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1.
Artigo em Inglês | MEDLINE | ID: mdl-33949212

RESUMO

The outcomes of coronavirus disease 2019 (COVID-19) vary between men and women. Some statistical reports have shown that men have a higher risk of developing COVID-19 and suffer from worse outcomes than females. While there are many factors that can explain the high prevalence of COVID-19 in men, such as lifestyle habits and the different profile of comorbidities among sexes, the distinctions between male and female immune systems cannot be ignored. It has been sufficiently shown that sex differences have a critical influence on the shaping of immune response, which then leads to different pathogenesis in infectious diseases. Compared with males, females typically have a more effective innate and adaptive immune response to viral infections in COVID-19. What's more, there is a growing body of evidence showing that estrogen exerts an effect on the regulation of immune response. This article examines the effect and mechanism of estrogen on COVID-19.

2.
Pathogens ; 10(3)2021 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-33809851

RESUMO

The novel coronavirus disease 2019 (COVID-19) pandemic has led to an unprecedented threat to the international community and raised major concerns in terms of public health safety. Although our current understanding of the complexity of COVID-19 pathogenesis remains limited, the infection is largely mediated by the interaction of viral spike protein and angiotensin-converting enzyme 2 (ACE2). The functional importance of ACE2 in different demographic and comorbid conditions may explain the significant variation in incidence and mortality of COVID-19 in vulnerable groups, and highlights its candidacy as a potential therapeutic target. We provide evidence supporting the idea that differences in incidence and severity of COVID-19 infection may be related to ACE2. Emerging data based on the prevalence and severity of COVID-19 among those with established high levels of ACE2 expression strongly support our hypothesis. Considering the burden of COVID-19 infection in these vulnerable groups and the impact of the potential therapeutic and preventive measures that would result from adopting ACE2-driven anti-viral strategies, our hypothesis may expedite global efforts to control the current COVID-19 pandemic.

3.
Molecules ; 26(6)2021 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-33808811

RESUMO

Deep eutectic solvents (DESs) are considered as efficient and green solvents for the extraction of bioactive compounds from medicinal plants. In this work, a novel method of DES-based ultrasound-assisted extraction of bioactive compounds from Baphicacanthus cusia leaves (BCL) was established. Systematic screening and the morphology of the original and treated BCL were observed with scanning electron microscopy to determine the extraction efficiency of different solvents. The extraction conditions were optimized by Box-Behnken design (BBD) tests and the optimal extraction conditions were as follows: lactic acid/L-menthol ratio of 5: 2 (mol/mol), solid-liquid ratio of 80.0 mL/g and temperature of 60.5 °C. The extraction yields of tryptanthrin, indigo and indirubin reached 0.356, 1.744 and 0.562 mg/g, respectively. The results of a 2,2-diphenyl-1-picrylhydrazy (DPPH) radical scavenging activity test indicated the feasibility of DESs in the extraction of bioactive compounds. This study indicated that L-menthol/lactic acid was a green and efficient solvent for the extraction of bioactive compounds from BCL, and DES-based ultrasound-assisted extraction could be used as an effective application strategy for the extraction of bioactive compounds from medicinal plants.

