Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 193
Filtrar
1.
J Cell Mol Med ; 28(9): e18295, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38722284

RESUMO

The RNA-binding protein PNO1 plays an essential role in ribosome biogenesis. Recent studies have shown that it is involved in tumorigenesis; however, its role in hepatocellular carcinoma (HCC) is not well understood. The purpose of this study was to examine whether PNO1 can be used as a biomarker of HCC and also examine the therapeutic potential of PNO1 knockout for the treatment of HCC. PNO1 expression was upregulated in HCC and associated with poor prognosis. PNO1 expression was positively associated with tumour stage, lymph node metastasis and poor survival. PNO1 expression was significantly higher in HCC compared to that in fibrolamellar carcinoma or normal tissues. Furthermore, HCC tissues with mutant Tp53 expressed higher PNO1 than those with wild-type Tp53. PNO1 knockout suppressed cell viability, colony formation and EMT of HCC cells. Since activation of Notch signalling pathway promotes HCC, we measured the effects of PNO1 knockout on the components of Notch pathway and its targets. PNO1 knockout suppressed Notch signalling by modulating the expression of Notch ligands and their receptors, and downstream targets. PNO1 knockout also inhibited genes involved in surface adhesion, cell cycle, inflammation and chemotaxis. PNO1 knockout also inhibited colony and spheroid formation, cell migration and invasion, and markers of stem cells, pluripotency and EMT in CSCs. Overall, our data suggest that PNO1 can be used as a diagnostic and prognostic biomarker of HCC, and knockout of PNO1 by CRISPR/Cas9 can be beneficial for the management of HCC by targeting CSCs.


Assuntos
Biomarcadores Tumorais , Carcinoma Hepatocelular , Regulação Neoplásica da Expressão Gênica , Neoplasias Hepáticas , Proteínas de Ligação a RNA , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Biomarcadores Tumorais/metabolismo , Biomarcadores Tumorais/genética , Masculino , Proteínas de Ligação a RNA/metabolismo , Proteínas de Ligação a RNA/genética , Linhagem Celular Tumoral , Feminino , Prognóstico , Pessoa de Meia-Idade , Transdução de Sinais , Proteína Supressora de Tumor p53/metabolismo , Proteína Supressora de Tumor p53/genética , Receptores Notch/metabolismo , Receptores Notch/genética , Movimento Celular/genética , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Transição Epitelial-Mesenquimal/genética , Proliferação de Células , Relevância Clínica
2.
Brief Bioinform ; 25(3)2024 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-38701422

RESUMO

In this review article, we explore the transformative impact of deep learning (DL) on structural bioinformatics, emphasizing its pivotal role in a scientific revolution driven by extensive data, accessible toolkits and robust computing resources. As big data continue to advance, DL is poised to become an integral component in healthcare and biology, revolutionizing analytical processes. Our comprehensive review provides detailed insights into DL, featuring specific demonstrations of its notable applications in bioinformatics. We address challenges tailored for DL, spotlight recent successes in structural bioinformatics and present a clear exposition of DL-from basic shallow neural networks to advanced models such as convolution, recurrent, artificial and transformer neural networks. This paper discusses the emerging use of DL for understanding biomolecular structures, anticipating ongoing developments and applications in the realm of structural bioinformatics.


Assuntos
Biologia Computacional , Aprendizado Profundo , Biologia Computacional/métodos , Redes Neurais de Computação , Humanos
3.
Sci Data ; 11(1): 180, 2024 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-38336857

RESUMO

Computing binding affinities is of great importance in drug discovery pipeline and its prediction using advanced machine learning methods still remains a major challenge as the existing datasets and models do not consider the dynamic features of protein-ligand interactions. To this end, we have developed PLAS-20k dataset, an extension of previously developed PLAS-5k, with 97,500 independent simulations on a total of 19,500 different protein-ligand complexes. Our results show good correlation with the available experimental values, performing better than docking scores. This holds true even for a subset of ligands that follows Lipinski's rule, and for diverse clusters of complex structures, thereby highlighting the importance of PLAS-20k dataset in developing new ML models. Along with this, our dataset is also beneficial in classifying strong and weak binders compared to docking. Further, OnionNet model has been retrained on PLAS-20k dataset and is provided as a baseline for the prediction of binding affinities. We believe that large-scale MD-based datasets along with trajectories will form new synergy, paving the way for accelerating drug discovery.


