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1.
Int J Mol Sci ; 22(16)2021 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-34445594

RESUMO

The sarco-endoplasmic reticulum calcium ATPase (SERCA) is responsible for maintaining calcium homeostasis in all eukaryotic cells by actively transporting calcium from the cytosol into the sarco-endoplasmic reticulum (SR/ER) lumen. Calcium is an important signaling ion, and the activity of SERCA is critical for a variety of cellular processes such as muscle contraction, neuronal activity, and energy metabolism. SERCA is regulated by several small transmembrane peptide subunits that are collectively known as the "regulins". Phospholamban (PLN) and sarcolipin (SLN) are the original and most extensively studied members of the regulin family. PLN and SLN inhibit the calcium transport properties of SERCA and they are required for the proper functioning of cardiac and skeletal muscles, respectively. Myoregulin (MLN), dwarf open reading frame (DWORF), endoregulin (ELN), and another-regulin (ALN) are newly discovered tissue-specific regulators of SERCA. Herein, we compare the functional properties of the regulin family of SERCA transmembrane peptide subunits and consider their regulatory mechanisms in the context of the physiological and pathophysiological roles of these peptides. We present new functional data for human MLN, ELN, and ALN, demonstrating that they are inhibitors of SERCA with distinct functional consequences. Molecular modeling and molecular dynamics simulations of SERCA in complex with the transmembrane domains of MLN and ALN provide insights into how differential binding to the so-called inhibitory groove of SERCA-formed by transmembrane helices M2, M6, and M9-can result in distinct functional outcomes.


Assuntos
Proteínas de Ligação ao Cálcio/metabolismo , Cálcio/metabolismo , Proteínas Musculares/metabolismo , Proteolipídeos/metabolismo , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo , Animais , Proteínas de Ligação ao Cálcio/genética , Humanos , Modelos Moleculares , Proteínas Musculares/genética , Proteolipídeos/genética , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/genética
2.
Nutrients ; 13(8)2021 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-34444950

RESUMO

The purpose of this research was to investigate the prophylactic effects of glutamine on muscle protein synthesis and degradation in rats with ethanol-induced liver injury. For the first 2 weeks, Wistar rats were divided into two groups and fed a control (n = 16) or glutamine-containing diet (n = 24). For the following 6 weeks, rats fed the control diet were further divided into two groups (n = 8 per group) according to whether their diet contained no ethanol (CC) or did contain ethanol (CE). Rats fed the glutamine-containing diet were also further divided into three groups (n = 8 per group), including a GG group (glutamine-containing diet without ethanol), GE group (control diet with ethanol), and GEG group (glutamine-containing diet with ethanol). After 6 weeks, results showed that hepatic fatty change, inflammation, altered liver function, and hyperammonemia had occurred in the CE group, but these were attenuated in the GE and GEG groups. Elevated intestinal permeability and a higher plasma endotoxin level were observed in the CE group, but both were lower in the GE and GEG groups. The level of a protein synthesis marker (p70S6K) was reduced in the CE group but was higher in both the GE and GEG groups. In conclusion, glutamine supplementation might elevate muscle protein synthesis by improving intestinal health and ameliorating liver damage in rats with chronic ethanol intake.


Assuntos
Glutamina/administração & dosagem , Hepatopatias Alcoólicas/prevenção & controle , Proteínas Musculares/metabolismo , Biossíntese de Proteínas/efeitos dos fármacos , Proteólise/efeitos dos fármacos , Animais , Suplementos Nutricionais , Modelos Animais de Doenças , Etanol , Inflamação , Mucosa Intestinal/metabolismo , Fígado/metabolismo , Hepatopatias Alcoólicas/etiologia , Ratos , Ratos Wistar
3.
Int J Mol Sci ; 22(15)2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-34360974

