scholarly journals Unbiased Approach for the Identification of Molecular Mechanisms Sensitive to Chemical Exposures

2020 ◽  
Author(s):  
Alexander Suvorov ◽  
Victoria Salemme ◽  
Joseph McGaunn ◽  
Anthony Poluyanoff ◽  
Menna Teffera ◽  
...  
Keyword(s):  
Public Health ◽  
Cellular Response ◽  
Molecular Mechanisms ◽  
Future Research ◽  
Gene Interactions ◽  
Molecular Pathways ◽  
Toxic Response ◽  
Mechanisms Of Toxicity ◽  
Chemical Exposures

Background: Targeted methods that dominated toxicological research until recently did not allow for screening of all molecular changes involved in toxic response. Therefore, it is difficult to infer if all major mechanisms of toxicity have already been discovered, or if some of them are still overlooked. Objectives: To identify molecular mechanisms sensitive to chemical exposures in an unbiased manner. Methods: We used data on 641,516 unique chemical-gene interactions from the Comparative Toxicogenomic Database. Only data from high-throughput gene expression experiments with human, rat or mouse cells/tissues were extracted. The total number of chemical-gene interactions was calculated for every gene, and used as a measure of gene sensitivity to chemical exposures. These values were further used in enrichment analyses to identify molecular mechanisms sensitive to chemical exposures. Results: Remarkably, use of different input subsets with non-overlapping lists of chemical compounds identified largely the same genes and molecular pathways as most sensitive to chemical exposures, indicative of an unbiased nature of our analysis. One of the most important findings of this study is that almost every known molecular mechanism may be affected by chemical exposures. Predictably, xenobiotic metabolism pathways and mechanisms of cellular response to stress and damage were among the most sensitive. Additionally, our analysis identified a range of highly sensitive molecular pathways, which are not widely recognized by modern toxicology as major targets of toxicants, including lipid metabolism pathways, longevity regulation cascade and cytokine mediated signaling. Discussion: Molecular mechanisms identified as the most sensitive to chemical exposures are relevant for significant public health problems, such as aging, cancer, metabolic and autoimmune disease. Thus, public health system will likely benefit from future research focus on these sensitive molecular mechanisms. Additionally, approach used in this study may guide identification of priority adverse outcome pathways (AOP) for in-vitro and in-silico toxicity testing methods.

The role of probiotics and natural bioactive compounds in modulation of the common molecular pathways in pathogenesis of atherosclerosis and cancer

Biologia ◽  
2012 ◽  
Vol 67 (1) ◽  
pp. 1-13 ◽  
Author(s):  
Alojz Bomba ◽  
Andrea Brandeburová ◽  
Júlia Ričanyová ◽  
Ladislav Strojný ◽  
Anna Chmelárová ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Unsaturated Fatty Acids ◽  
Disease Risk ◽  
Disease Process ◽  
Experimental Models ◽  
Future Research ◽  
Molecular Pathways ◽  
Bioactive Substances

AbstractAtherosclerosis and cancer are ranked among the most serious health problems in human medicine. Various predictive and etiological factors, biomarkers and molecular pathways of disease development and progression common to atherosclerosis and cancer suggest that the two most common diseases in worldwide dimension are far more closely aligned than previously believed. It is hypothesized that atherosclerosis and cancer are variants of a similar disease process. Shared disease progression in atherosclerosis and cancer is the emergence of similar novel approaches to therapy. On previous knowledge, it may be hypothesized that not only common approaches to therapy but also preventive strategies could be efficacious in both diseases. The results of in vitro and in vivo animal experiments, clinical and epidemiological studies and also the results of our experiments using animal experimental models of atherosclerosis and carcinogenesis indicate that probiotics, prebiotics, plants and their extracts and poly-unsaturated fatty acids could be effectively used in prevention of both atherosclerosis and colorectal cancer and decrease the disease risk. Future research should answer the question whether probiotic microorganisms and natural bioactive substances could effectively influence the molecular mechanisms in pathogenesis of atherosclerosis and cancer.

