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1.
Food Chem ; 366: 130541, 2022 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-34273855

RESUMO

Penicillium oxalicum has been used as a biocontrol fungus in agriculture for many years, but the antimicrobial substances are still uncertain. Herein, we isolated a linear peptide named Sanxiapeptin in the culture broth of Penicillium oxalicum SG-4 collecting from the Three Gorges riparian zone. Sanxiapeptin exhibited potent inhibitory effect on citrus green mold Penicillium digitatum, the main fungi responsible for postharvest decay. Sanxiapeptin was elucidated as composing of five amino acids, which were ß-amino-α-methoxybutyric acid (Amoba), N-Me-l-Thr, d-Thr, N-Me-l-Val and l-Ser. By analyzing three chemically synthesized oligopeptides with similar structures, we found that the first amino acid of Amoba was crucial to the antifungal activity, as was the methylation of peptide bond. Sanxiapeptin may act as an antimicrobial agent by affecting the function of cell membranes or walls. The antimicrobial spectrum, safety and stability analysis supported that Sanxiapeptin was a promising antifungal agent for citrus preservation.

2.
Seizure ; 92: 76-81, 2021 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-34474329

RESUMO

PURPOSE: Felt stigma and social anxiety are both common in patients with epilepsy (PWE) and they share an important relationship. Here in the present study, we investigated how social anxiety and different concepts of felt stigma relate to each other in PWE in order to provide some suggestions for the prevention and intervention of social anxiety and felt stigma in PWE. METHODS: A total of 189 patients with epilepsy were enrolled in our study. Social anxiety was evaluated with the Liebowitz social anxiety scale. Felt stigma was evaluated with the Kilifi stigma scale for epilepsy. The data were subjected to network analysis. RESULTS: The findings indicated that eight edges with the strongest regularized partial correlations existed in the network, such as the edge between S3 "Embarrassed" and S4 "Disappointed", and the edge between S14 "Discriminate" and S15 "Outcast". In addition, S10 "Inferior" and S11 "Avoid" had the highest strength and predictability. The flow network of social anxiety indicated that most concepts of felt stigma were directly connected with social anxiety. The strongest edge existed between S8 "Uncomfortable" and social anxiety, while S6 "Society" and S5 "Rewarding life" were also closely connected with social anxiety. CONCLUSION: The current study highlighted the critical central concept S10 "Inferior" and critical concepts associated with social anxiety, including S8 "Uncomfortable", S6 "Society" and S5 "Rewarding life". The findings revealed in this study may offer some help in the clinical prevention and intervention of felt stigma and social anxiety in PWE. However, all of the conclusions above need further confirmatory studies to validate them.

3.
Leg Med (Tokyo) ; 53: 101957, 2021 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-34481193

RESUMO

The Microreader™ 19X Direct ID System was a newly developed multiplex PCR kit, which could detect 19 X-chromosomal STR loci (DXS6795, DXS9907, DXS6803, GATA172D05, DXS6807, GATA31E08, DXS7423, DXS6810, DXS101, DXS9902, DXS7133, DXS6800, DXS981, DXS10162, DXS6809, DXS10135, HPRTB, GATA165B12, DXS10079) and the sex determination locus of AMEL simultaneously. Different from other X-STR multiplex PCR kits, no linkage groups are included in this system, so the likelihood ratios could be calculated without the consideration of linkage groups. In this study, PCR conditions, sensitivity, species specificity, stability, DNA mixtures, concordance, stutter, sizing precision and population studies were conducted according to the SWGDAM developmental validation guidelines. The results indicated that this new X-STRs multiplex system was an efficient and reliable detection system, which could facilitate human kinship analysis and identification testing, as a powerful supplementary to autosomal STR kits.

