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1.
Eur J Med Chem ; 216: 113313, 2021 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-33667846

RESUMO

P2Y14 nucleotide receptor plays important roles in series of physiological and pathologic events especially associated with immune and inflammation. Based on the 3-amide benzoic acid scaffold reported by our group previously, a series of 5-aryl-3-amide benzoic acid derivatives were designed as novel P2Y14 antagonists with improved pharmacokinetic properties. Among which compound 11m showed most potent P2Y14 antagonizing activity with an IC50 value of 2.18 nM, furnishing greatly improved water solubility and bioavailability compared with PPTN. In MSU-induced acute gouty arthritis model in mice, 11m exerted promising in vivo efficacy in alleviating mice paw swelling and inflammatory infiltration. Mechanistically, compound 11m notably blocked pyroptosis of macrophages through inhibiting NLRP3 inflammasome activation. This work may contribute to the identification of potential therapeutic agents to intervene in acute gouty arthritis.

3.
Aging (Albany NY) ; 13(4): 5906-5927, 2021 02 17.
Artigo em Inglês | MEDLINE | ID: mdl-33612478

RESUMO

In this study, we investigated associations between single nucleotide polymorphisms (SNPs) in the tubulin beta class I (TUBB) and WW domain-containing oxidoreductase (WWOX) genes, gene-gene interactions, and gene-environment interactions and dyslipidemia in the Chinese Maonan ethnic group. Four SNPs (rs3132584, rs3130685, rs2222896, and rs2548861) were genotyped in unrelated subjects with normal lipid levels (864) or dyslipidemia (1129). While 5.0% of Maonan subjects carried the rs3132584TT genotype, none of the Chinese Han in Beijing subjects did. Allele and genotype frequencies differed between the normal and dyslipidemia groups for three SNPs (rs3132584, rs3130685, and rs2222896). rs2222896G allele carriers in the normal group had higher low-density lipoprotein cholesterol and lower high-density lipoprotein cholesterol levels. The rs3132584GG, rs3130685CC+TT, and rs2222896GG genotypes as well as the rs2222896G-rs2548861G and rs2222896G-rs2548861T haplotypes were associated with an elevated risk of dyslipidemia; the rs2222896A-rs2548861T and rs2222896A-rs2548861G haplotypes were associated with a reduced risk of dyslipidemia. Among the thirteen TUBB-WWOX interaction types identified, rs3132584T-rs3130685T-rs2222896G-rs2548861T increased the risk of dyslipidemia 1.371-fold. Fourteen two- to four-locus optimal interactive models for SNP-SNP, haplotype-haplotype, gene-gene, and gene-environment interactions exhibited synergistic or contrasting effects on dyslipidemia. Finally, the interaction between rs3132584 and rs2222896 increased the risk of dyslipidemia 2.548-fold and predicted hypertension.

4.
Int J Nanomedicine ; 16: 315-327, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33469288

RESUMO

Background: Castration-resistant prostate cancer (CRPC) is still considered incurable, even though the mechanisms of CRPC had been extensively researched. Studies have demonstrated that exosomes in the tumor microenvironment contribute to prostate cancer development and progression. However, the role of exosomes in the process of CRPC progression has not yet been determined. Methods: Co-culturing and exosome treatment assays combined with in vitro and in vivo assays were performed to determine the function of exosomes in the transformation of androgen-dependent prostate cancer (ADPC) cells into androgen-independent cells. Then, the mRNA expression profiles of ADPC cells and ADPC cells co-cultured with androgen-independent prostate cancer (AIPC) cell-derived exosomes were studied using microarrays. After silencing the expression of heme oxygenase-1 (HMOX1), Western blotting, quantitative real-time PCR, immunohistochemistry (IHC) studies, and MTS assay were used to confirm the mechanisms of exosome participation in CRPC progression. Results: The results showed that ADPC cells acquired tolerance for androgen deprivation due to the exosome-mediated communication between cells. AIPC cell-derived exosomes promoted the transformation of ADPC cells into androgen-independent cells in vivo and in vitro. Microarray analysis revealed that HMOX1 in ADPC cells was up-regulated after treatment with AIPC cell-derived exosomes. Further results showed that HMOX1 is overexpressed in human AIPC specimens and protects ADPC cells from androgen deprivation. Conclusions: Our findings revealed that exosomes contribute to CRPC progression via promoting the transition of prostate cancer cells into an androgen-independent growth stage by activating HMOX1.