RESUMO

Erythropoietin (EPO) downregulates hepcidin expression to increase the availability of iron; the downregulation of hepcidin is mediated by erythroferrone (ERFE) secreted by erythroblasts. Erythroblasts also express transferrin receptor 2 (TFR2); however, the possible role of TFR2 in hepcidin downregulation is unclear. The purpose of the study was to correlate liver expression of hepcidin with the expression of ERFE and TFR2 in murine bone marrow and spleen at 4, 16, 24, 48, 72 and 96 h following administration of a single dose of EPO. Splenic Fam132b expression increased 4 h after EPO injection; liver hepcidin mRNA was decreased at 16 h. In the spleen, expression of TFR2 and transferrin receptor (TFR1) proteins increased by an order of magnitude at 48 and 72 h after EPO treatment. The EPO-induced increase in splenic TFR2 and TFR1 was associated with an increase in the number of Tfr2- and Tfr1-expressing erythroblasts. Plasma exosomes prepared from EPO-treated mice displayed increased amount of TFR1 protein; however, no exosomal TFR2 was detected. Overall, the results confirm the importance of ERFE in stress erythropoiesis, support the role of TFR2 in erythroid cell development, and highlight possible differences in the removal of TFR2 and TFR1 from erythroid cell membranes.


Assuntos
Eritropoetina/farmacologia , Receptores da Transferrina/genética , Animais , Células Cultivadas , Citocinas/genética , Citocinas/metabolismo , Eritroblastos/efeitos dos fármacos , Eritroblastos/metabolismo , Exossomos/metabolismo , Hepcidinas/genética , Hepcidinas/metabolismo , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Receptores da Transferrina/metabolismo , Baço/metabolismo
4.
Molecules ; 26(16)2021 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-34443492

RESUMO

Muscle wasting and cachexia are prominent comorbidities in cancer. Treatment with polyphenolic compounds may partly revert muscle wasting. We hypothesized that treatment with curcumin or resveratrol in cancer cachectic mice may improve muscle phenotype and total body weight through attenuation of several proteolytic and signaling mechanisms in limb muscles. In gastrocnemius and soleus muscles of cancer cachectic mice (LP07 adenocarcinoma cells, N = 10/group): (1) LC-induced cachexia, (2) LC-cachexia+curcumin, and (3) LC-cachexia + resveratrol, muscle structure and damage (including blood troponin I), sirtuin-1, proteolytic markers, and signaling pathways (NF-κB and FoxO3) were explored (immunohistochemistry and immunoblotting). Compared to nontreated cachectic mice, in LC-cachexia + curcumin and LC-cachexia + resveratrol groups, body and muscle weights (gastrocnemius), limb muscle strength, muscle damage, and myofiber cross-sectional area improved, and in both muscles, sirtuin-1 increased, while proteolysis (troponin I), proteolytic markers, and signaling pathways were attenuated. Curcumin and resveratrol elicited beneficial effects on fast- and slow-twitch limb muscle phenotypes in cachectic mice through sirtuin-1 activation, attenuation of atrophy signaling pathways, and proteolysis in cancer cachectic mice. These findings have future therapeutic implications as these natural compounds, separately or in combination, may be used in clinical settings of muscle mass loss and dysfunction including cancer cachexia.


Assuntos
Caquexia/etiologia , Caquexia/fisiopatologia , Curcumina/farmacologia , Músculos/patologia , Músculos/fisiopatologia , Neoplasias/complicações , Proteólise , Resveratrol/farmacologia , Animais , Biomarcadores/metabolismo , Linhagem Celular , Feminino , Camundongos Endogâmicos BALB C , Proteínas Musculares/metabolismo , Músculos/efeitos dos fármacos , Atrofia Muscular/metabolismo , Fenótipo , Proteólise/efeitos dos fármacos , Transdução de Sinais , Sirtuína 1/metabolismo
5.
Nat Commun ; 12(1): 4900, 2021 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-34385433

RESUMO

Skeletal muscle subsarcolemmal mitochondria (SSM) and intermyofibrillar mitochondria subpopulations have distinct metabolic activity and sensitivity, though the mechanisms that localize SSM to peripheral areas of muscle fibers are poorly understood. A protein interaction study and complexome profiling identifies PERM1 interacts with the MICOS-MIB complex. Ablation of Perm1 in mice reduces muscle force, decreases mitochondrial membrane potential and complex I activity, and reduces the numbers of SSM in skeletal muscle. We demonstrate PERM1 interacts with the intracellular adaptor protein ankyrin B (ANKB) that connects the cytoskeleton to the plasma membrane. Moreover, we identify a C-terminal transmembrane helix that anchors PERM1 into the outer mitochondrial membrane. We conclude PERM1 functions in the MICOS-MIB complex and acts as an adapter to connect the mitochondria with the sarcolemma via ANKB.


