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1.
Arch. argent. pediatr ; 120(1): e39-e42, feb 2022. tab, ilus
Article in Spanish | LILACS, BINACIS | ID: biblio-1353777

ABSTRACT

Las nuevas metodologías de secuenciación masiva han permitido caracterizar e identificar variantes genéticas asociadas a diferentes patologías. En este trabajo se presenta el caso de una paciente con una mutación del gen RARS2 que codifica la enzima arginino-ARNt ligasa para la codificación de proteínas. Esta alteración genética se manifiesta en hipoplasia pontocerebelosa tipo 6, con una prevalencia de <1/1 000 0000, caracterizada por un cerebelo y un puente de menor tamaño asociados a un retraso grave en el neurodesarrollo. El análisis de caso permite un mejor conocimiento de enfermedades de origen genético, específicamente, de aquellas con patrones de herencia autosómicos recesivos de padres no consanguíneos. Su estudio sobre todo en lo relacionado con el ámbito familiar y socioeconómico, y su base genética, ayuda a una mejor calidad de vida de los pacientes y su familia.


The latest method of next-generation sequencing has allowed the characterization and identification of genetic variants associated to diverse pathologies. In this article, we present the case of female patient with a mutation of the RARS2 gene that encodes the enzyme for arginyl tRNA synthetase for coding of proteins. This genetic alteration manifests in pontocerebellar hypoplasia type 6, with a prevalence of <1/1,000,0000, characterized by a cerebellum and pons that are smaller in size and are associated with severe neurodevelopmental delay. The analysis of the case of this patient provides better knowledge of diseases of genetic origin; specifically, regarding genetic diseases of autosomal recessive patterns of inheritance from non-consanguineous parents. The impact of these studies; specially within the family, social, economic and genetic aspects helps provide a better quality of life for these patients and their family.


Subject(s)
Humans , Female , Child, Preschool , Arginine-tRNA Ligase/genetics , Quality of Life , Magnetic Resonance Imaging , Sequence Analysis , Colombia , Mutation
2.
Chinese Journal of Gastroenterology ; (12): 321-327, 2022.
Article in Chinese | WPRIM | ID: wpr-1016104

ABSTRACT

Background: Disrupted circadian rhythms have been associated with the development of irritable bowel syndrome (IBS). In some IBS patients, the symptoms may present with circadian fluctuations. Enterochromaffin cells (EC cells) and tryptophan hydroxylase 1 (TPH1) - 5 - hydroxytryptamine (5 - HT) signaling pathway are currently recognized as the key pathophysiological mechanism of IBS. Aims: To explore whether Bmal1, the core circadian clock gene, is involved in the occurrence of IBS by regulating TPH1-5-HT signaling pathway in EC cells. Methods: Normal Sprague-Dawley (SD) rats and IBS-model SD rats, as well as wild type (WT) and intestine-specific Bmal1 knockout (Bmal1

3.
Chinese Journal of Biochemistry and Molecular Biology ; (12): 1015-1022, 2022.
Article in Chinese | WPRIM | ID: wpr-1015802

ABSTRACT

As people age, the population of the elderly increases rapidly. With the change of work and lifestyle, the problems such as reduced physical activity and irregular routine become more serious, which results in the significantly increased incidence of skeletal muscle atrophy, and reduced health status and life quality of elderly. At the same time, the imbalance of diets, the decrease of physical activity, and the fluctuation of hormone levels further aggravate the occurrence of skeletal muscle atrophy, and its pathological mechanisms mainly correlated with chronic inflammation, mitochondrial dysfunction, deficient autophagy, increased apoptosis, impaired muscle satellite cell function, and disrupted circadian rhythm. Skeletal muscles, as the largest peripheral biological clock of the body, can affect the fiber structure, mitochondrial function, and muscle mass of skeletal muscles by regulating the circadian core genes BMAL1 and CLOCK. As an important intervention strategy to improve skeletal muscle masses, exercise can also activate the circadian signal pathway and regulate its phase, thus improving muscle regeneration and muscle strengths and delaying muscle atrophy. Therefore, from the perspective of circadian rhythm, this article summarizes the occurrence of muscular atrophy and the molecular mechanism of potential exercise intervention to provide new ideas for the targeted regulation of the prevention, treatment, and rehabilitation of muscular atrophy.

