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1.
Biochem Pharmacol ; 185: 114435, 2021 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-33539817

RESUMO

Bromodomain and extra-terminal domain (BET) family proteins are promising anticancer targets. Most BET inhibitors in clinical trials are monovalent. They competitively bind to one of the bromodomains (BD1 and BD2) in BET proteins and exhibit relatively weak anticancer activity, poor pharmacokinetics, and low metabolic stability. Here, we evaluated the anticancer activity of a novel bivalent BET inhibitor, N2817, which consists of two molecules of the monovalent BET inhibitor 8124-053 connected by a common piperazine ring, rendering a long linker unnecessary. Compared with ABBV-075, one of the potent monovalent BET inhibitors reported to date, N2817 showed greater potency in inhibiting proliferation, arresting cell-cycle, inducing apoptosis, and suppressing the growth of tumor xenografts. Moreover, N2817 showed high metabolic stability, a relatively long half-life, and no brain penetration after oral administration. Additionally, N2817 directly bound and inhibited another BD-containing protein, TAF1 (BD2), as evidenced by a reduction in mRNA and protein levels. TAF1 inhibition contributed to the anticancer effect of N2817. Therefore, this study offers a new paradigm for designing bivalent BET inhibitors and introduces a novel potent bivalent BET inhibitor and a new anticancer mechanism.

2.
Biomed Chromatogr ; : e5097, 2021 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-33608928

RESUMO

A simple and sensitive analytical approach for determining pinoxaden residues in soil was established and validated. The dissipation and adsorption-desorption of pinoxaden in four kinds of Chinese soil were comprehensively investigated for the first time; and the possible metabolic products and pathways were identified. The developed method was successfully applied in dissipation and adsorption-desorption trials. Several influential factors, including temperature, organic matter and moisture content, affected the dissipation rate of pinoxaden in soil. During the dissipation process, one hydrolytic intermediate and thirteen possible transformation products were identified, and predicted metabolic pathways were composed of electron rearrangement, oxidation, cyclization, carboxylation, etc. Both the adsorption and desorption isotherms of pinoxaden in four kinds of Chinese soil followed the Freundlich equation, and the Freundlich Kf values were positively correlated with the soil cation exchange capacity. According to the calculated Gibbs free energies, the adsorption of pinoxaden was an endothermic reaction and mainly physical process. These results could provide some useful data for the determination of pinoxaden in other matrices and the evaluation of the environmental fate of pinoxaden in soil and other ecosystems.

3.
Eur J Endocrinol ; 2021 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-33630753

RESUMO

Fertility and ovarian protection against chemotherapy-associated ovarian damage has formed a new field called oncofertility, which is driven by the pursuit of fertility protection as well as good life quality by numerous female cancer survivors. However, the choice of fertility and ovarian protection method is a difficult problem during chemotherapy and there is no uniform guideline at present. To alleviate ovarian toxicity caused by anticancer drugs, effective methods combined with individualized treatment that integrate an optimal strategy for preserving and restoring reproductive function should be offered from well-established to experimental stages before, during, and after chemotherapy. Although embryo, oocyte, and ovarian tissue cryopreservation are the major methods that have been proven effective and feasible for fertility protection, they are also subject to many limitations. Therefore, this paper mainly discusses the future potential methods and corresponding mechanisms for fertility protection in chemotherapy-associated ovarian damage.