Assuntos
Anquirinas/metabolismo , Mitocôndrias Musculares/metabolismo , Complexos Multiproteicos/metabolismo , Proteínas Musculares/metabolismo , Sarcolema/metabolismo , Animais , Membrana Celular/metabolismo , Citoesqueleto/metabolismo , Potencial da Membrana Mitocondrial/genética , Potencial da Membrana Mitocondrial/fisiologia , Camundongos Knockout , Proteínas Mitocondriais/metabolismo , Proteínas Musculares/genética , Músculo Esquelético/metabolismo , Músculo Esquelético/fisiologia
6.
FASEB J ; 35(8): e21773, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34324735

RESUMO

Acute hypoxia has previously been suggested to potentiate resistance training-induced hypertrophy by activating satellite cell-dependent myogenesis rather than an improvement in protein balance in human. Here, we tested this hypothesis after a 4-week hypoxic vs normoxic resistance training protocol. For that purpose, 19 physically active male subjects were recruited to perform 6 sets of 10 repetitions of a one-leg knee extension exercise at 80% 1-RM 3 times/week for 4 weeks in normoxia (FiO2 : 0.21; n = 9) or in hypoxia (FiO2 : 0.135, n = 10). Blood and skeletal muscle samples were taken before and after the training period. Muscle fractional protein synthetic rate was measured over the whole period by deuterium incorporation into the protein pool and muscle thickness by ultrasound. At the end of the training protocol, the strength gain was higher in the hypoxic vs the normoxic group despite no changes in muscle thickness and in the fractional protein synthetic rate. Only early myogenesis, as assessed by higher MyoD and Myf5 mRNA levels, appeared to be enhanced by hypoxia compared to normoxia. No effects were found on myosin heavy chain expression, markers of oxidative metabolism and lactate transport in the skeletal muscle. Though the present study failed to unravel clearly the mechanisms by which hypoxic resistance training is particularly potent to increase muscle strength, it is important message to keep in mind that this training strategy could be effective for all athletes looking at developing and optimizing their maximal muscle strength.


Assuntos
Proteínas Musculares/metabolismo , Força Muscular/fisiologia , Músculo Esquelético/anatomia & histologia , Oxigênio/metabolismo , Treinamento de Força/métodos , Regulação da Expressão Gênica , Humanos , Masculino , Músculo Esquelético/fisiologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Células Satélites de Músculo Esquelético/fisiologia , Adulto Jovem
7.
Am J Physiol Cell Physiol ; 321(3): C453-C470, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34260300

RESUMO

The myotendinous junction (MTJ) is a specialized interface for transmitting high forces between the muscle and tendon and yet the MTJ is a common site of strain injury with a high recurrence rate. The aim of this study was to identify previously unknown MTJ components in mature animals and humans. Samples were obtained from the superficial digital flexor (SDF) muscle-tendon interface of 20 horses, and the tissue was separated through a sequential cryosectioning approach into muscle, MTJ (muscle tissue enriched in myofiber tips attached to the tendon), and tendon fractions. RT-PCR was performed for genes known to be expressed in the three tissue fractions and t-distributed stochastic neighbor embedding (t-SNE) plots were used to select the muscle, MTJ, and tendon samples from five horses for RNA sequencing. The expression of previously known and unknown genes identified through RNA sequencing was studied by immunofluorescence on human hamstring MTJ tissue. The main finding was that RNA sequencing identified the expression of a panel of 61 genes enriched at the MTJ. Of these, 48 genes were novel for the MTJ and 13 genes had been reported to be associated with the MTJ in earlier studies. The expression of known [COL22A1 (collagen XXII), NCAM (neural cell adhesion molecule), POSTN (periostin), NES (nestin), OSTN (musclin/osteocrin)] and previously undescribed [MNS1 (meiosis-specific nuclear structural protein 1), and LCT (lactase)] MTJ genes was confirmed at the protein level by immunofluorescence on tissue sections of human MTJ. In conclusion, in muscle-tendon interface tissue enriched with myofiber tips, we identified the expression of previously unknown MTJ genes representing diverse biological processes, which may be important in the maintenance of the specialized MTJ.