4.
Acta Pharmaceutica Sinica B ; (6): 763-780, 2021.
Article in English | WPRIM | ID: wpr-881168

ABSTRACT

Intestinal toxicity induced by chemotherapeutics has become an important reason for the interruption of therapy and withdrawal of approved agents. In this study, we demonstrated that chemotherapeutics-induced intestinal damage were commonly characterized by the sharp upregulation of tryptophan (Trp)-kynurenine (KYN)-kynurenic acid (KA) axis metabolism. Mechanistically, chemotherapy-induced intestinal damage triggered the formation of an interleukin-6 (IL-6)-indoleamine 2,3-dioxygenase 1 (IDO1)-aryl hydrocarbon receptor (AHR) positive feedback loop, which accelerated kynurenine pathway metabolism in gut. Besides, AHR and G protein-coupled receptor 35 (GPR35) negative feedback regulates intestinal damage and inflammation to maintain intestinal integrity and homeostasis through gradually sensing kynurenic acid level in gut and macrophage, respectively. Moreover, based on virtual screening and biological verification, vardenafil and linagliptin as GPR35 and AHR agonists respectively were discovered from 2388 approved drugs. Importantly, the results that vardenafil and linagliptin significantly alleviated chemotherapy-induced intestinal toxicity

5.
Acta Pharmaceutica Sinica B ; (6): 33-41, 2020.
Article in English | WPRIM | ID: wpr-781552

ABSTRACT

Sepsis is an infection-induced systemic inflammatory syndrome. The immune response in sepsis is characterized by the activation of both proinflammatory and anti-inflammatory pathways. When sepsis occurs, the expression and activity of many inflammatory cytokines are markedly affected. Xenobiotic receptors are chemical-sensing transcription factors that play essential roles in the transcriptional regulation of drug-metabolizing enzymes (DMEs). Xenobiotic receptors mediate the functional crosstalk between sepsis and drug metabolism because the inflammatory cytokines released during sepsis can affect the expression and activity of xenobiotic receptors and thus impact the expression and activity of DMEs. Xenobiotic receptors in turn may affect the clinical outcomes of sepsis. This review focuses on the sepsis-induced inflammatory response and xenobiotic receptors such as pregnane X receptor (PXR), aryl hydrocarbon receptor (AHR), glucocorticoid receptor (GR), and constitutive androstane receptor (CAR), DMEs such as CYP1A, CYP2B6, CYP2C9, and CYP3A4, and drug transporters such as p-glycoprotein (P-gp), and multidrug resistance-associated protein (MRPs) that are affected by sepsis. Understanding the xenobiotic receptor-mediated effect of sepsis on drug metabolism will help to improve the safe use of drugs in sepsis patients and the development of new xenobiotic receptor-based therapeutic strategies for sepsis.

6.
Biol. Res ; 53: 25, 2020. tab, graf
Article in English | LILACS | ID: biblio-1124210

ABSTRACT

BACKGROUND: Hypoxia inducible factor-1 (HIF-1) is considered as the most activated transcriptional factor in response to low oxygen level or hypoxia. HIF-1 binds the hypoxia response element (HRE) sequence in the promoter of different genes, mainly through the bHLH domain and activates the transcription of genes, especially those involved in angiogenesis and EMT. Considering the critical role of bHLH in binding HIF-1 to the HRE sequence, we hypothesized that bHLH could be a promising candidate to be targeted in hypoxia condition. METHODS: We inserted an inhibitory bHLH (ibHLH) domain in a pIRES2-EGFP vector and transfected HEK293T cells with either the control vector or the designed construct. The ibHLH domain consisted of bHLH domains of both HIF-1a and Arnt, capable of competing with HIF-1 in binding to HRE sequences. The transfected cells were then treated with 200 µM of cobalt chloride (CoCl2) for 48 h to induce hypoxia. Real-time PCR and western blot were performed to evaluate the effect of ibHLH on the genes and proteins involved in angiogenesis and EMT. RESULTS: Hypoxia was successfully induced in the HEK293T cell line as the gene expression of VEGF, vimentin, and ß-catenin were significantly increased after treatment of untransfected HEK293T cells with 200 µM CoCl2. The gene expression of VEGF, vimentin, and ß-catenin and protein level of ß-catenin were significantly decreased in the cells transfected with either control or ibHLH vectors in hypoxia. However, ibHLH failed to be effective on these genes and the protein level of ß-catenin, when compared to the control vector. We also observed that overexpression of ibHLH had more inhibitory effect on gene and protein expression of N-cadherin compared to the control vector. However, it was not statistically significant. CONCLUSION: bHLH has been reported to be an important domain involved in the DNA binding activity of HIF. However, we found that targeting this domain is not sufficient to inhibit the endogenous HIF-1 transcriptional activity. Further studies about the function of critical domains of HIF-1 are necessary for developing a specific HIF-1 inhibitor.