Assuntos
Androgênios/farmacologia , Exossomos/metabolismo , Heme Oxigenase-1/metabolismo , Neoplasias da Próstata/patologia , Regulação para Cima/efeitos dos fármacos , Animais , Linhagem Celular Tumoral , Progressão da Doença , Exossomos/ultraestrutura , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Camundongos Endogâmicos NOD , Camundongos SCID , Neoplasias da Próstata/genética , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/patologia , Receptores Androgênicos/metabolismo , Microambiente Tumoral
5.
Front Plant Sci ; 11: 579120, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33304362

RESUMO

Leucine-rich repeat (LRR)-receptor-like protein kinases (LRR-RLKs) play vital roles in plant growth, development, and responses to environmental stresses. In this study, a new LRR-RLK gene, ZmRLK7, was isolated from maize, and its function within plant development was investigated through ectopic expression in Arabidopsis. The spatial expression pattern analysis reveals that ZmRLK7 is highly expressed in embryos prior to programmed cell death (PCD) of starchy endosperm tissues, and its encoded protein has been localized to both plasm and nuclear membranes subcellularly. Overexpression of sense ZmRLK7 reduced the plant height, organ size (e.g., petals, silique, and seeds), and 1000-seed weight in transgenic lines, while the antisense transgene enlarged these traits. Cytological analysis suggested that ZmRLK7 negatively regulates petal size through restricting both cell expansion and proliferation. In addition, abnormal epidermal cell structure was observed, and the stomata number decreased obviously in sense ZmRLK7 transgenic lines with a lower stomatal index than that in the wild type. Quantitative RT-PCR analysis indicated that transcript levels of genes that are involved in the brassinosteroid and ERACTA signaling pathways were coordinately altered, which could partially explain the phenotypic variation. Moreover, overexpression of antisense ZmRLK7 substantially rescued the Arabidopsis bak1-3 mutant phenotype. All these results together suggest that ZmRLK7 can serve as an important regulator in regulating plant architecture and organ size formation. This work will provide insight into the function of ZmRLK7 in maize.

6.
Asia Pac J Clin Nutr ; 29(4): 668-680, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33377360

RESUMO

BACKGROUND AND OBJECTIVES: Obesity is caused by excessive fat accumulation or abnormal fat distribution and has become one of the biggest health challenges worldwide. Considering the high thermogenic ability of brown fat tissue (BAT) and the plasticity of fat tissue, to induce the browning of white fat tissue (WAT), so increasing BAT activity provides an attractive option for the prevention and resolution of obesity. The aim of the present narrative review was to understand the relationship between diet, BAT, and obesity. METHODS AND STUDY DESIGN: PubMed and Embase databases were searched to identify eligible studies. RESULTS: Although cold exposure has long been known to be effective in the browning of WAT and activation of BAT, it is societally impractical for everyday body weight management aside from the tolerance of ambient temperature. An alternative is to identify specific dietary components with similar effects to cold exposure on BAT. Current evidence indicates that capsaicin and capsinoids, catechins, curcumin, quercetin, berberine, lipoic acid, polyunsaturated fatty acids, royal jelly, and some natural sweeteners are effective promoters of WAT browning, increase BAT activity and improve obesity related traits. However, only capsaicin, capsinoids, and catechins have demonstrated efficacy in clinical trials. Evidence for effects of curcumin, quercetin, berberine, lipoic acid, polyunsaturated fatty acids, royal jelly and natural sweeteners on BAT have only been observed in animal or in vitro studies, with clinical trials awaited for verification. CONCLUSIONS: Several dietary components can induce WAT browning and activate BAT, offering potential targets for obesity prevention and management.