Assuntos
Músculos Isquiossurais/metabolismo , Tendões dos Músculos Isquiotibiais/metabolismo , Fibras Musculares Esqueléticas/metabolismo , Proteínas Musculares/genética , RNA Mensageiro/genética , Adulto , Animais , Moléculas de Adesão Celular/genética , Moléculas de Adesão Celular/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Colágeno/genética , Colágeno/metabolismo , Feminino , Imunofluorescência , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Ontologia Genética , Cavalos , Humanos , Masculino , Anotação de Sequência Molecular , Proteínas Musculares/classificação , Proteínas Musculares/metabolismo , Nestina/genética , Nestina/metabolismo , Moléculas de Adesão de Célula Nervosa/genética , Moléculas de Adesão de Célula Nervosa/metabolismo , RNA Mensageiro/classificação , RNA Mensageiro/metabolismo , Análise de Sequência de RNA , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
8.
Biomolecules ; 11(7)2021 06 29.
Artigo em Inglês | MEDLINE | ID: mdl-34209658

RESUMO

Epithelial cell adhesion molecule (EpCAM) is a transmembrane glycoprotein expressed in epithelial tissues. EpCAM forms intercellular, homophilic adhesions, modulates epithelial junctional protein complex formation, and promotes epithelial tissue homeostasis. EpCAM is a target of molecular therapies and plays a prominent role in tumor biology. In this review, we focus on the dynamic regulation of EpCAM expression during epithelial-to-mesenchymal transition (EMT) and the functional implications of EpCAM expression on the regulation of EMT. EpCAM is frequently and highly expressed in epithelial cancers, while silenced in mesenchymal cancers. During EMT, EpCAM expression is downregulated by extracellular signal-regulated kinases (ERK) and EMT transcription factors, as well as by regulated intramembrane proteolysis (RIP). The functional impact of EpCAM expression on tumor biology is frequently dependent on the cancer type and predominant oncogenic signaling pathways, suggesting that the role of EpCAM in tumor biology and EMT is multifunctional. Membrane EpCAM is cleaved in cancers and its intracellular domain (EpICD) is transported into the nucleus and binds ß-catenin, FHL2, and LEF1. This stimulates gene transcription that promotes growth, cancer stem cell properties, and EMT. EpCAM is also regulated by epidermal growth factor receptor (EGFR) signaling and the EpCAM ectoderm (EpEX) is an EGFR ligand that affects EMT. EpCAM is expressed on circulating tumor and cancer stem cells undergoing EMT and modulates metastases and cancer treatment responses. Future research exploring EpCAM's role in EMT may reveal additional therapeutic opportunities.


Assuntos
Molécula de Adesão da Célula Epitelial/fisiologia , Transição Epitelial-Mesenquimal/fisiologia , Linhagem Celular Tumoral , Molécula de Adesão da Célula Epitelial/genética , Molécula de Adesão da Célula Epitelial/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Expressão Gênica/genética , Regulação da Expressão Gênica/genética , Regulação da Expressão Gênica/fisiologia , Humanos , Proteínas com Homeodomínio LIM/metabolismo , Proteínas Musculares/metabolismo , Neoplasias/metabolismo , Neoplasias/fisiopatologia , Células Neoplásicas Circulantes/metabolismo , Células-Tronco Neoplásicas/fisiologia , Transdução de Sinais/fisiologia , Fatores de Transcrição/metabolismo , beta Catenina/metabolismo
9.
Int J Mol Sci ; 22(14)2021 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-34299206