Role of the ligand in intracellular receptor function: receptor affinity determines activation in vitro of the latent dioxin receptor to a DNA-binding form

1991 ◽  
Vol 11 (1) ◽  
pp. 401-411
Author(s):  
S Cuthill ◽  
A Wilhelmsson ◽  
L Poellinger
Keyword(s):  
Dna Binding ◽  
Cellular Response ◽  
Molecular Mechanisms ◽  
Nuclear Translocation ◽  
Rank Order ◽  
Receptor Ligands ◽  
Free System ◽  
Dioxin Receptor

To reconstitute the molecular mechanisms underlying the cellular response to soluble receptor ligands, we have exploited a cell-free system that exhibits signal- (dioxin-)induced activation of the latent cytosolic dioxin receptor to an active DNA-binding species. The DNA-binding properties of the in vitro-activated form were qualitatively indistinguishable from those of in vivo-activated nuclear receptor extracted from dioxin-treated cells. In vitro activation of the receptor by dioxin was dose dependent and was mimicked by other dioxin receptor ligands in a manner that followed the rank order of their relative affinities for the receptor in vitro and their relative potencies to induce target gene transcription in vivo. Thus, in addition to triggering the initial release of inhibition of DNA binding and presumably allowing nuclear translocation, the ligand appears to play a crucial role in the direct control of the level of functional activity of a given ligand-receptor complex.

scholarly journals Delphinidin and Its Glycosides’ War on Cancer: Preclinical Perspectives

2021 ◽  
Vol 22 (21) ◽  
pp. 11500
Author(s):  
Anshul Sharma ◽  
Hyo-Kyoung Choi ◽  
Yeon-Kye Kim ◽  
Hae-Jeung Lee
Keyword(s):  
Molecular Mechanisms ◽  
Future Research ◽  
Natural Health Products ◽  
Cell Protection ◽  
Anticancer Properties ◽  
Dietary Antioxidant ◽  
Health Products ◽  
Antioxidant Supplements

Until now, several studies have looked at the issue of anthocyanin and cancer, namely the preventive and inhibitory effects of anthocyanins, as well as the underlying molecular processes. However, no targeted review is available regarding the anticarcinogenic effects of delphinidin and its glycosides on various cancers and their plausible molecular mechanisms. Considerable evidence shows significant anticancer properties of delphinidin-rich preparations and delphinidin alone both in vitro and in vivo. This review covers the in vitro and preclinical implications of delphinidin-mediated cell protection and cancer prevention; thus, we strongly recommend that delphinidin-rich preparations be further investigated as potential functional food, dietary antioxidant supplements, and natural health products targeting specific chronic diseases, including cancer. In addition to in vitro investigations, future research should focus on more animal and human studies to determine the true potential of delphinidin.

scholarly journals Evaluation of radical scavenging system in amoeba Chaos carolinense during nutrient deprivation

2017 ◽  
Vol 7 (4) ◽  
pp. 20160113 ◽  
Author(s):  
Yuru Deng ◽  
Edlyn Li-Hui Lee ◽  
Ketpin Chong ◽  
Zakaria A. Almsherqi
Keyword(s):  
Oxidative Stress ◽  
Oxidative Damage ◽  
Nucleic Acids ◽  
Cellular Response ◽  
Molecular Mechanisms ◽  
Antioxidant Activities ◽  
Radical Scavenging ◽  
Cellular Responses ◽  
Biological Macromolecules

The frequent appearance of non-lamellar membrane arrangements such as cubic membranes (CMs) in cells under stressed or pathological conditions points to an intrinsic cellular response mechanism. CM represents highly curved, three-dimensional nano-periodic structures that correspond to mathematically well-defined triply periodic minimal surfaces. Specifically, cellular membrane may transform into CM organization in response to pathological, inflammatory and oxidative stress conditions. CM organization, thus, may provide an advantage to cope with various types of stress. The identification of inducible membrane systems, such as in the mitochondrial inner membranes to cubic morphology upon starvation, opens new avenues for understanding the molecular mechanisms of cellular responses to oxidative stress. In this study, we compared the cellular responses of starved and fed amoeba Chaos carolinense to oxidative stress. Food deprivation from C. carolinense induces a significant increase in prooxidants such as superoxide and hydrogen peroxide. Surprisingly, we observed a significant lower rate of biomolecular damage in starved cells (with higher free radicals generation) when compared with fed cells. Specifically, lipid and RNA damages were significantly less in starved cells compared with fed cells. This observation was not due to the upregulation of intracellular antioxidants, as starved amoeba show reduced antioxidant enzymatic activities; however, it could be attributed to CM formation. CM could uptake and retain short segments of nucleic acids (resembles cellular RNA) in vivo and in vitro. Previous results showed that nucleic acids retained within CM sustain a minimal oxidative damage in vitro upon exposure to high level of superoxide. We thus propose that CM may act as a ‘protective’ shelter to minimize the oxidation of biologically essential macromolecules such as RNA. In summary, we examined enzymatic antioxidant activities as well as oxidative damage biomarkers in starved amoeba C. carolinense in correlation with the potential role of CM as an optimal intracellular membrane organization for the protection of biological macromolecules against oxidative damage.

