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1.
Adv Exp Med Biol ; 1339: 409-414, 2021.
Article in English | MEDLINE | ID: mdl-35023133

ABSTRACT

MicroRNAs (miRNAs) are small noncoding regulatory RNA molecules that play a significant role in targeted downregulation of gene expression by RNA silencing and posttranscriptional regulation. Mounting evidence of recent studies indicates that there is dysregulation of expression level of a wide range of miRNAs in a variety of cardiovascular diseases related to thrombosis including venous thromboembolism, coronary artery disease, stroke, and myocardial infarction. In this review, the current knowledge on the role of miRNAs in thrombosis is discussed. Future research may further unravel the involvement of miRNAs in the pathogenesis of thrombosis as well as possibly clarify the clinical usefulness of miRNAs as biomarkers and potential therapeutic targets.


Subject(s)
MicroRNAs , Myocardial Infarction , Thrombosis , Biomarkers , Gene Expression Regulation , Humans , MicroRNAs/genetics , RNA Interference , Thrombosis/genetics
2.
J Physiol Pharmacol ; 72(4)2021 Aug.
Article in English | MEDLINE | ID: mdl-34987126

ABSTRACT

5-aminosalicylic acid (5-ASA) is commonly used as the first-line treatment for ulcerative colitis (UC). In this study, we show that the mechanism responsible for the protective effect of 5-ASA is associated with the modulation of non-coding microRNA molecule (miRNA) expression. Stimulation of human intestinal epithelial cells (Caco-2) with 1000 µM of 5-ASA suppressed the levels of miR-125b, miR-150, miR-155, miR-346 and miR-506, which are known to be involved in the regulation of colitis and/or colorectal cancer in patients with inflammatory bowel disease. The 5-ASA-induced inhibitions of these miRNAs were associated with significant inductions of their target genes such as vitamin D receptor (VDR), suppressor of cytokine signaling (SOCS1), Forkhead box O (FOXO3a) and DNA methyltransferase 1 (DNMT1). The relationships between the selected miRNAs and their target genes were further confirmed in Caco-2 cells transfected of with specific miRNA inhibitors or miRNA mimics. Moreover, we showed that 5-ASA has the potential to hinder miR-155 expression induced by the transfection of miR-155 mimic into Caco-2 cells. These findings underline the anti-inflammatory and chemoprotective effects of 5-ASA treatment.


Subject(s)
Colitis, Ulcerative , MicroRNAs , Caco-2 Cells , Colitis, Ulcerative/drug therapy , Colitis, Ulcerative/genetics , Gene Expression Regulation , Humans , Mesalamine/pharmacology , MicroRNAs/genetics
3.
BMC Bioinformatics ; 23(1): 13, 2022 Jan 05.
Article in English | MEDLINE | ID: mdl-34986805

ABSTRACT

BACKGROUND: The temporal progression of many fundamental processes in cells and organisms, including homeostasis, differentiation and development, are governed by gene regulatory networks (GRNs). GRNs balance fluctuations in the output of their genes, which trace back to the stochasticity of molecular interactions. Although highly desirable to understand life processes, predicting the temporal progression of gene products within a GRN is challenging when considering stochastic events such as transcription factor-DNA interactions or protein production and degradation. RESULTS: We report a method to simulate and infer GRNs including genes and biochemical reactions at molecular detail. In our approach, we consider each network element to be isolated from other elements during small time intervals, after which we synchronize molecule numbers across all network elements. Thereby, the temporal behaviour of network elements is decoupled and can be treated by local stochastic or deterministic solutions. We demonstrate the working principle of this modular approach with a repressive gene cascade comprising four genes. By considering a deterministic time evolution within each time interval for all elements, our method approaches the solution of the system of deterministic differential equations associated with the GRN. By allowing genes to stochastically switch between on and off states or by considering stochastic production of gene outputs, we are able to include increasing levels of stochastic detail and approximate the solution of a Gillespie simulation. Thereby, CaiNet is able to reproduce noise-induced bi-stability and oscillations in dynamically complex GRNs. Notably, our modular approach further allows for a simple consideration of deterministic delays. We further infer relevant regulatory connections and steady-state parameters of a GRN of up to ten genes from steady-state measurements by identifying each gene of the network with a single perceptron in an artificial neuronal network and using a gradient decent method originally designed to train recurrent neural networks. To facilitate setting up GRNs and using our simulation and inference method, we provide a fast computer-aided interactive network simulation environment, CaiNet. CONCLUSION: We developed a method to simulate GRNs at molecular detail and to infer the topology and steady-state parameters of GRNs. Our method and associated user-friendly framework CaiNet should prove helpful to analyze or predict the temporal progression of reaction networks or GRNs in cellular and organismic biology. CaiNet is freely available at https://gitlab.com/GebhardtLab/CaiNet .