Subject(s)
Humans , Basic Helix-Loop-Helix Transcription Factors/metabolism , Hypoxia-Inducible Factor 1/metabolism , Hypoxia/metabolism , Gene Expression , Transcriptional Activation/genetics , Blotting, Western , Basic Helix-Loop-Helix Transcription Factors/genetics , Hypoxia-Inducible Factor 1/genetics , HEK293 Cells , Real-Time Polymerase Chain Reaction , Hypoxia/genetics
7.
Annals of Dermatology ; : 407-413, 2017.
Article in English | WPRIM | ID: wpr-86521

ABSTRACT

BACKGROUND: Filaggrin (FLG) is the major component of the epidermal granular layer and binds to and condenses the keratin cytoskeleton. FLG thus contributes to cell compaction and serves as a natural moisturizing factor by promoting unfolding and degradation into hygroscopic amino acids. Loss or downregulation of FLG has been shown to result in a weak stratum corneum, which causes water loss and increases the possibility of skin barrier-related seizure. Adiponectin (Acrp30) contributes to the functional recovery of somatic cells, including human normal epidermal keratinocytes (NHEKs). OBJECTIVE: To investigate the effect of Acrp30 in FLG expression and identifying its signal transduction mechanism. METHODS: Normal human keratinocytes were treated with Acrp30 and the levels of FLG were examined. Silent mating type information regulation 2 homolog (SIRT)-targeting siRNA and aryl hydrocarbon receptor nuclear translocator (ARNT)-targeting siRNA were used to identify the role of various signal transduction pathway components. RESULTS: Acrp30 upregulated SIRT1 and ARNT expression in NHEKs, resulting in increased FLG expression. Treatment with both SIRT1-targeting siRNA and ARNT-targeting siRNA blocked Acrp30 stimulation and silenced FLG expression. CONCLUSION: Adiponectin upregulates FLG expression through a SIRT1-mediated pathway. Our results suggest that Acrp30 is a promising agent for skin barrier permeability improvement.


Subject(s)
Humans , Adiponectin , Amino Acids , Aryl Hydrocarbon Receptor Nuclear Translocator , Cytoskeleton , Down-Regulation , Keratinocytes , Permeability , RNA, Small Interfering , Seizures , Signal Transduction , Skin , Water
8.
Acta Pharmaceutica Sinica B ; (6): 378-389, 2015.
Article in English | WPRIM | ID: wpr-310013

ABSTRACT

Hypoxia-inducible factor-1 (HIF-1) has been recognized as an important cancer drug target. Many recent studies have provided convincing evidences of strong correlation between elevated levels of HIF-1 and tumor metastasis, angiogenesis, poor patient prognosis as well as tumor resistance therapy. It was found that hypoxia (low O2 levels) is a common character in many types of solid tumors. As an adaptive response to hypoxic stress, hypoxic tumor cells activate several survival pathways to carry out their essential biological processes in different ways compared with normal cells. Recent advances in cancer biology at the cellular and molecular levels highlighted the HIF-1α pathway as a crucial survival pathway for which novel strategies of cancer therapy could be developed. However, targeting the HIF-1α pathway has been a challenging but promising progresses have been made in the past twenty years. This review summarizes the role and regulation of the HIF-1α in cancer, and recent therapeutic approaches targeting this important pathway.