4.
Metabolism ; : 154874, 2021 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-34517014

RESUMO

AIMS/HYPOTHESIS: We aimed to evaluate the effect of NAFLD on the risk of incident cardiovascular disease (CVD) and estimated glomerular filtration rate (eGFR)-based chronic kidney disease (CKD), and further test the joint effects and interactions between NAFLD status and individual metabolic element, as well as the total 'ABCs' metabolic goal achievement, on the CVD and CKD risk among 101,296 patients with prediabetes or diabetes from a prospective cohort study. METHODS: We conducted the study based on the China Cardiometabolic Disease and Cancer Cohort (4C) study, a large-scale, population-based prospective cohort. After excluding alcohol abuse and other cause of hepatic diseases, we used fatty liver index (FLI) ≥ 60 as a proxy of NAFLD and stratified the probability of fibrosis by aspartate transaminase / alanine transaminase ratio (AAR) with cut-offs of 0.8 and 1.4. 'ABCs' metabolic goal was defined as subjects who had HbA1c < 6.5% (A), SBP/DBP < 130/80 mmHg (B), and LDL-C < 100 mg/dL (C). During 3.8 years follow-up, we validated 2,340 CVD events based on medical records and identified 1,943 participants developed CKD based on centrally tested eGFR. RESULTS: The multivariable adjusted hazard ratios (HRs) were 1.15 (95% confidence interval (CI), 1.05-1.27) for CVD events and 1.33 (95% CI, 1.20-1.48) for CKD among NAFLD patients, compared with participants without NAFLD. Of NAFLD patients, relative to individuals with low AAR (< 0.8), those with high AAR (≥ 1.4) were more likely to experience CVD events [1.62 (1.21-2.18)] and CKD [1.63 (1.17-2.28)]. Participants with NAFLD and comorbid poorly controlled metabolic risk factors had higher risk of CVD events or CKD than having either alone, with a significant interaction between poor glycemic control and NAFLD on the risk of vascular complications. CONCLUSIONS: NAFLD was associated with incident CVD and CKD among patients with prediabetes or diabetes. Such associations were substantially modified by the comprehensive achievement of metabolic goal.

5.
J Mater Chem B ; 2021 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-34518860

RESUMO

Second near-infrared (NIR-II) absorbing organic photothermal agents (PTAs) usually suffer from laborious and time-consuming synthesis; therefore, it is of importance to develop a simple and easy-to-handle method for the preparation of NIR-II PTAs. Charge-transfer complexes (CTCs) can be easily used to construct NIR-II absorbing PTAs, although the relationship between their molecular structure and photophysical properties is yet to be uncovered. Herein, three kinds of electron donors with different substitutions (chloroethyl, ethyl, and methyl) were synthesized and assembled with electron-deficient F4TCNQ to afford corresponding CTC nanoparticles (Cl-F4, Et-F4, and Me-F4 NPs). The large energy gap (>0.61 eV) between HOMO of the donor and LUMO of the acceptor made the CTCs exhibit high charge transfer (>0.93) and dramatic differences in photophysical properties. Additionally, Et-F4 NPs possess the highest NIR-II absorption ability and best photothermal effect because of different packing modes (mass extinction coefficient of 11.0 L g-1 cm-1 and photothermal conversion efficiency of 40.2% at 1060 nm). The mixed stacking mode formed strong charge-transfer absorption bands, indicating that the photophysical properties of CTCs can be tailored by changing the molecular structure and aggregate behaviors. Furthermore, Et-F4 NPs with cyano groups could specifically react with cysteine to block the intracellular biosynthesis of GSH and result in ROS accumulation and ferroptosis. Et-F4 NPs possess outstanding antitumor efficacy for the combined actions of NIR-II triggered photothermal killing effect and ferroptosis in vivo.

6.
Nanoscale ; 2021 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-34515273

RESUMO

Rare earth (RE) materials such as neodymium (Nd) and others consist of unique electronic configurations which result in unique electronic, electrochemical, and photonic properties. The high temperature (>1100 °C) growth and low active surface areas of REs hinder their use as an efficient electrocatalyst. Herein, different morphologies of Nd were successfully fabricated in situ on the surface of graphene using a double-zone chemical vapor deposition (CVD) method. The morphology of the Nd material on graphene is controlled, which results in the significant enhancement of the large specific surface area and electrochemical active area of the composite material due to the spatial morphology of Nd, thereby improving the hydrogen evolution reaction (HER) performance in an alkaline medium. The significantly enhanced HER activity with an overpotential of 75 mV and a Tafel slope of 95 mV dec-1 at a current density of 10 mA cm-2 is observed in Nd-GF. Mainly, a high specific surface area of ∼2217 cm2 g-1 and the porosity of graphene play major roles in the enhancement of activity. Thus, the present work provides a new strategy for the neodymium engineering synthesis of efficient rare earth-graphene composite electrocatalysts with a high electrochemical active area.