Subject(s)
Gene Expression Regulation , Gene Regulatory Networks , Algorithms , Computer Simulation , Kinetics , Models, Genetic , Stochastic Processes , Transcription Factors
4.
BMC Genomics ; 23(1): 5, 2022 Jan 05.
Article in English | MEDLINE | ID: mdl-34983375

ABSTRACT

BACKGROUND: Aspergillus flavus, one of the causative agents of human fungal keratitis, can be phagocytosed by human corneal epithelial (HCE) cells and the conidia containing phagosomes mature into phagolysosomes. But the immunological responses of human corneal epithelial cells interacting with A. flavus are not clear. In this study, we report the expression of immune response related genes of HCE cells exposed to A. flavus spores using targeted transcriptomics. METHODS: Human corneal epithelial cell line and primary cultures were grown in a six-well plate and used for coculture experiments. Internalization of the conidia was confirmed by immunofluorescence microscopy of the colocalized endosomal markers CD71 and LAMP1. Total RNA was isolated, and the quantity and quality of the isolated RNA were assessed using Qubit and Bioanalyzer. NanoString nCounter platform was used for the analysis of mRNA abundance using the Human Immunology panel. R-package and nSolver software were used for data analysis. KEGG and FunRich 3.1.3 tools were used to analyze the differentially expressed genes. RESULTS: Different morphotypes of conidia were observed after 6 h of coculture with human corneal epithelial cells and found to be internalized by epithelial cells. NanoString profiling showed more than 20 differentially expressed genes in immortalized human corneal epithelial cell line and more than ten differentially expressed genes in primary corneal epithelial cells. Distinct set of genes were altered in their expression in cell line and primary corneal epithelial cells. KEGG pathway analysis revealed that genes associated with TNF signaling, NF-KB signaling, and Th17 signaling were up-regulated, and genes associated with chemokine signaling and B cell receptor signaling were down regulated. FunRich pathway analysis showed that pathways such as CDC42 signaling, PI3K signaling, and Arf6 trafficking events were activated by the clinical isolates CI1123 and CI1698 in both type of cells. CONCLUSIONS: Combining the transcript analysis data from cell lines and primary cultures, we showed the up regulation of immune defense genes in A. flavus infected cells. At the same time, chemokine signaling and B cell signaling pathways are downregulated. The variability in the expression levels in the immortalized cell line and the primary cultures is likely due to the variable epigenetic reprogramming in the immortalized cells and primary cultures in the absence of any changes in the genome. It highlights the importance of using both cell types in host-pathogen interaction studies.


Subject(s)
Aspergillus flavus , Epithelial Cells/immunology , Gene Expression Regulation/immunology , Aspergillus flavus/genetics , Cell Line , Chemokines/immunology , Cornea/cytology , Cornea/microbiology , Epithelial Cells/microbiology , Humans , Immunity , Signal Transduction , Spores, Fungal
5.
Anticancer Res ; 42(1): 609-617, 2022 Jan.
Article in English | MEDLINE | ID: mdl-34969770

ABSTRACT

BACKGROUND/AIM: We generated a novel disease mouse model in which a fructose-containing western diet (FD) induces development of non-alcoholic steatohepatitis (NASH). MATERIALS AND METHODS: C57BL/6J mice were fed FD for 60 weeks and body weight and blood pressure were monitored. Plasma cholesterol level was measured at the end of the experiments. Histopathology of NASH was examined by hematoxylin and eosin staining, Masson-Trichrome staining, periodic acid-Schiff staining, and immunohistochemistry against a proliferation marker. Circadian gene expression levels were compared by sampling the livers in 4-h intervals, followed by quantitative RT-PCR analysis. RESULTS: FD-fed mice developed obesity, transient hypertension, hypercholesterolemia, and liver adiposity. The mice spontaneously developed hepatic nodules, which were diagnosed as non-neoplastic nodular regenerative hyperplasia. FD-fed mice had increased expression of growth factor genes and cirrhosis markers compared to control mice. Circadian expression of lipid metabolism genes was deregulated by FD intake. CONCLUSION: C57BL/6J mice fed FD developed non-alcoholic steatohepatitis and nodular regenerative hyperplasia over time.


Subject(s)
Hyperplasia/genetics , Lipid Metabolism/genetics , Non-alcoholic Fatty Liver Disease/genetics , Obesity/genetics , Animals , Cholesterol/blood , Diet, Western/adverse effects , Disease Models, Animal , Fructose/adverse effects , Fructose/pharmacology , Gene Expression Regulation/drug effects , Humans , Hyperplasia/etiology , Hyperplasia/metabolism , Hyperplasia/pathology , Liver/metabolism , Liver/pathology , Mice , Non-alcoholic Fatty Liver Disease/etiology , Non-alcoholic Fatty Liver Disease/metabolism , Non-alcoholic Fatty Liver Disease/pathology , Obesity/etiology , Obesity/metabolism , Obesity/pathology
6.
PLoS One ; 16(12): e0259896, 2021.
Article in English | MEDLINE | ID: mdl-34972101

