scholarly journals Deficiency of Tristetraprolin Triggers Hyperthermia through Enhancing Hypothalamic Inflammation

2021 ◽  
Vol 22 (7) ◽  
pp. 3328
Author(s):  
Da Yeon Jeong ◽  
Nuri Song ◽  
Hye Rim Yang ◽  
Thai Hien Tu ◽  
Byong Seo Park ◽  
...  
Keyword(s):  
Energy Metabolism ◽  
Energy Homeostasis ◽  
Target Genes ◽  
Rna Binding ◽  
Inflammatory Responses ◽  
Core Body Temperature ◽  
Inflammatory Protein ◽  
Tightly Coupled ◽  
Hypothalamic Inflammation ◽  
The Stability

Tristetraprolin (TTP), an RNA-binding protein, controls the stability of RNA by capturing AU-rich elements on their target genes. It has recently been identified that TTP serves as an anti-inflammatory protein by guiding the unstable mRNAs of pro-inflammatory proteins in multiple cells. However, it has not yet been investigated whether TTP affects the inflammatory responses in the hypothalamus. Since hypothalamic inflammation is tightly coupled to the disturbance of energy homeostasis, we designed the current study to investigate whether TTP regulates hypothalamic inflammation and thereby affects energy metabolism by utilizing TTP-deficient mice. We observed that deficiency of TTP led to enhanced hypothalamic inflammation via stimulation of a variety of pro-inflammatory genes. In addition, microglial activation occurred in the hypothalamus, which was accompanied by an enhanced inflammatory response. In line with these molecular and cellular observations, we finally confirmed that deficiency of TTP results in elevated core body temperature and energy expenditure. Taken together, our findings unmask novel roles of hypothalamic TTP on energy metabolism, which is linked to inflammatory responses in hypothalamic microglial cells.

scholarly journals Sexual dimorphism in hypothalamic inflammation in the offspring of dams exposed to a diet rich in high fat and branched-chain amino acids

2019 ◽  
Vol 317 (3) ◽  
pp. E526-E534 ◽  
Author(s):  
Marianna Sadagurski ◽  
Lucas Kniess Debarba ◽  
Joao Pedro Werneck-de-Castro ◽  
Abear Ali Awada ◽  
Tess A. Baker ◽  
...  
Keyword(s):  
Energy Homeostasis ◽  
Maternal Nutrition ◽  
Inflammatory Responses ◽  
Maternal Diet ◽  
Female Offspring ◽  
Metabolic Effects ◽  
Standard Diet ◽  
High Fat ◽  
Hypothalamic Inflammation ◽  
Branched Chain

Branched-chain amino acid (BCAAs: leucine, isoleucine, and valine) contribute to the development of obesity-associated insulin resistance in the context of consumption of a high-fat diet (HFD) in humans and rodents. Maternal diet is a major determinant of offspring health, and there is strong evidence that maternal HFD alters hypothalamic developmental programming and disrupts offspring energy homeostasis in rodents. In this study, we exposed pregnant and lactating C57BL/6JB female mice to either HFD, HFD with supplemented BCAA (HFD+BCAA), or standard diet (SC), and we studied offspring metabolic phenotypes. Both maternal HFD and HFD supplemented with BCAA had similar effect rendering the offspring metabolic imbalance and impairing their ability to cope with HFD when challenged during aging. The metabolic effects of HFD challenge were more profound in females, worsening female offspring ability to cope with an HFD challenge by activating hypothalamic inflammation in aging. Moreover, the sex differences in hypothalamic estrogen receptor α (ER-α) expression levels were lost in female offspring upon HFD challenge, supporting a link between ER-α levels and hypothalamic inflammation in offspring and highlighting the programming potential of hypothalamic inflammatory responses and maternal nutrition.

scholarly journals Inflammatory responses, energy metabolism enzymes, oxidative status in Clostridium perfringens infection in broilers

2020 ◽  
Vol 9 (11) ◽  
pp. e4969119320
Author(s):  
Gabriela Miotto Galli ◽  
Marcel Manente Boiago ◽  
Carine Freitas de Souza ◽  
Lorenzo Binotto Abbad ◽  
Matheus Dellamea Baldissera ◽  
...  
Keyword(s):  
Energy Metabolism ◽  
Clostridium Perfringens ◽  
Energy Homeostasis ◽  
Inflammatory Responses ◽  
Basal Diet ◽  
Inflammatory Cells ◽  
Experimental Period ◽  
Feed Conversion ◽  
Oxidative Stress Biomarkers ◽  
Metabolism Enzymes

