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1.
Arch Pharm (Weinheim) ; : e2000063, 2020 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-33184958

RESUMO

Isocitrate dehydrogenase 2 (IDH2) is a key enzyme in the regulation of cell metabolism. Its mutated type can lead to the accumulation of 2-hydroxyglutarate, which is often related to malignancies such as acute myeloid leukemia. Therefore, it is necessary to find new inhibitors targeting mutant IDH2. Discriminatory analysis-based molecular docking was employed to screen the ChemDiv compound library, which resulted in the identification of three new IDH2R140Q inhibitors with moderate-to-good IC50 values. Among them, compounds 1 and 3 displayed good selectivity against other mutant or wild-type IDH proteins. The most potent compound 1, bearing the [1,2,4]triazolo[1,5-a]pyrimidin scaffold, was subjected to dynamic simulations to provide more information on the binding mode with IDH2R140Q , providing structural clues to further optimize compound 1 as a new mutant IDH2 inhibitor.

2.
J Hazard Mater ; : 124505, 2020 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-33191031

RESUMO

Fenpiclonil is an agricultural phenylpyrrole fungicide, which raise the concern about its ecotoxicological effects. In this paper, we investigate the indirect photochemical transformation mechanisms, environmental persistence and eco-toxicity of fenpiclonil initiated by various active oxidants (1O2, •OH and SO4•‾) in aquatic environments. The results shown that 1O2 can react with pyrrole ring by cycloaddition pathways to form the endo-peroxides. In addition, •OH and SO4•‾ initial mechanisms are calculated, suggesting that •OH-initiated mechanisms play a dominant role in the degradation process of fenpiclonil at high rate constants (2.26 ×109 M-1 s-1, at 298 K). The kinetic calculation results indicate that high temperature is more favorable for the degradation of fenpiclonil. To better understand the adverse effects of the transformation products formed during the subsequent reaction of •OH-adduct IM10, the computational toxicology has been used for the toxicity estimation. The results show that aquatic toxicity of these products decrease with degradation process, especially the decomposition products (TP3 and TP4). However, TP1 and TP2 are still toxic and developmental toxicant. The study provides guidance for further experimental research and industrial application of fungicide degradation from the perspective of theoretical calculation.

3.
Artigo em Inglês | MEDLINE | ID: mdl-33176045

RESUMO

Garnet structured solid-state electrolytes Li 6.75 La 3 Zr 1.75 Ta 0.25 O 12 (LLZTO), despite of the advantages of good chemical stability with Li-metal and high ionic conductivity, suffers from large interfacial resistance and quick short circuit owing to a poor wettability with Li-metal and severe Li-metal growth on both interface and inside. To address these issues, a dual layer ceramic electrolyte of Ti-doped LLZTO(Ti-LLZTO)/LLZTO electrolyte was developed with the electrochemically reducible Ti-LLZTO layer contacting the Li-metal and the LLZTO layer contacting the cathode. The employment of the identical crystal structures of Ti-LLZTO with LLZTO enables a seamless contact and a barrier less Li + transport between them. In the same preparation condition, the densities of Ti-LLZTO pellets are obviously higher than that of the undoped LLZTO. In addition, with an in-situ reduction of Ti-LLZTO by Li-metal, the interfacial wettability was improved and a mixed ion-electron conducting layer was established. Both features would not only reduce defects/pores on interface, but also homogenizes the interfacial ionic/electronic flux, facilitating the reduction of interfacial resistance and suppression of dendrites. With the help of Ti-LLZTO layer, long-term stable lithium plating/stripping was reached for a large areal capacity of 3.0 mAh cm -2 .

