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1.
Circulation ; 149(17): 1375-1390, 2024 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-38214189

RESUMO

BACKGROUND: Cardiac transverse tubules (T-tubules) are anchored to sarcomeric Z-discs by costameres to establish a regular spaced pattern. One of the major components of costameres is the dystrophin-glycoprotein complex (DGC). Nevertheless, how the assembly of the DGC coordinates with the formation and maintenance of T-tubules under physiological and pathological conditions remains unclear. METHODS: Given the known role of Ptpn23 (protein tyrosine phosphatase, nonreceptor type 23) in regulating membrane deformation, its expression in patients with dilated cardiomyopathy was determined. Taking advantage of Cre/Loxp, CRISPR/Cas9, and adeno-associated virus 9 (AAV9)-mediated in vivo gene editing, we generated cardiomyocyte-specific Ptpn23 and Actn2 (α-actinin-2, a major component of Z-discs) knockout mice. We also perturbed the DGC by using dystrophin global knockout mice (DmdE4*). MM 4-64 and Di-8-ANEPPS staining, Cav3 immunofluorescence, and transmission electron microscopy were performed to determine T-tubule structure in isolated cells and intact hearts. In addition, the assembly of the DGC with Ptpn23 and dystrophin loss of function was determined by glycerol-gradient fractionation and SDS-PAGE analysis. RESULTS: The expression level of Ptpn23 was reduced in failing hearts from dilated cardiomyopathy patients and mice. Genetic deletion of Ptpn23 resulted in disorganized T-tubules with enlarged diameters and progressive dilated cardiomyopathy without affecting sarcomere organization. AAV9-mediated mosaic somatic mutagenesis further indicated a cell-autonomous role of Ptpn23 in regulating T-tubule formation. Genetic and biochemical analyses showed that Ptpn23 was essential for the integrity of costameres, which anchor the T-tubule membrane to Z-discs, through interactions with α-actinin and dystrophin. Deletion of α-actinin altered the subcellular localization of Ptpn23 and DGCs. In addition, genetic inactivation of dystrophin caused similar T-tubule defects to Ptpn23 loss-of-function without affecting Ptpn23 localization at Z-discs. Last, inducible Ptpn23 knockout at 1 month of age showed Ptpn23 is also required for the maintenance of T-tubules in adult cardiomyocytes. CONCLUSIONS: Ptpn23 is essential for cardiac T-tubule formation and maintenance along Z-discs. During postnatal heart development, Ptpn23 interacts with sarcomeric α-actinin and coordinates the assembly of the DGC at costameres to sculpt T-tubule spatial patterning and morphology.

2.
Mol Ther ; 32(6): 1984-1999, 2024 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-38553852

RESUMO

Keloids are characterized by fibroblast hyperproliferation and excessive accumulation of extracellular matrix (ECM) and are a major global health care burden among cutaneous diseases. However, the function of long noncoding RNA (lncRNA)-mediated ECM remodeling during the pathogenesis of keloids is still unclear. Herein, we identified a long noncoding transcript, namely, lymphocyte-specific protein 1 pseudogene 5 (LSP1P5), that modulates ECM component deposition in keloids. First, high-throughput transcriptome analysis showed that LSP1P5 was selectively upregulated in keloids and correlated with more severe disease in a clinical keloid cohort. Therapeutically, the attenuation of LSP1P5 significantly decreased the expression of ECM markers (COL1, COL3, and FN1) both in vitro and in vivo. Intriguingly, an antifibrotic gene, CCAAT enhancer binding protein alpha (CEBPA), is a functional downstream candidate of LSP1P5. Mechanistically, LSP1P5 represses CEBPA expression by hijacking Suppressor of Zeste 12 to the promoter of CEBPA, thereby enhancing the polycomb repressive complex 2-mediated H3K27me3 and changing the chromosomal opening status of CEBPA. Taken together, these findings indicate that targeting LSP1P5 abrogates fibrosis in keloids through epigenetic regulation of CEBPA, revealing a novel antifibrotic therapeutic strategy that bridges our current understanding of lncRNA regulation, histone modification and ECM remodeling in keloids.


Assuntos
Proteínas Estimuladoras de Ligação a CCAAT , Matriz Extracelular , Queloide , RNA Longo não Codificante , Animais , Humanos , Camundongos , Proteínas Estimuladoras de Ligação a CCAAT/genética , Proteínas Estimuladoras de Ligação a CCAAT/metabolismo , Matriz Extracelular/metabolismo , Fibroblastos/metabolismo , Regulação da Expressão Gênica , Queloide/genética , Queloide/metabolismo , Queloide/patologia , Regiões Promotoras Genéticas , RNA Longo não Codificante/genética , Regulação para Cima
3.
Clin Transl Med ; 14(9): e70016, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39233335