4.
Clin Lab ; 67(2)2021 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-33616345

RESUMO

BACKGROUND: To investigate the correlations of serum homocysteine (Hcy), α2-Heremans-Schmid glycoprotein (AHSG), and C-reactive protein (CRP) with insulin resistance (IR), 25-hydroxyvitamin D (25-OH-VD), and blood lipids in patients with gestational diabetes mellitus (GDM) by detecting their levels. METHODS: A total of 72 GDM patients (GDM group) and 72 healthy pregnant women (control group) delivered in our hospital from February 2017 to January 2019 were randomly selected. The basic data, somatological parameters [height, weight, body mass index (BMI), waist circumference, hip circumference, waist-to-hip ratio (WHR), blood pressure, and body fat content], and biochemical indexes (glucose metabolism indexes, lipid metabolism indexes, Hcy, AHSG, CRP, and 25-OH-VD) were compared between the two groups. Additionally, Pearson's correlation analysis was employed to analyze the correlations among indicators. RESULTS: In comparison with the control group, the GDM group had a higher average rate of family history of DM (p < 0.05), larger waist circumference and WHR, and higher body fat content (p < 0.05). Besides, the fasting plasma glucose (FPG), 1-hour plasma glucose (1hPG) and 2-hour plasma glucose (2hPG), glycosylated hemoglobin (HbA1c), fasting insulin (FINS), homeostasis model assessment (HOMA)-IR, triglyceride (TG), total cholesterol (TC), and low density lipoprotein cholesterol (LDL-C) were higher in the GDM group than those in the control group (p < 0.05), while the high density lipoprotein cholesterol (HDL-C) was lower in the GDM group than that in the control group (p < 0.05). Compared with those in the control group, the serum Hcy, AHSG, and CRP levels rose, while the serum 25-OH-VD level declined in the GDM group (p < 0.05). The results of Pearson's correlation analysis revealed that HOMA-IR had positive correlations with FPG, FINS, TC, TG, Hcy, AHSG, and CRP (r = 0.591, 0.825, 0.312, 0.234, 0.458, 0.647, 0.487, p < 0.05) and negative correlation with 25-OH-VD (r = -0.323, p < 0.05). CRP was positively correlated with HOMA-IR, TC, and AHSG (r = 0.485, 0.331, 0.226, p < 0.05), negatively associated with 25-OH-VD (r = -0.443, p < 0.05), and had no correlation to TG and Hcy (r = 0.019, 0.058, p > 0.05). AHSG displayed positive correlations with HOMA-IR, TC, TG, and CRP (r = 0.647, 0.321, 0.314, 0.226, p < 0.05) and no association with Hcy and 25-OH-VD (r = 0.058, -0.034, p > 0.05). CONCLUSIONS: GDM patients have increased serum Hcy, AHSG, and CRP levels and a decreased serum 25-OH-VD level, indicating that serum Hcy, AHSG, CRP, and 25-OH-VD are correlated with glucose and lipid metabolism disorders in GDM patients.

5.
Nat Commun ; 12(1): 1259, 2021 02 24.
Artigo em Inglês | MEDLINE | ID: mdl-33627641

RESUMO

It is still challenging to make accurate diagnosis of biliary atresia (BA) with sonographic gallbladder images particularly in rural area without relevant expertise. To help diagnose BA based on sonographic gallbladder images, an ensembled deep learning model is developed. The model yields a patient-level sensitivity 93.1% and specificity 93.9% [with areas under the receiver operating characteristic curve of 0.956 (95% confidence interval: 0.928-0.977)] on the multi-center external validation dataset, superior to that of human experts. With the help of the model, the performances of human experts with various levels are improved. Moreover, the diagnosis based on smartphone photos of sonographic gallbladder images through a smartphone app and based on video sequences by the model still yields expert-level performances. The ensembled deep learning model in this study provides a solution to help radiologists improve the diagnosis of BA in various clinical application scenarios, particularly in rural and undeveloped regions with limited expertise.