4.
J Dairy Sci ; 2020 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-33162075

RESUMO

Streptococcus lutetiensis, previously termed Streptococcus bovis type II/1, has rarely been associated with bovine mastitis. The objectives of this work were to characterize the molecular diversity, antimicrobial resistance profiles, virulence genes of Strep. lutetiensis (n = 37) isolated from bovine clinical mastitis, as well as its pathogenic effects in a murine mastitis model. Genetic relationships of isolates were determined by random amplified polymorphic DNA (RAPD)-PCR, virulence genes were detected by PCR. Antimicrobial susceptibility testing was carried out by broth microdilution technique. The pathogenic effects of Strep. lutetiensis were studied with 2 infection models: bovine mammary epithelial cells cultured in vitro and murine mammary infection in vivo. Streptococcus Lutetiensis isolates were clustered into 5 RAPD-types (A-E), with a dominant type A representing 84% of isolates. Eighteen (49%), 16 (43%), and 9 (24%) isolates were resistant to ceftiofur, tetracycline, and erythromycin, respectively. Prevalence of multidrug resistance (resistant to ≥3 classes of antimicrobials) was 24% (9/37). The most prevalent virulence genes were bca (100%), speG (100%), hly (97%), scpB (95%), and ssa (95%). There was no difference between isolates from mild and moderate cases of bovine mastitis in prevalence of virulence genes. Streptococcus lutetiensis rapidly adhered to and subsequently invaded (1 and 3 h after infection, respectively) bovine mammary epithelial cells, resulting in elevated lactate dehydrogenase release (4 h after infection). Edema and hyperemia were observed in challenged mammary glands and bacteria were consistently isolated at 12, 24, and 48 h after infection. In addition, numerous neutrophils migrated into gland alveoli and interstitium of infected mammary tissue. We concluded that Strep. lutetiensis had potential to spread within a dairy herd and good adaptive ability in bovine mammary cells or tissue, which are generally characteristics of a contagious mastitis pathogen.

5.
Lett Appl Microbiol ; 2020 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-33217003

RESUMO

A strain NQ1, which showed efficient asymmetric reduction of 3,5-bis(trifluoromethyl) acetophenone (BTAP) to enantiopure (S)-[3,5-bis(trifluoromethyl)phenyl]ethanol ((S)-BTPE), which is the key intermediate for the synthesis of a receptor antagonist and antidepressant, was isolated from a soil sample. Based on its morphological and internal transcribed spacer sequence, the strain NQ1 was identified to be Rhodotorula mucilaginosa NQ1. Some key reaction parameters involved in the bioreduction catalyzed by whole cells of R. mucilaginosa NQ1 were subsequently optimized, and the optimized conditions for the synthesis of (S)-BTPE were determined to be as follows: 5.0 ml phosphate buffer (200 mmol l-1 , pH 7.0), 80 mmol l-1 of BTAP, 250 g (wet weight) l-1 of resting cell, 35 g l-1 of glucose, and a reaction for 18 h at 30°C and 180 rpm. The strain NQ1 exhibited a best yield of 99% and an excellent enantiomeric excess of 99% for the preparation of (S)-BTPE under the above optimal conditions, and could also asymmetrically reduce a variety of bulky prochiral carbonyl compounds to their corresponding optical hydroxyl compound with excellent enantioselectivity. These results indicated that R. mucilaginosa NQ1 had a good capacity to reduce BTAP to its corresponding (S)-BTPE, and might be a new potential biocatalyst for the production of valuable chiral hydroxyl compounds in industry.

6.
Adv Healthc Mater ; : e2000573, 2020 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-33166086

RESUMO

Osteosarcoma is the most primary type of bone tumor occurring in the pediatric and adolescent age groups. In order to obtain the most appropriate prognosis, both tumor recurrence inhibition and bone repair promotion are required. In this study, a ternary nanoscale biomaterial/antitumor drug complex including hydroxyapatite (HA), bovine serum albumin (BSA) and paclitaxel (PTX) is prepared for post-surgical cancer treatment of osteosarcoma in situ. The HA-BSA-PTX nanoparticles, about 55 nm in diameter with drug loading efficiency (32.17 wt%), have sustained release properties of PTX and calcium ions (Ca2+ ) and low cytotoxicity to human fetal osteoblastic (hFOB 1.19) cells in vitro. However, for osteosarcoma (143B) cells, the proliferation, migration, and invasion ability are significantly inhibited. The in situ osteosarcoma model studies demonstrate that HA-BSA-PTX nanoparticles have significant anticancer effects and can effectively inhibit tumor metastasis. Meanwhile, the detection of alkaline phosphatase activity, calcium deposition, and reverse transcription-polymerase chain reaction proves that the HA-BSA-PTX nanoparticles can promote the osteogenic differentiation. Therefore, the HA-BSA-PTX nanodrug delivery system combined with sustained drug release, antitumor, and osteogenesis effects is a promising agent for osteosarcoma adjuvant therapy.