Food Derived Bioactive Peptides for Health Enhancement and Management of Some Chronic Diseases

2019 ◽  
pp. 1-11
Author(s):  
A. F. Ogori ◽  
A. T. Girgih ◽  
J. O. Abu ◽  
M. O. Eke
Keyword(s):  
Oxidative Stress ◽  
Chronic Diseases ◽  
Molecular Mechanisms ◽  
Bioactive Peptides ◽  
Food Sources ◽  
In Vivo Studies ◽  
Future Research ◽  
Target Cells

The bioactive peptides produced by enzymatic hydrolysis, acid hydrolysis and fermentation approach have been identified and used widely in research. These methods are important in enhancement or prevention and management of chronic diseases that are ravaging the world such as type -2-diabetes, hypertension, oxidative stress, cancer, and obesity. Sources of bioactive peptides have been established ranging from plant to animal and marine foods that have pharmacological effects; however these effects are dependent on target cells and peptides structure and conformations.  Plants such as hemp and animal source such as milk among others validate the findings of In vitro and In-vivo studies and the efficiency of these bioactive peptides in the management of certain chronic diseases. This article reviews the literature on bioactive peptides with concern on food sources, production and bioactive peptides application in enhancement of health and management of hypertension, diabetes and oxidative stress.  Future research efforts on bioactive peptides should be directed towards elucidating specific sequenced bioactive peptides and their molecular mechanisms, through In-vivo and In-vitro studies for specific health condition in human using nutrigenomics and peptideomic approaches.

scholarly journals Light quality affects the proliferation of in vitro cultured plantlets of Camellia oleifera Huajin

PeerJ ◽  
2020 ◽  
Vol 8 ◽  
pp. e10016
Author(s):  
Chaoyin He ◽  
Yanling Zeng ◽  
Yuzhong Fu ◽  
Jiahao Wu ◽  
Qin Liang
Keyword(s):  
Tissue Culture ◽  
Molecular Mechanisms ◽  
Light Quality ◽  
Southern China ◽  
Stomatal Density ◽  
Leaf Shape ◽  
Control Treatment ◽  
Future Research ◽  
Camellia Oleifera

Background Camellia oleifera is an important oil-yielding woody plant native to China. Tea oil extracted from the seeds is rich in health-beneficial compounds. Huajin is a high-yielding elite variety of C. oleifera, with large fruits and remarkable resilience, widely cultivated in southern China; however, its seedling quality tends to be uneven. At present, techniques such as grafting, and cuttings are primarily adopted to propagate C. oleifera. These approaches are susceptible to environmental constraints owing to the long growth period, resulting in the lack of C. oleifera seedlings. Methods to make the cultivation more economical are warranted; this can be facilitated by tissue culture technology to provide good-quality seedlings in a short time. Methods In vitro cultured plantlets of C. oleifera Huajin were exposed to red light (RL), blue light (BL), red:blue light at a 4:1 ratio (R4:B1), and red:blue light at a 1:4 ratio (R1:B4); white light (WL) was used as the control treatment. To investigate the influence of light spectral quality on the proliferation coefficient, photosynthetic pigments, soluble proteins, plant height, leaf shape, Rubisco enzyme activity, and stomata and leaf anatomical features. Results The highest proliferation coefficient was observed under combined red and blue (4:1) light. In addition, this treatment resulted in the second highest chlorophyll content, the thickest palisade and spongy tissues, and consequently, the thickest leaves. The same treatment resulted in the second highest stomatal density, albeit concomitantly with the smallest average stomatal length and width. Discussion These results indicate that high-quality propagation of Huajin shoots can be achieved by culturing the plants in vitro under a combination of red and blue (4:1) lights. Previous studies have shown that red and blue lights improve rooting and transplanting rates of tissue culture seedlings. Hence, future research should focus on the effect of light quality on rooting and transplanting of tissue culture plantlets of Huajin and its specific molecular mechanisms.