The aim of this study was to determine whether infection by Clostridium perfringens negatively interferes with the oxidant/antioxidant status and activity of energy metabolism enzymes (creatine kinase (CK), adenylate kinase (AK) and pyruvate kinase (PK)), as well as the zootechnical performance of broilers. A completely randomized design with three treatments, with five replications by treatment, and 10 birds by repetitions was used: T1: non-infected group; T2: group infected with C. perfringens; T3: group infected with C. perfringens, and basal diet with performance enhancers (antibiotic and coccidiostatic). At 21 days of age, the birds were experimentally infected orally with 4.0 x 108 CFU/mL C. perfringens. At strategic moments during the experimental period, zootechnical data and blood samples were collected. There were no significant differences among treatments in terms of weight gain, feed intake, or feed conversion. At 20 days, heterophils counts were significantly lower in the T3 group birds than in the others. A significant reduction in the number of total leukocytes, because of the lower number of lymphocytes, was observed in groups T2 and T3 on day 34. Neutrophil and monocyte counts were significantly lower in group T3 than in group T1 on day 34. On day 42, there were significantly lower levels of total protein and globulin in birds in T3 than in T1. On day 27, PK activity was significantly higher in groups T2 and T3; similar behavior observed on day 34 when CK and PK activities in T2 and T3 were significantly higher than those of T1. AK activity was significantly higher in the serum of T3 birds than in those of the other groups at 34 days. At 41 days, CK and PK activities were significantly higher only in birds in group T3 compared to other groups. The levels of reactive oxygen species and lipoperoxidation, as well as the activity of glutathione S-transferase, were significantly lower in birds from group T3 compared to other groups at age 20 days. After a challenge with C. perfringens, there were fluctuations in the behavior of oxidative stress biomarkers; in particular, at 41 days of age, birds in T2 had elevated levels of lipoperoxidation, different from what was seen in birds in T3 that consumed feed with a performance enhancer. Preliminary results suggest that clostridiosis affects serum activity of enzymes in the phosphotransfer network, requiring compensatory enzymatic changes in an attempt to maintain energy homeostasis. In addition, the infection reduces the number of inflammatory cells and causes oxidant/antioxidant imbalance that may contribute to the pathophysiology of the disease. Además, la infección reduce el número de células inflamatorias y provoca un desequilibrio en el estado oxidante / antioxidante que puede contribuir a la fisiopatología de la enfermedad.

scholarly journals Cross-talk among writers, readers, and erasers of m6A regulates cancer growth and progression

2018 ◽  
Vol 4 (10) ◽  
pp. eaar8263 ◽  
Author(s):  
Subbarayalu Panneerdoss ◽  
Vijay K. Eedunuri ◽  
Pooja Yadav ◽  
Santosh Timilsina ◽  
Subapriya Rajamanickam ◽  
...  
Keyword(s):  
Target Genes ◽  
Rna Binding ◽  
Transforming Growth Factor ◽  
Epithelial Mesenchymal Transition ◽  
Cancer Growth ◽  
Stability Factor ◽  
Sequencing Analysis ◽  
Aberrant Expression ◽  
Mesenchymal Transition ◽  
The Stability

The importance of RNA methylation in biological processes is an emerging focus of investigation. We report that altering m6A levels by silencing eitherN6-adenosine methyltransferase METTL14 (methyltransferase-like 14) or demethylase ALKBH5 (ALKB homolog 5) inhibits cancer growth and invasion. METTL14/ALKBH5 mediate their protumorigenic function by regulating m6A levels of key epithelial-mesenchymal transition and angiogenesis-associated transcripts, including transforming growth factor–β signaling pathway genes. Using MeRIP-seq (methylated RNA immunoprecipitation sequencing) analysis and functional studies, we find that these target genes are particularly sensitive to changes in m6A modifications, as altered m6A status leads to aberrant expression of these genes, resulting in inappropriate cell cycle progression and evasion of apoptosis. Our results reveal that METTL14 and ALKBH5 determine the m6A status of target genes by controlling each other’s expression and by inhibiting m6A reader YTHDF3 (YTHN6-methyladenosine RNA binding protein 3), which blocks RNA demethylase activity. Furthermore, we show that ALKBH5/METTL14 constitute a positive feedback loop with RNA stability factor HuR to regulate the stability of target transcripts. We discover that hypoxia alters the level/activity of writers, erasers, and readers, leading to decreased m6A and consequently increased expression of target transcripts in cancer cells. This study unveils a previously undefined role for m6A in cancer and shows that the collaboration among writers-erasers-readers sets up the m6A threshold to ensure the stability of progrowth/proliferation-specific genes, and protumorigenic stimulus, such as hypoxia, perturbs that m6A threshold, leading to uncontrolled expression/activity of those genes, resulting in tumor growth, angiogenesis, and progression.