7.
Nefrologia ; 2020 Nov 02.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-33153776

RESUMO

BACKGROUND: Glomerular filtration rate (GFR) is a useful index in many clinical conditions. However, very few studies have assessed the performance of full age spectrum (FAS) equation and the Asian modified Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) equation in the approximation of GFR in Chinese patients with chronic kidney disease. OBJECTIVE: This study aimed to compare the diagnostic performance of the above two creatinine-based equations. METHODS: A well designed single-center cross-sectional study was performed and the GFR was determined by 3 methods separately in the same day: technetium-99m-diethylene triamine pentaacetic acid (99mTc-DTPA) dual plasma sample clearance method (mGFR); FAS equation method; Asian modified CKD-EPI equation method. The gold standard method was the mGFR. Equations performance criteria considered correlation coefficient, bias, precision, accuracy and the ability to detect the mGFR less than 60ml/min/1.73m2. RESULTS: A total of 160 patients were enrolled. The diagnostic performance of FAS showed no significant difference in the correlation coefficient (0.89 vs 0.89), precision (15.9 vs 16.1ml/min/1.73m2), accuracy (75.0% vs 76.3%) and the ability to detect the mGFR less than 60ml/min/1.73m2 (0.94 vs 0.94) compared with the Asian modified CKD-EPI equation in all participants. The FAS showed a negative bias, while the new CKD-EPI equation showed a positive bias (-1.20 vs 1.30ml/min/1.73m2, P<0.001). However, they were all near to zero. In the mGFR<60ml/min/1.73m2 subgroup and mGFR>60ml/min/1.73m2 subgroup were consistent with that in the whole cohort. The precision and accuracy decreased when GFR>60ml/min/1.73m2 in both equations. CONCLUSIONS: The FAS equation and the Asian modified CKD-EPI equation had similar performance in determining the glomerular filtration rate in the Chinese patients with chronic kidney disease. Both the FAS equation and Asian modified CKD-EPI can be a satisfactory method and may be the most suitable creatinine-based equation.

8.
Clin Nutr ; 2020 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-33143929

RESUMO

BACKGROUND & AIMS: Although disorders of iron metabolism are among the most common diseases and dietary intakes of vitamin A, B2, B6, C, E, and folic acid are known to affect the absorption or oxidation of iron, limited data are available on the association of dietary iron and these vitamins with mortality in the same population. Specifically, the holistic dietary vitamins intake and its combined effect with iron on mortality are unclear. The purpose of this study was to evaluate the association of dietary iron, holistic dietary vitamins, and their interactive effect with total and cause-specific mortality. METHODS: We evaluated the effects of dietary total/heme/non-heme iron, vitamins, and their interaction on all-cause/cardiovascular disease (CVD)/cancer mortality among 14,826 US adults in the National Health and Nutrition Examination Survey (NHANES), a population-based nationally representative study. We developed a vitamin score to represent the holistic dietary intakes of vitamin A, B2, B6, C, E, and folic acid. RESULTS: A total of 2154 deaths occurred during a median follow-up of 9.3 years. Results from multivariate Cox proportional hazards models showed that higher vitamin score was associated lower risk of all-cause mortality (P-trend = 0.027). Negative interactions between dietary heme iron and vitamin score were observed on all-cause/CVD mortality. Dietary higher vitamins combined with lower heme iron was associated with lower risk of all-cause and CVD mortality (HR (95% confidence intervals (CIs)): 0.80 (0.64-0.98) and 0.55 (0.31-0.98), respectively). Higher dietary vitamins combined with higher total/non-heme iron was associated with lower risk of CVD mortality (HR (95%CIs): 0.69 (0.48-0.99) and 0.70 (0.48-0.99), respectively). These results remained significant even excluding participants with iron supplementation. CONCLUSION: Our findings suggested that interactive effect of holistic dietary vitamins and iron play a protective role in decreasing all-cause and CVD mortality. Future studies, including cohort studies and clinical trials, are necessary to confirm these findings.

