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1.
J Biomol Struct Dyn ; : 1-14, 2020 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-32410504

RESUMO

Sever acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a single-stranded RNA (ssRNA) virus, responsible for severe acute respiratory disease (COVID-19). A large number of natural compounds are under trial for screening compounds, possessing potential inhibitory effect against the viral infection. Keeping in view the importance of marine compounds in antiviral activity, we investigated the potency of some marine natural products to target SARS-CoV-2 main protease (Mpro) (PDB ID 6MO3). The crystallographic structure of Mpro in an apo form was retrieved from Protein Data Bank and marine compounds from PubChem. These structures were prepared for docking and the complex with good docking score was subjected to molecular dynamic (MD) simulations for a period of 100ns. To measure the stability, flexibility, and average distance between the target and compounds, root means square deviations (RMSD), root means square fluctuation (RMSF), and the distance matrix were calculated. Among five marine compounds, C-1 (PubChem CID 11170714) exhibited good activity, interacting with the active site and surrounding residues, forming many hydrogen and hydrophobic interactions. The C-1 also attained a stable dynamic behavior, and the average distance between compound and target remains constant. In conclusion, marine natural compounds may be used as a potential inhibitor against SARS-CoV-2 for better management of COVID-19.

2.
Nanoscale ; 12(17): 9824-9832, 2020 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-32338669

RESUMO

Ternary PtFeCo alloys as alternatives to conventional Pt electrocatalysts are highly important in the field of the methanol oxidation reaction. In this study, we demonstrate a one-pot two-step reduction method for the synthesis of graphene supported PtFeCo alloy nanocomposites as an integrated binder-free catalyst. The synergistic effect of alloying with Fe and Co as well as graphene decorating contributes to an increase in the utilization of the noble metal, namely, reducing the amount of Pt in the nanocomposites to 7%. After tailoring the elemental composition of the alloys, Pt52Fe29Co19@G-7% exhibits a mass activity/specific activity of 1758.2 mA mg-1Pt/3.42 mA cm-2 that is 3.13/3.45 times that of commercial Pt/C in an acidic medium. Impressively, it showed a superior mass current density of 9356.1 mA mg-1Pt at 60 °C which is close to the operating temperature of direct methanol fuel cells. Moreover, the as-obtained Pt52Fe29Co19@G-7% also exhibited excellent CO tolerance and reliable stability compared to commercial Pt/C. The structural characterization further verifies that the surface strain and electronic effect play a critical role in determining the electrocatalytic properties of PtFeCo@G nanocomposites for the methanol oxidation reaction.

3.
J Tradit Chin Med ; 40(2): 267-274, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32242392

RESUMO

OBJECTIVE: To evaluate the effect of acupuncture on neuroinflammation in traumatic brain injury (TBI) rats by stimulating Yamen (GV 15), Fengfu (GV 16), Baihui (GV 20), Shuigou (GV 26) and Hegu (LI 4) acupoints and to investigate the mechanism underpinning this effect. METHODS: A TBI model was induced in Sprague- Dawley rats using Feeney's freefall impact method. Acupuncture to stimulate the Yamen (GV 15), Fengfu (GV 16), Baihui (GV 20), Shuigou (GV 26) and Hegu (LI 4) acupoints was performed on the TBI rats. After 3 consecutive days of acupuncture treatment, we investigated signal molecules, receptors and microglia related to neuroinflammation in brain tissue of the TBI rats and analyzed the possible mechanism underlying the effect of acupuncture on neuroinflammation. RESULTS: After the acupuncture treatment, ionized calcium binding adaptor molecule 1(Iba1), a protein specific to microglia, was investigated. In the cortical layer of damaged brain tissue in TBI rats, the Iba1-positive area was 3.3% ± 0.9% in the rats that received acupuncture compared with 5.2% ± 1.4% in the TBI rats that did not receive acupuncture, and the microglia were smaller with more slender protrusions in the acupuncture-treated rats. This result indicates that acupuncture can significantly reduce microglia activation in TBI rats. A possible mechanism for this effect is that acupuncture reduces the expression of autotaxin and lysophosphatidic acid. Together, these constitute the autotaxin-lysophosphatidic acid axis, which induces microglial activation in the brains of TBI rats. Acupuncture treatment may downregulate the expression of Lysophosphatidic acid (LPA) receptor (LPAR) 1 and LPAR2 on the microglial cytomembrane, which affects the microglia activation process. CONCLUSION: Acupuncture stimulating the Yamen (GV 15), Fengfu (GV 16), Baihui (GV 20), Shuigou (GV 26) and Hegu (LI 4) acupoints can effectively inhibit the development of neuroinflammation after TBI. One possible mechanism for this effect is that acupuncture downregulates LPA synthesis and affects the LPA-LPAR pathway by inhibiting LPAR1 and LPAR2, thereby inhibiting microglial activation and reducing neuroinflammation.