7.
Signal Transduct Target Ther ; 6(1): 328, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34471088

RESUMO

Understanding the pathological features of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in an animal model is crucial for the treatment of coronavirus disease 2019 (COVID-19). Here, we compared immunopathological changes in young and old rhesus macaques (RMs) before and after SARS-CoV-2 infection at the tissue level. Quantitative analysis of multiplex immunofluorescence staining images of formalin-fixed paraffin-embedded (FFPE) sections showed that SARS-CoV-2 infection specifically induced elevated levels of apoptosis, autophagy, and nuclear factor kappa-B (NF-κB) activation of angiotensin-converting enzyme 2 (ACE2)+ cells, and increased interferon α (IFN-α)- and interleukin 6 (IL-6)-secreting cells and C-X-C motif chemokine receptor 3 (CXCR3)+ cells in lung tissue of old RMs. This pathological pattern, which may be related to the age-related pro-inflammatory microenvironment in both lungs and spleens, was significantly correlated with the systemic accumulation of CXCR3+ cells in lungs, spleens, and peripheral blood. Furthermore, the ratio of CXCR3+ to T-box protein expression in T cell (T-bet)+ (CXCR3+/T-bet+ ratio) in CD8+ cells may be used as a predictor of severe COVID-19. These findings uncovered the impact of aging on the immunopathology of early SARS-CoV-2 infection and demonstrated the potential application of CXCR3+ cells in predicting severe COVID-19.

8.
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).

10.
Adv Sci (Weinh) ; : e2100460, 2021 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-34494387

RESUMO

Benefiting from the blooming interaction of nanotechnology and biotechnology, biosynthetic cellular membrane vesicles (Bio-MVs) have shown superior characteristics for therapeutic transportation because of their hydrophilic cavity and hydrophobic bilayer structure, as well as their inherent biocompatibility and negligible immunogenicity. These excellent cell-like features with specific functional protein expression on the surface can invoke their remarkable ability for Bio-MVs based recombinant protein therapy to facilitate the advanced synergy in poly-therapy. To date, various tactics have been developed for Bio-MVs surface modification with functional proteins through hydrophobic insertion or multivalent electrostatic interactions. While the Bio-MVs grow through genetically engineering strategies can maintain binding specificity, sort orders, and lead to strict information about artificial proteins in a facile and sustainable way. In this progress report, the most current technology of Bio-MVs is discussed, with an emphasis on their multi-functionalities as "tailorable shells" for delivering bio-functional moieties and therapeutic entities. The most notable success and challenges via genetically engineered tactics to achieve the new generation of Bio-MVs are highlighted. Besides, future perspectives of Bio-MVs in novel bio-nanotherapy are provided.

11.
Food Chem ; 369: 130959, 2021 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-34469836

RESUMO

The huge economic loss of citrus fruit after harvest called for safe and efficient preservatives, as chemically synthesized agents threatened the environment and human health. Herein a biocontrol fungus Chaetomium globosum QY-1 near the orchard in riparian area was identified to have antimicrobial, antioxidant and tyrosinase inhibition activity, which meets the requirements of an ideal preservative. Metabolite profiling based on bioassay-guided fractionation was carried out, and eight polyketones were determined by MS and NMR. The most abundant CheA exhibited strong inhibition to Penicillium digitatum, the main pathogen caused citrus fruit rot. Among these metabolites, Epicoccone and Epicoccolide B showed higher antioxidant activity, while Epicoccone and CheA had higher tyrosinase inhibitory activity. All the activities were close to or even better than the positive control (Vc; glutathione; Vc and arbutin; Bellkute), implying that the metabolites of C. globosum had comprehensive effects as natural preservatives.