scholarly journals Food Derived Bioactive Peptides for Health Enhancement and Management of Some Chronic Diseases

2019 ◽  
pp. 1-11
Author(s):  
A. F. Ogori ◽  
A. T. Girgih ◽  
J. O. Abu ◽  
M. O. Eke
Keyword(s):  
Oxidative Stress ◽  
Chronic Diseases ◽  
Molecular Mechanisms ◽  
Bioactive Peptides ◽  
Food Sources ◽  
In Vivo Studies ◽  
Future Research ◽  
Target Cells

The bioactive peptides produced by enzymatic hydrolysis, acid hydrolysis and fermentation approach have been identified and used widely in research. These methods are important in enhancement or prevention and management of chronic diseases that are ravaging the world such as type -2-diabetes, hypertension, oxidative stress, cancer, and obesity. Sources of bioactive peptides have been established ranging from plant to animal and marine foods that have pharmacological effects; however these effects are dependent on target cells and peptides structure and conformations.  Plants such as hemp and animal source such as milk among others validate the findings of In vitro and In-vivo studies and the efficiency of these bioactive peptides in the management of certain chronic diseases. This article reviews the literature on bioactive peptides with concern on food sources, production and bioactive peptides application in enhancement of health and management of hypertension, diabetes and oxidative stress.  Future research efforts on bioactive peptides should be directed towards elucidating specific sequenced bioactive peptides and their molecular mechanisms, through In-vivo and In-vitro studies for specific health condition in human using nutrigenomics and peptideomic approaches.

scholarly journals In silico drug discovery strategies identified ADMET properties of decoquinate RMB041 and its potential drug targets against Mycobacterium Tuberculosis

2021 ◽  
Author(s):  
Kirsten Elke Knoll ◽  
Mietha M. van der Walt ◽  
Du toit Loots
Keyword(s):  
Mycobacterium Tuberculosis ◽  
In Silico ◽  
Drug Targets ◽  
Cellular Response ◽  
Molecular Mechanisms ◽  
Antimicrobial Agents ◽  
Screening Methods ◽  
Discovery Studio ◽  
Optimal Drug

The highly adaptive cellular response of Mycobacterium tuberculosis to various antibiotics and the high costs for clinical trials, hampers the development of novel antimicrobial agents with improved efficacy and safety. Subsequently, in silico drug screening methods are more commonly being used for the discovery and development of drugs, and have been proven useful for predicting the pharmacokinetics, toxicities, and targets, of prospective new antimicrobial agents. In this investigation, we used a reversed target fishing approach to determine potential hit targets and their possible interactions between M. tuberculosis and decoquinate RMB041, a propitious new antituberculosis compound. Two of the thirteen identified targets, Cyp130 and BlaI, were strongly proposed as optimal drug-targets for dormant M. tuberculosis, of which the first showed the highest comparative binding affinity to decoquinate RMB041. The metabolic pathways associated to the selected target proteins were compared to previously published molecular mechanisms of decoquinate RMB041 against M. tuberculosis, whereby we confirmed disrupted metabolism of proteins, cell wall components, and DNA. We also described the steps within these pathways that are inhibited and elaborated on decoquinate RMB041's activity against dormant M. tuberculosis. This compound has previously showed promising in vitro safety and good oral bioavailability, which were both supported by this in silico study. The pharmacokinetic properties and toxicity of this compound were predicted and investigated using the online tools pkCSM and SwissADME, and Discovery Studio software, which furthermore supports previous safety and bioavailability characteristics of decoquinate RMB041 for use as an antimycobacterial medication.

scholarly journals Genes encoding proteins regulating fatty acid metabolism and cellular response to lipids are differentially expressed in porcine luminal epithelium during long-term culture

2019 ◽  
Vol 7 (2) ◽  
pp. 58-65
Author(s):  
Magdalena Kulus ◽  
Blanka Borowiec ◽  
Małgorzata Popis ◽  
Piotr Celichowski ◽  
Michal Jeseta ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Epithelial Cells ◽  
Cellular Response ◽  
Molecular Mechanisms ◽  
In Vitro Cultivation ◽  
Beta Oxidation ◽  
Physiological Processes ◽  
Genes Encoding ◽  
Fatty Acid Beta Oxidation