4.
Am J Reprod Immunol ; 83(5): e13233, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32187420

RESUMO

PROBLEM: To investigate EMT phenotype and SALL4 expression of circulating tumour cells (CTCs) in patients with gestational trophoblastic neoplasm (GTN). METHOD OF STUDY: CanPatrol CTC detection system in combination with SALL4 RNA in situ hybridization was used to investigate the profile of CTCs in different types of gestational trophoblastic disease (GTD). Circulating CTCs were phenotyped and annotated with SALL4 expression in 41 GTD patients, including 12 HM and 29 GTN, as well as 22 pregnant volunteers. RESULTS: A positive correlation between the number of CTC and serum ß-hCG concentration was found among the GTN patients. The number of E/M-CTC was positively correlated with serum ß-hCG, while M-CTC was positively correlated with prognostic score. Comparison among malignant GTD, benign GTD and healthy pregnant women revealed a significant difference in the number of total CTC, E/M-CTC, and M-CTC but not in E-CTC. ROC analysis was conducted to evaluate the performance of CTC phenotypes in distinguishing GTD patients from healthy pregnant women yielding an AUC as 0.826. Youden's index was maximal at the cutoff value of 8.5/4 mL with sensitivity and specificity at 53.66% and 100%, respectively. SALL4 expression was evaluated in GTD patients with CTC count greater than cutoff value. SALL4 high expressing CTCs (>2 signal dots) were detected in 66.67% (10/15) of malignant GTD patients but not in benign patients (0/5). CONCLUSION: Differential expression of SALL4 was seen in CTCs derived from hydatidiform moles and GTN. CTC profiling may be developed as an adjunct marker to diagnose GTN.

5.
J Vet Pharmacol Ther ; 43(2): 179-188, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32039497

RESUMO

Biopharmaceutics Classification System (BCS) has gained broad acceptance in promoting the development of human drugs. To date, the applicability of existing human BCS criteria has not been evaluated in chickens. The objective of this study was to discuss the feasibility of BCS extrapolation between species and establish a preliminary chicken BCS by classifying seven veterinary commonly used drugs including metronidazole, amoxicillin, sulfamethoxazole, sulfadiazine, ciprofloxacin hydrochloride, doxycycline hydrochloride, and trimethoprim. Firstly, we finished the determination of physiological parameters affecting solubility in chickens, including body temperature, gastrointestinal pH, and the fluid volume in the gastrointestinal tract (GI), and the drug is considered highly soluble in chicken BCS when the highest dose strength is soluble in 20.40 ml (fed) or 6.73 ml (fasted) over the pH range of 1-8 at 41°C. Drug solubility classification was based on dose number calculation. Metronidazol and amoxicillin were classed differently under fed and fasted conditions. Secondly, we discussed the effect of ABC transporters (MDCK vs. MDCK-chAbcb1/Abcg2) and pH (5.5 vs. 7.4) on drug permeability and classification. The drug is classified as highly permeable when its permeability is equal to or greater than metoprolol tartrate. Though ABC transporters and pH significantly affected the permeability values of drugs (p < .05), the permeability classification of the drugs has not been changed except for sulfamethoxazole. This work highlights some of the significant challenges that would be encountered in order to develop a chicken BCS, this valuable information could serve as a helpful tool during chicken drugs development and to minimize the potential risks when developing formulations.