7.
Food Funct ; 2020 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-33237064

RESUMO

OBJECTIVE: The aim of the present study was to explore whether combined calcium and vitamin D supplementation is beneficial for osteoporosis in postmenopausal women. METHODS: We searched the PubMed, Cochrane library, Web of science and Embase databases and reference lists of eligible articles up to Feb, 2020. Randomized controlled trials (RCTs) evaluating the effect of combined calcium and vitamin D on osteoporosis in postmenopausal women were included in the present study. RESULTS: Combined calcium and vitamin D significantly increased total bone mineral density (BMD) (standard mean differences (SMD) = 0.537; 95% confidence interval (CI): 0.227 to 0.847), lumbar spine BMD (SMD = 0.233; 95% CI: 0.073 to 0.392; P < 0.001), arms BMD (SMD = 0.464; 95% CI: 0.186 to 0.741) and femoral neck BMD (SMD = 0.187; 95% CI: 0.010 to 0.364). It also significantly reduced the incidence of hip fracture (RR = 0.864; 95% CI: 0.763 to 0.979). Subgroup analysis showed that combined calcium and vitamin D significantly increased femoral neck BMD only when the dose of the vitamin D intake was no more than 400 IU d-1 (SMD = 0.335; 95% CI: 0.113 to 0.558), but not for a dose more than 400 IU d-1 (SMD = -0.098; 95% CI: -0.109 to 0.305), and calcium had no effect on the femoral neck BMD. Subgroup analysis also showed only dairy products fortified with calcium and vitamin D had a significant influence on total BMD (SMD = 0.784; 95% CI: 0.322 to 1.247) and lumbar spine BMD (SMD = 0.320; 95% CI: 0.146 to 0.494), but not for combined calcium and vitamin D supplement. CONCLUSION: Dairy products fortified with calcium and vitamin D have a favorable effect on bone mineral density. Combined calcium and vitamin D supplementation could prevent osteoporosis hip fracture in postmenopausal women.

8.
Front Neurol ; 11: 986, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33192957

RESUMO

A stroke prediction model based on the Prediction for Atherosclerotic Cardiovascular Disease Risk in China (China-PAR) project was developed. We compared its predictive ability with the revised Framingham Stroke Risk Score (R-FSRS) for 5-year stroke incidence in a community cohort of Chinese adults, namely the Beijing Longitudinal Study of Aging (BLSA). Calibration, discrimination, and recalibration were used to compare the predictive ability between the two prediction models. Category-less net reclassification improvement (NRI) and integrated discrimination improvement (IDI) values were also assessed. During a mean follow-up duration of 5.1 years, 106 incidents of fatal or non-fatal strokes occurred among 1,203 participants aged 55-84 years. The R-FSRS applied to our cohort underestimated the 5-year risk for stroke in men and women. China-PAR performed better than the R-FSRS in terms of calibration (men, R-FSRS: χ2-value 144.2 [P < 0.001], China-PAR: 10.4 [P = 0.238]; women, R-FSRS: 280.1 [P < 0.001], China-PAR: 12.5 [P = 0.129]). In terms of discrimination, R-FSRS and China-PAR models performed modestly in our cohort (C-statistic 0.603 [95% CI: 0.560-0.644] for men using China-PAR and 0.568 [95% CI: 0.524-0.610] using the R-FSRS; the corresponding numbers for women were 0.602 [95% CI: 0.564-0.639] and 0.575 [95% CI: 0.537-0.613). The recalibrated China-PAR model significantly improved the discrimination in C statistics and produced higher category-less NRI and IDI for stroke incidence than the R-FSRS. Although China-PAR fairly estimated stroke risk in our cohort, it did not sufficiently identify adults at high risk of stroke. Caution would be exercised by practitioners in applying the original China-PAR to Chinese older adults. Further studies are needed to develop an adequate prediction model based on the recalibrated China-PAR or to find new risk markers which could upgrade this model.