Assuntos
Ligantes , Proteínas , Descoberta de Drogas , Aprendizado de Máquina , Ligação Proteica , Proteínas/química , Humanos , Animais
4.
Commun Biol ; 6(1): 902, 2023 09 04.
Artigo em Inglês | MEDLINE | ID: mdl-37667032

RESUMO

High-quality reference genome assemblies, representative of global heterotic patterns, offer an ideal platform to accurately characterize and utilize genetic variation in the primary gene pool of hybrid crops. Here we report three platinum grade de-novo, near gap-free, chromosome-level reference genome assemblies from the active breeding germplasm in pearl millet with a high degree of contiguity, completeness, and accuracy. An improved Tift genome (Tift23D2B1-P1-P5) assembly has a contig N50 ~ 7,000-fold (126 Mb) compared to the previous version and better alignment in centromeric regions. Comparative genome analyses of these three lines clearly demonstrate a high level of collinearity and multiple structural variations, including inversions greater than 1 Mb. Differential genes in improved Tift genome are enriched for serine O-acetyltransferase and glycerol-3-phosphate metabolic process which play an important role in improving the nutritional quality of seed protein and disease resistance in plants, respectively. Multiple marker-trait associations are identified for a range of agronomic traits, including grain yield through genome-wide association study. Improved genome assemblies and marker resources developed in this study provide a comprehensive framework/platform for future applications such as marker-assisted selection of mono/oligogenic traits as well as whole-genome prediction and haplotype-based breeding of complex traits.


Assuntos
Pennisetum , Pennisetum/genética , Embaralhamento de DNA , Estudo de Associação Genômica Ampla , Melhoramento Vegetal , Agricultura
5.
Plant Biotechnol J ; 21(11): 2348-2357, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37530223

RESUMO

Millets are a class of nutrient-rich coarse cereals with high resistance to abiotic stress; thus, they guarantee food security for people living in areas with extreme climatic conditions and provide stress-related genetic resources for other crops. However, no platform is available to provide a comprehensive and systematic multi-omics analysis for millets, which seriously hinders the mining of stress-related genes and the molecular breeding of millets. Here, a free, web-accessible, user-friendly millets multi-omics database platform (Milletdb, http://milletdb.novogene.com) has been developed. The Milletdb contains six millets and their one related species genomes, graph-based pan-genomics of pearl millet, and stress-related multi-omics data, which enable Milletdb to be the most complete millets multi-omics database available. We stored GWAS (genome-wide association study) results of 20 yield-related trait data obtained under three environmental conditions [field (no stress), early drought and late drought] for 2 years in the database, allowing users to identify stress-related genes that support yield improvement. Milletdb can simplify the functional genomics analysis of millets by providing users with 20 different tools (e.g., 'Gene mapping', 'Co-expression', 'KEGG/GO Enrichment' analysis, etc.). On the Milletdb platform, a gene PMA1G03779.1 was identified through 'GWAS', which has the potential to modulate yield and respond to different environmental stresses. Using the tools provided by Milletdb, we found that the stress-related PLATZs TFs (transcription factors) family expands in 87.5% of millet accessions and contributes to vegetative growth and abiotic stress responses. Milletdb can effectively serve researchers in the mining of key genes, genome editing and molecular breeding of millets.


Assuntos
Embaralhamento de DNA , Milhetes , Humanos , Milhetes/genética , Estudo de Associação Genômica Ampla , Multiômica , Genômica/métodos
6.
Artigo em Inglês | MEDLINE | ID: mdl-37635009

RESUMO

OBJECTIVE: Surgical innovation led to an endoscopic-assisted intraoral approach for managing condyle fractures. The purpose of this systematic review is to purview the role of the endoscope and determine the range of information, summarizing the evidence for the benefit of surgeons on an endoscopic-assisted intraoral approach. STUDY DESIGN: A literature search was conducted in PubMed, Google Scholar, Semantic Scholar, and Cochrane Library databases for studies mentioning the endoscopic intraoral approach for managing mandibular condylar fractures. Outcomes include the role of the endoscope, challenges, adjunct armamentarium, duration, and complications associated with the transoral and transbuccal approach for screw fixation. The meta-analysis was conducted with prevalence estimates and standardized means using STATA. RESULTS: Thirty-nine studies were included. A 30° angulated, 4-mm-thick endoscope was the most commonly used endoscope. Two mini plates were most commonly used for fixation. Facial nerve weakness was higher in the transbuccal approach (1.24%) than in the transoral approach (0.8%). Pooled analysis (6 studies) showed that the duration of the surgical procedure was less in the transoral approach compared with the transbuccal approach for screw fixation. The bailout was 1.49%. CONCLUSIONS: The endoscopic-assisted intraoral approach is reliable for condylar fracture management. The transoral and transbuccal approaches can be used for screw fixation with comparable outcomes.