9.
Emerg Microbes Infect ; 9(1): 2348-2357, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33048025

RESUMO

Balamuthia mandrillaris infection is a rare and fatal disease. We have recorded 28 cases of Balamuthia mandrillaris infection during the past 20 years. Eighteen patients (64%) were male and 10 (36%) were female. Patient age ranged from 3 to 74 (mean, 27) years. Patient locations were distributed among 12 Provinces in China. Twenty-seven (96%) patients lived in rural areas, and 17 (61%) patients reported a history of trauma before the appearance of skin lesions. All cases presented with skin lesions as the primary symptom, and 16 (57%) cases developed encephalitis. Histopathology of skin lesions revealed granulomatous changes with histiocytes, lymphocytes, and plasma cells infiltration. Amebas were identified in all cases with immunohistochemical staining. Follow-up information was available in 27 (96%) cases. Fifteen (56%) patients died due to encephalitis and 12 (44%) were free of disease after treatment. Our results show that the clinical characteristics of Balamuthia mandrillaris infection in China are very different from those in the US. Infection of traumatized skin may play an important role in the pathogenesis of the disease in China. Encephalitis usually develops 3-4 years after skin lesions in Chinese cases. Patients with only skin lesions have a higher cure rate than patients with encephalitis.

10.
J Dairy Sci ; 103(12): 12091-12103, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33010914

RESUMO

The major circadian clock gene PER2 is closely related to cell proliferation and lipid metabolism in various nonruminant cell types. Objectives of the study were to evaluate circadian clock-related mRNA abundance in cultured goat ruminal epithelial cells (REC), and to determine effects of PER2 on cell proliferation and mRNA abundance of short-chain fatty acid (SCFA) transporters, genes associated with lipid metabolism, cell proliferation, and apoptosis. Ruminal epithelial cells were isolated from weaned Boer goats (n = 3; 2 mo old; ∼10 kg of body weight) by serial trypsin digestion and cultured at 37°C for 24 h. Abundance of CLOCK and PER2 proteins in cells was determined by immunofluorescence. The role of PER2 was assessed through the use of a knockout model with short interfering RNA, and sodium butyrate (15 mM) was used to assess the effect of upregulating PER2. Both CLOCK and PER2 were expressed in REC in vitro. Sodium butyrate stimulation increased mRNA and protein abundance of PER2 and PER3. Furthermore, PER2 gene silencing enhanced cell proliferation and reduced cellular apoptosis in isolated REC. In contrast, PER2 overexpression in response to sodium butyrate led to lower cellular proliferation and ratio of cells in the S phase along with greater ratio of cells in the G2/M phase. Those responses were accompanied by downregulated mRNA abundance of CCND1, CCNB1, CDK1, and CDK2. Among the SCFA transporters, PER2 silencing upregulated mRNA abundance of MCT1 and MCT4. However, it downregulated mRNA abundance of PPARA and PPARG. Overexpression of PER2 resulted in lower mRNA abundance of MCT1 and MCT4, and greater PPARA abundance. Overall, data suggest that CLOCK and PER2 might play a role in the control of cell proliferation, SCFA, and lipid metabolism. Further studies should be conducted to evaluate potential mechanistic relationships between circadian clock and SCFA absorption in vivo.

11.
Plant Signal Behav ; 15(12): 1836883, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-33100175

RESUMO

The circadian clock is a universal timing system that involved in plant physical responses to abiotic stresses. Moreover, OSCA1 is an osmosensor responsible for [Ca2+]i increases induced by osmotic stress in plants. However, there is little information on osmosensor involved osmotic stress-triggered circadian clock responses. Using an aequorin-based Ca2+ imaging assay, we found the gradient (0 mM, 200 mM, 500 mM) osmotic stress (induced by sorbitol) both altered the primary circadian parameter of WT and osca1 mutant. This means the plant switch to a fast day/night model to avoid energy consumption. In contrast, the period of WT and osca1 mutant became short since the sorbitol concentration increased from 0 mM to 500 mM. As the sorbitol concentration increased, the phase of the WT becomes more extensive compared with osca1 mutant, which means WT is more capable of coping with the environmental change. Moreover, the amplitude of WT also becomes broader than osca1 mutant, especially in high (500 mM) sorbitol concentration, indicate the WT shows more responses in high osmotic stress. In a word, the WT has much more flexibility to cope with the osmotic stress than osca1 mutant. It implies the OSCA1 might be involved in the circadian gated plant adaptation to the environmental osmotic stress, which opens an avenue to study Ca2+ processes with other circadian signaling pathways.