6.
PLoS One ; 15(2): e0229159, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32059028

RESUMO

Durum wheat, genetic resource with favorable alleles is considered as natural gene pool for wheat breeding. Kernel size and weight are important factors affecting grain yield in crops. Here, association analysis was performed to dissect the genetic constitution of kernel-related traits in 150 lines collected from 46 countries and regions using a set of EST-derived and genome-wide SNP markers with five consecutive years of data. Total 109 significant associations for eight kernel-related traits were detected under a mix linear model, generating 54 unique SNP markers distributed on 13 of 14 chromosomes. Of which, 19 marker-trait associations were identified in two or more environments, including one stable and pleiotropic SNP BE500291_5_A_37 on chromosome 5A correlated with six kernel traits. Although most of our SNP loci were overlapped with the previously known kernel weight QTLs, several novel loci for kernel traits in durum were reported. Correlation analysis implied that the moderate climatic variables during growth and development of durum are needed for the large grain size and high grain weight. Combined with our previous studies, we found that chromosome 5A might play an important role in durum growth and development.


Assuntos
Polimorfismo de Nucleotídeo Único , Triticum/genética , Cromossomos de Plantas/genética , Fenótipo , Triticum/crescimento & desenvolvimento
7.
Genes (Basel) ; 11(2)2020 02 10.
Artigo em Inglês | MEDLINE | ID: mdl-32050731

RESUMO

Breast cancer resistance protein (BCRP), an ATP-binding cassette (ABC) half transporter encoded by the Abcg2 gene, is reported to influence the pharmacokinetics of substrate drugs during clinical therapy. The aim of this study was to clarify the mechanisms that regulate the transcription of the chicken Abcg2 gene through cloning and characterization of its promoter region. Results showed that the Abcg2 gene is transcribed by a TATA-less promoter with several putative Sp1 sites upstream from two putative CpG islands. A luciferase reporter assay conducted both in chicken leghorn male hepatoma (LMH) cells and chicken primary hepatocytes mapped a basal promoter to nucleotides -110 to +30, which is responsible for the constitutive expression of Abcg2. The 5'-region upstream of the basal promoter was characterized by both positive and negative regulatory domains. Further, using the cell-based reporter gene assay combined with RT-PCR and drug accumulation analysis, we found that four xenobiotics, daidzein, clotrimazole, ivermectin, and lipopolysaccharide (LPS), influence the expression and function of BCRP through significant regulation of the Abcg2 gene promoter. Interaction sites with the Abcg2 gene promoter of these four selected regulators were clarified by progressive deletions and mutation assays. This study shed some light on the regulatory mechanisms involved in chicken Abcg2 gene expression and the results may have far-reaching significance regarding the usage and development of veterinary drugs.

8.
Cancer Immunol Immunother ; 69(6): 951-967, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32076794

RESUMO

Dendritic cell (DC) based immunotherapy is a promising approach to clinical cancer treatment. miRNAs are a class of small non-coding RNA molecules that bind to RNAs to mediate multiple events which are important in diverse biological processes. miRNA mimics and antagomirs may be potent agents to enhance DC-based immunotherapy against cancers. miRNA array analysis was used to identify a representative miR-5119 potentially regulating PD-L1 in DCs. We evaluated levels of ligands of immune cell inhibitory receptors (IRs) and miR-5119 in DCs from immunocompetent mouse breast tumor-bearing mice, and examined the molecular targets of miR-5119. We report that miRNA-5119 was downregulated in spleen DCs from mouse breast cancer-bearing mice. In silico analysis and qPCR data showed that miRNA-5119 targeted mRNAs encoding multiple negative immune regulatory molecules, including ligands of IRs such as PD-L1 and IDO2. DCs engineered to express a miR-5119 mimic downregulated PD-L1 and prevented T cell exhaustion in mice with breast cancer homografts. Moreover, miR-5119 mimic-engineered DCs effectively restored function to exhausted CD8+ T cells in vitro and in vivo, resulting in robust anti-tumor cell immune response, upregulated cytokine production, reduced T cell apoptosis, and exhaustion. Treatment of 4T1 breast tumor-bearing mice with miR-5119 mimic-engineered DC vaccine reduced T cell exhaustion and suppressed mouse breast tumor homograft growth. This study provides evidence supporting a novel therapeutic approach using miRNA-5119 mimic-engineered DC vaccines to regulate inhibitory receptors and enhance anti-tumor immune response in a mouse model of breast cancer. miRNA/DC-based immunotherapy has potential for advancement to the clinic as a new strategy for DC-based anti-breast cancer immunotherapy.