Assuntos
Côndilo Mandibular , Fraturas Mandibulares , Humanos , Côndilo Mandibular/cirurgia , Fixação Interna de Fraturas/métodos , Endoscopia/métodos , Fraturas Mandibulares/cirurgia , Parafusos Ósseos , Resultado do Tratamento , Placas Ósseas
7.
J Lab Physicians ; 15(2): 259-263, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-37323604

RESUMO

Objective Indian hospitals (especially government-run public sector hospitals) have a nonexistent antimicrobial stewardship program (AMSP). After successfully initiating AMSPs in tertiary care hospitals of India, the Indian Council of Medical Research envisages implementing AMSP in secondary care hospitals. This study is about the baseline data on antibiotic consumption in secondary care hospitals. Materials and Methods It was a prospective longitudinal observational chart review type of study. Baseline data on antibiotic consumption was captured by a 24-hour point prevalence study of antibiotic usage and bacterial culture rate. The prescribed antibiotics were classified according to the World Health Organization (WHO) Access, Watch, and Reserve classification. All data were collated in Microsoft Excel and summarized as percentages. Results Out of the 864 patients surveyed, overall antibiotic usage was 78.9% (71.5% in low-priority areas vs. 92.2% in high-priority areas). Most of the antibiotic usage was empirical with an extremely low bacterial culture rate (21.9%). Out of the prescribed drugs, 53.1% were from the WHO watch category and 5.5% from the reserve category. Conclusion Even after 5 years of the launch of the national action plan on AMR (NAP-AMR) of India, AMSP is still non-existent in small- and medium-level hospitals in urban cities. The importance of trained microbiologists in the health care system is identified as a fulcrum in combating antimicrobial resistance (AMR); however, their absence in government-run district hospitals is a matter of grave concern and needs to be addressed sooner than later.

8.
Epigenomes ; 7(2)2023 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-37218871

RESUMO

Epigenetic modifications are heritable, reversible changes in histones or the DNA that control gene functions, being exogenous to the genomic sequence itself. Human diseases, particularly cancer, are frequently connected to epigenetic dysregulations. One of them is histone methylation, which is a dynamically reversible and synchronously regulated process that orchestrates the three-dimensional epigenome, nuclear processes of transcription, DNA repair, cell cycle, and epigenetic functions, by adding or removing methylation groups to histones. Over the past few years, reversible histone methylation has become recognized as a crucial regulatory mechanism for the epigenome. With the development of numerous medications that target epigenetic regulators, epigenome-targeted therapy has been used in the treatment of malignancies and has shown meaningful therapeutic potential in preclinical and clinical trials. The present review focuses on the recent advances in our knowledge on the role of histone demethylases in tumor development and modulation, in emphasizing molecular mechanisms that control cancer cell progression. Finally, we emphasize current developments in the advent of new molecular inhibitors that target histone demethylases to regulate cancer progression.

9.
Nat Genet ; 55(3): 507-518, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36864101

RESUMO

Pearl millet is an important cereal crop worldwide and shows superior heat tolerance. Here, we developed a graph-based pan-genome by assembling ten chromosomal genomes with one existing assembly adapted to different climates worldwide and captured 424,085 genomic structural variations (SVs). Comparative genomics and transcriptomics analyses revealed the expansion of the RWP-RK transcription factor family and the involvement of endoplasmic reticulum (ER)-related genes in heat tolerance. The overexpression of one RWP-RK gene led to enhanced plant heat tolerance and transactivated ER-related genes quickly, supporting the important roles of RWP-RK transcription factors and ER system in heat tolerance. Furthermore, we found that some SVs affected the gene expression associated with heat tolerance and SVs surrounding ER-related genes shaped adaptation to heat tolerance during domestication in the population. Our study provides a comprehensive genomic resource revealing insights into heat tolerance and laying a foundation for generating more robust crops under the changing climate.