ABSTRACT

Magnolol is a bioactive polyphenolic compound commonly found in Magnolia officinalis. The aim of this study is to clarify the contribution of the magnolol additive on the growth performance of Linwu ducklings aging from 7 to 28 d, comparing to the effects of antibiotic additive (colistin sulphate). A total of 325, 7-d-old ducklings were assigned to 5 groups. Each group had 5 cages with 13 ducklings in each cage. The ducklings in different groups were fed with diets supplemented with 0, 100, 200 and 300 mg/kg magnolol additive (MA) (Control, MA100, MA200 and MA300) and 30 mg/kg colistin sulphate (CS30) for 3 weeks, respectively. Parameters regarding to the growth performance, intestinal mucosal morphology, serum biochemical indices, antioxidant and peroxide biomarkers and the expression levels of antioxidant-related genes were evaluated by one way ANOVA analysis. The results showed that 30 mg/kg colistin sulphate, 200 and 300 mg/kg magnolol additive improved the average final weight (P = 0.045), average daily body weight gain (P = 0.038) and feed/gain ratios (P = 0.001) compared to the control group. 200 and 300 mg/kg magnolol additive significantly increased the villus height/crypt depth ratio of ileum, compared to the control and CS30 groups (P = 0.001). Increased serum level of glucose (P = 0.011) and total protein (P = 0.006) were found in MA200 or MA300 group. In addition, comparing to the control and CS30 groups, MA200 or MA300 significantly increased the levels of superoxide dismutase (P = 0.038), glutathione peroxidase (P = 0.048) and reduced glutathione (P = 0.039) in serum. Moreover, the serum and hepatic levels of 8-hydroxy-2'-deoxyguanosine (P = 0.043 and 0.007, respectively) were lower in all MA groups compared to those of the control and CS30 group. The hepatic mRNA expression levels of superoxide dismutase-1, catalase and nuclear factor erythroid-2-related factor 2/erythroid-derived CNC-homology factor were also increased significantly in MA200 and MA300 groups (P < 0.05). Taken together, these data demonstrated that MA was an effective feed additive enhancing the growth performance of Linwu ducklings at 7 to 28 d by improving the antioxidant and intestinal mucosal status. It suggested that MA could be a potential ingredient to replace the colistin sulphate in diets.


Subject(s)
Antioxidants/metabolism , Biphenyl Compounds/pharmacology , Ducks/growth & development , Lignans/pharmacology , Animals , Biomarkers/blood , Diet , Ducks/blood , Female , Gene Expression Regulation/drug effects , Intestinal Mucosa/drug effects , Liver/drug effects , Liver/metabolism , Nutrients , Peroxides/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolism
7.
PLoS One ; 16(12): e0254466, 2021.
Article in English | MEDLINE | ID: mdl-34972106

ABSTRACT

Relaxin/insulin-like family peptide receptor 1 (RXFP1) mediates relaxin's antifibrotic effects and has reduced expression in the lung and skin of patients with fibrotic interstitial lung disease (fILD) including idiopathic pulmonary fibrosis (IPF) and systemic sclerosis (SSc). This may explain the failure of relaxin-based anti-fibrotic treatments in SSc, but the regulatory mechanisms controlling RXFP1 expression remain largely unknown. This study aimed to identify regulatory elements of RXFP1 that may function differentially in fibrotic fibroblasts. We identified and evaluated a distal regulatory region of RXFP1 in lung fibroblasts using a luciferase reporter system. Using serial deletions, an enhancer upregulating pGL3-promoter activity was localized to the distal region between -584 to -242bp from the distal transcription start site (TSS). This enhancer exhibited reduced activity in IPF and SSc lung fibroblasts. Bioinformatic analysis identified two clusters of activator protein 1 (AP-1) transcription factor binding sites within the enhancer. Site-directed mutagenesis of the binding sites confirmed that only one cluster reduced activity (-358 to -353 relative to distal TSS). Co-expression of FOS in lung fibroblasts further increased enhancer activity. In vitro complex formation with a labeled probe spanning the functional AP-1 site using nuclear proteins isolated from lung fibroblasts confirmed a specific DNA/protein complex formation. Application of antibodies against JUN and FOS resulted in the complex alteration, while antibodies to JUNB and FOSL1 did not. Analysis of AP-1 binding in 5 pairs of control and IPF lung fibroblasts detected positive binding more frequently in control fibroblasts. Expression of JUN and FOS was reduced and correlated positively with RXFP1 expression in IPF lungs. In conclusion, we identified a distal enhancer of RXFP1 with differential activity in fibrotic lung fibroblasts involving AP-1 transcription factors. Our study provides insight into RXFP1 downregulation in fILD and may support efforts to reevaluate relaxin-based therapeutics alongside upregulation of RXFP1 transcription.