9.
BMC Plant Biol ; 20(1): 45, 2020 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-31996140

RESUMO

BACKGROUND: Wheat grain avenin-like proteins (ALPs) belong to a recently discovered class of wheat grain storage protein. ALPs in wheat grains not only have beneficial effects on dough quality but also display antifungal activities, which is a novel observation for wheat storage proteins. Previous studies have shown that ALPs are likely present in the albumin/globulin fractions of total protein extract from wheat flour. However, the accumulation characteristics of these ALPs in the mature wheat grain remains unknown. RESULTS: In the present study, a total of 13 ALPs homologs were isolated and characterized in the albumin/globulin fractions of the wheat protein extract. A combination of multiple techniques including RP-HPLC, SDS-PAGE, MALDI-TOF and peptide sequencing were used for accurate separation and identification of individual ALP homolog. The C-terminal TaALP-by-4AL/7DS, TaALP-by-4AL/7AS/7DS, TaALP-bx/4AL/7AS/7DS, TaALP-ay-7DS, TaALP-ay-4AL, TaALP-ax-4AL, TaALP-ax-7AS, and TaALP-ax-7DS, were separated as individual protein bands from wheat flour for the first time. These unique ALPs peptides were mapped to the latest wheat genome assembly in the IWGSC database. The characteristic defence related proteins present in albumin and globulin fractions, such as protein disulfide-isomerase (PDI), grain softness protein (GSP), alpha-amylase inhibitors (AAIs) and endogenous alpha-amylase/subtilisin inhibitor were also found to co-segregate with these identified ALPs, avenin-3 and α-gliadins. The molecular weight range and the electrophoresis segregation properties of ALPs were characterised in comparison with the proteins containing the tryp_alpha_amyl domain (PF00234) and the gliadin domain (PF13016), which play a role in plant immunity and grain quality. We examined the phylogenetic relationships of the AAIs, GSP, avenin-3, α-gliadins and ALPs, based on the alignment of their functional domains. MALDI-TOF profiling indicated the occurrence of certain post-translations modifications (PTMs) in some ALP subunits. CONCLUSIONS: We reported for the first time the complete profiling of ALPs present in the albumin/globulin fractions of wheat grain protein extracts. We concluded that majority of the ALPs homologs are expressed in wheat grains. We found clear evidence of PTMs in several ALPs peptides. The identification of both gliadin domain (PF13016) and Tryp_alpha_amyl domain (PF00234) in the mature forms of ALPs highlighted the multiple functional properties of ALPs in grain quality and disease resistance.

10.
J Nanosci Nanotechnol ; 20(6): 3340-3347, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-31748025

RESUMO

This work describes a "turn-off-on" fluorescence probe based on carbon quantum dots for sensing Fe3+ and ascorbic acid. The carbon quantum dots are prepared by hydrothermal method using a biocarbon source of black sesame. When excited at 355 nm, the carbon quantum dots show a strong bright blue emission peak centered at 438 nm. Obviously, the decrease of the fluorescence intensity of carbon quantum dots can be seen upon addition of Fe3+. Interestingly, the fluorescence quenching can be regained after the addition of ascorbic acid. The mechanism is that the added Fe3+ was destroyed by reductive ascorbic acid because of the redox reaction between ascorbic acid and Fe3+, making the fluorescence of the system recovered. The obtained curves are linear for Fe3+ and ascorbic acid over the range 50-1500 µM and 32.2-987.6 µM, respectively. The detection limits for Fe3+ and ascorbic acid are 2.78 µM and 0.0344 µM, respectively. Thus the carbon quantum dots can be used as a dual-function fluorescent sensor to achieve sensitive detection of Fe3+ and ascorbic acid.

11.
J Biomol Struct Dyn ; : 1-9, 2020 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-31870207

RESUMO

Anti-cancer peptides (ACPs) play a vital role in the cell signaling process. Antimicrobial peptides (AMPs) provide immunity against pathogenic microbes, AMPs present activity against pathogenic microbes. Some of them are known to possess both anticancer and antimicrobial activity. However, so far, no tools have been developed that could predict potential ACPs from wild and mutated cancerous protein sequences in the numerous public databases. In the present study, we developed a A-CaMP tool that allows rapid fingerprinting of the anti-cancer and antimicrobial peptides, which play a crucial role in current bioinformatics research. Besides, we compared the performance and functionality of our A-CaMP tool with those of other methods available online. A-CaMP scans the target protein sequences provided by the user against the datasets. It possesses a robust coding architecture, has been developed in PERL language and is scalable of therefore has extensive applications in bioinformatics. It was observed to achieve a prediction accuracy of 93.4%, which is much higher than that of any of the existing tools. Sequence alignment studies also highlight the potential use of A-CaMP as a tool for the identification of AMPs. A-CaMP is the first open source tool that uses clinical data and proposes final peptides along with the necessary information; this includes wild and mutant sequence and peptides, which lays the foundation for its application in therapies for cancer and bacterial infections. Communicated by Ramaswamy H. Sarma.