RESUMO

BACKGROUND: Elevated extracellular matrix (ECM) accumulation is a major contributing factor to the pathogenesis of fibrotic diseases. Recent studies have indicated that N6-methyladenosine (m6A) RNA modification plays a pivotal role in modulating RNA stability and contribute to the initiation of various pathological conditions. Howbeit, the precise mechanism by which m6A influences ECM deposition remains unclear. METHODS: In this study, we used hypertrophic scars (HTSs) as a paradigm to investigate ECM-related diseases. We focused on the role of ALKBH5-mediated m6A demethylation within the pathological progression of HTSs and examined its correlation with clinical stages. The effects of ALKBH5 ablation on ECM components were studied both in vivo and in vitro. Downstream targets of ALKBH5, along with their underlying mechanisms, were identified using integrated high-throughput analysis, RNA-binding protein immunoprecipitation and RNA pull-down assays. Furthermore, the therapeutic potential of exogenous ALKBH5 overexpression was evaluated in fibrotic scar models. RESULTS: ALKBH5 was decreased in fibroblasts derived from HTS lesions and was negatively correlated with their clinical stages. Importantly, ablation of ALKBH5 promoted the expression of COL3A1, COL1A1, and ELN, leading to pathological deposition and reconstruction of the ECM both in vivo and in vitro. From a therapeutic perspective, the exogenous overexpression of ALKBH5 significantly inhibited abnormal collagen deposition in fibrotic scar models. As determined by integrated high-throughput analysis, key ECM components including COL3A1, COL1A1, and ELN are direct downstream targets of ALKBH5. By means of its mechanism, ALKBH5 inhibits the expression of COL3A1, COL1A1, and ELN by removing m6A from mRNAs, thereby decreasing their stability in a YTHDF1-dependent manner. CONCLUSIONS: Our study identified ALKBH5 as an endogenous suppressor of pathological ECM deposition, contributing to the development of a reprogrammed m6A-targeted therapy for HTSs.


Assuntos
Homólogo AlkB 5 da RNA Desmetilase , Matriz Extracelular , Fibrose , Homólogo AlkB 5 da RNA Desmetilase/metabolismo , Homólogo AlkB 5 da RNA Desmetilase/genética , Matriz Extracelular/metabolismo , Fibrose/metabolismo , Humanos , Camundongos , Animais , Desmetilação , Colágeno Tipo III/metabolismo , Colágeno Tipo III/genética , Colágeno Tipo I/metabolismo , Colágeno Tipo I/genética , Adenosina/análogos & derivados , Adenosina/metabolismo , Adenosina/genética , Masculino , Cadeia alfa 1 do Colágeno Tipo I/genética , Cadeia alfa 1 do Colágeno Tipo I/metabolismo , Fibroblastos/metabolismo
4.
Heliyon ; 9(2): e13623, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36879745

RESUMO

How patterns are formed to scale with tissue size remains an unresolved problem. Here we investigate embryonic patterns of gap gene expression along the anterior-posterior (AP) axis in Drosophila. We use embryos that greatly differ in length and, importantly, possess distinct length-scaling characteristics of the Bicoid (Bcd) gradient. We systematically analyze the dynamic movements of gap gene expression boundaries in relation to both embryo length and Bcd input as a function of time. We document the process through which such dynamic movements drive both an emergence of a global scaling landscape and evolution of boundary-specific scaling characteristics. We show that, despite initial differences in pattern scaling characteristics that mimic those of Bcd in the anterior, such characteristics of final patterns converge. Our study thus partitions the contributions of Bcd input and regulatory dynamics inherent to the AP patterning network in shaping embryonic pattern's scaling characteristics.

5.
Cell Death Discov ; 9(1): 288, 2023 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-37543696

RESUMO

Regulation of protein translation initiation is tightly associated with cell growth and survival. Here, we identify Paip1, the Drosophila homolog of the translation initiation factor PAIP1, and analyze its role during development. Through genetic analysis, we find that loss of Paip1 causes reduced protein translation and pupal lethality. Furthermore, tissue specific knockdown of Paip1 results in apoptotic cell death in the wing imaginal disc. Paip1 depletion leads to increased proteotoxic stress and activation of the integrated stress response (ISR) pathway. Mechanistically, we show that loss of Paip1 promotes phosphorylation of eIF2α via the kinase PERK, leading to apoptotic cell death. Moreover, Paip1 depletion upregulates the transcription factor gene Xrp1, which contributes to apoptotic cell death and eIF2α phosphorylation. We further show that loss of Paip1 leads to an increase in Xrp1 translation mediated by its 5'UTR. These findings uncover a novel mechanism that links translation impairment to tissue homeostasis and establish a role of ISR activation and Xrp1 in promoting cell death.