RESUMO

Despite the intensive investigation of the molecular mechanism of skeletal muscle hypertrophy, the underlying signaling processes are not completely understood. Therefore, we used an overload model, in which the main synergist muscles (gastrocnemius, soleus) of the plantaris muscle were surgically removed, to cause a significant overload in the remaining plantaris muscle of 8-month-old Wistar male rats. SIRT1-associated pro-anabolic, pro-catabolic molecular signaling pathways, NAD and H2S levels of this overload-induced hypertrophy were studied. Fourteen days of overload resulted in a significant 43% (p < 0.01) increase in the mass of plantaris muscle compared to sham operated animals. Cystathionine-ß-synthase (CBS) activities and bioavailable H2S levels were not modified by overload. On the other hand, overload-induced hypertrophy of skeletal muscle was associated with increased SIRT1 (p < 0.01), Akt (p < 0.01), mTOR, S6 (p < 0.01) and suppressed sestrin 2 levels (p < 0.01), which are mostly responsible for anabolic signaling. Decreased FOXO1 and SIRT3 signaling (p < 0.01) suggest downregulation of protein breakdown and mitophagy. Decreased levels of NAD+, sestrin2, OGG1 (p < 0.01) indicate that the redox milieu of skeletal muscle after 14 days of overloading is reduced. The present investigation revealed novel cellular interactions that regulate anabolic and catabolic processes in the hypertrophy of skeletal muscle.


Assuntos
Cistationina beta-Sintase/metabolismo , Proteínas Musculares/metabolismo , Músculo Esquelético/patologia , Animais , Hipertrofia/genética , Hipertrofia/metabolismo , Hipertrofia/patologia , Masculino , Proteínas Musculares/genética , Músculo Esquelético/metabolismo , Proteínas do Tecido Nervoso/antagonistas & inibidores , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Proteínas Nucleares/antagonistas & inibidores , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Wistar , Proteínas Quinases S6 Ribossômicas/genética , Proteínas Quinases S6 Ribossômicas/metabolismo , Sirtuína 1/genética , Sirtuína 1/metabolismo , Sirtuínas/antagonistas & inibidores , Sirtuínas/genética , Sirtuínas/metabolismo , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo
10.
Int J Mol Sci ; 22(12)2021 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-34198655

RESUMO

A decline in the body's motor functions has been linked to decreased muscle mass and function in the oral cavity and throat; however, aging of the junctions of the muscles and bones has also been identified as an associated factor. Basic and clinical studies on the muscles, tendons and bones, each considered independently, have been published. In recent years, however, research has focused on muscle attachment as the muscle-tendon-bone complex from various perspectives, and there is a growing body of knowledge on SRY-box9 (Sox9) and Mohawk(Mkx), which has been identified as a common controlling factor and a key element. Myostatin, a factor that inhibits muscle growth, has been identified as a potential key element in the mechanisms of lifetime structural maintenance of the muscle-tendon-bone complex. Findings in recent studies have also uncovered aspects of the mechanisms of motor organ complex morphostasis in the superaged society of today and will lay the groundwork for treatments to prevent motor function decline in older adults.


Assuntos
Desenvolvimento Ósseo/fisiologia , Morfogênese , Desenvolvimento Muscular/fisiologia , Tendões/crescimento & desenvolvimento , Animais , Pesquisa Biomédica , Humanos , Proteínas Musculares/metabolismo
11.
Nutrients ; 13(6)2021 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-34200501