9.
Eur Urol ; 2020 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-33203548

RESUMO

BACKGROUND: Intracorporeal urinary diversion is considered to be effective in improving intestinal function recovery and reducing the occurrence of early complications after radical cystectomy. Almost all neobladders constructed via intracorporeal laparoscopy have used the ileum. OBJECTIVE: To present our intracorporeal detaenial sigmoid neobladder technique that replicates open surgery principles and to present oncological and functional outcomes and complication rates. DESIGN, SETTING, AND PARTICIPANTS: This is a case series from a single tertiary referral hospital from September 11, 2018 to April 19, 2019, including 12 selected patients with pathologically confirmed muscle-invasive or refractory non-muscle-invasive bladder cancer. SURGICAL PROCEDURE: Laparoscopic radical cystectomy including pelvic lymph-node dissection and intracorporeal detaenial sigmoid neobladder, which is demonstrated in the accompanying video. MEASUREMENTS: Demographic, clinical, and pathological data were collected. Perioperative outcomes and 1-yr oncological and functional outcomes are reported. RESULTS AND LIMITATIONS: All surgeries were successful without severe complications or conversion to open surgery. The mean operative time (± standard deviation) was 414.6 ± 52.2 min, with 33.8 ± 6.80 min for neobladder construction. Surgical margins and lymph nodes were all negative for metastasis. All patients were encouraged to do ambulation exercise 1 d after surgery, and oral liquid intake was resumed between days 2 and 4. However, because this was a retrospective study in a single centre with very few cases, it is difficult to reach a definitive conclusion. CONCLUSIONS: Intracorporeal detaenial sigmoid neobladder is technically feasible with no need for additional medical equipment. Encouraging outcomes were observed during short-term follow-up. This approach could represent another alternative choice for patients undergoing laparoscopic radical cystectomy. Longer-term follow-up data are needed to evaluate oncological and functional outcomes. PATIENT SUMMARY: We describe our stepwise technique for intracorporeal detaenial sigmoid neobladder while replicating established open surgery principles. In addition to retaining the advantages of a neobladder, better postoperative recovery is achieved.

10.
J Hepatol ; 2020 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-33031845

RESUMO

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer with limited therapeutic options. Here, we investigated the mechanisms of HCC in response to ROS1-targeted therapy. METHODS: Recombinant RNases were purified, and the ligand-receptor relationship between RNase7 and ROS1 was validated in HCC cell lines by Duolink, immunofluorescence, and immunoprecipitation assays. Potential interacting residues between ROS1 and RNase7 were predicted by protein-protein docking approach. Oncogenic function of RNase7 was analyzed by cell proliferation, migration, invasion assays and xenograft mouse model. The anti-ROS1 inhibitor treatment efficacy was evaluated in HCC patient-derived xenograft (PDX) and orthotopic models. Two independent HCC patient cohorts were analyzed to evaluate the pathological relevance by immunohistochemistry. Plasma level of RNase7 in HCC patient was detected by ELISA. RESULTS: RNase7 associated with ROS1's N3-P2 domain and promoted ROS1-mediated oncogenic transformation. HCC patients exhibited elevated plasma RNase7 levels compared with normal subjects. High ROS1 and RNase7 expression were highly associated with poor prognosis in HCC. In both HCC PDX and orthotopic mouse models, ROS1 inhibitor treatment markedly suppressed RNase7-induced tumorigenesis and led to decreased plasma RNase7 level with tumor shrinkage in mice. CONCLUSIONS: RNase7 serves as a high-affinity ligand for ROS1, and plasma RNase7 has the potential to function as a biomarker to stratify HCC patients for anti-ROS1 treatment.