6.
JAMA Dermatol ; 2021 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-33533924

RESUMO

Importance: Prospective data are limited on pregnancy outcomes among women with psoriasis who may be receiving biologic or conventional systemic therapy. Objective: To report pregnancy outcomes observed in the Psoriasis Longitudinal Assessment and Registry (PSOLAR). Design, Setting, and Participants: This cohort study used data from PSOLAR, a multicenter, disease-based, observational registry evaluating long-term safety and clinical outcomes for patients receiving or eligible to receive treatment for psoriasis with biologics and/or conventional systemic therapies. Of 12 090 enrollees, 5456 were women (45.1%), and 2224 women were of childbearing age (18-45 years). Participants had a total of 12 929 patient-years of follow-up (median, 7.2 [range, 3.3-8.0] years per patient). Data were collected from June 20, 2007, to August 23, 2019, and analyzed from April 23 to June 23, 2020. Exposures: Exposure to biologics within the prenatal period (≤1 year before birth or ≤6 months before spontaneous abortion) or at any other time. Main Outcomes and Measures: Descriptive summaries of pregnancies and pregnancy-related outcomes were self-reported in PSOLAR, including births, stillbirths, spontaneous abortions, and elective terminations. Live birth characteristics collected in PSOLAR include whether a birth was full-term (≥37 weeks) or premature (<37 weeks) and whether neonatal adverse events or congenital anomalies occurred. Results: A total of 298 pregnancies occurred among 220 women (mean [SD] age, 27.8 [5.2] years), and the general fertility rate was 18.9 per 1000 women aged 18 to 45 years. Of the 298 pregnancies, 244 (81.9%) resulted in birth, 41 (13.8%) ended in spontaneous abortion, and 13 (4.4%) were electively terminated. Gestational age was available for 243 births; 221 infants (90.9%) were full-term, and 22 (9.1%) were born prematurely. Birth outcomes included 231 healthy newborns, 10 infants with a neonatal problem, 2 infants with a congenital anomaly, and 1 stillbirth. Of the 298 pregnancies, 252 were associated with biologic exposure before or during pregnancy. Pregnancy outcomes for women exposed to biologics were similar to those for women exposed to nonbiologics. Among women who became pregnant, mean (SD) age at the time of pregnancy outcome was 30.9 (4.8) years; at enrollment into the registry, 74 of 219 (33.8%) had obesity, and 121 of 220 (55.0%) were past or current smokers. Conclusions and Relevance: The findings of this cohort study suggest that pregnancy outcomes in PSOLAR have remained consistent with previous reports. Overall and live birth outcomes were similar to those for the general population.

7.
J Clin Invest ; 131(4)2021 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-33586674

RESUMO

Abnormal angiogenesis and regression of the diseased retinal vasculature are key processes associated with ischemic retinopathies, but the underlying mechanisms that regulate vascular remodeling remain poorly understood. Here, we confirmed the specific expression of semaphorin 3G (Sema3G) in retinal endothelial cells (ECs), which was required for vascular remodeling and the amelioration of ischemic retinopathy. We found that Sema3G was elevated in the vitreous fluid of patients with proliferative diabetic retinopathy (PDR) and in the neovascularization regression phase of oxygen-induced retinopathy (OIR). Endothelial-specific Sema3G knockout mice exhibited decreased vessel density and excessive matrix deposition in the retinal vasculature. Moreover, loss of Sema3G aggravated pathological angiogenesis in mice with OIR. Mechanistically, we demonstrated that HIF-2α directly regulated Sema3G transcription in ECs under hypoxia. Sema3G coordinated the functional interaction between ß-catenin and VE-cadherin by increasing ß-catenin stability in the endothelium through the neuropilin-2 (Nrp2)/PlexinD1 receptor. Furthermore, Sema3G supplementation enhanced healthy vascular network formation and promoted diseased vasculature regression during blood vessel remodeling. Overall, we deciphered the endothelium-derived Sema3G-dependent events involved in modulating physiological vascular remodeling and regression of pathological blood vessels for reparative vascular regeneration. Our findings shed light on the protective effect of Sema3G in ischemic retinopathies.

8.
PLoS Pathog ; 17(2): e1009317, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33600488

RESUMO

The transmembrane protein 33 (TMEM33) was originally identified as an endoplasmic reticulum (ER) protein that influences the tubular structure of the ER and modulates intracellular calcium homeostasis. However, the role of TMEM33 in antiviral immunity in vertebrates has not been elucidated. In this article, we demonstrate that zebrafish TMEM33 is a negative regulator of virus-triggered interferon (IFN) induction via two mechanisms: mitochondrial antiviral signaling protein (MAVS) ubiquitination and a decrease in the kinase activity of TANK binding kinase 1 (TBK1). Upon stimulation with viral components, tmem33 was remarkably upregulated in the zebrafish liver cell line. The IFNφ1 promoter (IFNφ1pro) activity and mRNA level induced by retinoic acid-inducible gene (RIG)-I-like receptors (RLRs) were significantly inhibited by TMEM33. Knockdown of TMEM33 increased host ifn transcription. Subsequently, we found that TMEM33 was colocalized in the ER and interacted with the RLR cascades, whereas MAVS was degraded by TMEM33 during the K48-linked ubiquitination. On the other hand, TMEM33 reduced the phosphorylation of mediator of IFN regulatory factor 3 (IRF3) activation (MITA)/IRF3 by acting as a decoy substrate of TBK1, which was also phosphorylated. A functional domain assay revealed that the N-terminal transmembrane domain 1 (TM1) and TM2 regions of TMEM33 were necessary for IFN suppression. Finally, TMEM33 significantly attenuated the host cellular antiviral capacity by blocking the IFN response. Taken together, our findings provide insight into the different mechanisms employed by TMEM33 in cellular IFN-mediated antiviral process.