6.
J Diabetes ; 13(3): 200-210, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32734598

RESUMO

BACKGROUND: This study aimed to analyze the genetics and treatments of the patients with the triad of diabetic ketoacidosis (DKA), hypertriglyceridemia, and acute pancreatitis (AP). METHODS: We conducted a retrospective study of six patients with the triad of AP, hypertriglyceridemia, and DKA at our hospital. All patients underwent plasmapheresis as part of their treatment. The clinical characteristics of the patients were obtained from the hospital information system and analyzed. Whole exome sequencing was performed using samples of one patient (case 6) and his family members. RESULTS: The average triglyceride level before plasmapheresis was 3282.17 ± 2975.43 mg/dL (range: 1646-9332 mg/dL). The triglyceride levels dropped by approximately 80% after plasmapheresis. None of the patients developed complications related from plasmapheresis. During follow-up, patients 5 and 6 developed recurrent pancreatitis for several times and showed the formation of pancreatic pseudocysts. We identified three novel heterozygous missense mutations in the family of patient 6, including c.12614C > T (p.Pro4205Leu) in APOB, c.160G > C (p.Glu54Gln) in CILP2, and c.1199C > A (p.Ala400Glu) in PEPD. CONCLUSIONS: Three novel heterozygous missense mutations, including c.12614C > T (p.Pro4205Leu) in APOB, c.160G > C (p.Glu54Gln) in CILP2, and c.1199C > A (p.Ala400Glu) in PEPD were first identified in a patient with the triad of DKA, hypertriglyceridemia, and AP. The combination of plasmapheresis, hydration, and insulin therapy may have the greatest clinical benefits for these patients.


Assuntos
Apolipoproteínas B/genética , Cetoacidose Diabética/genética , Dipeptidases/genética , Sequenciamento do Exoma/métodos , Hipertrigliceridemia/genética , Proteínas Associadas aos Microtúbulos/genética , Mutação de Sentido Incorreto , Pancreatite/genética , Doença Aguda , Adulto , Sequência de Bases , Cetoacidose Diabética/terapia , Feminino , Predisposição Genética para Doença/genética , Humanos , Hipertrigliceridemia/terapia , Masculino , Pancreatite/terapia , Polimorfismo de Nucleotídeo Único , Estudos Retrospectivos , Triglicerídeos/metabolismo
7.
Medicine (Baltimore) ; 99(41): e22247, 2020 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-33031264

RESUMO

BACKGROUND: Small nucleolar RNA host gene 12 (SNHG12) has been demonstrated to be a long noncoding RNA (lncRNA) that facilitates the progression of several solid malignant tumors. However, whether the expression level of SNHG12 in solid malignant tumors is associated with patients prognosis have not been investigated. METHODS: We systematically searched PubMed, EMBASE and Cochrane Library from Jan 1, 1950 to Mar 24, 2020 for randomized controlled trials published in English on SNHG12 expression in solid malignant tumors. We used the Newcastle-Ottawa Scale to assess the quality of articles. The HRs and 95%CI that extracted from Kaplan-Meier curves were used to perform the forest plot using a fixed-effects model. The meta-analysis was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. RESULTS: Thirteen articles containing 821 patients were included in this systematic review and meta-analysis. The result showed that high lncRNA SNHG12 expression is significantly associated with poor overall survival (OS) (HR = 1.94, 95% CI: 1.56-2.41, P < .001) and the studies are lack of statistically significant heterogeneity (P= .878, I = 0.0%). Beggs plot and Eggers test were applied to testify no publication bias existence in these studies. Subgroup analyses were performed and the result showed that TNM stage, lymph node metastasis and tumor type can influence the patients outcome, while there was no significantly correlation between SNHG12 expression and gender. CONCLUSIONS: The systematical review and meta-analysis synthetically analyzed 13 articles including 821 patients with ten types of solid malignant tumors, concluding that higher lncRNA SNHG12 expression is significantly associated with worse clinical prognosis.


Assuntos
Regulação Neoplásica da Expressão Gênica , RNA Longo não Codificante/genética , RNA Nucleolar Pequeno/genética , Progressão da Doença , Humanos , Prognóstico
9.
Zhongguo Zhen Jiu ; 32(11): 1054-6, 2012 Nov.
Artigo em Zh | MEDLINE | ID: mdl-23214003

RESUMO

Through the collection of the literatures published in recent years on the opportunity of acupuncture therapy for post-stroke dysphagia, the therapy of acupuncture-moxibustion combined with the rehabilitation training is regardes as the optimal program in the paper. In this program, the timing of acupuncture intervention is a key factor to impact the efficacy on post-stroke dysphagia. It is vitally significant to grasp the intervention timing of acupuncture-moxibustion in the recovery of swallowing function as well as articulation function with dysphagia involved.


Assuntos
Terapia por Acupuntura , Transtornos de Deglutição/terapia , Moxibustão , Acidente Vascular Cerebral/complicações , Animais , Transtornos de Deglutição/etiologia , Humanos
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