12.
Am J Cancer Res ; 10(9): 2768-2784, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33042616

RESUMO

Despite the use of immune checkpoint blockade (ICB) therapy for hepatocellular carcinoma (HCC), developing more effective immunotherapy and predicting HCC's response to ICB therapy remain top priorities. Ribosomal protein S3A (RPS3A) is a multifunctional molecule, but its association with tumor immune cell infiltration and prognosis in HCC patients is unknown. Thus, we aimed to investigate the correlation of RPS3A with HCC immune cell infiltration and prognosis to explore novel therapeutic strategies and prognostic biomarkers for this disease. Here, we showed that RPS3A expression levels were higher in HCC cell lines and samples than in normal hepatocytes and adjacent tumor-free tissues, respectively, and patients with high RPS3A expression had worse overall and recurrence-free survival durations than did patients with low expression. Moreover, single-sample gene set enrichment analysis (ssGSEA) and immunohistochemistry demonstrated a strongly negative correlation between RPS3A expression and tumor immune cell infiltration. Meanwhile, RPS3A was revealed to be positively correlated with that of most examined immune checkpoint molecules. GSEA also suggested that high RPS3A expression promoted the biological processes related to tumorigenesis, metastasis, and immunosuppression. Finally, RPS3A-based nomograms were constructed and exhibited better predictive accuracy for HCC prognosis and more net clinical benefits when compared with traditional prognosis-prediction staging systems. In short, these findings suggest that high RPS3A expression correlates with low tumor immune cell infiltration and poor prognosis in HCC patients. Furthermore, RPS3A-based nomograms are robust HCC prognostic predictors. RPS3A therefore may serve as a therapeutic target in and predict the efficacy of ICB therapy for HCC.

13.
J Cancer ; 11(22): 6633-6641, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33046984

RESUMO

Nitroxoline is considered to be an effective treatment for the urinary tract infections. Recently, it has been found to be effective against several cancers. However, few studies have examined the anti-tumor activity of nitroxoline in bladder cancer. The purpose of the study was to reveal the possible mechanisms how nitroxoline inhibited bladder cancer progression. In vitro assay, we demonstrated that nitroxoline inhibited bladder cancer cell growth and migration in a concentration-related manner. Western blot analysis demonstrated that nitroxoline downregulated the expressions of epithelial mesenchymal transition (EMT)-related proteins. Furthermore, treatment with nitroxoline in the C3H/He mice bladder cancer subcutaneous model resulted in significant inhibition of tumor growth. Moreover, the percentage of myeloid-derived suppressor cells (MDSC) in peripheral blood cells significantly decreased after treatment of nitroxoline. Taken together, our results suggested that nitroxoline may be used as a potential drug for bladder cancer.

14.
Biomed Res Int ; 2020: 5425612, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33062682

RESUMO

Chromodomain helicase DNA-binding protein 5 (CHD5) plays a crucial tumor suppressor role in multiple types of tumors. For this study, we investigated its clinical significance and the molecular mechanism(s) underlying tumorigenesis in renal cell carcinoma (RCC). Initially, CHD5 expression was assessed in primary tumor tissue and in tissue array. Correlations among CHD5 expression and clinicopathological characteristics were analyzed. Next, lentivirus-mediated CHD5 overexpression in the ACHN and 769-P cells was used to assess effects on proliferation, migration, invasion ability, and the regulation of the p14ARF/p53 and p16INK4a/RB signaling pathways. Finally, a xenograft mouse model was used to verify its impact on tumor growth in vivo. Results demonstrated that CHD5 was downregulated in tumor tissues and that low CHD5 expression was correlated with advanced TNM stage, high Fuhrman grade, lymph node metastasis, and poor survival. Overexpression of CHD5 inhibited proliferation, migration, and invasion in vitro; prompted cell cycle G1 phase arrest; induced apoptosis; and suppressed tumor growth in vivo. Furthermore, we confirmed that CHD5 activates the p53 and RB pathways to inhibit tumorigenesis in RCC. In summary, CHD5 is involved in the initiation and progression of RCC and may serve as a diagnostic biomarker and a potential therapeutic target for RCC.