Progress on the Mechanism for Aspirin’s Anti-tumor Effects

2020 ◽  
Vol 22 (1) ◽  
pp. 105-111
Author(s):  
Lin Zheng ◽  
Weibiao Lv ◽  
Yuanqing Zhou ◽  
Xu Lin ◽  
Jie Yao
Keyword(s):  
Platelet Aggregation ◽  
Energy Metabolism ◽  
Side Effects ◽  
Energy Production ◽  
Immune Escape ◽  
Inflammatory Responses ◽  
Mechanisms Of Action ◽  
Proliferation And Metastasis ◽  
Review Current ◽  
Granule Release

: Since its discovery more than 100 years ago, aspirin has been widely used for its antipyretic, analgesic, anti-inflammatory, and anti-rheumatic activities. In addition to these applications, it is increasingly becoming clear that the drug also has great potential in the field of cancer. Here, we briefly review current insights of aspirin’s anti-tumor effects. These are multiple and vary from inhibiting the major cellular mTOR pathways, acting as a calorie-restricted mimetic by inhibition of energy production, suppressing platelet aggregation and granule release, inhibiting immune escape of tumor cells, to decreasing inflammatory responses. We consider these five mechanisms of action the most significant of aspirin’s anti-tumor effects, whereby the anti-tumor effect may ultimately stem from its inhibition of energy metabolism, platelet function, and inflammatory response. As such, aspirin can play an important role to reduce the occurrence, proliferation, and metastasis of various types of tumors. However, most of the collected data are still based on epidemiological investi-gations. More direct and effective evidence is needed, and the side effects of aspirin intake need to be solved before this drug can be widely applied in cancer treatment.

scholarly journals MAC5, an RNA-binding protein, protects pri-miRNAs from SERRATE-dependent exoribonuclease activities

2020 ◽  
Vol 117 (38) ◽  
pp. 23982-23990 ◽  
Author(s):  
Shengjun Li ◽  
Mu Li ◽  
Kan Liu ◽  
Huimin Zhang ◽  
Shuxin Zhang ◽  
...  
Keyword(s):  
Rna Binding ◽  
Rna Binding Protein ◽  
Dual Role ◽  
Mirna Biogenesis ◽  
Core Component ◽  
Stem Loop ◽  
Loop Region ◽  
Nuclear Rna ◽  
Efficient Processing ◽  
The Stability

MAC5 is a component of the conserved MOS4-associated complex. It plays critical roles in development and immunity. Here we report that MAC5 is required for microRNA (miRNA) biogenesis. MAC5 interacts with Serrate (SE), which is a core component of the microprocessor that processes primary miRNA transcripts (pri-miRNAs) into miRNAs and binds the stem-loop region of pri-miRNAs. MAC5 is essential for both the efficient processing and the stability of pri-miRNAs. Interestingly, the reduction of pri-miRNA levels inmac5is partially caused by XRN2/XRN3, the nuclear-localized 5′-to-3′ exoribonucleases, and depends on SE. These results reveal that MAC5 plays a dual role in promoting pri-miRNA processing and stability through its interaction with SE and/or pri-miRNAs. This study also uncovers that pri-miRNAs need to be protected from nuclear RNA decay machinery, which is connected to the microprocessor.

scholarly journals Flavonoids: Nutraceuticals for Rheumatic Diseases via Targeting of Inflammasome Activation

2021 ◽  
Vol 22 (2) ◽  
pp. 488
Author(s):  
Young-Su Yi
Keyword(s):  
Rheumatic Diseases ◽  
Fruits And Vegetables ◽  
Inflammatory Responses ◽  
Protein Complexes ◽  
Cellular Damage ◽  
Inflammatory Rheumatic Diseases ◽  
Inflammasome Activation ◽  
Central Feature ◽  
Inflammatory Protein ◽  
Anti Inflammatory

