molecular functions
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2021 ◽  
pp. 101401
Author(s):  
Shahina Akhter ◽  
Walid Hossain ◽  
Sharmin Sultana ◽  
Zannatul Ferdous Jharna ◽  
Nigar Sultana Meghla ◽  
...  

2021 ◽  
Vol 2021 ◽  
pp. 1-14
Author(s):  
Chenghao Lv ◽  
Caiqiong Wang ◽  
Ping Li ◽  
Yiwen Huang ◽  
Xiangyang Lu ◽  
...  

Garlic organic sulfides are dietary bioactive components with multiple biofunctions to prevent chronic diseases/inflammation and promote human health. DADS (diallyl disulfide), DATS (diallyl trisulfide), and DTS (diallyl tetrasulfide) are typical organic sulfides with similar structures from garlic. However, the structure-activity relationship of garlic organic sulfides remained unknown. The aim of the present study was to investigate the effect of DADS, DATS, and DTS on the gene expression profiling of human hepatocellular carcinoma cells (HepG2) by application of microarray and specialized analysis software, GO, Bio-Plex-based cytokines assay and IPA and analyze their structure-activity relationship according to antioxidant, anti-inflammatory, and metabolic-related properties. According to the microarray data, with the increase of S atom in garlic organic sulfides, its biological activity was gradually enhanced. In the general catalog of GO, garlic organic sulfides mainly affect biological process, molecular function, and cellular component. RT-qPCR results indicated that the microarray data is trustworthy, and the structure-activity analysis data found that more sulfur atoms have more powerful properties; thus, microarray data of DTS was preceded to the subsequent IPA analysis. The results of IPA analysis showed that the top 5 signaling pathways and molecular functions were disturbed by DTS; the molecular functions with the highest scores affected by DTS are cancer, cell apoptosis, and cell proliferation, which imply that the occurrence or metabolism of these diseases is related to the differential expression of the above-mentioned related genes and the activation of signaling channels, and the core of the most significant molecular network is inflammation. Finally, the results found that the secretions of 6 cytokines in macrophages were significantly inhibited by DTS treatment. This is the first study that analyzed the structure-activity relationship of garlic organic sulfides, which will provide useful genetic information for its multi-biofunction and promote their clinical application in the near future.


2021 ◽  
Vol 22 (23) ◽  
pp. 12757
Author(s):  
Sung-jun Jung ◽  
Hyun Kim

Most secreted and membrane proteins are targeted to and translocated across the endoplasmic reticulum (ER) membrane through the Sec61 protein-conducting channel. Evolutionarily conserved Sec62 and Sec63 associate with the Sec61 channel, forming the Sec complex and mediating translocation of a subset of proteins. For the last three decades, it has been thought that ER protein targeting and translocation occur via two distinct pathways: signal recognition particle (SRP)-dependent co-translational or SRP-independent, Sec62/Sec63 dependent post-translational translocation pathway. However, recent studies have suggested that ER protein targeting and translocation through the Sec translocon are more intricate than previously thought. This review summarizes the current understanding of the molecular functions of Sec62/Sec63 in ER protein translocation.


2021 ◽  
Author(s):  
Violeta Larios-Serrato ◽  
José Darío Martínez-Ezquerro ◽  
Hilda-Alicia Valdez-Salazar ◽  
Javier Torres ◽  
Margarita Camorlinga-Ponce ◽  
...  

Gastric cancer (GC) is a malignancy with the highest mortality among diseases of the digestive system worldwide. The study of GC-alterations is crucial to understand tumor biology, to establish important aspects of cancer prognosis and treatment response. Here, we purified DNA and performed whole-genome analysis with high-density arrays in samples from Mexican patients diagnosed with GC: diffuse (DGC) or intestinal (IGC), or non-atrophic gastritis (NAG) samples that served as controls. We identified shared and unique copy number alterations (CNA) between these altered tissues involving key genes and signaling pathways associated with cancer, allowing their molecular distinction and identification of the most relevant molecular functions impacted. When focused on epithelial-mesenchymal transition (EMT) genes, our bioinformatic analysis revealed that the altered network associated with chromosomal alterations included 11 genes shared between DGC, IGC, and NAG, as well as 19 DGC- and 7 IGC-exclusive genes, whose main molecular functions included adhesion, angiogenesis, migration, metastasis, morphogenesis, proliferation, and survival. This study presents the first whole-genome high-density array study in GC from Mexican patients and reveals shared and exclusive CNA-genes in DGC and IGC. In addition, we provide a bioinformatically predicted network focused on CNA-altered genes involved in the EMT, associated with the hallmarks of cancer, as well as precancerous alterations that could lead to gastric cancer. Implications: Molecular signatures of diffuse and intestinal GC, predicted bioinformatically, involve common and distinct CNA-EMT genes related to the hallmarks of cancer that are potential candidates for screening GC biomarkers, including early stages.


Animals ◽  
2021 ◽  
Vol 11 (11) ◽  
pp. 3286
Author(s):  
Purichaya Disbanchong ◽  
Wichayaporn Punmanee ◽  
Anyaphat Srithanasuwan ◽  
Noppason Pangprasit ◽  
Kanruethai Wongsawan ◽  
...  