12.
Chem Asian J ; 2021 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-34506068

RESUMO

Based on the previous works, most of the Transition metal phosphides(TMPs) were directly prepared by decomposing NaH 2 PO 2 with the precursors at high temperatures, which resulted in different degrees of phosphidation in the final product. Therefore, it is necessary to design a wholly innovative approach to enhance the degree of phosphidation in the material using crystal defects. In this approach, oxygen-vacancy iron oxide/iron foam (Ov-Fe 2 O 3 /IF) was firstly prepared by generating oxygen vacancy in situ in iron foam through heating in vacuum conditions. Subsequently, FeP/IF was formed by phosphating Ov-Fe 2 O 3 /IF. Under the effects of oxygen vacancies, oxygen-vacancy iron oxide could be completely phosphatized to produce more active sites on the surface of the material. This, in turn, could result in a catalyst with exceptional hydrogen evolution activity. Thus, the successful fabrication of FeP demonstrated in this work provides an effective and feasible way for the preparation of other high-efficiency catalysts.

13.
Oral Dis ; 2021 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-34479400

RESUMO

BACKGROUND: Oral squamous cell carcinoma (OSCC), a main type of squamous cell cancer, is associated with considerable morbidity and mortality. Recent reports suggested methyltransferase-like 3 (METTL3)-mediated N6-methyladenosine (m6A) modification to be an essential regulator in the fate determination of stem cells. However, the functional significance of METTL3 in OSCC remains largely unknown. METHODS: METTL3 expression was examined in OSCC patient samples, followed by correlation analysis against clinical tumor features. Functional assays, such as assessment of surface marker expression, colony forming, BrdU incorporation, tumor xenograft assay, and m6A dot blot, were conducted to study the impact of METTL3 knockdown (KD) in OSCC cells. RESULTS: High METTL3 expression was positively correlated with more severe clinical features of OSCC tumors. METTL3 KD caused impairment of stem-like capacities in OSCC cells, such as tumorigenicity in vivo and colony-forming ability in vitro. Furthermore, METTL3-KD and cycloleucine, a methylation inhibitor, decreased m6A levels and down-regulated p38 expression in OSCC cells. On the contrary, the impaired cell proliferation capacity of OSCC cells after METTL3-KD was restored by exogenous expression of p38. CONCLUSION: Our findings identified m6A methyltransferase METTL3 as a key element in the regulation of tumorigenesis in OSCC.

14.
Int J Pharm ; : 121082, 2021 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-34506925

RESUMO

A transdermal/topical absorption classification system for the characterization of the systemic or local delivery of drugs is the theoretical basis for the design and evaluation of transdermal/topical formulations. A classification system was established on the basis of the in vitro and in vivo skin permeation/retention behaviors of 12 model drugs. Drug skin penetration/retention exhibited a significant correlation with physicochemical parameters (log KO/W, molecular weight, polar surface area, and polarizability). Four representative model drugs were selected to clarify the molecular mechanisms of drug skin permeation/retention behaviors. The excellent lipid-disrupting effect and enhanced partitioning exhibited by propranolol (high permeation-high retention) and zolmitriptan (high permeation-low retention) via the formation of moderate H-bonds with skin lipids were proven by ATR-FTIR (ΔνasCH2 > 2 cm-1), Raman spectra (ΔLPP, SPP > 0.2 nm), and X-ray scattering (lipid crystallization) and were supported by 13C-NMR results. The low lipid miscibility of zolmitriptan (ΔHzolmitriptan-lipid = 126.92 J/g) caused the low skin retention of this drug. High polarizabiltiy (α = 38.5 × 10-24 cm3) and low H-bond forming capability (EH-bond = 0 kcal/mol) restricted terbinafine (low permeation-high retention) in terms of partitioning (kD-SC = 0.09). Diclofenac (low permeation-low retention) stabilized skin lipids through the formation of strong H-bonds and exhibited excessive drug-lipid miscibility (ΔHdiclofenac-skin = -128.73 J/g), thus restricting its skin absorption. This classification system reflects the most essential drug skin absorption characteristics and provides a theoretical basis for the design of transdermal/topical formulations.