9.
Cytokine ; 140: 155426, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33517197

RESUMO

PURPOSE: To investigate whether Sp1 can ameliorate sepsis-induced myocardial injury and explore the potential molecular mechanism. METHODS: The embryonic cardiomyocyte cell line H9C2 and primary cultured mouse neonatal cardiomyocytes (CMNCs) were treated with LPS or phosphate-buffered saline (PBS). A mouse model of LPS-induced sepsis was established using male C57BL/6J mice and their cardiomyocytes were collected. Real-time reverse transcription-PCR (qRT-PCR) assay was used to detect the expression levels of Sp1 and ZFAS1 in cardiomyocytes. Western blotting analysis was used to assess the protein expression levels of Sp1, apoptosis-associated proteins and Notch signaling pathway related proteins. Luciferase assay was used to detect the interaction between Sp1 and ZFAS1. Cell transfection was used to generate H9C2 cells with overexpressed or knocked down of Sp1 or ZFAS1. MTT assay and flow cytometry analysis were used to test the cell proliferation and cell apoptosis ratio. RESULTS: Our data revealed that the expressions of ZFAS1 and Sp1 were significantly reduced in LPS-treated H9C2 cells and primary CMNCs. The downregulation of ZFAS1 and Sp1 were also found in cardiomyocytes obtained from LPS-challenged mice. LPS induced H9C2 cell apoptosis and depressed cell proliferation was ameliorated by ZFAS1 overexpression and aggravated by ZFAS1 knockdown. Mechanistically, Luciferase assay indicated that Sp1 could bind to ZFAS1, and positively regulated ZFAS1 expression. Moreover, Notch signaling pathway participates in H9C2 cell apoptosis mediated by Sp1. CONCLUSION: The present study demonstrates that Sp1 regulates LPS-induced cardiomyocyte apoptosis via ZFAS1/Notch signaling pathway, which may serve as therapeutic targets for sepsis-induced myocardial injury.

10.
Cancer Gene Ther ; 2021 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-33514882

RESUMO

Chimeric antigen receptor T-cell immunotherapy (CAR-T) has shown remarkable efficacy in treating tumors of lymphopoietic origin. Herein, we demonstrate an effective CAR-T cell treatment for recurrent and malignant CD30-positive peripheral T-cell lymphomas (PTCL) has been demonstrated. The extracellular fragment gene sequences of CD30 were obtained from tumor tissues of PTCL patients and cloned into a plasmid vector to express the CD30 antigen. The CD30 targeting single-chain antibody fragment (scFv) was obtained from CD30-positive monoclonal hybridoma cells, which were obtained from CD30 antigen immunized mice. After a second-generation of CAR lentiviral construction, CD30 CAR T cells were produced and used to determine the cytotoxicity of this construct toward Karpas 299 cells. The results of CD30 CAR T-mediated cell lysis show that 9C11-2 CAR T cells could significantly promote the lysis of CD30-positive Karpas 299 cells in both LDH and real-time cell electronic sensing (RTCA) assays. In vivo data show that 9C11-2 CAR T cells effectively suppress the tumor growth in a Karpas 299 cell xenograft NCG mouse model. The CD30 CAR T cells exhibited an efficient cytotoxic effect after being co-cultured with the target cells and they also exhibited a significant tumor-inhibiting ability after being intravenously injected into PTCL xenograft tumors; these observations suggest that the new CD30 CAR-T cell may be a promising therapeutic candidate for cancer therapy.