12.
Inflammation ; 2020 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-33125572

RESUMO

To investigate the beneficial effects of oridonin, a diterpenoid compound isolated from Rabdosia rubescens, on the inflammatory response in TNBS-induced post-inflammatory irritable bowel syndrome (PI-IBS) model and the underlying mechanism. Using the PI-IBS rat model and Caco-2 cell lines, we found that intestinal barrier function reflected by lactulose/mannitol (L/M) ratio and tight junction protein level was significantly ameliorated by oridonin. We also demonstrated that oridonin abrogated inflammation through inhibiting the phosphorylation of NF-κBp65 as well as its downstream gene (iNOS, COX-2, IL-1ß, and IL-6) level. Molecular docking studies confirmed the good binding activity between oridonin and PXR. In Caco-2 cell lines, oridonin markedly inhibited LPS-induced NF-κB activation in a PXR-dependent manner. Meanwhile, PXR and its target genes CYP3A4 and P-gp were induced by oridonin, which was associated with the decreased expression of NF-κB and the recovery of intestinal barrier. This study indicated that the therapeutic effect of oridonin on experimental PI-IBS through repairing intestinal barrier function may be closely associated with the regulatory role of PXR/NF-κB signaling pathway. Oridonin may serve as a PXR ligand for the development of drugs in the therapy for PI-IBS.

13.
Pharm Res ; 37(11): 228, 2020 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-33098017

RESUMO

PURPOSES: The main purposes of this article are to describe an unprecedented phenomenon in which significant amount of a shoulder peak impurity was observed during normal non-reducing capillary electrophoresis-sodium dodecyl sulfate (CE-SDS) analysis of a recombinant fusion protein X, and to evaluate the root cause for this phenomenon. METHODS: A series of experiments were conducted to study the nature of this degradation. Effects of iodoacetamide (IAM), heating temperature, duration, and SDS on the formation of this specific impurity were evaluated using a variety of characterization techniques. RESULTS: The formation of the impurity as observed in CE-SDS was actually due to alkylation of lysine and serine residues with IAM, as confirmed by peptide mapping and LC-MS/MS, which increased the molecular weight and therefore decreased the electrophoretic mobility. The amount of impurity was also strongly dependent on sample preparation conditions including the presence or absence of SDS. CONCLUSIONS: Our study clearly suggested that even though IAM has been used extensively as an alkylation reagent in the traditional non-reducing CE-SDS analysis of monoclonal antibodies and other proteins, alkylation with IAM could potentially lead to additional impurity peak, and therefore complicating analysis. Therefore, before performing CE-SDS and other analyses, the effects of sample preparation procedures on analytical results must be evaluated. For protein X, IAM should be excluded for CE-SDS analysis.

14.
Int Wound J ; 2020 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-33124156

RESUMO

The purpose of this study was to evaluate the therapeutic effects of artificial dermis combined with autologous split-thickness skin grafting (STSG) compared with autologous intermediate-thickness skin grafting (ITSG) alone in severely burned patients. Fifty-six severely burned patients admitted to our hospital from December 2017 to January 2019 were enrolled and evenly grouped according to the random number table method [AD-STSG group: 28 patients, receiving the treatment of artificial dermis (AD) combined with autologous STSG; ITSG group: 28 patients, receiving autologous ITSG treatment alone]. The healing time and Vancouver Scar Scale (VSS) score of the donor area and graft area, survival rate and infection status of the autologous skin, psychological status (determined by Self-rating Anxiety Scale and Self-rating Depression Scale), and the activity of functional parts of all enrolled patients were included in the evaluation. General items of patients in AD-STSG group and ITSG group, including age, sex, and degree of burn, were all comparable. A significantly shortened healing time of donor skin in AD-STSG group was observed when compared with ITSG group (P < .05) while the recipient skin healed in the same tendency between the two groups. In addition, 21 days after the operation, AD-STSG group presented with significantly higher survival rate of graft skin than ITSG group (P < .05) while same infection status was observed in the two groups. Significantly lower VSS scores were found in AD-STSG group than that in ITSG group 3-, 6- and 10-months after operation (P < .05). Statistical difference regarding psychological status of patients from two groups was unobservable before operation while significantly lower Self-rating Anxiety Scale (SAS) and Self-rating Depression Scale (SDS) scores were found in AD-STSG group than that in ITSG group 3-, 6- and 10-months after operation (P < .05). Also, AD-STSG group presented improved mobility of functional part than that in ITSG group 10-months after operation without statistical difference (P = .051). Artificial dermis combined with autologous split-thickness skin grafting showed better therapeutic outcomes for the treatment of severely burned patients than autologous intermediate-thickness skin grafting in terms of graft healing time, scar formation, psychological recovery, and perhaps in functional reconstruction.