15.
Nano Lett ; 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34468149

RESUMO

Recently, MnBi2Te4 has been demonstrated to be an intrinsic magnetic topological insulator and the quantum anomalous Hall (QAH) effect was observed in exfoliated MnBi2Te4 flakes. Here, we used molecular beam epitaxy (MBE) to grow MnBi2Te4 films with thickness down to 1 septuple layer (SL) and performed thickness-dependent transport measurements. We observed a nonsquare hysteresis loop in the antiferromagnetic state for films with thickness greater than 2 SL. The hysteresis loop can be separated into two AH components. We demonstrated that one AH component with the larger coercive field is from the dominant MnBi2Te4 phase, whereas the other AH component with the smaller coercive field is from the minor Mn-doped Bi2Te3 phase. The extracted AH component of the MnBi2Te4 phase shows a clear even-odd layer-dependent behavior. Our studies reveal insights on how to optimize the MBE growth conditions to improve the quality of MnBi2Te4 films.

16.
Bioorg Chem ; 116: 105321, 2021 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-34500305

RESUMO

Hyperuricemia is a principal factor mediating gout and kidney damage, and xanthine oxidase (XOD) is a key enzyme in the pathogenesis of hyperuricemia. In this context, a series of geniposide derivatives were designed and synthesized, and antihyperuricemic and nephroprotective effects of all derivatives was evaluated in vitro and in vivo. Compound 2e emerged as the most potent XOD inhibitor, with an IC50 value of 6.67 ± 0.46 µM. Simultaneously, cell viability, ROS generation, and SOD levels assay showed that compound 2e could repair the damage of HKC cells by inhibiting the oxidative stress response. The results of the study indicated compound 2e significantly decreased uric acid levels by inhibiting the XOD activity, and repaired kidney damage by inhibiting the expression of TLR4/TLR2/MyD88/NF-κB and NALP3/ASC/caspase-1 signaling pathways. Enzyme inhibition kinetics suggested that compound 2e functioned via reversible mixed competitive inhibition. Moreover, a molecular docking study was performed to gain insight into the binding mode of compound 2e with XOD. These results suggest that geniposide derivatives were potential to be developed into a novel medicine to reveal healthy benefits in natural prevention and reduction risk of hyperuricemia and kidney damage.

17.
Int J Pharm ; 607: 120945, 2021 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-34363912

RESUMO

The aim of present work was to investigate the influence of drug physicochemical properties on the enhancement effect of enhancers, which guided the application of enhancers in different drug transdermal prescriptions. Firstly, Polyglyceryl-3 dioleate (POCC) was selected as a model enhancer and its enhancement effect on ten drugs was assessed by in vitro skin permeation experiment. Secondly, the correlation analysis of physicochemical properties of drugs was carried out from the aspects of partition and permeation. The interactions of drug-skin-POCC were elucidated by FT-IR, molecular docking, solubility parameters calculation, ATR-FTIR, Raman study, molecular dynamics simulation and confocal laser scanning microscopy (CLSM). The results showed that the enhancement ratio (ER) of drugs was ranging from 2.23 to 7.45. On one hand, the miscibility between drugs with low polar surface area (P.S.A) and donor solution was decreased more pronounced by the addition of POCC because of the drug was difficult to form hydrogen-bond with POCC, facilitating the vehicle/SC partition of drugs. On the other hand, the permeation of drugs with low P.S.A and polarizability was enhanced more significantly by POCC because the drug was less likely to interact with skin lipids compared to others, causing that POCC had more chance to interact with skin lipids to improve permeation drugs across the SC more easily. In conclusion, the different strength of drug-skin-POCC interactions was the main reason for the discrepancy in the enhancement effect of the POCC on ten drugs, which laid a basis for the research on the drug-specific molecular mechanisms of enhancers.