Inflammation, an innate immune response that prevents cellular damage caused by pathogens, consists of two successive mechanisms, namely priming and triggering. While priming is an inflammation-preparation step, triggering is an inflammation-activation step, and the central feature of triggering is the activation of inflammasomes and intracellular inflammatory protein complexes. Flavonoids are natural phenolic compounds predominantly present in plants, fruits, and vegetables and are known to possess strong anti-inflammatory activities. The anti-inflammatory activity of flavonoids has long been demonstrated, with the main focus on the priming mechanisms, while increasing numbers of recent studies have redirected the research focus on the triggering step, and studies have reported that flavonoids inhibit inflammatory responses and diseases by targeting inflammasome activation. Rheumatic diseases are systemic inflammatory and autoimmune diseases that primarily affect joints and connective tissues, and they are associated with numerous deleterious effects. Here, we discuss the emerging literature on the ameliorative role of flavonoids targeting inflammasome activation in inflammatory rheumatic diseases.

scholarly journals Optimizations for identifying reference genes in bone and cartilage bioengineering

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Fei Xiong ◽  
Xiangyun Cheng ◽  
Chao Zhang ◽  
Roland Manfred Klar ◽  
Tao He
Keyword(s):  
Gene Expression ◽  
Skeletal Muscle ◽  
Adipose Tissue ◽  
Real Time ◽  
Reference Gene ◽  
Muscle Tissue ◽  
Reference Genes ◽  
Target Genes ◽  
The Stability ◽  
And Cartilage

Abstract Background Reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR) remains one of the best-established techniques to assess gene expression patterns. However, appropriate reference gene(s) selection remains a critical and challenging subject in which inappropriate reference gene selction can distort results leading to false interpretations. To date, mixed opinions still exist in how to choose the most optimal reference gene sets in accodrance to the Minimum Information for Publication of Quantitative Real-Time PCR Experiments (MIQE) guideline. Therefore, the purpose of this study was to investigate which schemes were the most feasible for the identification of reference genes in a bone and cartilage bioengineering experimental setting. In this study, rat bone mesenchymal stem cells (rBMSCs), skeletal muscle tissue and adipose tissue were utilized, undergoing either chondrogenic or osteogenic induction, to investigate the optimal reference gene set identification scheme that would subsequently ensure stable and accurate interpretation of gene expression in bone and cartilage bioengineering. Results The stability and pairwise variance of eight candidate reference genes were analyzed using geNorm. The V0.15- vs. Vmin-based normalization scheme in rBMSCs had no significant effect on the eventual normalization of target genes. In terms of the muscle tissue, the results of the correlation of NF values between the V0.15 and Vmin schemes and the variance of target genes expression levels generated by these two schemes showed that different schemes do indeed have a significant effect on the eventual normalization of target genes. Three selection schemes were adopted in terms of the adipose tissue, including the three optimal reference genes (Opt3), V0.20 and Vmin schemes, and the analysis of NF values with eventual normalization of target genes showed that the different selection schemes also have a significant effect on the eventual normalization of target genes. Conclusions Based on these results, the proposed cut-off value of Vn/n + 1 under 0.15, according to the geNorm algorithm, should be considered with caution. For cell only experiments, at least rBMSCs, a Vn/n + 1 under 0.15 is sufficient in RT-qPCR studies. However, when using certain tissue types such as skeletal muscle and adipose tissue the minimum Vn/n + 1 should be used instead as this provides a far superior mode of generating accurate gene expression results. We thus recommended that when the stability and variation of a candidate reference genes in a specific study is unclear the minimum Vn/n + 1 should always be used as this ensures the best and most accurate gene expression value is achieved during RT-qPCR assays.

scholarly journals The Combined Human Genotype of Truncating TTN and RBM20 Mutations Is Associated with Severe and Early Onset of Dilated Cardiomyopathy

Genes ◽  
2021 ◽  
Vol 12 (6) ◽  
pp. 883
Author(s):  
Anna Gaertner ◽  
Julia Bloebaum ◽  
Andreas Brodehl ◽  
Baerbel Klauke ◽  
Katharina Sielemann ◽  
...  
Keyword(s):  
Heart Failure ◽  
Dilated Cardiomyopathy ◽  
Early Onset ◽  
Target Genes ◽  
Frameshift Mutation ◽  
Rna Binding ◽  
Splicing Factor ◽  
Binding Motif ◽  
Rich Domain ◽  
Generation Sequencing

