cavity of the pseudoaneurysm; in addition, the size of the pseudoaneurysm was gradually increasing. Therefore, the patient underwent a second stent implantation for iliac artery pseudoaneurysm, and the condition improved further. Conclusion: The importance of early diagnosis of BD should be recognized, and the choice of interventional and surgical procedures should be carefully evaluated, as this may trigger further damage to vascular access in BD patients with aneurysm.


Assuntos
Falso Aneurisma , Síndrome de Behçet , Trombose Venosa , Adulto , Falso Aneurisma/diagnóstico por imagem , Falso Aneurisma/etiologia , Falso Aneurisma/terapia , Anticoagulantes , Síndrome de Behçet/complicações , Síndrome de Behçet/diagnóstico , Síndrome de Behçet/terapia , Humanos , Extremidade Inferior , Masculino , Dor , Trombose Venosa/etiologia , Trombose Venosa/terapia
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