18.
Theranostics ; 11(17): 8550-8569, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34373758

RESUMO

Heart failure is a serious clinical and public health problem. Currently there is an unmet demand for effective therapies for heart failure. Herein we reported noninvasive inhalation delivery of nanotherapies to prevent heart failure. Methods: A reactive oxygen species (ROS)-scavenging material (TPCD) was synthesized, which was processed into antioxidative and anti-inflammatory nanoparticles (i.e., TPCD NP). By decoration with a mitochondrial-targeting moiety, a multilevel targeting nanotherapy TTPCD NP was engineered. Pulmonary accumulation of inhaled TPCD NP and underlying mechanisms were examined in mice. In vivo efficacies of nanotherapies were evaluated in mice with doxorubicin (DOX)-induced cardiomyopathy. Further, an antioxidative, anti-inflammatory, and pro-resolving nanotherapy (i.e., ATTPCD NP) was developed, by packaging a peptide Ac2-26. In vitro and in vivo efficacies of ATTPCD NP were also evaluated. Results: TPCD NP alleviated DOX-induced oxidative stress and cell injury by internalization in cardiomyocytes and scavenging overproduced ROS. Inhaled TPCD NP can accumulate in the heart of mice by transport across the lung epithelial and endothelial barriers. Correspondingly, inhaled TPCD NP effectively inhibited DOX-induced heart failure in mice. TTPCD NP showed considerably enhanced heart targeting capability, cellular uptake efficiency, and mitochondrial localization capacity, thereby potentiating therapeutic effects. Notably, TPCD NP can serve as bioactive and ROS-responsive nanovehicles to achieve combination therapy with Ac2-26, affording further enhanced efficacies. Importantly, inhaled TPCD NP displayed good safety at a dose 5-fold higher than the efficacious dose. Conclusions: Inhalation delivery of nanoparticles is an effective, safe, and noninvasive strategy for targeted treatment of heart diseases. TPCD NP-based nanotherapies are promising drugs for heart failure and other acute/chronic heart diseases associated with oxidative stress.

19.
Biol Chem ; 402(10): 1247-1256, 2021 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-34363384

RESUMO

Renal cell carcinoma (RCC) is the third most frequent malignancy within urological oncology. Sunitinib has been used as the standard of treatment for first-line RCC therapy. Understanding mechanisms of sunitinib resistance in RCC cell is important for clinical therapy and drug development. We established sunitinib resistant RCC cells by treating cells with increasing concentrations of sunitinib and named resistant cells as RCC/SR. Lefty A, an important embryonic morphogen, was increased in RCC/SR cells. Targeted inhibition of Lefty via its siRNAs restored the sensitivity of renal resistant cells to sunitinib treatment. It was due to that si-Lefty can decrease the expression of interleukin-8 (IL-8) in RCC/SR cells. Knockdown of IL-8 abolished Lefty-regulated sunitinib sensitivity of RCC cells. Mechanistically, Lefty can regulate IL-8 transcription via activation of p65, one major transcription factor of IL-8. Collectively, our present revealed that Lefty A can regulate sunitinib sensitivity of RCC cells of via NF-κB/IL-8 signals. It indicated that targeted inhibition of Lefty might be a potent approach to overcome sunitinib resistance of RCC.

20.
Endocrinol Metab (Seoul) ; 36(4): 778-789, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34372624

RESUMO

BACKGROUND: Subclinical hypothyroidism (SCH) is the most common thyroid dysfunction, and its relationship with blood pressure (BP) has been controversial. The aim of the study was to analyze the association between SCH and newly-diagnosed hypertension. METHODS: Based on data from the Thyroid disease, Iodine nutrition and Diabetes Epidemiology (TIDE) study, 49,433 euthyroid individuals and 7,719 SCH patients aged ≥18 years were enrolled. Patients with a history of hypertension or thyroid disease were excluded. SCH was determined by manufacturer reference range. Overall hypertension and stage 1 and 2 hypertension were diagnosed according to the guidelines issued by the American College of Cardiology/American Heart Association in 2017. RESULTS: The prevalence of overall hypertension (48.7%), including stage 1 (28.9%) and 2 (19.8%) hypertension, increased significantly in SCH patients compared with euthyroid subjects. With elevated serum thyroid stimulating hormone (TSH) level, the hypertension prevalence also increased significantly from the euthyroid to different SCH subgroups, which was more profound in females or subjects aged <65 years. The age- and sex-specific regression analysis further demonstrated the same trends in the general population and in the 1:1 propensity matched population. Similarly, several BP components (i.e., systolic, diastolic, and mean arterial BP) were positively associated with TSH elevation, and regression analysis also confirmed that all BP components were closely related with SCH in female subjects aged <65 years. CONCLUSION: The prevalence of hypertension increases for patients with SCH. SCH tends to be associated with hypertension and BP components in females younger than 65 years.

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