4.
Circulation ; 143(19): 1894-1911, 2021 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-33793303

RESUMO

BACKGROUND: Mutations in tafazzin (TAZ), a gene required for biogenesis of cardiolipin, the signature phospholipid of the inner mitochondrial membrane, causes Barth syndrome (BTHS). Cardiomyopathy and risk of sudden cardiac death are prominent features of BTHS, but the mechanisms by which impaired cardiolipin biogenesis causes cardiac muscle weakness and arrhythmia are poorly understood. METHODS: We performed in vivo electrophysiology to define arrhythmia vulnerability in cardiac-specific TAZ knockout mice. Using cardiomyocytes derived from human induced pluripotent stem cells and cardiac-specific TAZ knockout mice as model systems, we investigated the effect of TAZ inactivation on Ca2+ handling. Through genome editing and pharmacology, we defined a molecular link between TAZ mutation and abnormal Ca2+ handling and contractility. RESULTS: A subset of mice with cardiac-specific TAZ inactivation developed arrhythmias, including bidirectional ventricular tachycardia, atrial tachycardia, and complete atrioventricular block. Compared with wild-type controls, BTHS-induced pluripotent stem cell-derived cardiomyocytes had increased diastolic Ca2+ and decreased Ca2+ transient amplitude. BTHS-induced pluripotent stem cell-derived cardiomyocytes had higher levels of mitochondrial and cellular reactive oxygen species than wild-type controls, which activated CaMKII (Ca2+/calmodulin-dependent protein kinase II). Activated CaMKII phosphorylated the RYR2 (ryanodine receptor 2) on serine 2814, increasing Ca2+ leak through RYR2. Inhibition of this reactive oxygen species-CaMKII-RYR2 pathway through pharmacological inhibitors or genome editing normalized aberrant Ca2+ handling in BTHS-induced pluripotent stem cell-derived cardiomyocytes and improved their contractile function. Murine Taz knockout cardiomyocytes also exhibited elevated diastolic Ca2+ and decreased Ca2+ transient amplitude. These abnormalities were ameliorated by Ca2+/calmodulin-dependent protein kinase II or reactive oxygen species inhibition. CONCLUSIONS: This study identified a molecular pathway that links TAZ mutation with abnormal Ca2+ handling and decreased cardiomyocyte contractility. This pathway may offer therapeutic opportunities to treat BTHS and potentially other diseases with elevated mitochondrial reactive oxygen species production.

5.
Am J Physiol Renal Physiol ; 320(5): F984-F1000, 2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-33843271

RESUMO

Sepsis-associated acute kidney injury (SA-AKI) is a significant problem in the critically ill that causes increased death. Emerging understanding of this disease implicates metabolic dysfunction in its pathophysiology. This study sought to identify specific metabolic pathways amenable to potential therapeutic intervention. Using a murine model of sepsis, blood and tissue samples were collected for assessment of systemic inflammation, kidney function, and renal injury. Nuclear magnetic resonance (NMR)-based metabolomics quantified dozens of metabolites in serum and urine that were subsequently submitted to pathway analysis. Kidney tissue gene expression analysis confirmed the implicated pathways. Septic mice had elevated circulating levels of inflammatory cytokines and increased levels of blood urea nitrogen and creatinine, indicating both systemic inflammation and poor kidney function. Renal tissue showed only mild histological evidence of injury in sepsis. NMR metabolomic analysis identified the involvement of mitochondrial pathways associated with branched-chain amino acid metabolism, fatty acid oxidation, and de novo NAD+ biosynthesis in SA-AKI. Renal cortical gene expression of enzymes associated with those pathways was predominantly suppressed. Renal cortical fatty acid oxidation rates were lower in septic mice with high inflammation, and this correlated with higher serum creatinine levels. Similar to humans, septic mice demonstrated renal dysfunction without significant tissue disruption, pointing to metabolic derangement as an important contributor to SA-AKI pathophysiology. Metabolism of branched-chain amino acid and fatty acids and NAD+ synthesis, which all center on mitochondrial function, appeared to be suppressed. Developing interventions to activate these pathways may provide new therapeutic opportunities for SA-AKI.NEW & NOTEWORTHY NMR-based metabolomics revealed disruptions in branched-chain amino acid metabolism, fatty acid oxidation, and NAD+ synthesis in sepsis-associated acute kidney injury. These pathways represent essential processes for energy provision in renal tubular epithelial cells and may represent targetable mechanisms for therapeutic intervention.

6.
Zhongguo Zhong Yao Za Zhi ; 46(1): 57-61, 2021 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-33645052

RESUMO

Natural borneol is an important traditional Chinese medicine herb with resuscitation-inducing, antipyretic and analgesic effects, and has been widely used in the fields of medicine, perfume and chemical industry. At present, natural borneol is short supply, with promising market development prospects. This paper summarized the distribution of borneol plant resources, cultivation status and molecular biological research progress, in the expectation of providing basis and ideas for the research and application of natural borneol.