12.
Onco Targets Ther ; 12: 6813-6824, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31686839

RESUMO

Purpose: Cervical cancer is the second leading cause of women's cancer-related death. MiR-940 has been reported as a critical factor in various cancers. Based on the high transfection efficiency and low side effect, the clinical application of microbubble ultrasound contrast agent in gene treatment has attracted a widespread attention. In this study, we determined the mechanism of miR-940 inhibiting cell proliferation and cycle procession, and promoting cell apoptosis in cervical cancer Hela cells. In addition, we compared the effects of different transfection methods, including liposome, microbubble, ultrasound, and microbubble coupled with ultrasound. Patients and methods: MTT assay, PI staining, and Annexin-Ⅴ/PI staining assays were, respectively, performed to evaluate cell proliferation status, cell cycle progression, and apoptosis status. RT-PCR and Western blot were conducted to measure the levels of cell cycle- and apoptosis-related factors, and the phosphorylation levels of PI3K and Akt. Results: Results showed that the overexpression of miR-940 inhibited cell proliferation, blocked cell cycle, and promoted apoptosis by regulating cell cycle-related factors (such as inhibited Cyclin D1 and CDK4) and apoptosis-related factors (such as promoted Puma and Bax, inhibited Bcl-2 and Cleaved caspase9), and inhibiting the phosphorylation and activation of PI3K/AKT pathway. Among all of them, miR-940 transfected with microbubble and ultrasound showed the greatest changes. Conclusion: It provides evidence that miR-940 could be a wonderful biomarker and treatment agent for cervical cancer, and microbubble ultrasound would have more wide application in the clinical treatment of cancers.

13.
Open Biol ; 9(10): 190061, 2019 10 31.
Artigo em Inglês | MEDLINE | ID: mdl-31594465

RESUMO

Blockade of inhibitory receptors (IRs) is one of the most effective immunotherapeutic approaches to treat cancer. Dysfunction of miRNAs is a major cause of aberrant expression of IRs and contributes to the immune escape of cancer cells. How miRNAs regulate immune checkpoint proteins in breast cancer remains largely unknown. In this study, downregulation of miRNAs was observed in PD-1-overexpressing CD8+ T cells using miRNA array analysis of mouse breast cancer homografts. The data reveal that miR-149-3p was predicted to bind the 3'UTRs of mRNAs encoding T-cell inhibitor receptors PD-1, TIM-3, BTLA and Foxp1. Treatment of CD8+ T cells with an miR-149-3p mimic reduced apoptosis, attenuated changes in mRNA markers of T-cell exhaustion and downregulated mRNAs encoding PD-1, TIM-3, BTLA and Foxp1. On the other hand, T-cell proliferation and secretion of effector cytokines indicative of increased T-cell activation (IL-2, TNF-α, IFN-γ) were upregulated after miR-149-3p mimic treatment. Moreover, the treatment with a miR-149-3p mimic promoted the capacity of CD8+ T cells to kill targeted 4T1 mouse breast tumour cells. Collectively, these data show that miR-149-3p can reverse CD8+ T-cell exhaustion and reveal it to be a potential antitumour immunotherapeutic agent in breast cancer.