Subject(s)
Enhancer Elements, Genetic/genetics , Fibroblasts/metabolism , Lung/cytology , Receptors, G-Protein-Coupled/genetics , Receptors, Peptide/genetics , Transcription Factor AP-1/metabolism , Base Sequence , Binding Sites , Chromosome Mapping , Gene Expression Regulation/drug effects , Genome, Human , Humans , Promoter Regions, Genetic/genetics , Protein Binding/drug effects , Proto-Oncogene Proteins c-fos/metabolism , Proto-Oncogene Proteins c-jun/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolism , Receptors, G-Protein-Coupled/metabolism , Receptors, Peptide/metabolism
8.
Nutrients ; 13(12)2021 Dec 17.
Article in English | MEDLINE | ID: mdl-34960078

ABSTRACT

Numerous beneficial effects of food restriction on aging and age-related pathologies are well documented. It is also well-established that both short- and long-term food restriction regimens induce elevated circulating levels of glucocorticoids, stress-induced hormones produced by adrenal glands that can also exert deleterious effects on the brain. In the present study, we examined the effect of long-term food restriction on the glucocorticoid hormone/glucocorticoid receptor (GR) system in the cortex during aging, in 18- and 24-month-old rats. Corticosterone level was increased in the cortex of aged ad libitum-fed rats. Food restriction induced its further increase, accompanied with an increase in the level of 11ß-hydroxysteroid dehydrogenase type 1. However, alterations in the level of GR phosphorylated at Ser232 were not detected in animals on food restriction, in line with unaltered CDK5 level, the decrease of Hsp90, and an increase in a negative regulator of GR function, FKBP51. Moreover, our data revealed that reduced food intake prevented age-related increase in the levels of NFκB, gfap, and bax, confirming its anti-inflammatory and anti-apoptotic effects. Along with an increase in the levels of c-fos, our study provides additional evidences that food restriction affects cortical responsiveness to glucocorticoids during aging.


Subject(s)
Aging/physiology , Cerebral Cortex/metabolism , Corticosterone/metabolism , Food Deprivation , Receptors, Glucocorticoid/metabolism , 11-beta-Hydroxysteroid Dehydrogenase Type 1/genetics , 11-beta-Hydroxysteroid Dehydrogenase Type 1/metabolism , Animals , Cyclin-Dependent Kinase 5/genetics , Cyclin-Dependent Kinase 5/metabolism , Gene Expression Regulation , Glial Fibrillary Acidic Protein/genetics , Glial Fibrillary Acidic Protein/metabolism , HSP90 Heat-Shock Proteins/genetics , HSP90 Heat-Shock Proteins/metabolism , Male , NF-kappa B/genetics , NF-kappa B/metabolism , Neuroprotection , Proto-Oncogene Proteins c-fos/genetics , Proto-Oncogene Proteins c-fos/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolism , Random Allocation , Rats , Rats, Wistar , Tacrolimus Binding Proteins/genetics , Tacrolimus Binding Proteins/metabolism , Time Factors , bcl-2-Associated X Protein/genetics , bcl-2-Associated X Protein/metabolism
9.
Nutrients ; 13(12)2021 Dec 17.
Article in English | MEDLINE | ID: mdl-34960084

ABSTRACT

High plasma fibroblast growth factor 23 (FGF23) and low potassium intake have each been associated with incident hypertension. We recently demonstrated that potassium supplementation reduces FGF23 levels in pre-hypertensive individuals. The aim of the current study was to address whether 24-h urinary potassium excretion, reflecting dietary potassium intake, is associated with FGF23, and whether FGF23 mediates the association between urinary potassium excretion and incident hypertension in the general population. At baseline, 4194 community-dwelling individuals without hypertension were included. Mean urinary potassium excretion was 76 (23) mmol/24 h in men, and 64 (20) mmol/24 h in women. Plasma C-terminal FGF23 was 64.5 (54.2-77.8) RU/mL in men, and 70.3 (56.5-89.5) RU/mL in women. Urinary potassium excretion was inversely associated with FGF23, independent of age, sex, urinary sodium excretion, bone and mineral parameters, inflammation, and iron status (St. ß -0.02, p < 0.05). The lowest sex-specific urinary potassium excretion tertile (HR 1.18 (95% CI 1.01-1.37)), and the highest sex-specific tertile of FGF23 (HR 1.17 (95% CI 1.01-1.37)) were each associated with incident hypertension, compared with the reference tertile. FGF23 did not mediate the association between urinary potassium excretion and incident hypertension. Increasing potassium intake, and reducing plasma FGF23 could be independent targets to reduce the risk of hypertension in the general population.