Assuntos
Canfanos , Medicamentos de Ervas Chinesas , Medicina Tradicional Chinesa
7.
BMC Genomics ; 22(1): 217, 2021 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-33765915

RESUMO

BACKGROUND: Many recent studies have shown that miRNAs play important roles in the regulation of animal reproduction, including seasonal reproduction. The pineal gland is a crucial hub in the regulation of seasonal reproduction. However, little is known about the expression characteristics of pineal miRNAs in different reproductive seasons (anestrus and breeding season). Therefore, the expression profiles and regulatory roles of ovine pineal miRNAs were investigated during different reproductive stages using Solexa sequencing technology and dual luciferase reporter assays. RESULTS: A total of 427 miRNAs were identified in the sheep pineal gland. Significant differences in miRNA expression were demonstrated between anestrus and the breeding season in terms of the frequency distributions of miRNA lengths, number of expressed miRNAs, and specifically and highly expressed miRNAs in each reproductive stage. KEGG analysis of the differentially expressed (DE) miRNAs between anestrus and the breeding season indicated that they are significantly enriched in pathways related to protein synthesis, secretion and uptake. Furthermore, transcriptome analysis revealed that many target genes of DE miRNAs in the ribosome pathway showed relatively low expression in the breeding season. On the other hand, analyses combining miRNA-gene expression data with target relationship validation in vitro implied that miR-89 may participate in the negative regulation of aralkylamine N-acetyltransferase (AANAT) mRNA expression by targeting its 3'UTR at a unique binding site. CONCLUSIONS: Our results provide new insights into the expression characteristics of sheep pineal miRNAs at different reproductive stages and into the negative regulatory effects of pineal miRNAs on AANAT mRNA expression.

8.
Sleep Med ; 81: 1-7, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33621789

RESUMO

PURPOSE: Our aim was to investigate the association between sleep and the development of metabolic syndrome (MetS) in Chinese older adults and to accumulate evidence for the prevention of MetS through sleep management. METHODS: This prospective study followed 3005 participants aged over 60 derived from the Weitang Geriatric Diseases Study who were without MetS at baseline. MetS was defined according to the Adult Treatment Panel III (ATP III) criteria. Logistic regression models were fit to assess the association between sleep and MetS incident and a linear regression model was used to examine the impact of sleep duration on every component of MetS. Data on sleep-related parameters were obtained based on a self-reported questionnaire. RESULTS: After five-year follow-up, 13.51% participants developed MetS, of which 46.86% were women. The incidence of MetS was highest among adults who slept 6 h or less and lowest among those who slept 7 h after adjusted for multiple variables. Subgroup analyses showed no gender specificity. The variation of fasting plasma glucose (FBG) for ≥9 h per night was significantly lower than that for 7.01-7.99 h per night (ß = -0.18, P < 0.05). Sleeping for 8-8.99 h also decreased the variation of diastolic blood pressure (DBP) compared to 7.01-7.99 h (ß = -0.84, P < 0.05). CONCLUSION: We conclude that both short and long sleep duration are risk factors for MetS incident in older adults.

9.
Sci Rep ; 11(1): 4652, 2021 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-33633339

RESUMO

It remains unclear whether leukocyte-related parameters could be used as biomarkers to differentiate metabolically unhealthy overweight/obesity (MUO) from metabolically healthy overweight/obesity (MHO). We aimed to examine the differences in the distribution of leukocyte-related parameters between older adults with MHO and MUO and the correlations of leukocyte-related parameters with individual components of metabolic abnormality. In the Weitang Geriatric Diseases Study on older Chinese adults aged 60 years or above, 404 individuals with MHO and 480 with MUO contributed to the analysis. Overweight/obesity was defined as body mass index (BMI) of 25 kg/m2 or more. MHO and MUO were discriminated based on the Adult Treatment Panel III (ATP III) criteria. Leukocyte-related parameters were assessed using an automated hematology analyzer. All leukocyte-related parameters except monocytes were elevated in MUO group compared with MHO group (all P < 0.05). The prevalence of MUO increased by 24% with each 109/L increase of leukocytes after adjusting for confounders in the multiple-adjusted model (P < 0.01) and each unit elevation of other parameters except lymphocytes and monocytes were significantly associated with the presence of MUO (all P < 0.01). Trend tests revealed a linear trend for the association between MUO and all the leukocyte-related parameters (all P for trend < 0.05). Significant interactions between leukocyte-related parameters and sex on the presence of MUO were observed (all P value for interaction < 0.05). Higher leukocyte-related parameters were found in patients with MUO than those with MHO and were associated with higher prevalence of MUO which seems to be sex-dependent. Further studies are needed to see whether these parameters could be used as biomarkers for the screening or diagnosis for MUO in clinical or public health practice.