9.
Acta Pharmaceutica Sinica B ; (6): 113-122, 2015.
Article in English | WPRIM | ID: wpr-329685

ABSTRACT

Mounting research evidence demonstrates a significant negative impact of circadian disruption on human health. Shift work, chronic jet lag and sleep disturbances are associated with increased incidence of metabolic syndrome, and consequently result in obesity, type 2 diabetes and dyslipidemia. Here, these associations are reviewed with respect to liver metabolism and disease.

10.
Journal of Korean Medical Science ; : 581-588, 2002.
Article in English | WPRIM | ID: wpr-48197

ABSTRACT

Hypoxia-inducible factor-1 (HIF-1) is composed of HIF-1alpha and HIF-1beta, and is a master regulator of oxygen homeostasis, playing critical roles in physiological and pathological processes. Normally, the formation and transcriptional activity of HIF-1 depend on the amount of HIF-1alpha, and the expression of HIF-1alpha is tightly controlled by the cellular oxygen tension. Recent progress in the study of its regulation mechanism provided clues as to how HIF-1alpha is regulated by oxygen. It appears that HIF-1alpha is not regulated only by the oxygen tension, but also by various other stimuli, such as transition metals, nitric oxide, reactive oxygen species, growth factors, and mechanical stresses. In this review, we summarize the oxygen-dependent and -independent regulation of HIF-1alpha, and the respective physiological and pathological meanings.


Subject(s)
Animals , Humans , Growth Substances/metabolism , Hypoxia-Inducible Factor 1, alpha Subunit , Molecular Structure , Nitric Oxide/metabolism , Oxygen/metabolism , Reactive Oxygen Species/metabolism , Stress, Mechanical , Transcription Factors/chemistry , Transition Elements/metabolism
11.
Chinese Journal of Pathophysiology ; (12)2000.
Article in Chinese | WPRIM | ID: wpr-528266

ABSTRACT

AIM: To analyze the subcellular localization of Arnt2 in rat cerebellar granule neurons (CGNs). METHODS: Based on the amino acids sequence of Arnt2 (LOCUS:NP_036913), the subcellular localization of Arnt2 in eukaryotic cells and the nuclear export signals (NES) of Arnt2 were predicted in CBS bioinformatics database. The subcellular localization of Arnt2 in rat cerebellar granule neurons was detected by the method of laser scanning confocal microscopy (LSM) analysis. RESULTS: It was predicted that Arnt2 located in nuclei of eukaryotic cells with the most probability, while located in cytoplasmic mitochondria with a slight possibility. A nuclear export signal was found in Arnt2 amino acids sequence, it was identified to be the leucine of No.143 that located in N-terminal of Arnt2 amino acids sequence. Finally, the result of LSM analysis shows nuclear localization of Arnt2 in rat CGNs. CONCLUSION: Arnt2 is located in nuclei of normal rat CGNs, it suggests that Arnt2 has the tendency to translocate into mitochondria after induced by some of inducible factors, for both the possibility of mitochondria localization and NES exist in Arnt2 amino acids sequence.

12.
Chinese Journal of Pathophysiology ; (12)1986.
Article in Chinese | WPRIM | ID: wpr-524460

ABSTRACT

AIM: To observe the expression of neuronal Aryl hydrocarbon receptor nuclear translocator 2 (ARNT2) involved in neuronal apoptosis evoked by low K + and to investigate the relationship between ARNT2 and neuronal apoptosis. METHODS: After neuron apoptosis model was established, the changes of mRNA and protein of ARNT2 during apoptosis were investigated by RT-PCR and Western blotting, respectively. Immunofluorescence was analyzed by confocal microscopy to probe the subcellular localization of ARNT2. RESULTS: Induced by low K +, the expression of ARNT2 mRNA was up-regulated obviously at the point of 30 min, and peaks at the point of 1 h. This up-regulated expression lasted for 12 h, and the variation of ARNT2 protein was similar to that of mRNA. The results of immunofluorescence analyzed by confocal microscopy showed that the localization of ARNT2 protein was in the nucleus. CONCLUSION: ARNT2 locate in nuclei of normal cerebellar granule neurons of rat. During the process of apoptosis evoked by low K +, both mRNA and protein of ARNT2 are overexpressed.

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