Subject(s)
/blood , Hypertension/prevention & control , Potassium, Dietary/administration & dosage , Potassium, Dietary/pharmacology , Potassium/urine , Adult , Cohort Studies , Female , /metabolism , Gene Expression Regulation/drug effects , Humans , Hypertension/urine , Male , Middle Aged , Risk Factors
10.
Nutrients ; 13(12)2021 Dec 15.
Article in English | MEDLINE | ID: mdl-34960032

ABSTRACT

Hepatic glycolipid metabolism disorder is considered as one of the key factors in the pathogenesis of many chronic diseases. The objective of this study was to investigate the protective effect and underlying mechanisms of Rhus chinensis Mill. fruits against hepatic glycolipid metabolic disorders in rats induced by a high fat/high sugar diet. Results showed that ethanol extract, especially at a dose of 600 mg/kg b.w., could effectively ameliorate glycolipid metabolic disorders in rats. The biochemical indexes, including CAT, GSH and HOMA-IR, were significantly improved by the administration of ethanol extract. Immunohistochemistry and Western blot analysis revealed that ethanol extract up-regulated the expression levels of PI3K/AKT, PPAR-α, and the phosphorylation of IRS1 and AMPK proteins, and down-regulated the expressions of SREBP-1 and FAS proteins in the liver, which are closely related to hepatic glycolipid metabolism. Those findings suggested that R. chinensis Mill. fruits could be developed as functional foods and/or nutraceuticals for preventing or controlling some chronic diseases related to hepatic glycolipid metabolism disorder.


Subject(s)
Fruit , Glycolipids/metabolism , Liver Diseases/drug therapy , Liver/drug effects , Plant Extracts/pharmacology , Rhus/chemistry , Adiposity , Animals , Diet, High-Fat/adverse effects , Dietary Carbohydrates/administration & dosage , Dietary Carbohydrates/adverse effects , Dose-Response Relationship, Drug , Gene Expression Regulation/drug effects , Insulin Resistance , Liver/metabolism , Male , Plant Extracts/chemistry , Rats , Rats, Sprague-Dawley
11.
Nutrients ; 13(12)2021 Dec 15.
Article in English | MEDLINE | ID: mdl-34960038

ABSTRACT

It is suggested that clock genes link the circadian rhythm to glucose and lipid metabolism. In this study, we explored the role of the clock gene Bmal1 in the hypothalamic paraventricular nucleus (PVN) in glucose metabolism. The Sim1-Cre-mediated deletion of Bmal1 markedly reduced insulin secretion, resulting in impaired glucose tolerance. The pancreatic islets' responses to glucose, sulfonylureas (SUs) and arginine vasopressin (AVP) were well maintained. To specify the PVN neuron subpopulation targeted by Bmal1, the expression of neuropeptides was examined. In these knockout (KO) mice, the mRNA expression of Avp in the PVN was selectively decreased, and the plasma AVP concentration was also decreased. However, fasting suppressed Avp expression in both KO and Cre mice. These results demonstrate that PVN BMAL1 maintains Avp expression in the PVN and release to the circulation, possibly providing islet ß-cells with more AVP. This action helps enhance insulin release and, consequently, glucose tolerance. In contrast, the circadian variation of Avp expression is regulated by feeding, but not by PVN BMAL1.


Subject(s)
ARNTL Transcription Factors/metabolism , Circadian Clocks/physiology , Gene Expression Regulation/physiology , Glucose/metabolism , Paraventricular Hypothalamic Nucleus/physiology , ARNTL Transcription Factors/genetics , Animals , Arginine Vasopressin/genetics , Arginine Vasopressin/metabolism , Glucose Intolerance , Insulin/metabolism , Mice , Mice, Knockout , Neurons , RNA, Messenger/genetics , RNA, Messenger/metabolism
12.
Nutrients ; 13(12)2021 Dec 14.
Article in English | MEDLINE | ID: mdl-34960014

ABSTRACT

Mounting evidence has shown that single-targeted therapy might be inadequate to achieve satisfactory effects. Thus, drug combinations are gaining attention as they can regulate multiple targets to obtain more beneficial effects. Heat shock protein 90 (HSP90) is a molecular chaperone that assists the protein assembly and folding of client proteins and maintains their stability. Interfering with the interaction between HSP90 and its client proteins by inhibiting the latter's activity may offer a new approach toward combination therapy. The HSP90 client protein AKT plays an important role in the inflammatory response syndrome caused by infections. In this study, the dietary flavone baicalein was identified as a novel inhibitor of HSP90 that targeted the N-terminal ATP binding pocket of HSP90 and hindered the chaperone cycle, resulting in AKT degradation. Combining baicalein with genipin, which was extracted from Gardenia jasminoides, could inhibit the pleckstrin homology domain of AKT, significantly increasing the anti-inflammatory effects both in vitro and in vivo. This synergistic effect was attributed to the reduction in AKT expression and phosphorylation. Thus, elucidating the mechanism underlying this effect will provide a new avenue for the clinical application and development of synergistic anti-inflammatory drugs.