10.
Artigo em Inglês | MEDLINE | ID: mdl-33629163

RESUMO

This paper discusses how the pollution prevention mandate imposed by China's central government triggers water pollution across provincial borders. Because the central government has put the pollutant reduction into the promotion evaluation, and pollution control in the downstream area of a province mainly brings benefit to other regions, the provincial officials are incentivized to reduce the water pollutants away from the downstream city and strengthen environmental regulation within the province. We apply the difference-in-differences-differences (DDD) method to the dataset on water quality in cities along 18 major rivers in China from 2007 through 2016. We find that compared with the interior cities, the most downstream city of a province faces worse water quality. Besides, we find that environmental policy significantly increases the extent of pollution across jurisdictional boundaries. Then, we turn on the mechanism and find that the pollutant reduction target is significantly lower in the most downstream city of a province. Unanticipated provincial government behavior leads to severe transboundary water pollution.

11.
Artigo em Inglês | MEDLINE | ID: mdl-33604875

RESUMO

The etiology and pathogenesis of human immunodeficiency virus type-I (HIV)-associated neurocognitive disorders (HAND) remain undetermined and are likely the produce of multiple mechanisms. This can mainly include neuronal injury from HIV, inflammatory processes, and mental health issues. As a result, a variety of treatment options have been tested including NeuroHIV-targeted regimens based on the central nervous system (CNS) penetration effectiveness (CPE) of antiretroviral therapy (ART) and adjuvant therapies for HAND. NeuroHIV-targeted ART regimens have produced consistent and statistically significant HIV suppression in the CNS, but this is not the case for cognitive and functional domains. Most adjuvant therapies such as minocycline, memantine, and selegiline have negligible benefit in the improvement of cognitive function of people living with HIV (PLWH) with mild to moderate neurocognitive impairment. Newer experimental treatments have been proposed to target cognitive and functional symptoms of HAND as well as potential underlying pathogenesis. This review aims to provide an analytical overview of the clinical treatment options and clinical trials for HAND by focusing on NeuroHIV-targeted ART regimen development, CPE, and adjuvant therapies.

12.
Folia Histochem Cytobiol ; 59(1): 22-29, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33560516

RESUMO

INTRODUCTION: The occurrence of aortic dissection is related to the proliferation and metastasis of vascular smooth muscle cells. In our present study, we found that the expression of miR-140-5p was inhibited in the wall of abdominal aorta of aortic dissection patients. However, the mechanism of miR-140-5p in the development of aortic dissection is unclear. MATERIAL AND METHODS: We detected the expression of miR-140-5p and NCK Associated Protein 1 (NCKAP1) in blood vessel of aortic dissection patients and normal people by PCR. Next, we established the miR-140-5p overexpression and miR-140-5p inhibition vascular smooth muscle cells (CRL-1999 cells). The BrdU assays, wound healing assays and transwell assays were performed to detect the proliferation and invasion ability of these cells. Finally, luciferase reporter assay was performed to detect the relationship between miR-140-5p and NCKAP1. RESULTS: The expression of miR-140-5p was suppressed in blood vessel of aortic dissection patients, and the levels of NCKAP1 in those tissues were upregulated. Overexpression of miR-140-5p inhibited the proliferation, migration and invasion of vascular smooth muscle cells. miR-140-5p targeted and suppressed the expression of NCKAP1. CONCLUSIONS: miR-140-5p repressed the proliferation, migration and invasion of vascular smooth muscle cells by targeting and inhibiting the expression of NCKAP1. Furthermore, the results of our study suggest new strategies and targets for the clinical treatment of arterial dissection.

14.
Planta ; 253(2): 30, 2021 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-33423087

RESUMO

MAIN CONCLUSION: 46 monocot chimeric jacalins (MCJs) were mined from wheat genome. They were divided into three subfamilies with the activity of mannose-specific lectins and had effects on dehydration tolerance or disease resistance. Monocot chimeric jacalin (MCJ) is a newly identified subfamily of plant lectins that exclusively exists in Poaceae. The MCJs are modular proteins consisting of a dirigent domain and a jacalin-related lectin domain. Their unique evolution and various functions are not fully understood as only few members of MCJ have so for been investigated. From wheat, 46 MCJs were identified and phylogenetically classified into three subfamilies, in which subfamily I represented the early evolutionary cluster. MCJ genes are evenly distributed among three subgenomes of wheat, indicating that MCJ might be an ancient gene in Poaceae. qRT-PCR analysis showed that TaMCJ1 and TaMCJ2 were mainly expressed in leaves while TaMCJ3 in root tissues. All these TaMCJ genes are JA or ABA inducible. All three proteins exhibited agglutinating activity but different preference to mannose-binding. The overexpression of TaMCJ3 in tobacco increased dehydration tolerance, while TaMCJ1 enhanced wildfire disease resistance. The lignin biosynthetic genes were temporarily induced after pathogen inoculation in transgenic tobacco overexpressing TaMCJ, but the specific association with TaMCJ was not established. This evidence argued against the notion that the dirigent domain in TaMCJ is directly linked with lignin metabolism. Taken together, these results pave the way for a better understanding of the manifold functionality of MCJs and offer important insights to the evolutionary history of MCJ.


