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QKI regulates adipose tissue metabolism by acting as a brake on thermogenesis and promoting obesity.

Adipose tissue controls numerous physiological processes, and its dysfunction has a causative role in the development of systemic metabolic disorders. The role of posttranscriptional regulation in adipose metabolism has yet to be fully understood. Here, we show that the RNA-binding protein quaking (QKI) plays an important role in controlling metabolic homeostasis of the adipose tissue. QKI-deficient mice are resistant to high-fat-diet (HFD)-induced obesity. Additionally, QKI depletion increased brown fat energy dissipation and browning of subcutaneous white fat. Adipose tissue-specific depleti

The Role of Interferon Receptors α/β/γ Ablation During Western Diet-Induced Obesity and Insulin Resistance in the Inflectional Model AG129 Mice Strain.

Diet-induced obesity triggers elevation of circulating pro-inflammatory cytokines and acute-phase proteins, including interferons (IFNs). IFNs strongly contribute to low-grade inflammation associated with obesity-related complications, such as nonalcoholic fat liver disease and diabetes. In this study, AG129 mice model (double-knockout strain for IFN α/β/γ receptors) was fed with a high-fat high-sucrose (HFHS) diet (Western diet) for 20 weeks aiming to understand the impact of IFN receptor ablation on diet-induced obesity, insulin resistance, and nonalcoholic fat liver disease. Mice were respo

β-Hydroxybutyrate promotes cancer metastasis through β-hydroxybutyrylation-dependent stabilization of Snail.

β-Hydroxybutyrylation (Kbhb) modification regulates protein molecular fates in either physiology or pathology, including cancer. However, the function and regulatory mechanism of Kbhb remain completely unknown in cancer metastasis. Here, we report that β-hydroxybutyrate (BHB) is clinically associated with the progression of pancreatic cancer and functionally promotes pancreatic cancer cell metastasis. Mechanistically, BHB induces Kbhb modification of Snail at lysine 152 to enhance Snail stabilization, which is regulated by Kbhb modification enzyme CREB-binding protein (CBP), and subsequently p…

Mechanisms for neuronal cell death and dysfunction in Huntington's disease: pathological cross-talk between the nucleus and the mitochondria?

Huntington's disease (HD) is a hereditary neurodegenerative condition caused by a characteristic mutation in the huntingtin (htt) gene. This gene was identified in 1993. Both the mitochondria and the nucleus play an important role in HD pathology. However, the precise molecular mechanisms remain unclear. A key strategy for understanding HD pathology is to identify signaling cascades initiated by mutant Htt that lead to neuronal cell death and dysfunction. Apoptotic stress induces greater mitochondrial depolarization in HD lymphoblasts than in control subjects. This leads to overactivation of c

CRISPR Интерференция CBP и p300 выборочно ввела синтетическую летопальность в раковые клетки бладера in Vitro.

Связующие белки CREB (CBP) и p300 являются аденовальными белками E1A, связанными с различными клеточными процессами, включая эмбриональное развитие, гомеостаз, дифференциацию клеток и активацию транскрипции. Предыдущее исследование показало, что синтетическая летальность между CBP и p300 ингибиторами легких и гематопоиетических рака. Однако механизм, лежащий в основе CBP и p300 паралога рака мочевого пузыря, остается неизвестным. В этом исследовании мы обнаружили, что комбинация CBP и p300 ингибиционного распространения клеток и вызвала апоптоз раковых клеток мочевого пузыря и нормальную уроте

Совпадение в аннотации оригинала
The transcriptional coactivator CREB-binding protein (CBP) and p300 are adenoviral E1A-binding proteins involved in various cellular processes, including embryonic development, homeostasis, cell differentiation and transcription activation. Previous study suggested that synthetic lethality between CBP and p300 inhibition in lung and hematopoietic cancers. Ho…

Activated PRDM1-CREBBP contributes to preeclampsia by regulating apoptosis and invasion of the human trophoblast cells.

Preeclampsia (PE) is a multifactorial disorder of pregnancy, characterized by new-onset gestational hypertension. High-throughput mRNA seque … optosis under hypoxia/reoxygenation (H/R) conditions. RNA-seq data indicated that the expression of CREB-binding protein (CREBBP), a transcriptional coactivator, was upregulated in preeclamptic placentas and showed a positive correlation with that of PRDM1. Genetic and pharmacological inhibition of CREBBP exhibited anti-apoptotic and pro-invasive roles. H/R stimulatio …

NFκB and Cyclic AMP Response Element Sites Mediate the Valproic Acid and UL138 Responsiveness of the Human Cytomegalovirus Major Immediate Early Enhancer and Promoter.