RESUMO

Adequate dietary protein is important for many aspects of health with current evidence suggesting that exercising individuals need greater amounts of protein. When assessing protein quality, animal sources of protein routinely rank amongst the highest in quality, largely due to the higher levels of essential amino acids they possess in addition to exhibiting more favorable levels of digestibility and absorption patterns of the amino acids. In recent years, the inclusion of plant protein sources in the diet has grown and evidence continues to accumulate on the comparison of various plant protein sources and animal protein sources in their ability to stimulate muscle protein synthesis (MPS), heighten exercise training adaptations, and facilitate recovery from exercise. Without question, the most robust changes in MPS come from efficacious doses of a whey protein isolate, but several studies have highlighted the successful ability of different plant sources to significantly elevate resting rates of MPS. In terms of facilitating prolonged adaptations to exercise training, multiple studies have indicated that a dose of plant protein that offers enough essential amino acids, especially leucine, consumed over 8-12 weeks can stimulate similar adaptations as seen with animal protein sources. More research is needed to see if longer supplementation periods maintain equivalence between the protein sources. Several practices exist whereby the anabolic potential of a plant protein source can be improved and generally, more research is needed to best understand which practice (if any) offers notable advantages. In conclusion, as one considers the favorable health implications of increasing plant intake as well as environmental sustainability, the interest in consuming more plant proteins will continue to be present. The evidence base for plant proteins in exercising individuals has seen impressive growth with many of these findings now indicating that consumption of a plant protein source in an efficacious dose (typically larger than an animal protein) can instigate similar and favorable changes in amino acid update, MPS rates, and exercise training adaptations such as strength and body composition as well as recovery.


Assuntos
Adaptação Fisiológica , Exercício Físico/fisiologia , Proteínas de Plantas/farmacologia , Animais , Humanos , Proteínas Musculares/metabolismo , Músculo Esquelético/fisiologia , Plantas/química
13.
Life Sci ; 281: 119756, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34175316

RESUMO

Duchenne Muscular Dystrophy (DMD) is caused by mutations in the dystrophin gene, accompanied by aberrant extracellular matrix synthesis and muscle damage. ADAMTS1 metalloproteinase was reported increased in dystrophin-deficient mdx mouse. The aim of this study was to explore the role of ADAMTS1 in muscle function, fibrosis and damage, and respiratory function of mdx mice. 102 DMD patients and their mothers were included in this study. Multiplex ligation dependent probe amplification (MLPA) assay and Next-generation sequencing (NGS) were adopted to do genetic diagnosis. Dystrophin-deficient mdx mice were treated with anti-ADAMTS1 antibody (anti-ADAMTS1) for three weeks. The results showed that ADAMTS1 was increased in gastrocnemius muscle of mdx mice and serum of DMD patients. Anti-ADAMTS1 treatment increased Versican transcription but suppressed versican protein expression. Besides, we found anti-ADAMTS1 improved muscle strength, diaphragm and extensor digitorum longus muscles functions in mdx mice. Meanwhile, muscle fibrosis and damage were attenuated in anti-ADAMTS1 treated dystrophic mice. In summary, anti-ADAMTS1 antibody relieved muscle dysfunction and fibrosis in dystrophic mice. It is suggested that ADAMTS1 is a potential target for developing new biological therapies for DMD.


Assuntos
Proteína ADAMTS1/antagonistas & inibidores , Anticorpos Monoclonais/uso terapêutico , Músculo Esquelético/efeitos dos fármacos , Distrofia Muscular de Duchenne/terapia , Proteína ADAMTS1/genética , Proteína ADAMTS1/imunologia , Proteína ADAMTS1/metabolismo , Animais , Modelos Animais de Doenças , Distrofina/genética , Fibrose/terapia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos mdx , Proteínas Musculares/metabolismo , Força Muscular/imunologia , Músculo Esquelético/patologia , Músculo Esquelético/fisiopatologia , Distrofia Muscular de Duchenne/genética , RNA Mensageiro/metabolismo , Versicanas/imunologia
14.
DNA Cell Biol ; 40(7): 949-968, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34115542