A major cause of heart failure is cardiomyopathies, with dilated cardiomyopathy (DCM) as the most common form. Over 40 genes are linked to DCM, among them TTN and RBM20. Next Generation Sequencing in clinical DCM cohorts revealed truncating variants in TTN (TTNtv), accounting for up to 25% of familial DCM cases. Mutations in the cardiac splicing factor RNA binding motif protein 20 (RBM20) are also known to be associated with severe cardiomyopathies. TTN is one of the major RBM20 splicing targets. Most of the pathogenic RBM20 mutations are localized in the highly conserved arginine serine rich domain (RS), leading to a cytoplasmic mislocalization of mutant RBM20. Here, we present a patient with an early onset DCM carrying a combination of (likely) pathogenic TTN and RBM20 mutations. We show that the splicing of RBM20 target genes is affected in the mutation carrier. Furthermore, we reveal RBM20 haploinsufficiency presumably caused by the frameshift mutation in RBM20.

scholarly journals Anti-NLRP3 Inflammasome Natural Compounds: An Update

Biomedicines ◽  
2021 ◽  
Vol 9 (2) ◽  
pp. 136
Author(s):  
Baolong Liu ◽  
Jiujiu Yu
Keyword(s):  
Nlrp3 Inflammasome ◽  
Protein Complex ◽  
Molecular Mechanisms ◽  
Inflammatory Responses ◽  
Natural Compounds ◽  
Pyrin Domain ◽  
Inflammatory Protein ◽  
Wide Range ◽  
Activation Mechanisms ◽  
Stress Signals

The nucleotide-binding domain and leucine-rich repeat related (NLR) family, pyrin domain containing 3 (NLRP3) inflammasome is a multimeric protein complex that recognizes various danger or stress signals from pathogens, the host, and the environment, leading to activation of caspase-1 and inducing inflammatory responses. This pro-inflammatory protein complex plays critical roles in pathogenesis of a wide range of diseases including neurodegenerative diseases, autoinflammatory diseases, and metabolic disorders. Therefore, intensive efforts have been devoted to understanding its activation mechanisms and to searching for its specific inhibitors. Approximately forty natural compounds with anti-NLRP3 inflammasome properties have been identified. Here, we provide an update about new natural compounds that have been identified within the last three years to inhibit the NLRP3 inflammasome and offer an overview of the underlying molecular mechanisms of their anti-NLRP3 inflammasome activities.

scholarly journals Novel Insights into YB-1 Signaling and Cell Death Decisions

Cancers ◽  
2021 ◽  
Vol 13 (13) ◽  
pp. 3306
Author(s):  
Aneri Shah ◽  
Jonathan A. Lindquist ◽  
Lars Rosendahl ◽  
Ingo Schmitz ◽  
Peter R. Mertens
Keyword(s):  
Stress Responses ◽  
Rna Splicing ◽  
Cell Cycle Progression ◽  
Rna Binding ◽  
Inflammatory Responses ◽  
Rna Binding Proteins ◽  
Inflammatory Diseases ◽  
Therapeutic Option ◽  
Tumor Therapy ◽  
Inflammatory Microenvironment

YB-1 belongs to the evolutionarily conserved cold-shock domain protein family of RNA binding proteins. YB-1 is a well-known transcriptional and translational regulator, involved in cell cycle progression, DNA damage repair, RNA splicing, and stress responses. Cell stress occurs in many forms, e.g., radiation, hyperthermia, lipopolysaccharide (LPS) produced by bacteria, and interferons released in response to viral infection. Binding of the latter factors to their receptors induces kinase activation, which results in the phosphorylation of YB-1. These pathways also activate the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), a well-known transcription factor. NF-κB is upregulated following cellular stress and orchestrates inflammatory responses, cell proliferation, and differentiation. Inflammation and cancer are known to share common mechanisms, such as the recruitment of infiltrating macrophages and development of an inflammatory microenvironment. Several recent papers elaborate the role of YB-1 in activating NF-κB and signaling cell survival. Depleting YB-1 may tip the balance from survival to enhanced apoptosis. Therefore, strategies that target YB-1 might be a viable therapeutic option to treat inflammatory diseases and improve tumor therapy.

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