The major immediate early enhancer and promoter (MIEP) of human cytomegalovirus (HCMV) drives the transcription of the immediate early one (IE1) and IE2 genes, whose encoded proteins stimulate productive, lytic replication. The MIEP is activated by the virally encoded and tegument-delivered pp71 protein at the start of de novo lytic infections of fully differentiated cells. Conversely, the MIEP is silenced at the start of de novo latent infections within incompletely differentiated myeloid cells in part because tegument-delivered pp71 is sequestered in the cytoplasm in these cells, but also by

Electrically induced brain-derived neurotrophic factor release from Schwann cells.

Regulating the production of brain-derived neurotrophic factor (BDNF) in Schwann cells (SCs) is critical for their application in traumatic nerve injury, neurodegenerative disorders, and demyelination disease in both central and peripheral nervous systems. The present study investigated the possibility of using electrical stimulation (ES) to activate SCs to release BDNF. We found that short-term ES was capable of promoting BDNF production from SCs, and the maximal BDNF release was achieved by ES at 6 V (3 Hz, 30 min). We further examined the involvement of intracellular calcium ions ([Ca2+]i)

Iloprost, a prostacyclin analogue, stimulates meiotic maturation and early embryonic development in pigs.

Oviduct fluid contains various cytokines and growth factors that enhance the embryo development during the preimplantation period. In hatched embryos, prostacyclin (PGI(2)) improves implantation, but its role during oocyte maturation and early embryo development remains contentious. Therefore, in the present study, we examined the effects of a PGI(2) analogue (iloprost) on meiotic maturation and early embryonic development in pigs, as well on the structural integrity, mitochondrial membrane potential and apoptosis in blastocysts. First, meiotic maturation in pig oocytes was examined in the pre

The cyclic AMP-dependent protein kinase A pathway is involved in progesterone effects on calcitonin secretion from TT cells.

It is well known that gonadal steroid hormones influence the level of plasma calcitonin (CT), but the mechanism by which progesterone affects CT secretion is not clear. Immortalized TT cells are a reliable model system for studying the endocrine function of human parafollicular cells. In the present study, the effects of progesterone on CT secretion were examined in TT cells. TT cells were incubated in medium containing vehicle (DMSO), progesterone or BSA-progesterone for 60 or 150 min, and then the levels of CT in the medium, progesterone receptors, cAMP accumulation and CT mRNA expression we

Behavioral and Neurochemical Changes in Rats with Recurrent Depression induced by chronic unpredictable stress.

OBJECTIVES: The mechanism of recurrent depression remains unclear. This study aimed to evaluate the behavioural and neurochemical patterns of rats with recurrent depression. MATERIALS AND METHODS: An animal model of recurrent depression was established using chronic unpredictable stress and imipramine hydrochloride. The behaviour of the rats was tested during the first onset and recurrence periods of depression. The levels of adrenocorticotropic hormone (ACTH), corticosterone (CORT), and cyclic adenosine monophosphate (cAMP) in serum were detected by ELISA. The protein expressions of brain-de

The endocannabinoid system is altered in the post-mortem prefrontal cortex of alcoholic subjects.

There is strong biochemical, pharmacological and genetic evidence for the involvement of the endocannabinoid system (ECS) in alcohol dependence. However, the majority of studies have been performed in animal models. The aim of the present study was to assess the state of the CB1 receptor, the enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), and the extracellular signal-regulated kinase (ERK) and cyclic-AMP response element-binding protein (CREB) in the post-mortem prefrontal cortex of alcoholic subjects. Experiments were performed in samples from 44 subjects classi

Involvement of TORC2, a CREB co-activator, in the in vivo-specific transcriptional control of HTLV-1.

BACKGROUND: Human T-cell leukemia virus type 1 (HTLV-1) causes adult T -cell leukemia (ATL) but the expression of HTLV-1 is strongly suppressed in the peripheral blood of infected people. However, such suppression, which may explain the long latency in the development of ATL, is readily reversible, and viral expression resumes quickly with ex vivo culture of infected T -cells. To investigate the mechanism of in vivo -specific transcriptional suppression, we established a mouse model in which mice were intraperitoneally administered syngeneic EL4 T -lymphoma cells transduced with a recombinant

Diaryl terephthalamides as small-molecule disruptors of the c-Myb-CBP/p300 KIX protein-protein interaction: Mechanistic insights and biochemical validation.