14.
Plant J ; 2019 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-31571294

RESUMO

Functional divergence after gene duplication plays a central role in plant evolution. Among cereals, only barley, wheat and rye accumulate delphinidin-derived (blue) anthocyanins in the aleurone layer of grains, but not rice, maize and sorghum. The underlying genetic basis for this natural occurence remains elusive. Here, we mapped the barley Blx1 locus involved in blue aleruone to a ~ 1.13 Mb genetic interval on chromosome 4HL, thus identifying a trigenic cluster named MbHF35 (containing HvMYB4H, HvMYC4H and HvF35H). Sequence and expression data supported the role of these genes in conferring blue-coloured (blue aleurone) grains. Synteny analyses across monocot species showed that MbHF35 has only evolved within distinct Triticeae lineages, as a result of dispersed gene duplication. Phylogeny analyses revealed a shared evolution pattern for MbHF35 in Triticeae, suggesting that these genes have co-evolved together. We also identified a Pooideae-specific flavonoid 3',5'-hydroxylase (F3'5'H) lineage, termed here Mo_F35H2 which has higher amino acid similarity with eudicot F3'5'Hs, demonstrating a scenario of convergent evolution. Indeed, selection tests identified 13 amino acid residues in Mo_F35H2 which underwent positive selection, possibly driven by protein thermostablility selection. Furthermore, by inquiring the barley germplasm there's evidence that HvMYB4H and HvMYC4H have underwent human selection. Collectively, our study favours blue aleurone as a recently evolved trait resulting from environmental adaptation. Our findings provide an evolutionary explanation for the absence of blue anthocyanins in other cereals and highlight the importance of gene functional divergence for plant diversity and environmental adaptation.

15.
BMC Genomics ; 20(1): 748, 2019 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-31619177

RESUMO

BACKGROUND: The homeodomain-leucine zipper (HD-Zip) gene family is one of the plant-specific transcription factor families, involved in plant development, growth, and in the response to diverse stresses. However, comprehensive analysis of the HD-Zip genes, especially those involved in response to drought and salinity stresses is lacking in sesame (Sesamum indicum L.), an important oil crop in tropical and subtropical areas. RESULTS: In this study, 45 HD-Zip genes were identified in sesame, and denominated as SiHDZ01-SiHDZ45. Members of SiHDZ family were classified into four groups (HD-Zip I-IV) based on the phylogenetic relationship of Arabidopsis HD-Zip proteins, which was further supported by the analysis of their conserved motifs and gene structures. Expression analyses of SiHDZ genes based on transcriptome data showed that the expression patterns of these genes were varied in different tissues. Additionally, we showed that at least 75% of the SiHDZ genes were differentially expressed in responses to drought and salinity treatments, and highlighted the important role of HD-Zip I and II genes in stress responses in sesame. CONCLUSIONS: This study provides important information for functional characterization of stress-responsive HD-Zip genes and may contribute to the better understanding of the molecular basis of stress tolerance in sesame.


Assuntos
Regulação da Expressão Gênica de Plantas , Genoma de Planta/genética , Proteínas de Homeodomínio/genética , Proteínas de Plantas/genética , Sesamum/genética , Estresse Fisiológico/genética , Fatores de Transcrição/genética , Mapeamento Cromossômico , Cromossomos de Plantas/genética , Secas , Perfilação da Expressão Gênica , Regulação da Expressão Gênica de Plantas/genética , Genes de Plantas/genética , Proteínas de Homeodomínio/química , Zíper de Leucina , Família Multigênica , Especificidade de Órgãos , Pressão Osmótica , Filogenia , Proteínas de Plantas/química , Salinidade , Sesamum/classificação , Sesamum/fisiologia , Fatores de Transcrição/química
16.
Mar Drugs ; 17(10)2019 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-31561525

RESUMO

Pyrazinamide (PZA) is the only drug for the elimination of latent Mycobacterium tuberculosis (MTB) isolates. However, due to the increased number of PZA-resistance, the chances of the success of global TB elimination seems to be more prolonged. Recently, marine natural products (MNPs) as an anti-TB agent have received much attention, where some compounds extracted from marine sponge, Haliclona sp. exhibited strong activity under aerobic and hypoxic conditions. In this study, we screened articles from 1994 to 2019 related to marine natural products (MNPs) active against latent MTB isolates. The literature was also mined for the major regulators to map them in the form of a pathway under the dormant stage. Five compounds were found to be more suitable that may be applied as an alternative to PZA for the better management of resistance under latent stage. However, the mechanism of actions behind these compounds is largely unknown. Here, we also applied synthetic biology to analyze the major regulatory pathway under latent TB that might be used for the screening of selective inhibitors among marine natural products (MNPs). We identified key regulators of MTB under latent TB through extensive literature mining and mapped them in the form of regulatory pathway, where SigH is negatively regulated by RshA. PknB, RshA, SigH, and RNA polymerase (RNA-pol) are the major regulators involved in MTB survival under latent stage. Further studies are needed to screen MNPs active against the main regulators of dormant MTB isolates. To reduce the PZA resistance burden, understanding the regulatory pathways may help in selective targets of MNPs from marine natural sources.