AbstractAmong many factors, the epithelium lining the oviductal lumenis very important for the development of the oocyte and its subsequent fertilization. The oviductal epithelium is characterized by the presence of ciliary cells, supporting the movement of cumulus-oocyte complexes towards the uterus. By interacting with the semen, the epithelium of the fallopian tube makes the sperm acquire the ability to fertilize. So far, the exact molecular mechanisms of these changes have not been known. Hence, understanding the metabolism of oviduct epithelial cells and the level of expression of individual groups of genes seems to be a way to deepen the knowledge about the broadly understood reproduction.In our research, we decided to culture oviductal epithelial cells (OECs) in vitro for a long period of time. After 24h, 7, 15 and 30 days, the OECs were harvested, with their RNA isolated. Transcriptomic changes were analyzed using microarrays. The “cellular response to lipid” group was represented by the following genes: MUC1, CYP24A1, KLF4, IL24, SNAI2, CXCL10, PPARD, TNC, ABCA10, while the genes belonging to the “cellular lipid metabolic processes” were: LIPG, ARSK, ACADL, FADS3, P2RX7, ACSS2, PPARD, KITLG, SPTLC3, ERBB3, KLF4, CRABP2. Additionally, PPARD and ACADL were members of the “fatty acid beta-oxidation” ontology group. Our study describes genes that are not directly related to fertility processes. However, significant changes in their expression in in vitro cultured OECs may indicate their usefulness as markers of OECs’ physiological processes.Running title: Fatty acids changes in porcine oviductal epithelial cells in in vitro cultivation

scholarly journals Coagulotoxic Cobras: Clinical Implications of Strong Anticoagulant Actions of African Spitting Naja Venoms That Are Not Neutralised by Antivenom but Are by LY315920 (Varespladib)

Toxins ◽  
2018 ◽  
Vol 10 (12) ◽  
pp. 516 ◽  
Author(s):  
Mátyás A. Bittenbinder ◽  
Christina N. Zdenek ◽  
Bianca op den Brouw ◽  
Nicholas J. Youngman ◽  
James S. Dobson ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Area Under The Curve ◽  
Factor Xa ◽  
Well Being ◽  
Coagulation Cascade ◽  
Clotting Factor ◽  
Future Research ◽  
Thrombin Inhibition ◽  
Clinically Significant

Snakebite is a global tropical disease that has long had huge implications for human health and well-being. Despite its long-standing medical importance, it has been the most neglected of tropical diseases. Reflective of this is that many aspects of the pathology have been underinvestigated. Snakebite by species in the Elapidae family is typically characterised by neurotoxic effects that result in flaccid paralysis. Thus, while clinically significant disturbances to the coagulation cascade have been reported, the bulk of the research to date has focused upon neurotoxins. In order to fill the knowledge gap regarding the coagulotoxic effects of elapid snake venoms, we screened 30 African and Asian venoms across eight genera using in vitro anticoagulant assays to determine the relative inhibition of the coagulation function of thrombin and the inhibition of the formation of the prothrombinase complex through competitive binding to a nonenzymatic site on Factor Xa (FXa), thereby preventing FXa from binding to Factor Va (FVa). It was revealed that African spitting cobras were the only species that were potent inhibitors of either clotting factor, but with Factor Xa inhibited at 12 times the levels of thrombin inhibition. This is consistent with at least one death on record due to hemorrhage following African spitting cobra envenomation. To determine the efficacy of antivenom in neutralising the anticoagulant venom effects, for the African spitting cobras we repeated the same 8-point dilution series with the addition of antivenom and observed the shift in the area under the curve, which revealed that the antivenom performed extremely poorly against the coagulotoxic venom effects of all species. However, additional tests with the phospholipase A2 inhibitor LY315920 (trade name: varespladib) demonstrated a powerful neutralisation action against the coagulotoxic actions of the African spitting cobra venoms. Our research has important implications for the clinical treatment of cobra snakebites and also sheds light on the molecular mechanisms involved in coagulotoxicity within Naja. As the most coagulotoxic species are also those that produce characteristic extreme local tissue damage, future research should investigate potential synergistic actions between anticoagulant toxins and cytotoxins.

Sign in / Sign up

Export Citation Format

Share Document