Subject(s)
Flavanones/pharmacology , Inflammation/chemically induced , Inflammation/drug therapy , Iridoids/pharmacology , Proto-Oncogene Proteins c-akt/metabolism , Pseudomonas Infections/drug therapy , Animals , Antioxidants/administration & dosage , Antioxidants/pharmacology , Cholagogues and Choleretics/administration & dosage , Cholagogues and Choleretics/pharmacology , Diet , Drug Delivery Systems , Drug Therapy, Combination , Flavanones/administration & dosage , Gene Expression Regulation/drug effects , HSP90 Heat-Shock Proteins/genetics , HSP90 Heat-Shock Proteins/metabolism , Iridoids/administration & dosage , Lipopolysaccharides/toxicity , Male , Mice , Phosphorylation , Proto-Oncogene Proteins c-akt/genetics , Pseudomonas aeruginosa , RAW 264.7 Cells , Random Allocation
13.
Mol Cells ; 44(12): 861-878, 2021 Dec 31.
Article in English | MEDLINE | ID: mdl-34963103

ABSTRACT

The human genome contains many retroviral elements called human endogenous retroviruses (HERVs), resulting from the integration of retroviruses throughout evolution. HERVs once were considered inactive junk because they are not replication-competent, primarily localized in the heterochromatin, and silenced by methylation. But HERVs are now clearly shown to actively regulate gene expression in various physiological and pathological conditions such as developmental processes, immune regulation, cancers, autoimmune diseases, and neurological disorders. Recent studies report that HERVs are activated in patients suffering from coronavirus disease 2019 (COVID-19), the current pandemic caused by SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection. In this review, we describe internal and external factors that influence HERV activities. We also present evidence showing the gene regulatory activity of HERV LTRs (long terminal repeats) in model organisms such as mice, rats, zebrafish, and invertebrate models of worms and flies. Finally, we discuss several molecular and cellular pathways involving various transcription factors and receptors, through which HERVs affect downstream cellular and physiological events such as epigenetic modifications, calcium influx, protein phosphorylation, and cytokine release. Understanding how HERVs participate in various physiological and pathological processes will help develop a strategy to generate effective therapeutic approaches targeting HERVs.


Subject(s)
Autoimmune Diseases/genetics , Endogenous Retroviruses/genetics , Gene Expression Regulation , Models, Animal , Neoplasms/genetics , Terminal Repeat Sequences/genetics , Animals , Autoimmune Diseases/virology , COVID-19/genetics , COVID-19/virology , Humans , Neoplasms/virology , SARS-CoV-2/physiology
14.
FASEB J ; 36(1): e22129, 2022 01.
Article in English | MEDLINE | ID: mdl-34958689

ABSTRACT

Visually induced changes in the expression of early growth response-1 (EGR1), FBJ osteosarcoma oncogene (FOS), and NGFI-A binding protein-2 (NAB2) appear to form a part of a retinal network fundamental to ocular growth regulation, and thus, the development of myopia (short-sightedness). However, it is unclear how environmental (visual) cues are translated into these molecular changes. One possibility is through epigenetic modifications such as DNA methylation, a known regulator of such processes. By sequencing bisulfite-converted DNA amplicons, this study examined whether changes in DNA methylation occur within specific regulatory and promoter regions of EGR1, FOS, and NAB2 during the periods of increased and decreased ocular growth in chicks. Visually induced changes in ocular growth rates were associated with single-point, but not large-scale, shifts in methylation levels within the investigated regions. Analysis of methylation pattern variability (entropy) demonstrated that the observed methylation changes are occurring within small subpopulations of retinal cells. This concurs with previous observations that EGR1 and FOS are differentially regulated at the peptide level within specific retinal cell types. Together, the findings of this study support a potential role for DNA methylation in the translation of external visual cues into molecular changes critical for ocular growth regulation and myopia development.


Subject(s)
Avian Proteins/biosynthesis , DNA Methylation , Eye Proteins/biosynthesis , Gene Expression Regulation , Myopia/metabolism , Animals , Avian Proteins/genetics , Chickens , Eye Proteins/genetics , Humans , Male , Myopia/genetics
15.
Biomolecules ; 11(12)2021 12 07.
Article in English | MEDLINE | ID: mdl-34944487

ABSTRACT

Atopic dermatitis and psoriasis are two of the most common chronic skin conditions. Current target therapies represent viable and safe solutions for the most severe cases of these two dermatoses but, presently, several limitations exist in terms of efficacy and side effects. A new class of products, epithelium-derived cytokines (TSLP, IL-25, IL-33), show an increasing potential for use in target therapy for these patients, and demonstrate a direct link between a generalized inflammatory and oxidative stress status and the human skin. A review was conducted to better understand their role in the aforementioned conditions. Of these three molecules, TSLP led has been most often considered in studies regarding target therapies, and most of the results in the literature are related to this cytokine. These three cytokines share common stimuli and are linked to each other in both acute and chronic phases of these diseases, and have been challenged as target therapies or biomarkers of disease activity. The results lead to the conclusion that epithelium-derived cytokines could represent a therapeutic opportunity for these patients, especially in itch control. Furthermore, they might work better when paired together with currently available therapies or in combination with in-development treatments. Further studies are needed in order to verify the efficacy and safety of the biologic treatments currently under development.