15.
Asia Pac J Clin Nutr ; 29(3): 513-522, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32990611

RESUMO

BACKGROUND AND OBJECTIVES: The association between diet and macrocytic and hypochromic anemia in young Chinese men and women remains unclear. The present study aimed to investigate the relationship between dietary pattern and macrocytic and hypochromic microcytic anemia in young Chinese men and women. METHODS AND STUDY DESIGN: Some 4,840 first-year students (2,385 men and 2,455 women) were recruited for this study from Qingdao University, China. Biochemical and hematological parameters, and food frequency questionnaires were obtained from the subjects. Based on dietary intake, participants were divided into three dietary patterns: seafood dietary pattern (SDP), vegan dietary pattern (VDP) and omnivorous dietary pattern (ODP). The risks for macrocytic and microcytic hypochromic anemia in three dietary patterns were assessed. RESULTS: Macrocytic and hypochromic anemia were less common in participants who adhered to the omnivorous dietary pattern than to the vegan or seafood dietary patterns (p<0.05). Adhering to an omnivorous dietary pattern was negatively associated with macrocytic anemia in men [odds ratio (95% CI): 0.74 (0.62, 0.89), p<0.001] and microcytic, hypochromic anemia in both genders [men: odds ratio (95% CI): 0.64 (0.45, 0.92), p=0.01; women: odds ratio (95% CI): 0.71 (0.51, 0.99), p=0.04]. CONCLUSIONS: Adhering to an omnivorous dietary pattern was associated with less common macrocytic anemia in young men and microcytic, hypochromic anemia. Dietary diversity is important in preventing macrocytic anemia in men and also microcytic, hypochromic anemia in young men and women. Excessive alcohol intake is the most plausible explanation for macrocytosis in the young men.

16.
Nat Cell Biol ; 22(10): 1264-1275, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32929201

RESUMO

Although pyroptosis is critical for macrophages against pathogen infection, its role and mechanism in cancer cells remains unclear. PD-L1 has been detected in the nucleus, with unknown function. Here we show that PD-L1 switches TNFα-induced apoptosis to pyroptosis in cancer cells, resulting in tumour necrosis. Under hypoxia, p-Stat3 physically interacts with PD-L1 and facilitates its nuclear translocation, enhancing the transcription of the gasdermin C (GSDMC) gene. GSDMC is specifically cleaved by caspase-8 with TNFα treatment, generating a GSDMC N-terminal domain that forms pores on the cell membrane and induces pyroptosis. Nuclear PD-L1, caspase-8 and GSDMC are required for macrophage-derived TNFα-induced tumour necrosis in vivo. Moreover, high expression of GSDMC correlates with poor survival. Antibiotic chemotherapy drugs induce pyroptosis in breast cancer. These findings identify a non-immune checkpoint function of PD-L1 and provide an unexpected concept that GSDMC/caspase-8 mediates a non-canonical pyroptosis pathway in cancer cells, causing tumour necrosis.