Herbal phytochemicals featuring active ingredients including quercetin and curcumin have shown potential in treating human and animal diseases. The current study investigated their potential function in vitro for host immunomodulation associated with Streptococcus agalactiae subclinical bovine mastitis via milk-isolated neutrophils. Our results showed a positive influence on cellular migration, reactive oxygen species (ROS) generation, phagocytosis, and bacterial killing as well as neutrophil extracellular traps (NETs) release. This study also highlighted several important molecular aspects of quercetin and curcumin in milk-isolated neutrophils. Gene expression analyses by RT-PCR revealed significant changes in the expression of proinflammatory cytokines (IL1B, IL6, and TNF), ROS (CYBA), phagocytosis (LAMP1), and migration (RAC). The expression levels of apoptotic genes or proteins in either pro-apoptosis (CASP3 and FAS) or anti-apoptosis (BCL2, BCL2L1, and CFLAR) were significantly manipulated by the effects of either quercetin or curcumin. A principal component analysis (PCA) identified the superior benefit of quercetin supplementation for increasing both cellular and molecular functions in combating bacterial mastitis. Altogether, this study showed the existing and potential benefits of these test compounds; however, they should be explored further via in vivo studies.


Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1869-1869
Author(s):  
Juan L Coelho-Silva ◽  
Diego A Pereira-Martins ◽  
Virginia Campos Silvestrini ◽  
João Agostinho Machado-Neto ◽  
Eduardo M Rego ◽  
...  

Abstract Background: Preclinical rationale for targeting the insulin-like growth factor 1 (IGF1R)-Insulin Receptor Substrates 1 and 2 (IRS1/2) signaling in acute myeloid leukemia (AML), particularly in cells harboring the FLT3-ITD mutation, has been recently provided [Blood (2018) 132 Supp: 1512 and [Blood (2019) 134 Supp: 2689]. However, little is known about the non-canonical molecular mechanisms regulated by IGF1R-IRS1/2 signaling and pharmacological inhibition of this pathway in AML. Aims: To depict distinctive non-explicit molecular effects of linsitinib (IGF1R tyrosine kinase inhibitor) and NT157 (IGF1R-IRS1/2 allosteric inhibitor) treatment in FLT3-ITD-mutated AML cells. Material and methods: The MOLM-13 (homozygous) and MV4-11 (heterozygous) FLT3-ITD-mutated AML cell lines were treated with linsitinib (10 µM) or NT157 (1 µM) for 24 hours and used for label-free proteomic quantification analysis (n=3). Raw MS/MS data were processed using the SORCERER system and proteins were identified with built-in Andromeda search engine based on the human Uniprot proteome database. False discovery rate cutoffs were set to 1% on peptide, protein, and site decoy level, only allowing high quality identification to pass. Expression values were normalized across experimental conditions by quantile normalization based on the Limma-Voom pipeline, and then systematically compared similarities and differences in protein expression across experimental conditions by applying the Benjamin-Hochberg correction for multiple comparisons. To depict pathways associated to IGF1R, IRS1 and IRS2 gene expression related to processes identified by the proteomic data, we performed a gene-set enrichment analysis (GSEA) using the curated genesets for oncogenic events and molecular functions (MSigDB, Broad Institute) from RNA-seq data of the Cancer Genome Atlas AML cohort (n=173). Results: Considering a ≥ 2-fold change difference in both directions, linsitinib treatment downregulated 6 and 18 and upregulated 13 and 116 proteins in MOLM-13 and MV4-11 cells, respectively. Likewise, NT157 downregulated 12 and 126 and upregulated 204 and 297 proteins. When compared directly, linsitinib reduced expression of 11 and 35 and increased expression of 110 and 70 proteins in MOLM-13 and MV4-11 cells, respectively. Gene ontology identified that linsitinib resulted in upregulation of 7 molecular functions, while the NT157 ensued the upregulation of 18 and downregulation of 17 molecular functions pathways in a consistently manner between all comparisons. Of note, linsitinib activates post-transcriptional regulatory mechanisms, RNA metabolism (RNA binding P=1.15E-12; RNA processing P=8.64E-7) and reduced the protein and macromolecule metabolism (cellular protein metabolism P=3.86E-6). NT157 affected several of mitochondrial functions (increasing proton transmembrane transport activity P=1.55E-12, reducing oxidoreductase activity P=9.11E-10, and oxidative phosphorylation P=5.19E-8). Altogether, these data highlighted that NT157 profounder cytotoxic effect is a result of reprogramming of cellular energetics metabolism, and that linsitinib altered transcription and translation processes, probably as a result of autophagy, a mechanism originally described by our group [Blood (2017) 130 Supp: 3966]. GSEA analysis revealed that high IGF1R expression is positively enriched with RPS14 signature (Normalized Enriched Score [NES]=2.23; FDR-q<0.001), a ribosomal protein related to pathophysiology of myeloid neoplasms related to chromosome 5q deletion. Both IRS1 and IRS2 transcriptional signatures were associated with cellular growth signaling, such as AKT (NES=1.86; FDR-q= 0.006) and MYC (NES=1.67; FDR-q= 0.005), mitochondrial function [mitochondrial gene expression (NES=1.71; FDR-q= 0.001)]. Conclusion: Our proteomic data shed light on new and non-explicit mechanisms related to IGF1R-IRS1/2 inhibitors. Linsitinib modulates molecular processes related to RNA transcription and translation, while NT157 profoundly affect the cellular energetics, and, at least in part, explain the differential pre-clinical efficiency. Moreover, allosteric pharmacological inhibition of IGF1R-IRS1/2 pathway seems a more promising strategy than the tyrosine kinase inhibition, especially for AML subgroup more dependent of mitochondrial metabolism, such as AML with FLT3 mutation. Disclosures No relevant conflicts of interest to declare.