Subject(s)
Cytokines/metabolism , Dermatitis, Atopic/immunology , Interleukin-17/metabolism , Interleukin-33/metabolism , Psoriasis/immunology , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/therapeutic use , Dermatitis, Atopic/drug therapy , Epithelium/drug effects , Epithelium/immunology , Gene Expression Regulation/drug effects , Humans , Molecular Targeted Therapy , Oxidative Stress/drug effects , Psoriasis/drug therapy
16.
Biomolecules ; 11(12)2021 11 30.
Article in English | MEDLINE | ID: mdl-34944434

ABSTRACT

Ferroptosis, a newly described type of iron-dependent programmed cell death that is distinct from apoptosis, necroptosis, and other types of cell death, is involved in lipid peroxidation (LP), reactive oxygen species (ROS) production, and mitochondrial dysfunction. Accumulating evidence has highlighted vital roles for ferroptosis in multiple diseases, including acute kidney injury, cancer, hepatic fibrosis, Parkinson's disease, and Alzheimer's disease. Therefore, ferroptosis has become one of the research hotspots for disease treatment and attracted extensive attention in recent years. This review mainly summarizes the relationship between ferroptosis and various diseases classified by the system, including the urinary system, digestive system, respiratory system, nervous system. In addition, the role and molecular mechanism of multiple inhibitors and inducers for ferroptosis are further elucidated. A deeper understanding of the relationship between ferroptosis and multiple diseases may provide new strategies for researching diseases and drug development based on ferroptosis.


Subject(s)
Digestive System Diseases/metabolism , Ferroptosis , Nervous System Diseases/metabolism , Urologic Diseases/metabolism , Digestive System Diseases/drug therapy , Ferroptosis/drug effects , Gene Expression Regulation/drug effects , Gene Regulatory Networks/drug effects , Humans , Lipid Peroxidation/drug effects , Molecular Targeted Therapy , Nervous System Diseases/drug therapy , Reactive Oxygen Species/metabolism , Urologic Diseases/drug therapy
17.
Biomolecules ; 11(12)2021 11 30.
Article in English | MEDLINE | ID: mdl-34944443

ABSTRACT

The SNCA (Synuclein Alpha) gene represents a major risk gene for Parkinson's disease (PD) and SNCA polymorphisms have been associated with the common sporadic form of PD. Numerous Genome-Wide Association Studies showed strong signals located in the SNCA 3' UTR (untranslated region) region indicating that variants in 3' UTRs of PD-associated genes could contribute to neurodegeneration and may regulate the risk for PD. Genetic variants in 3' UTR can affect miRNA activity and consequently change the translation process. The aim of this study was to access the differences in 3' UTR variants of SNCA genes in a cohort of PD patients and control subjects from Croatia. The cohort consisted of 52 PD patients and 23 healthy control subjects. Differences between 3' UTR allele and genotype frequencies were accessed through next generation sequencing approach from whole blood samples. In our study, we identified four previously reported single nucleotide polymorphisms (SNPs) and one insertion in the 3' UTR region of SNCA gene, namely rs1045722, rs3857053, rs577490090, rs356165, and rs777296100, and five variants not reported in the literature, namely rs35270750, rs529553259, rs377356638, rs571454522, and rs750347645. Our results indicate a significantly higher occurrence of the rs571454522 variant in the PD population. To the best of our knowledge, this variant has not been reported until now in the literature. We analyzed our results in the context of previous research, creating a brief overview of the importance of 3' UTR variants of the SNCA gene. Further studies will be needed to gain a more profound insight regarding their role in PD development, which will help to assess the role and impact of post-transcriptional regulation on disease pathology.


Subject(s)
Parkinson Disease/genetics , Polymorphism, Single Nucleotide , Sequence Analysis, DNA/methods , alpha-Synuclein/genetics , 3' Untranslated Regions , Aged , Case-Control Studies , Croatia , Female , Gene Expression Regulation , Genetic Predisposition to Disease , Genome-Wide Association Study , High-Throughput Nucleotide Sequencing , Humans , Male , Middle Aged
18.
Biomolecules ; 11(12)2021 11 30.
Article in English | MEDLINE | ID: mdl-34944440

ABSTRACT

Neuroinflammation, which is mediated by microglia and astrocytes, is associated with the progression of neurodegenerative diseases. Increasing evidence shows that activated microglia induce the expression and secretion of various lysosomal cathepsins, particularly during the early stage of neuroinflammation. This trigger signaling cascade that aggravate neurodegeneration. To date, most research on neuroinflammation has focused on the role of cysteine cathepsins, the largest cathepsin family. Cysteine cathepsins are primarily responsible for protein degradation in lysosomes; however, they also play a role in regulating a number of other important physiological and pathological processes. This review focuses on the functional roles of cysteine cathepsins in the central nervous system during neuroinflammation, with an emphasis on their roles in the polarization of microglia and neuroinflammation signaling, which in turn causes neuronal death and thus neurodegeneration.