11.
J Cell Physiol ; 2021 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-33393107

RESUMO

Transforming growth factor (TGF-ß) plays an important role in the development of deer antlers. The purpose of this study was to investigate the role of long noncoding RNA in the transcriptional regulation of TGF-ß1 and its relationship with the proliferation and differentiation of antler chondrocytes. High-throughput sequencing was used to screen lncRNAs related to TGF-ß1. Next, the overexpression plasmid and interference sequence of target lncRNA27785.1 were constructed and transfected into chondrocytes. We found that lncRNA27785.1 inhibited the proliferation and migration of chondrocytes and delayed the transition of cells from G1 to S phase. qRT-PCR and Western blot analysis indicated that the overexpression of lncRNA27785.1 may downregulate mRNA and protein expression of TGF-BR2, Smad3, pSmad3, and Smad4. Our findings highlight lncRNA27785.1 as an inhibitor of chondrocytes proliferation and differentiation by negatively regulating the TGF-ß/Smad signaling pathway; this implicates an important regulatory role for long noncoding RNA in the regeneration of antler.

12.
Ann Anat ; 235: 151672, 2021 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-33434657

RESUMO

Cellular FLICE-inhibitory protein (c-FLIP), an anti-apoptotic regulator, shows remarkable similarities to caspase-8, which plays a key role in the cleavage of gasdermin D (GSDMD). It has been reported that the oxygen-glucose deprivation/recovery (OGD/R) model and lipopolysaccharide (LPS)/adenosine triphosphate (ATP) treatment could induce inflammation and pyroptosis. However, the regulatory role of c-FLIP in the pyroptotic death of retinal neurons is unclear. In this study, we hypothesized that c-FLIP might regulate retinal neuronal pyroptosis by GSDMD cleavage. To investigate this hypothesis, we induced retinal neuronal damage in vitro (OGD/R and LPS/ATP) and in vivo (acute high intraocular pressure [aHIOP]). Our results demonstrated that the three injuries triggered the up-regulation of pyroptosis-related proteins, and c-FLIP could cleave GSDMD to generate a functional N-terminal (NT) domain of GSDMD, causing retinal neuronal pyroptosis. In addition, c-FLIP knockdown in vivo ameliorated the already established visual impairment mediated by acute IOP elevation. Taken together, these findings revealed that decreased c-FLIP expression protected against pyroptotic death of retinal neurons possibly by inhibiting GSDMD-NT generation. Therefore, c-FLIP might provide new insights into the pathogenesis of pyroptosis-related diseases and help to elucidate new therapeutic targets and potential treatment strategies.

13.
Int Urol Nephrol ; 2021 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-33387222

RESUMO

BACKGROUND: The recent outbreak of Coronavirus Disease 2019 (COVID-19) is a public health emergency of international concern. In China, Wuhan, Hubei Province was the epicenter. The disease is more severe in patients with high comorbidities and dialysis patients fall into this category. METHODS: In this report, we reviewed the whole course of the epidemic emerged in the HD center of Wuhan NO.1 Hospital by 28 February 2020. We compared the differences on the epidemiological characteristics and clinical features between patients surviving from COVID-19 and patients who died. RESULT: In this hospital, at time of the present report, 627 patients were on chronic hemodialysis and the prevalence of affected cases was 11.8% (74/627).The median age of the COVID-19-positive patients was 63 years (range 31-88), with an almost even gender distribution (females accounted for 54.4%).The most frequent presenting symptom was cough (41.9%), followed by fatigue (24.2%), fever (17.2%) and dyspnea (14.8%); 22.4% of the cases were and asymptomatic. Fourteen of the 74 patients died (19%), as for presenting symptoms, cough was more frequent in patients who died (P < 0.05). Surviving patients had higher levels of phosphate and albumin, and lower levels of C-reactive protein (CRP). Chest CT scan was positive in all cases, including in asymptomatic ones, and revealed in about three fourths of the cases bilateral (76.2%) lesions; in each lung lesions were multiple in about half of the cases of the cases (52.3%). After diagnosis, median time to death was 7 days in the 14 patients who died, with a range between 4 and 18 days. CONCLUSION: This preliminary, single Center study identifies hemodialysis patients as a population at high risk of severe, and deadly COVID-19 infection. While classic baseline clinical conditions, including age, kidney disease and gender, are not significantly associated with survival in COVID-19 infected hemodialysis, our study also suggests a significant association between risk of and death, poor nutritional status and less than optimal metabolic balance.