15.
World Neurosurg ; 2020 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-33059078

RESUMO

OBJECTIVE: An optimized Enhanced Recovery After Surgery (ERAS) program is lacking for adolescent idiopathic scoliosis (AIS). The aim of the present study was to evaluate the impact and feasibility of an optimized ERAS pathway in patients with surgically treated AIS. METHODS: In total, 79 patients with AIS who underwent corrective surgery without 3-column osteotomy were recruited from Xijing Hospital of the Fourth Military Medical University between 2012 and 2018. Forty-four patients were treated according to a traditional protocol and 35 were managed using an optimized ERAS pathway, which was designed and implemented by a multidisciplinary team. The following data were collected and retrospectively analyzed, demographic characteristics, Cobb angle, curve type (Lenke), surgical duration, fusion level, correction rate, estimated blood loss, postoperative hemoglobin level, postoperative pain score, pain relief time, hemovac drainage, drainage removal time, first ambulation time, length of hospital stay, and postoperative complications. RESULTS: There was no significant difference between the traditional and ERAS groups with respect to demographic characteristics, Cobb angle, curve type (Lenke), fusion level, and correction rate. However, the ERAS group had a shorter surgical duration, less blood loss and hemovac drainage, a higher postoperative hemoglobin level, and earlier pain relief, ambulation, and discharge. The rates of postoperative nausea and vomiting were lower in the ERAS group than in the traditional group. CONCLUSIONS: The ERAS pathway is capable of improving the perioperative status of patients with AIS by offering stronger analgesia, faster ambulation, and earlier discharge.

16.
PLoS One ; 15(10): e0239605, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33006971

RESUMO

The lily, a famous bulbous flower, is seriously affected by high temperatures, which affect their growth and production. To date, the signalling pathways and the molecular mechanisms related to heat response in Lilium have not been elucidated. In this study, a comparative transcriptome analysis was performed in an important thermo-tolerant flower, L. longiflorum, and a thermo-sensitive flower, L. distichum. Lily seedlings were first exposed to heat stress at 42°C for different lengths of time, and the optimal time-points (2 h and 24 h) were selected for RNA sequencing (RNA-seq). Approximately 66.51, 66.21, and 65.36 Mb clean reads were identified from three libraries of L. longiflorum (LL_CK, LL_T2h and LL_T24h, respectively) and 66.18, 66.03, and 65.16 Mb clean reads were obtained from three libraries of L. distichum (LD_CK, LD_T2h and LD_T24h, respectively) after rRNA removing. A total of 34,301 unigenes showed similarity to known proteins in the database NCBI non-redundant protein (NR), Swiss-Prot proteins, InterPro proteins, Clusters of Orthologous Groups (COG) and Kyoto Encyclopedia of Genes and Genomes (KEGG). In addition, 1,621 genes were differentially expressed in the overlapping libraries between LL_DEGs and LD_DEGs; of these genes, 352 DEGs were obviously upregulated in L. longiflorum and downregulated in L. distichum during heat stress, including 4-coumarate, CoA ligase (4CL), caffeoyl-CoA O-methyltransferase (CCoAOMT), peroxidase, pathogenesis-related protein 10 family genes (PR10s), 14-3-3 protein, leucine-rich repeat receptor-like protein kinase, and glycine-rich cell wall structural protein-like. These genes were mainly involved in metabolic pathways, phenylpropanoid biosynthesis, plant-pathogen interactions, plant hormone signal transduction, and kinase signalling pathways. Quantitative RT-PCR was performed to validate the expression profiling of these DEGs in RNA-seq data. Taken together, the results obtained in the present study provide a comprehensive sequence resource for the discovery of heat-resistance genes and reveal potential key components that are responsive to heat stress in lilies, which may help to elucidate the heat signal transcription networks and facilitate heat-resistance breeding in lily.