Assuntos
Antituberculosos/uso terapêutico , Produtos Biológicos/uso terapêutico , Resistência a Medicamentos/efeitos dos fármacos , Tuberculose Latente/tratamento farmacológico , Humanos , Testes de Sensibilidade Microbiana/métodos , Mutação/efeitos dos fármacos , Mycobacterium tuberculosis/efeitos dos fármacos , Pirazinamida/uso terapêutico
17.
Int J Mol Sci ; 20(16)2019 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-31412539

RESUMO

Sesame is a source of a healthy vegetable oil, attracting a growing interest worldwide. Abiotic stresses have devastating effects on sesame yield; hence, studies have been performed to understand sesame molecular responses to abiotic stresses, but the core abiotic stress-responsive genes (CARG) that the plant reuses in response to an array of environmental stresses are unknown. We performed a meta-analysis of 72 RNA-Seq datasets from drought, waterlogging, salt and osmotic stresses and identified 543 genes constantly and differentially expressed in response to all stresses, representing the sesame CARG. Weighted gene co-expression network analysis of the CARG revealed three functional modules controlled by key transcription factors. Except for salt stress, the modules were positively correlated with the abiotic stresses. Network topology of the modules showed several hub genes predicted to play prominent functions. As proof of concept, we generated over-expressing Arabidopsis lines with hub and non-hub genes. Transgenic plants performed better under drought, waterlogging, and osmotic stresses than the wild-type plants but did not tolerate the salt treatment. As expected, the hub gene was significantly more potent than the non-hub gene. Overall, we discovered several novel candidate genes, which will fuel investigations on plant responses to multiple abiotic stresses.


Assuntos
Adaptação Biológica/genética , Perfilação da Expressão Gênica , Regulação da Expressão Gênica de Plantas , Sesamum/genética , Estresse Fisiológico/genética , Transcriptoma , Biologia Computacional/métodos , Redes Reguladoras de Genes , Modelos Biológicos
18.
BMC Plant Biol ; 19(1): 347, 2019 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-31395025

RESUMO

BACKGROUND: Flavonoid 3'-hydroxlase (F3'H) is an important enzyme in determining the B-ring hydroxylation pattern of flavonoids. In monocots, previous studies indicated the presence of two groups of F3'Hs with different enzyme activities. One F3'H in rice was found to display novel chrysoeriol-specific 5'-hydroxylase activity. However, the evolutionary history of monocot F3'Hs and the molecular basis for the observed catalytic difference remained elusive. RESULTS: We performed genome-wide survey of 12 common monocot plants, and identified a total of 44 putative F3'H genes. The results showed that F3'H gene family had underwent volatile lineage-specific gene duplication and gene loss events in monocots. The expansion of F3'H gene family was mainly attributed to dispersed gene duplication. Phylogenetic analyses showed that monocot F3'Hs have evolved into two independent lineages (Class I and Class II) after gene duplication in the common ancestor of monocot plants. Evolutionary dynamics analyses had detected positive natural selection in Class II F3'Hs, acting on 7 specific amino acid sites. Protein modelling showed these selected sites were mainly located in the catalytic cavity of F3'H. Sequence alignment revealed that Class I and Class II F3'Hs displayed amino acid substitutions at two critical sites previously found to be responsible for F3'H and flavonoid 3'5'-hydroxylase (F3'5'H) activities. In addition, transcriptional divergence was also observed for Class I and Class II F3'Hs in four monocot species. CONCLUSIONS: We concluded that monocot F3'Hs have evolved into two independent lineages (Mono_F3'H Class I and Class II), after gene duplication during the common ancestor of monocot plants. The functional divergence of monocot F3'H Class II has been affected by positive natural selection, which acted on specific amino acid sites only. Critical amino acid sites have been identified to have high possibility to affect the substrate specificity of Class II F3'Hs. Our study provided an evolutionary and protein structural explanation to the previously observed chrysoeriol-specific 5'-hydroxylation activity for CYP75B4 in rice, which may also be true for other Class II F3'Hs in monocots. Our study presented clear evidence of plant-environmental interaction at the gene evolutionary level, and would guide future functional characterization of F3'Hs in cereal plants.