Assuntos
Pennisetum , Termotolerância , Pennisetum/genética , Termotolerância/genética , Adaptação Fisiológica/genética , Genômica , Perfilação da Expressão Gênica
10.
Front Plant Sci ; 14: 1123655, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36950360

RESUMO

Micronutrient malnutrition is a serious threat to the developing world's human population, which largely relies on a cereal-based diet that lacks diversity and micronutrients. Besides major cereals, millets represent the key sources of energy, protein, vitamins, and minerals for people residing in the dryland tropics and drought-prone areas of South Asia and sub-Saharan Africa. Millets serve as multi-purpose crops with several salient traits including tolerance to abiotic stresses, adaptation to diverse agro-ecologies, higher productivity in nutrient-poor soils, and rich nutritional characteristics. Considering the potential of millets in empowering smallholder farmers, adapting to changing climate, and transforming agrifood systems, the year 2023 has been declared by the United Nations as the International Year of Millets. In this review, we highlight recent genetic and genomic innovations that can be explored to enhance grain micronutrient density in millets. We summarize the advances made in high-throughput phenotyping to accurately measure grain micronutrient content in cereals. We shed light on genetic diversity in millet germplasm collections existing globally that can be exploited for developing nutrient-dense and high-yielding varieties to address food and nutritional security. Furthermore, we describe the progress made in the fields of genomics, proteomics, metabolomics, and phenomics with an emphasis on enhancing the grain nutritional content for designing competitive biofortified varieties for the future. Considering the close genetic-relatedness within cereals, upcoming research should focus on identifying the genetic and genomic basis of nutritional traits in millets and introgressing them into major cereals through integrated omics approaches. Recent breakthroughs in the genome editing toolbox would be crucial for mainstreaming biofortification in millets.

11.
J Cell Mol Med ; 27(3): 365-378, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36625087

RESUMO

Growth is crucially controlled by the functional ribosomes available in cells. To meet the enhanced energy demand, cancer cells re-wire and increase their ribosome biogenesis. The RNA-binding protein PNO1, a ribosome assembly factor, plays an essential role in ribosome biogenesis. The purpose of this study was to examine whether PNO1 can be used as a biomarker for lung adenocarcinoma and also examine the molecular mechanisms by which PNO1 knockdown by CRISPR/Cas9 inhibited growth and epithelial-mesenchymal transition (EMT). The expression of PNO1 was significantly higher in lung adenocarcinoma compared to normal lung tissues. PNO1 expression in lung adenocarcinoma patients increased with stage, nodal metastasis, and smoking. Lung adenocarcinoma tissues from males expressed higher PNO1 than those from females. Furthermore, lung adenocarcinoma tissues with mutant Tp53 expressed higher PNO1 than those with wild-type Tp53, suggesting the influence of Tp53 status on PNO1 expression. PNO1 knockdown inhibited cell viability, colony formation, and EMT, and induced apoptosis. Since dysregulated signalling through the Notch receptors promotes lung adenocarcinoma, we measured the effects of PNO1 inhibition on the Notch pathway. PNO1 knockdown inhibited Notch signalling by suppressing the expression of Notch receptors, their ligands, and downstream targets. PNO1 knockdown also suppressed CCND1, p21, PTGS-2, IL-1α, IL-8, and CXCL-8 genes. Overall, our data suggest that PNO1 can be used as a diagnostic biomarker, and also can be an attractive therapeutic target for the treatment of lung adenocarcinoma.


Assuntos
Adenocarcinoma de Pulmão , Adenocarcinoma , Neoplasias Pulmonares , Masculino , Feminino , Humanos , Sistemas CRISPR-Cas/genética , Adenocarcinoma de Pulmão/genética , Adenocarcinoma/patologia , Receptores Notch/genética , Receptores Notch/metabolismo , Neoplasias Pulmonares/patologia , Ribossomos/metabolismo , Ribossomos/patologia , Transição Epitelial-Mesenquimal/genética , Linhagem Celular Tumoral , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo
13.
Mol Biol Rep ; 50(1): 417-431, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36335522