14.
Histol Histopathol ; : 18297, 2021 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-33398872

RESUMO

Mesenchymal stem cells play an important role in tissue damage and repair. This role is mainly due to a paracrine mechanism, and extracellular vesicles (EVs) are an important part of the paracrine function. EVs play a vital role in many aspects of cell homeostasis, physiology, and pathology, and EVs can be used as clinical biomarkers, vaccines, or drug delivery vehicles. A large number of studies have shown that EVs derived from mesenchymal stem cells (MSC-EVs) play an important role in the treatment of various diseases. However, the problems of low production, low retention rate, and poor targeting of MSC-EVs are obstacles to current clinical applications. The engineering transformation of MSC-EVs can make up for those shortcomings, thereby improving treatment efficiency. This review summarizes the latest research progress of MSC-EV direct and indirect engineering transformation from the aspects of improving MSC-EV retention rate, yield, targeting, and MSC-EV visualization research, and proposes some feasible MSC-EV engineering methods of transformation.

15.
Cancer Gene Ther ; 2021 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-33402729

RESUMO

Multiple myeloma (MM) is a malignant disease of plasma cells with complex pathology, causing significant morbidity due to its end-organ destruction. The outcomes of patients with myeloma have significantly improved in the past couple of decades with the introduction of novel agents, such as proteasome inhibitors, immunomodulators, and monoclonal antibodies. However, MM remains incurable and presents considerable individual heterogeneity. MicroRNAs (miRNAs) are short, endogenous noncoding RNAs of 19-22 nucleotides that regulate gene expression at the posttranscriptional level. Numerous studies have shown that miRNA deregulation is closely related to MM pathology, including tumor initiation, progression, metastasis, prognosis, and drug response, which make the complicated miRNA network an attractive and marvelous area of investigation for novel anti-MM therapeutic approaches. Herein, we mainly summarized the current knowledge on the roles of miRNAs, which are of great significance in regulating pathological factors involved in MM progressions, such as bone marrow microenvironment, methylation, immune regulation, genomic instability, and drug resistance. Meanwhile, their potential as novel prognostic biomarkers and therapeutic targets was also discussed.

16.
Cancer Res ; 2021 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-33419773

RESUMO

Tumor mutational burden (TMB) is an emerging biomarker of response to immunotherapy in solid tumors. However, the extent to which variation in TMB between patients is attributable to germline genetic variation remains elusive. Here, using 7,004 unrelated patients of European descent across 33 cancer types from The Cancer Genome Atlas, we show that pan-cancer TMB is polygenic with ~13% of its variation explained by ~1.1 million common variants altogether. We identify germline variants that affect TMB in stomach adenocarcinoma through altering the expression levels of BAG5 and KLC1. Further analyses provide evidence that TMB is genetically associated with complex traits and diseases such as smoking, rheumatoid arthritis, height and cancers, and some of the associations are likely causal. Overall, these results provide new insights into the genetic basis of somatic mutations in tumors and may inform future efforts to use genetic variants to stratify patients for immunotherapy.

17.
Inflammation ; 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33452667

RESUMO

Cardiac dysfunction is a major cause leading to multiple organ failure in sepsis. Beclin-1-dependent autophagy has been evidenced to exert protective effects on hearts in sepsis. However, the mechanisms on how Beclin-1 and autophagy are regulated remains enigmatic. To explore the detailed mechanisms controlling Beclin-1-dependent autophagy in septic heart and whether melatonin could protect against sepsis via regulating cardiac autophagy, adult Sprague-Dawley (SD) rats were subjected to cecal ligation and puncture (CLP) to induce sepsis. Rats were intraperitoneally administrated with 30 mg/kg melatonin within 5-min post-CLP surgery. Our data showed that sepsis induced Becline-1 acetylation and inhibited autophagy in hearts, resulting in impaired cardiac function. However, melatonin treatment facilitated Beclin-1 deacetylation and increased autophagy in septic hearts, thus improved cardiac function. Moreover, melatonin increased the expression and activity of Sirtuin 1 (Sirt1), and inhibition of Sirt1 abolished the protective effects of melatonin on Beclin-1 deacetylation and cardiac function. In conclusion, increased Beclin-1 acetylation was involved in impaired autophagy in septic hearts, while melatonin contributed to Beclin-1 deacetylation via Sirt1, leading to improved autophagy and cardiac function in sepsis. Our study sheds light on the important role of Beclin-1 acetylation in regulating autophagy in sepsis and suggests that melatonin is a potential candidate drug for the treatment of sepsis.