18.
J Proteome Res ; 2020 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-33107303

RESUMO

Hyperuricemia is a well-known key risk factor for gout and can cause a variety of metabolic diseases. Several studies have shown that dioscin could improve metabolic symptoms and reduce the uric acid level in blood. However, there is no comprehensive metabolomic study on the anti-hyperuricemia effects of dioscin. A total of 29 adult male Kunming mice were divided into three groups: Normal (blank), PO (potassium oxonate-administrated, 200 mg/kg/day), and Dioscin (potassium oxonate + dioscin, potassium oxonate 200 mg/kg/day, dioscin 50 mg/kg/day). All mice were treated for 42 days via oral gavage. This paper implemented an untargeted metabolomics study based on 1H NMR and LC-MS to discover the comprehensive mechanism of dioscin. Furthermore, a targeted lipidomics was fulfilled to further analyze the lipid metabolism disorder. Finally, the metabolic pathway mediated by dioscin was verified at the gene level by means of transcriptomics. The results show 53 different metabolites were closely related to the improvement of dioscin in PO-induced hyperuricemia, and 19 of them were lipids. These metabolites are mainly involved in the tricarboxylic acid cycle, lipid metabolism, amino acid metabolism, and pyrimidine metabolism. According to the transcriptomics study, the levels of 89 genes were significantly changed in the PO group compared to the normal control. Among them, six gene levels were restored by the treatment of dioscin. The six changed genes (tx1b, Tsku, Tmem163, Psmc3ip, Tcap, Tbx15) are mainly involved in the cell cycle and energy metabolism. These metabolites and genes might provide useful information for further study of the therapeutic mechanism of dioscin.

19.
Drug Des Devel Ther ; 14: 3983-3993, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33061303

RESUMO

Introduction: Multiple myeloma (MM) is an extremely malignant and incurable hematological cancer. Increased expression of the c-Myc oncoprotein is closely associated with shorter overall survival of MM patients, implying that c-Myc is a potential therapeutic target. Main Methods: We identified a potential c-Myc inhibitor 7594-0037 by structure-based virtual screening from the ChemDiv database. CCK8 assay and flow cytometry were used to detect MM cell viability, cell cycle and apoptosis. Q-PCR and Western blot were used to measure corresponding mRNA and protein expression levels. Protein stability assay measured the stability of c-Myc. Results: Compound 7594-0037 exhibited stronger anti-proliferative activity against MM cells, and induced MM cell cycle G2 phase arrest and apoptosis. More importantly, compound 7594-0037 overcame myeloma resistance to bortezomib and exhibited a synergistic effect with bortezomib, resulting in increased MM cell death. The mechanism consists of compound 7594-0037 facilitating c-Myc protein degradation via decreasing the c-Myc S62 phosphorylation levels mediated by PIM1 kinase. Molecular dynamics simulation with the c-Myc/7594-0037 complex showed that compound 7594-0037 bound tightly to the N-terminus of c-Myc, and blocked the binding interaction of the two termini of c-Myc, which resulted in c-Myc entering into an unstable state. Conclusion: Overall, our study provides preliminary data for compound 7594-0037, which can be used as a novel c-Myc inhibitor and is a potential candidate therapeutic drug for multiple myeloma.

20.
Pharm Dev Technol ; : 1-9, 2020 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-33070673

RESUMO

Multidrug resistance (MDR) is a serious challenge in chemotherapy and also a major threat to breast cancer treatment. As an intracellular energy factory, mitochondria provide energy for drug efflux and are deeply involved in multidrug resistance. Mitochondrial targeted delivery of doxorubicin can overcome multidrug resistance by disrupting mitochondrial function. By incorporating a reactive oxygen species (ROS)-responsive hydrophobic group into the backbone structure of hyaluronic acid - a natural ligand for the highly expressed CD44 receptor on tumor surfaces, a novel ROS-responsive and CD44-targeting nano-carriers was constructed. In this study, mitochondria-targeted triphenylphosphine modified-doxorubicin (TPP-DOX) and amphipathic ROS-responsive hyaluronic acid derivatives (HA-PBPE) were synthesized and confirmed by 1H NMR. The nanocarriers TPP-DOX @ HA-PBPE was prepared in a regular shape and particle size of approximately 200 nm. Compared to free DOX, its antitumor activity in vitro and tumor passive targeting in vivo has been enhanced. The ROS-responsive TPP-DOX@HA-PBPE nanocarriers system provide a promising strategy for the reverse of MDR and efficient delivery of doxorubicin derivatives into drug-resistant cancer cells.

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