Assuntos
Sistema Enzimático do Citocromo P-450/genética , Grão Comestível/genética , Proteínas de Plantas/genética , Sistema Enzimático do Citocromo P-450/química , Grão Comestível/enzimologia , Evolução Molecular , Duplicação Gênica , Modelos Moleculares , Filogenia , Proteínas de Plantas/química , Seleção Genética , Alinhamento de Sequência
19.
Sci Rep ; 9(1): 11344, 2019 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-31383879

RESUMO

Stomach cancer involves hypoxia-specific microenvironments. Stoichiogenomics explores environmental resource limitation on biological macromolecules in terms of element usages. However, the patterns of oxygen usage by proteins and the ways that proteins adapt to a cancer hypoxia microenvironment are still unknown. Here we compared the oxygen and carbon contents ([C]) between proteomes of stomach cancer (hypoxia) and two stomach glandular cells (normal). Key proteins, genome locations, pathways, and functional dissection associated with stomach cancer were also studied. An association of oxygen content ([O]) and protein expression level was revealed in stomach cancer and stomach glandular cells. For differentially expressed proteins (DEPs), oxygen contents in the up regulated proteins were3.2%higherthan that in the down regulated proteins in stomach cancer. A total of 1,062 DEPs were identified; interestingly none of these proteins were coded on Y chromosome. The up regulated proteins were significantly enriched in pathways including regulation of actin cytoskeleton, cardiac muscle contraction, pathway of progesterone-mediated oocyte maturation, etc. Functional dissection of the up regulated proteins with high oxygen contents showed that most of them were cytoskeleton, cytoskeleton associated proteins, cyclins and signaling proteins in cell cycle progression. Element signature of resource limitation could not be detected in stomach cancer for oxygen, just as what happened in plants and microbes. Unsaved use of oxygen by the highly expressed proteins was adapted to the rapid growth and fast division of the stomach cancer cells. In addition, oxygen usage bias, key proteins and pathways identified in this paper laid a foundation for application of stoichiogenomics in precision medicine.

20.
BMC Med Genomics ; 12(1): 125, 2019 08 29.
Artigo em Inglês | MEDLINE | ID: mdl-31464612

RESUMO

BACKGROUND: The five-year survival rate and therapeutic effect of malignant glioma is low. Identification of key/associated proteins and pathways in glioma is necessary for developing effective diagnosis and targeted therapy of glioma. In addition, Glioma involves hypoxia-specific microenvironment, whether hypoxia restriction influences the stoichioproteomic characteristics of expressed proteins is unknown. METHODS: In this study, we analyzed the most comprehensive immunohistochemical data from 12 human glioma samples and 4 normal cell types of cerebral cortex, identified differentially expressed proteins (DEPs), and researched the oxygen contents of DEPs, highly and lowly expressed proteins. Further we located key genes on human genome to determine their locations and enriched them for key functional pathways. RESULTS: Our results showed that although no difference was detected on whole proteome, the average oxygen content of highly expressed proteins is 6.65% higher than that of lowly expressed proteins in glioma. A total of 1480 differentially expressed proteins were identified in glioma, including 226 up regulated proteins and 1254 down regulated proteins. The average oxygen content of up regulated proteins is 2.56% higher than that of down regulated proteins in glioma. The localization of differentially expressed genes on human genome showed that most genes were on chromosome 1 and least on Y. The up regulated proteins were significantly enriched in pathways including cell cycle, pathways in cancer, oocyte meiosis, DNA replication etc. Functional dissection of the up regulated proteins with high oxygen contents showed that 51.28% of the proteins were involved in cell cycle and cyclins. CONCLUSIONS: Element signature of oxygen limitation could not be detected in glioma, just as what happened in plants and microbes. Unsaved use of oxygen by the highly expressed proteins and DEPs were adapted to the fast division of glioma cells. This study can help to reveal the molecular mechanism of glioma, and provide a new approach for studies of cancer-related biomacromolecules. In addition, this study lays a foundation for application of stoichioproteomics in precision medicine.


Assuntos
Glioma/metabolismo , Oxigênio/metabolismo , Proteômica/métodos , Transdução de Sinais , Carbono/metabolismo , Córtex Cerebral/metabolismo , Regulação para Baixo , Regulação Neoplásica da Expressão Gênica , Genoma Humano , Glioma/genética , Humanos , Análise de Componente Principal , Regulação para Cima
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