The interaction between the transcription factor c-Myb and the CBP/p300 KIX domain is a functionally important protein-protein interface that supports oncogenic transcriptional programs in acute myeloid leukemia and therefore represents an attractive target for inhibitor discovery. Herein, we investigated diaryl terephthalamides as a new small-molecule chemotype for disruption of the c-Myb-CBP/p300 KIX interaction by integrating computational screening with experimental validation. A virtual-screening workflow was applied to a library diaryl terephthalamide derivatives affording five hit compo

Discovery of novel CBP bromodomain inhibitors through TR-FRET-based high-throughput screening.

The cAMP-responsive element binding protein (CREB) binding protein (CBP) and adenoviral E1A-binding protein (P300) are two closely related multifunctional transcriptional coactivators. Both proteins contain a bromodomain (BrD) adjacent to the histone acetyl transferase (HAT) catalytic domain, which serves as a promising drug target for cancers and immune system disorders. Several potent and selective small-molecule inhibitors targeting CBP BrD have been reported, but thus far small-molecule inhibitors targeting BrD outside of the BrD and extraterminal domain (BET) family are especially lacking

Stem Cell Factor-Inducible MITF-M Expression in Therapeutics for Acquired Skin Hyperpigmentation.

Rationale: Microphthalmia-associated transcription factor M (MITF-M) plays important roles in the pigment production, differentiation and survival of melanocytes. Stem cell factor (SCF) and its receptor KIT stimulate MITF-M activity via phosphorylation at the post-translation level. However, the phosphorylation shortens half-life of MITF-M protein over the course of minutes. Here, we investigated novel hypotheses of (i) whether SCF/KIT can regulate MITF-M activity through gene expression as the alternative process, and (ii) whether chemical inhibition of KIT activity can mitigate the acquired

Antidepressant-like effects of water extract of Gastrodia elata Blume on neurotrophic regulation in a chronic social defeat stress model.

ETHNOPHARMACOLOGY RELEVANCE: Gastrodia elata Blume (GE) is a traditional Chinese medicine commonly used to treat dizziness, epilepsy, paralysis and some emotional symptoms in east Asia. We previously showed that the water extract of Gastrodia elata Blume (WGE) possesses anti-depression like effects in a forced swimming test and chronic mild stress model. AIM OF THE STUDY: The aim of this study was to investigate the antidepressant-like effects of WGE and potential mechanisms related to brain-derived neurotrophic factor (BDNF) regulation in mice exposed to chronic social defeat stress (CSDS) m

Mucosal acidosis elicits a unique molecular signature in epithelia and intestinal tissue mediated by GPR31-induced CREB phosphorylation.

Metabolic changes associated with tissue inflammation result in significant extracellular acidosis (EA). Within mucosal tissues, intestinal epithelial cells (IEC) have evolved adaptive strategies to cope with EA through the up-regulation of SLC26A3 to promote pH homeostasis. We hypothesized that EA significantly alters IEC gene expression as an adaptive mechanism to counteract inflammation. Using an unbiased RNA sequencing approach, we defined the impact of EA on IEC gene expression to define molecular mechanisms by which IEC respond to EA. This approach identified a unique gene signature enri

Clinical and Genetic Management of a Patient with Rubinstein-Taybi Syndrome Type 1: A Case Report.

Rubinstein-Taybi Syndrome type 1 (RSTS1) is an uncommon autosomal dominant genetic disorder associated with neurodevelopmental impairments and multiple congenital anomalies, with an incidence of 1:100,000-125,000 live births. The syndrome, caused by de novo mutations in the CREBBP gene, is characterized by phenotypic variability, including intellectual disability, facial dysmorphisms, and systemic abnormalities. The current case report describes a 15-year-old Brazilian female diagnosed with RSTS1 through whole-exome sequencing, which identified a de novo heterozygous missense mutation in the C

Neuroprotective Effect of 1,3-dipalmitoyl-2-oleoylglycerol Derived from Rice Bran Oil against Cerebral Ischemia-Reperfusion Injury in Rats.

1,3-Dipalmitoyl-2-oleoylglycerol (POP) is a triacylglyceride found in oils from various natural sources, including palm kernels, sunflower seeds, and rice bran. In the current study, the neuroprotective effects and the specific mechanism of POP derived from rice bran oil were investigated for the first time using the middle cerebral artery occlusion/reperfusion (MCAO/R) model in rats. Orally administered POP at 1, 3, or 5 mg/kg (three times: 0.5 h before MCAO, after 1 h of MCAO, and after 1 h of reperfusion) markedly reduced the MCAO/R-induced infarct/edema volume and neurobehavioral deficits.