17.
Food Funct ; 11(9): 8237-8247, 2020 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-32966475

RESUMO

SCOPE: Studies have suggested that foods rich in dietary fiber may contribute to body weight loss and lower triacylglycerol (TG) levels. This study aimed to investigate the effect of flaxseed meal (FM) (a by-product of flaxseed after oil processing) supplemented biscuits on body weight, body composition, and blood lipids in overweight and obese participants. METHOD AND RESULTS: In a double-blind randomized controlled trial, 53 overweight and obese adults (18-36 years of age) were recruited and randomized to consume control biscuits or biscuits supplemented with FM for their breakfast for 60 days (approximately 100 g per day). Significant group × time interaction (P = 0.011) was observed for body weight, and the body weight of the FM group was significantly lower than that of the control group (P = 0.049). We also found significant group × time interactions for body mass index (BMI) (P = 0.008), TG (P = 0.041) and interleukin-6 (IL-6) (P = 0.016). In addition, after 60 days of intervention, the body weight, BMI and TG levels of the FM group significantly decreased compared to those of the control group. On day 60, the serum concentration of IL-6 in the FM group was significantly lower than that in the control group. CONCLUSIONS: FM supplemented biscuits have a beneficial effect on body weight, BMI and TG of overweight and obese subjects (ClinicalTrials.gov registration number: ChiCTR1900022833).

18.
J Phys Chem B ; 124(37): 8032-8041, 2020 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-32869996

RESUMO

Thioamide substitutions of the peptide backbone have been shown to stabilize therapeutic and imaging peptides toward proteolysis. In order to rationally design thioamide modifications, we have developed a novel Rosetta custom score function to classify thioamide positional effects on proteolysis in substrates of serine and cysteine proteases. Peptides of interest were docked into proteases using the FlexPepDock application in Rosetta. Docked complexes were modified to contain thioamides parametrized through the creation of custom atom types in Rosetta based on ab intio simulations. Thioamide complexes were simulated, and the resultant structural complexes provided features for machine learning classification as the decomposed values of the Rosetta score function. An ensemble, majority voting model was developed to be a robust predictor of previously unpublished thioamide proteolysis holdout data. Theoretical control simulations with pseudo-atoms that modulate only one physical characteristic of the thioamide show differential effects on prediction accuracy by the optimized voting classification model. These pseudo-atom model simulations, as well as statistical analyses of the full thioamide simulations, implicate steric effects on peptide binding as being primarily responsible for thioamide positional effects on proteolytic resistance.

20.
Biomed Res Int ; 2020: 2159460, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32802835

RESUMO

Background: This study is aimed at investigating natriuretic peptide B (NPPB) coexpression genes and their pathways involved in heart failure (HF) among patients both with and without type 2 diabetes mellitus (T2DM). Methods: The microarray dataset GSE26887, containing 19 postischemic HF patients' peripheral blood samples (7 with T2DM and 12 without T2DM), was examined to detect the genes coexpressed with NPPB using the corr.test function in the R packet. Furthermore, using online analytical tools, we determined the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, Gene Ontology (GO) annotation, and protein-protein interaction (PPI) network of the coexpression genes. The modules and hub genes of the PPI network were then identified using the Cytoscape software. Results: In patients with T2DM, a total of 41 biological processes (BP), 20 cellular components (CC), 13 molecular functions (MF), and 41 pathways were identified. Furthermore, a total of 61 BPs, 16 CCs, 13 MFs, and 22 pathways in patients without T2DM were identified. In both groups of patients, 17 BPs, 10 CCs, 6 MFs, and 13 pathways were enriched. We also identified 173 intersectional coexpression genes (63 positively, 106 negatively, and 4 differently coexpressed in patients with and without T2DM, respectively) in both types of patients, which were enriched in 16 BPs, 8 CCs, 3 MFs, and 8 KEGG pathways. Moreover, the PPI network (containing 237 edges and 170 nodes) with the top module significantly enriched in 4 BPs (tricarboxylic acid metabolic process, citrate metabolic process, tricarboxylic acid cycle, and aerobic respiration) and 3 pathways (citrate cycle, malaria parasite metabolic pathway, and AGE-RAGE signaling pathway in diabetic complications) was constructed. DECR1, BGN, TIMP1, VCAN, and CTCF are the top hub genes. Conclusions: Our findings may elucidate the functions and roles of the NPPB gene in patients with postischemic HF and facilitate HF management.

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