RESUMO

BACKGROUND: Tobacco's PR-1a gene is induced by pathogen attack or exogenous application of salicylic acid (SA). Nucleosome mapping and chromatin immunoprecipitation assay were used to delineate the histone modifications on the PR-1a promoter. However, the epigenetic modifications of the inducible promoter of the PR-1a gene are not fully understood yet. METHODS AND RESULTS: Southern approach was used to scan the promoter of PR-1a to identify presence of nucleosomes, ChIP assays were performed using anti-histones antibodies of repressive chromatin by di- methylated at H3K9 and H4K20 or active chromatin by acetylated H3K9/14 and H4K16 to find epigenetic malleability of nucleosome over core promoter in uninduced or induced state post SA treatment. Class I and II mammalian histone deacetylase (HDAC) inhibitor TSA treatment was used to enhance the expression of PR-1a by facilitating the histone acetylation post SA treatment. Here, we report correlated consequences of the epigenetic modifications correspond to disassembly of the nucleosome (spans from - 102 to + 55 bp, masks TATA and transcription initiation) and repressor complex from core promoter, eventually initiates the transcription of PR-1a gene post SA treatment. While active chromatin marks di and trimethylation of H3K4, acetylation of H3K9 and H4K16 are increased which are associated to the transcription initiation of PR-1a following SA treatment. However, in uninduced state constitutive expression of a negative regulator (SNI1) of AtPR1, suppresses AtPR1 expression by six-fold in Arabidopsis thaliana. Further, we report 50-to-1000-fold increased expression of AtPR1 in uninduced lsd1 mutant plants, up to threefold increased expression of AtPR1 in uninduced histone acetyl transferases (HATs) mutant plants, SNI1 dependent negative regulation of AtPR1, all together our results suggest that inactive state of PR-1a is indeed maintained by a repressive complex. CONCLUSION: The study aimed to reveal the mechanism of transcription initiation of tobacco PR-1a gene in presence or absence of SA. This is the first study that reports nucleosome and repressor complex over core promoter region maintains the inactivation of gene in uninduced state, and upon induction disassembling of both initiates the downstream gene activation process.


Assuntos
Proteínas de Arabidopsis , Arabidopsis , Animais , Nucleossomos/genética , Nucleossomos/metabolismo , Ácido Salicílico/farmacologia , Ácido Salicílico/metabolismo , Nicotiana/genética , Nicotiana/metabolismo , Regiões Promotoras Genéticas/genética , Cromatina/metabolismo , Arabidopsis/genética , Arabidopsis/metabolismo , Epigênese Genética , Acetilação , Mamíferos/metabolismo , Proteínas Nucleares/genética , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo
14.
Int J Biometeorol ; 67(1): 67-77, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36264503

RESUMO

Due to the rapid increase in the novel coronavirus virulence, the entire world implemented the practice of lockdown along with the constraint of human movement. The obligation of quarantine halted most of the commercial and industrial movement that prominently disturbed the distinct key environmental parameters directly associated with the plant's and animal's health conditions. In this regard, the research aims to study the sudden shut-off of vehicular activity impact on the naturally growing lichen of the genus Pyxine cocoes. The results showed an increase in the pigments, Fv/Fm ratio, and phytohormones during the lockdown and concurrently the decreasing levels in the post-lockdown period. Interestingly, modulations in the phytohormones occur in the lockdown period as compared to the post-lockdown period. The metals Al, Cr, and Fe show the highest increasing trends in the unlocking period, whereas As, Cd, Pb, Cu, Hg, Mn, and Zn show very little variation during the running and post-lockdown phases. The lichen photosynthetic activity justifies further examination as initial biological indicators of the abrupt environmental variations prompted by such types of atmospheric situations and, to a greater extent, for the risk assessment in the near future. In conclusion, stress-phytohormone and amino acids play a significant role as stress reducers. Although lichens are well known for long environmental assessment, the present study will provide qualitative and quantitative variation in physiochemical changes in the short term and sudden environmental fluctuations. HIGHLIGHTS: • Qualitative and quantitative variation in biochemical parameters in lichen during and post-lockdown period was analyzed. • Stress-phytohormone and amino acids play a significant role as stress reducers. • Selectivity sequence reflection in heavy metal accumulation may be used in future studies.