Author(s):  
J. Eduardo Martinez-Hernandez ◽  
Zaynab Hammoud ◽  
Alessandra Mara de Sousa ◽  
Frank Kramer ◽  
Rubens L. do Monte-Neto ◽  
...  

This work opens a new path to fight parasites by targeting host molecular functions by repurposing available and approved drugs. We created a novel approach to identify key proteins involved in any biological process by combining gene regulatory networks and expression profiles.


2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Man Wang ◽  
Feng Zhou ◽  
Hong Mei Wang ◽  
De Xing Xue ◽  
Yao-Guang Liu ◽  
...  

Abstract Background Plant mitochondrial transcription termination factor (mTERF) family members play important roles in development and stress tolerance through regulation of organellar gene expression. However, their molecular functions have yet to be clearly defined. Results Here an mTERF gene V14 was identified by fine mapping using a conditional albino mutant v14 that displayed albinism only in the first two true leaves, which was confirmed by transgenic complementation tests. Subcellular localization and real-time PCR analyses indicated that V14 encodes a chloroplastic protein ubiquitously expressed in leaves while spiking in the second true leaf. Chloroplastic gene expression profiling in the pale leaves of v14 through real-time PCR and Northern blotting analyses showed abnormal accumulation of the unprocessed transcripts covering the rpoB-rpoC1 and/or rpoC1-rpoC2 intercistronic regions accompanied by reduced abundance of the mature rpoC1 and rpoC2 transcripts, which encode two core subunits of the plastid-encoded plastid RNA polymerase (PEP). Subsequent immunoblotting analyses confirmed the reduced accumulation of RpoC1 and RpoC2. A light-inducible photosynthetic gene psbD was also found down-regulated at both the mRNA and protein levels. Interestingly, such stage-specific aberrant posttranscriptional regulation and psbD expression can be reversed by high temperatures (30 ~ 35 °C), although V14 expression lacks thermo-sensitivity. Meanwhile, three V14 homologous genes were found heat-inducible with similar temporal expression patterns, implicating their possible functional redundancy to V14. Conclusions These data revealed a critical role of V14 in chloroplast development, which impacts, in a stage-specific and thermo-sensitive way, the appropriate processing of rpoB-rpoC1-rpoC2 precursors and the expression of certain photosynthetic proteins. Our findings thus expand the knowledge of the molecular functions of rice mTERFs and suggest the contributions of plant mTERFs to photosynthesis establishment and temperature acclimation.


2021 ◽  
Author(s):  
Shuang Han ◽  
Qingchen Zhang ◽  
Xiaoqin Zhu ◽  
Dongli Pei

Abstract Low light is a primary regulator of chrysanthemum growth. Herein, we conducted a transcriptomic analysis of leaf samples from the ‘Nannonggongfen’ and ‘Nannongxuefeng’ chrysanthemum cultivars following a 5-day exposure to optimal light (70%, control [CK]) or low-light (20%, LL) conditions. Gene Ontology (GO) classification of upregulated genes revealed these genes to be associated with 11 cellular components, 9 molecular functions, and 15 biological processes, with the majority being localized to the chloroplast, highlighting the role of chloroplast proteins as regulators of shading tolerance. Downregulated genes were associated with 11 cellular components, 8 molecular functions, and 16 biological processes. Heat map analyses suggested that basic helix–loop–helix domain genes and elongation factors were markedly downregulated in ‘Nannongxuefeng’ leaves, consistent with the maintenance of normal stem length, whereas no comparable changes were observed in ‘Nanonggongfen’ leaves. Subsequent qPCR analyses revealed that phytochrome-interacting factors and dormancy-associated genes were significantly upregulated under LL conditions relative to CK conditions, while succinate dehydrogenase 1, elongated hypocotyls 5, and auxin-responsive gene of were significantly downregulated under LL conditions. These findings suggest that LL plants were significantly lower than those of the CK plants. Low-light tolerant chrysanthemum cultivars may maintain reduced indole-3-acetic acid (IAA) and elongation factor expression as a means of preventing the onset of shade-avoidance symptoms.


Author(s):  
Shaohui Chen ◽  
Xiangyang Deng ◽  
Hansong Sheng ◽  
Yuxi Rong ◽  
Yanhao Zheng ◽  
...  

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