Subject(s)
Cysteine Proteases/metabolism , Microglia/physiology , /physiopathology , Disease Progression , Gene Expression Regulation , Humans , Lysosomes/metabolism , Microglia/metabolism , Proteolysis
19.
Biomolecules ; 11(12)2021 11 30.
Article in English | MEDLINE | ID: mdl-34944445

ABSTRACT

Pulmonary hypertension (PH) is characterized by vascular remodeling caused by marked proliferation of pulmonary artery smooth muscle cells (PASMCs). Andrographolide (ANDRO) is a potent anti-inflammatory agent which possesses antioxidant, and has anticarcinogenic activity. The present study examined potential therapeutic effects of ANDRO on PH in both chronic hypoxia and Sugen5416/hypoxia mouse PH models. Effects of ANDRO were also studied in cultured human PASMCs isolated from either healthy donors or PH patients. In vivo, ANDRO decreased distal pulmonary arteries (PAs) remodeling, mean PA pressure and right ventricular hypertrophy in chronic hypoxia- and Sugen/hypoxia-induced PH in mice. ANDRO reduced cell viability, proliferation and migration, but increased cell apoptosis in the PASMCs isolated from PH patients. ANDRO also reversed the dysfunctional bone morphogenetic protein receptor type-2 (BMPR2) signaling, suppressed [Ca2+]i elevation, reactive oxygen species (ROS) generation, and the upregulated expression of IL-6 and IL-8, ET-1 and VEGF in PASMCs from PH patients. Moreover, ANDRO significantly attenuated the activation of TLR4/NF-κB, ERK- and JNK-MAPK signaling pathways and reversed the inhibition of p38-MAPK in PASMCs of PH patients. Further, ANDRO blocked hypoxia-triggered ROS generation by suppressing NADPH oxidase (NOX) activation and augmenting nuclear factor erythroid 2-related factor 2 (Nrf2) expression both in vitro and in vivo. Conventional pulmonary vasodilators have limited efficacy for the treatment of severe PH. We demonstrated that ANDRO may reverse pulmonary vascular remodeling through modulation of NOX/Nrf2-mediated oxidative stress and NF-κB-mediated inflammation. Our findings suggest that ANDRO may have therapeutic value in the treatment of PH.


Subject(s)
Anti-Inflammatory Agents/administration & dosage , Diterpenes/administration & dosage , Hypertension, Pulmonary/drug therapy , Indoles/adverse effects , Pyrroles/adverse effects , Vascular Remodeling/drug effects , Animals , Anti-Inflammatory Agents/pharmacology , Cell Movement/drug effects , Cell Proliferation/drug effects , Cell Survival/drug effects , Cells, Cultured , Disease Models, Animal , Diterpenes/pharmacology , Female , Gene Expression Regulation/drug effects , Humans , Hypertension, Pulmonary/chemically induced , Hypertension, Pulmonary/metabolism , Male , Mice , Primary Cell Culture , Signal Transduction/drug effects
20.
Biomolecules ; 11(12)2021 12 20.
Article in English | MEDLINE | ID: mdl-34944551

ABSTRACT

Galectins comprise a family of soluble ß-galactoside-binding proteins, which regulate a variety of key biological processes including cell growth, differentiation, survival, and death. This paper aims to address the current knowledge on the unique properties, regulation, and expression of the galectin-16 gene (LGALS16) in human cells and tissues. To date, there are limited studies on this galectin, with most focusing on its tissue specificity to the placenta. Here, we report the expression and 8-Br-cAMP-induced upregulation of LGALS16 in two placental cell lines (BeWo and JEG-3) in the context of trophoblastic differentiation. In addition, we provide the results of a bioinformatics search for LGALS16 using datasets available at GEO, Human Protein Atlas, and prediction tools for relevant transcription factors and miRNAs. Our findings indicate that LGALS16 is detected by microarrays in diverse human cells/tissues and alters expression in association with cancer, diabetes, and brain diseases. Molecular mechanisms of the transcriptional and post-transcriptional regulation of LGALS16 are also discussed based on the available bioinformatics resources.


Subject(s)
Computational Biology/methods , Galectins/genetics , Galectins/metabolism , Cell Line , Cell Line, Tumor , Databases, Genetic , Galectins/chemistry , Gene Expression Regulation , Humans , Models, Molecular , Protein Conformation , Sequence Analysis, DNA , Sequence Analysis, RNA , Tissue Distribution
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