Assuntos
COVID-19 , Líquens , Humanos , Líquens/química , Líquens/metabolismo , Reguladores de Crescimento de Plantas/metabolismo , Controle de Doenças Transmissíveis , Aminoácidos/metabolismo , Monitoramento Ambiental/métodos
15.
Front Plant Sci ; 13: 981295, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36212352

RESUMO

Blast [Magnaporthe grisea (Herbert) Barr] is an economically important disease in Asian pearl millet production ecologies. The recurrent occurrence of blast in the past one decade has caused enormous strain on grain and forage production. Identification of resistance genes is an important step to develop durable varieties. The present study is the first attempt to use RNA-Seq to investigate the transcript dynamics in a pearl millet inbred ICMB 93333, which had a unique differential reaction to two isolates-Pg 45 (avirulent) and Pg 174 (virulent) of M. grisea. The inbred was inoculated by both isolates and samples taken at six different time intervals for genome-wide RNA-Seq experiment. The transcriptome results revealed the differential expression of more than 2,300 genes. The time-specific comparison showed activation or repression of specific genes in various pathways. Genes and transcriptions factors related to pathogenesis-related proteins, reactive oxygen species generating and its scavenging genes, cell wall defense, primary and secondary metabolic pathways, and signaling pathways were identified by comparing the host-plant compatible and incompatible interactions. The genes identified from this experiment could be useful to understand the host-plant resistance and design novel strategies to manage blast disease in pearl millet.

16.
Indian J Plast Surg ; 55(2): 174-178, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-36017405

RESUMO

Gender affirmation laryngeal and voice surgeries are components of "voice-lift" or cosmetic voice surgeries. Feminization surgery can modify vocal folds (fundamental frequency [Fo]) and vocal tract (resonance frequency). For increased pitch, vocal folds should be shorter, thinner, and tighter. Cricothyroid approximation (CTA) surgery increases tension of the vocal folds. Endoscopic procedures for pitch raising are done by shortening the length and reducing mass of vocal folds. This shortening is achieved by surgically creating anterior glottic web. Comparing the results of various open and endoscopic surgical techniques, fundamental frequency (Fo) is raised maximally and remains stable after GL as compared with CTA.

17.
Sci Rep ; 12(1): 11062, 2022 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-35773307

RESUMO

Most cancer cells rely on aerobic glycolysis to support uncontrolled proliferation and evade apoptosis. However, pancreatic cancer cells switch to glutamine metabolism to survive under hypoxic conditions. Activation of the Wnt/ß-catenin pathway induces aerobic glycolysis by activating enzymes required for glucose metabolism and regulating the expression of glutamate transporter and glutamine synthetase. The results demonstrate that riluzole inhibits pancreatic cancer cell growth and has no effect on human pancreatic normal ductal epithelial cells. RNA-seq experiments identified the involvement of Wnt and metabolic pathways by riluzole. Inhibition of Wnt-ß-catenin/TCF-LEF pathway by riluzole suppresses the expression of PDK, MCT1, cMyc, AXIN, and CyclinD1. Riluzole inhibits glucose transporter 2 expression, glucose uptake, lactate dehydrogenase A expression, and NAD + level. Furthermore, riluzole inhibits glutamate release and glutathione levels, and elevates reactive oxygen species. Riluzole disrupts mitochondrial homeostasis by inhibiting Bcl-2 and upregulating Bax expression, resulting in a drop of mitochondrial membrane potential. Finally, riluzole inhibits pancreatic cancer growth in KPC (Pdx1-Cre, LSL-Trp53R172H, and LSL-KrasG12D) mice. In conclusion, riluzole can inhibit pancreatic cancer growth by regulating glucose and glutamine metabolisms and can be used to treat pancreatic cancer.


Assuntos
Neoplasias Pancreáticas , Riluzol , Via de Sinalização Wnt , beta Catenina , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Glutamina/metabolismo , Camundongos , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/metabolismo , Riluzol/farmacologia , Via de Sinalização Wnt/efeitos dos fármacos , beta Catenina/metabolismo , Neoplasias Pancreáticas
18.
Front Microbiol ; 13: 818714, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35602011

RESUMO

Mycolic acids are the key constituents of mycobacterial cell wall, which protect the bacteria from antibiotic susceptibility, helping to subvert and escape from the host immune system. Thus, the enzymes involved in regulating and biosynthesis of mycolic acids can be explored as potential drug targets to kill Mycobacterium tuberculosis (Mtb). Herein, Kyoto Encyclopedia of Genes and Genomes is used to understand the fatty acid metabolism signaling pathway and integrative computational approach to identify the novel lead molecules against the mtFabH (ß-ketoacyl-acyl carrier protein synthase III), the key regulatory enzyme of the mycolic acid pathway. The structure-based virtual screening of antimycobacterial compounds from ChEMBL library against mtFabH results in the selection of 10 lead molecules. Molecular binding and drug-likeness properties of lead molecules compared with mtFabH inhibitor suggest that only two compounds, ChEMBL414848 (C1) and ChEMBL363794 (C2), may be explored as potential lead molecules. However, the spatial stability and binding free energy estimation of thiolactomycin (TLM) and compounds C1 and C2 with mtFabH using molecular dynamics simulation, followed by molecular mechanics Poisson-Boltzmann surface area (MM/PBSA) indicate the better activity of C2 (ΔG = -14.18 kcal/mol) as compared with TLM (ΔG = -9.21 kcal/mol) and C1 (ΔG = -13.50 kcal/mol). Thus, compound C1 may be explored as promising drug candidate for the structure-based drug designing of mtFabH inhibitors in the therapy of Mtb.