Assuntos
Genoma de Planta , Lectinas de Plantas , Proteínas de Plantas , Triticum , Resistência à Doença/genética , Genoma de Planta/genética , Lectinas de Plantas/química , Lectinas de Plantas/classificação , Lectinas de Plantas/genética , Lectinas de Plantas/metabolismo , Proteínas de Plantas/genética , Tabaco/genética , Triticum/genética
15.
Arch Gerontol Geriatr ; 94: 104343, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33493955

RESUMO

BACKGROUND AND OBJECTIVES: One possible pathway by which depressive symptoms influence all-cause mortality is through their relationship with markers of inflammatory response. We aimed to examine whether white blood cell (WBC) count mediated the relationship between the presence of depressive symptoms and all-cause mortality among older Chinese people. METHODS: This community-based cohort study targeted 4053 individuals aged 60 years or over. A bootstrapping approach was applied to examine whether WBC count mediated the relationship between the presence of depressive symptoms and all-cause mortality. WBC count was evaluated as a mediator. The presence of depressive symptoms was assessed by the nine-item Patient Health Questionnaire (PHQ-9). The mediating effect was considered significant if the 95% confidence interval (CI) did not include 0. RESULTS: Mediation analysis indicated that WBC count played an important mediating role in the relationship between PHQ-9 score and all-cause mortality based on the significance of indirect effect (ß = -0.0039, 95% CI = -0.01, -0.0009). The direct effect from PHQ-9 score to all-cause mortality was not statistically significant (P = 0.11) after adjusting for WBC count. CONCLUSION: WBC count was associated with depressive symptoms and all-cause mortality. The association of depressive symptoms with all-cause mortality was fully mediated by WBC count.

16.
Environ Pollut ; 273: 116427, 2021 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-33445128

RESUMO

To assess organochlorine compound (OC) contamination, its possible sources, and adverse health impacts on giant pandas, we collected soil, bamboo, and panda fecal samples from the habitat and research center of the Qinling panda (Ailuropoda melanoleuca qinlingensis)-the rarest recognized panda subspecies. The polychlorinated biphenyls (PCBs) and organochlorine pesticides (OCPs) concentrations were comparatively low which suggests that moderate sources of OC pollution currently. OC levels were lower in samples from nature reserve than in those collected from pandas held in captivity, and OC levels within the reserve increased between functional areas in the order: core, buffer and experimental. The distribution patterns, and correlation analyses, combined with congener distributions suggested PCBs and OCPs originated from similar sources, were dispersed by similar processes, being transported through atmosphere and characterized by historical residues. Backward trajectory analyses results, and detected DRINs (aldrin, dieldrin, endrin and isodrin) both suggest long-range atmospheric transport of pollution source. PCBs pose potential cancer risk, and PCB 126 was the most notable toxicant as assessed be the high carcinogenic risk index. We provide data for health risk assessment that can guide the identification of priority congeners, and recommend a long-term monitoring plan. This study proposes an approach to ecotoxicological threats whereby giant pandas may be used as sentinel species for other threatened or endangered mammals. By highlighting the risks of long-distance transmission of pollutants, the study emphasizes the importance of transboundary cooperation to safeguard biodiversity.