18.
Artigo em Inglês | MEDLINE | ID: mdl-33483930

RESUMO

Fluorosis is a chronic systemic disease induced by excessive intake of fluoride (F-). Fluoride in water and foods has been widely concerned, while limited reports focused on F- in soils and tobacco leaves which could transfer to human body. In the present study, we mainly focused on the distribution of F- in tobacco-planted soils and tobacco leaves in Bijie City, Southwest China. Soil total F- concentration ranged from 443.7 to 5,979 mg kg-1. The level of F- extracted by water (FH2O) and KCl solution (FKCl) ranged from 0.58 to 25.55 mg kg-1 and from 0.67 to 21.35 mg kg-1, respectively; hence, FH2O could be used to indicate the bioavailability of soil F- in the study area. The sequential extraction of F- show that the residual and exchangeable F- was the highest (97.44-99.73% of the total F-) and lowest (less than 0.25%) fractions of collected soil samples, respectively. According to the distribution of total and soluble F- in the soil profiles at the depth of 0-100 cm, soils were polluted mainly at the 0-40 cm layer. The soluble F- content in rhizosphere soils were higher than that in bulk soils, and tobacco leaves accumulated F- ranged from 16.73 to 111.3 mg kg-1 which was affected by soil pH and Ca content. Tobacco leaves F- level was related to the maturity of the leaves, with the F-content of medium leaves being higher than that of top leaves. More attention should be paid to tobacco with high F- content since F- pollution may transfer to human body via tobacco smoking.

19.
Food Res Int ; 139: 109913, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33509480

RESUMO

Polysaccharides from the fruit of Lycium barbarum (LBPs) are functional molecules with diverse biological functions in vivo and in vitro. This study investigated the long-term consumption of LBPs on host's health in BALB/c mice. Six-week-old male mice (n = 10 each group) were fed either a normal control (NC) diet or supplemented with 200 mg/kg (body weight)/d of LBPs for 14 weeks. Compared with the NC diet, the LBPs diet enhanced the expression of mucin 2 and Claudin5, improved the intestinal barrier morphologically, moreover, promoted the growth of Lactobacillus and strongly increased the production of short-chain fatty acids and IgA (p < 0.05). Feeding LBPs increased the levels of superoxide dismutase and reduced glutathione in the serum, liver and spleen while decreased the levels of alanine aminotransferase and lysozyme in serum and spleen. Besides, the LBPs diet increased the expression of cytokines including tumor necrosis factor α and interleukin-6 and related mRNA but decreased the level of lysozyme. To sum up, chronic intake of LBPs in BALB/c mice improved the oxidation resistance, changed the immune status especially promoted the intestinal immunity. These results may have important implications for LBPs as functional food supplement and for realizing the potential value of LBPs for host's health.

20.
J Agric Food Chem ; 69(2): 756-766, 2021 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-33404229

RESUMO

An effective and sensitive method for the determination of isopyrazam (IZM) isomers (syn-IZM and anti-IZM) and their metabolites (syn545364 and syn545449) in tomato and soil by ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was developed in the present study. The method showed excellent linearities (R2 = 0.999) at 0.005-5 mg/L. The recoveries were 92.0-107%, and the relative standard deviation (RSD) values were lower than 9.40% in tomato and soil matrices at 0.01, 0.1, and 10 mg/kg. The limits of detection (LODs) of the four compounds ranged from 6.88 × 10-5 to 2.70 × 10-4 mg/kg, while the limits of quantification (LOQs) ranged from 2.20 × 10-4 to 9.20 × 10-4 mg/kg. The storage stability test results showed that syn-IZM, anti-IZM, syn545449, and syn545364 were stable in tomato at -20 °C within 36 weeks, and the maximum degradation rates were 16.0, 12.0, 7.10, and 12.0%, respectively. The field dissipation test results showed that the half-lives of syn-IZM in tomato and soil were 2.60-10.2 and 13.6-33.0 days, respectively, while the half-lives of anti-IZM in soil were 21.7-46.2 days, and no residues of anti-IZM were detected in tomato. The terminal residue test results showed that the residue of syn-IZM and anti-IZM in tomato ranged from <0.0100-0.490 to <0.0100-0.0850 mg/kg. The present results showed that anti-IZM degraded faster than syn-IZM in tomato and soil, and had a lower residue level in tomato.

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