19.
Front Plant Sci ; 13: 781524, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35463391

RESUMO

Pearl millet [Pennisetum glaucum (L.) R. Br.] is a C4 crop cultivated for its grain and stover in crop-livestock-based rain-fed farming systems of tropics and subtropics in the Indian subcontinent and sub-Saharan Africa. The intensity of drought is predicted to further exacerbate because of looming climate change, necessitating greater focus on pearl millet breeding for drought tolerance. The nature of drought in different target populations of pearl millet-growing environments (TPEs) is highly variable in its timing, intensity, and duration. Pearl millet response to drought in various growth stages has been studied comprehensively. Dissection of drought tolerance physiology and phenology has helped in understanding the yield formation process under drought conditions. The overall understanding of TPEs and differential sensitivity of various growth stages to water stress helped to identify target traits for manipulation through breeding for drought tolerance. Recent advancement in high-throughput phenotyping platforms has made it more realistic to screen large populations/germplasm for drought-adaptive traits. The role of adapted germplasm has been emphasized for drought breeding, as the measured performance under drought stress is largely an outcome of adaptation to stress environments. Hybridization of adapted landraces with selected elite genetic material has been stated to amalgamate adaptation and productivity. Substantial progress has been made in the development of genomic resources that have been used to explore genetic diversity, linkage mapping (QTLs), marker-trait association (MTA), and genomic selection (GS) in pearl millet. High-throughput genotyping (HTPG) platforms are now available at a low cost, offering enormous opportunities to apply markers assisted selection (MAS) in conventional breeding programs targeting drought tolerance. Next-generation sequencing (NGS) technology, micro-environmental modeling, and pearl millet whole genome re-sequence information covering circa 1,000 wild and cultivated accessions have helped to greater understand germplasm, genomes, candidate genes, and markers. Their application in molecular breeding would lead to the development of high-yielding and drought-tolerant pearl millet cultivars. This review examines how the strategic use of genetic resources, modern genomics, molecular biology, and shuttle breeding can further enhance the development and delivery of drought-tolerant cultivars.

20.
3 Biotech ; 12(3): 74, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35251877

RESUMO

A wound-inducible promoter facilitates the regulated gene expression at the targeted site during the time of mechanical stress or infestation by the pathogen. The present work has aimed to identify a wound-inducible promoter that expresses at early time points preceding wound-stress treatment in Arabidopsis thaliana. The computational analysis of microarray data (GSE5627) resulted in the identification of five early inducible genes, viz., AT1G17380, AT1G80440, AT2G43530, AT3G48360, and AT5G13220. The RT-PCR analysis showed AT5G13220 (JASMONATE-ASSOCIATED 1) gene induced at a significantly higher level post 30 min of wounding. Thus, the promoter of the highly induced and early expressed wound-inducible gene, AT5G13220 (named PW220), was characterized by fusing with ß-glucuronidase (gusA) reporter or Cry1EC genes. The fluorometric analysis and histochemical staining of the gusA gene and quantitative estimation of Cry1EC protein in Nicotiana tabacum transgenic lines confirmed wound-induced expression characteristic of the selected promoter. Insect bioassay suggested that wound-inducible and constitutive expression of Cry1EC protein in transgenic lines showed a similar level of protection against different instar Spodoptera litura larvae. Furthermore, we identified that abscisic acid influenced the wound-specific expression of the selected PW220 promoter in the transgenic lines, which correlates with the presence of conserved cis-regulatory elements associated with dehydration and abscisic acid responses. Altogether, our results suggested that the wound-inducible promoter PW220 provides an excellent alternative for developing insect-tolerant transgenic crops in the future. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13205-022-03143-0.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...