17.
Nat Commun ; 12(1): 178, 2021 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-33420010

RESUMO

Tandem organic solar cells are based on the device structure monolithically connecting two solar cells to broaden overall absorption spectrum and utilize the photon energy more efficiently. Herein, we demonstrate a simple strategy of inserting a double bond between the central core and end groups of the small molecule acceptor Y6 to extend its conjugation length and absorption range. As a result, a new narrow bandgap acceptor BTPV-4F was synthesized with an optical bandgap of 1.21 eV. The single-junction devices based on BTPV-4F as acceptor achieved a power conversion efficiency of over 13.4% with a high short-circuit current density of 28.9 mA cm-2. With adopting BTPV-4F as the rear cell acceptor material, the resulting tandem devices reached a high power conversion efficiency of over 16.4% with good photostability. The results indicate that BTPV-4F is an efficient infrared-absorbing narrow bandgap acceptor and has great potential to be applied into tandem organic solar cells.

18.
Cell Death Dis ; 12(1): 85, 2021 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-33446653

RESUMO

Phosphoinositide-3 kinase alpha-specific inhibitors (PI3Kαi) displayed promising potential for the treatment of esophageal squamous cell carcinoma (ESCC) with frequent activation in PI3K signaling. However, acquired resistance is likely to develop and limit the efficacy of PI3Kαi like other targeted therapies. To identify genomic adaptation to PI3Kαi, we applied whole-genome sequencing and detected gene mutation and amplification in four lines of ESCC cells established with adapted resistance to a novel PI3Kαi CYH33. Particularly, HRASG12S mutation was found in KYSE180C cells. Overexpression of HRASG12S in ESCC parental cells rendered resistance to CYH33. By contrast, down-regulation of HRASG12S restored the sensitivity of KYSE180C1 cells to CYH33, and combination of CYH33 and MEK162 displayed synergistic effect against KYSE180C1 cells and xenografts. Furthermore, elevated mTORC1, mitogen-activated protein kinase (MAPK), and c-Myc signaling pathways were found in resistant cells by RNA sequencing and combination of CYH33 and RAD001, MEK162, or OTX015 overcame the resistance to CYH33, which was accompanied with enhanced inhibition on S6, extracellular signal-regulated kinase 1 (ERK), or c-Myc, respectively. Overall, we characterized the adaptations to PI3Kαi in ESCC cells and identified combinatorial regimens that may circumvent resistance.

20.
Proc Natl Acad Sci U S A ; 118(2)2021 01 12.
Artigo em Inglês | MEDLINE | ID: mdl-33361330

RESUMO

The paucity of knowledge about cardiomyocyte maturation is a major bottleneck in cardiac regenerative medicine. In development, cardiomyocyte maturation is characterized by orchestrated structural, transcriptional, and functional specializations that occur mainly at the perinatal stage. Sarcomeres are the key cytoskeletal structures that regulate the ultrastructural maturation of other organelles, but whether sarcomeres modulate the signal transduction pathways that are essential for cardiomyocyte maturation remains unclear. To address this question, here we generated mice with cardiomyocyte-specific, mosaic, and hypomorphic mutations of α-actinin-2 (Actn2) to study the cell-autonomous roles of sarcomeres in postnatal cardiomyocyte maturation. Actn2 mutation resulted in defective structural maturation of transverse-tubules and mitochondria. In addition, Actn2 mutation triggered transcriptional dysregulation, including abnormal expression of key sarcomeric and mitochondrial genes, and profound impairment of the normal progression of maturational gene expression. Mechanistically, the transcriptional changes in Actn2 mutant cardiomyocytes strongly correlated with those in cardiomyocytes deleted of serum response factor (SRF), a critical transcription factor that regulates cardiomyocyte maturation. Actn2 mutation increased the monomeric form of cardiac α-actin, which interacted with the SRF cofactor MRTFA and perturbed its nuclear localization. Overexpression of a dominant-negative MRTFA mutant was sufficient to recapitulate the morphological and transcriptional defects in Actn2 and Srf mutant cardiomyocytes. Together, these data indicate that Actn2-based sarcomere organization regulates structural and transcriptional maturation of cardiomyocytes through MRTF-SRF signaling.


Assuntos
Actinina/genética , Miócitos Cardíacos/metabolismo , Sarcômeros/metabolismo , Actinina/metabolismo , Animais , Núcleo Celular/metabolismo , Citoesqueleto/metabolismo , Regulação da Expressão Gênica/genética , Camundongos , Mitocôndrias/metabolismo , Morfogênese , Mutação , Miócitos Cardíacos/patologia , Sarcômeros/patologia , Fator de Resposta Sérica/metabolismo , Transdução de Sinais , Transativadores/metabolismo , Fatores de Transcrição/metabolismo
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