RESUMO

Glioma is the most common type of primary tumor in the central nervous system, and the molecular mechanisms remain elusive. N-myc downstream-regulated gene (NDRG) family is reported to take part in the pathogenesis of various diseases, including some preliminary exploration in glioma. However, there has been no bioinformatics analysis of NDRG family in glioma yet. Herein, we focused on the expression changes of NDRGs with their value in predicting patients' prognoses, upstream regulatory mechanisms (DNA mutation, DNA methylation, transcription factors, and microRNA regulation) and gene enrichment analysis based on co-expressed genes with data from public databases. Furthermore, the expression pattern of NDRGs was verified by the paired glioma and peritumoral samples in our institute. It was suggested that NDRGs were differentially expressed genes in glioma. In particular, the lower expression of NDRG2 or NDRG4 could serve as a predictor of higher grade tumor and poorer prognosis. Also, NDRGs might play a crucial role in signal transduction, energy metabolism, and cross-talk among cells in glioma, under the control of a complex regulatory network. This study enables us to better understand the role of NDRGs in glioma and with further research, it may contribute to the development of glioma treatment.


Assuntos
Glioma/genética , Proteínas Supressoras de Tumor/genética , Neoplasias Encefálicas/patologia , Proteínas de Ciclo Celular/genética , China , Biologia Computacional/métodos , Bases de Dados Genéticas , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica/genética , Glioma/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Prognóstico , Fatores de Transcrição/genética , Proteínas Supressoras de Tumor/metabolismo
15.
Mol Cell ; 81(14): 2929-2943.e6, 2021 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-34166608

RESUMO

The HCN1-4 channel family is responsible for the hyperpolarization-activated cation current If/Ih that controls automaticity in cardiac and neuronal pacemaker cells. We present cryoelectron microscopy (cryo-EM) structures of HCN4 in the presence or absence of bound cAMP, displaying the pore domain in closed and open conformations. Analysis of cAMP-bound and -unbound structures sheds light on how ligand-induced transitions in the channel cytosolic portion mediate the effect of cAMP on channel gating and highlights the regulatory role of a Mg2+ coordination site formed between the C-linker and the S4-S5 linker. Comparison of open/closed pore states shows that the cytosolic gate opens through concerted movements of the S5 and S6 transmembrane helices. Furthermore, in combination with molecular dynamics analyses, the open pore structures provide insights into the mechanisms of K+/Na+ permeation. Our results contribute mechanistic understanding on HCN channel gating, cyclic nucleotide-dependent modulation, and ion permeation.


Assuntos
Permeabilidade da Membrana Celular/fisiologia , Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização/metabolismo , Ativação do Canal Iônico/fisiologia , Íons/metabolismo , Proteínas Musculares/metabolismo , Canais de Potássio/metabolismo , Linhagem Celular , Microscopia Crioeletrônica/métodos , AMP Cíclico/metabolismo , Células HEK293 , Humanos , Marca-Passo Artificial
16.
Cell Death Dis ; 12(7): 624, 2021 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-34135313

RESUMO

Proteasomal activity is compromised in diabetic hearts that contributes to proteotoxic stresses and cardiac dysfunction. Osteocrin (OSTN) acts as a novel exercise-responsive myokine and is implicated in various cardiac diseases. Herein, we aim to investigate the role and underlying molecular basis of OSTN in diabetic cardiomyopathy (DCM). Mice received a single intravenous injection of the cardiotrophic adeno-associated virus serotype 9 to overexpress OSTN in the heart and then were exposed to intraperitoneal injections of streptozotocin (STZ, 50 mg/kg) for consecutive 5 days to generate diabetic models. Neonatal rat cardiomyocytes were isolated and stimulated with high glucose to verify the role of OSTN in vitro. OSTN expression was reduced by protein kinase B/forkhead box O1 dephosphorylation in diabetic hearts, while its overexpression significantly attenuated cardiac injury and dysfunction in mice with STZ treatment. Besides, OSTN incubation prevented, whereas OSTN silence aggravated cardiomyocyte apoptosis and injury upon hyperglycemic stimulation in vitro. Mechanistically, OSTN treatment restored protein kinase G (PKG)-dependent proteasomal function, and PKG or proteasome inhibition abrogated the protective effects of OSTN in vivo and in vitro. Furthermore, OSTN replenishment was sufficient to prevent the progression of pre-established DCM and had synergistic cardioprotection with sildenafil. OSTN protects against DCM via restoring PKG-dependent proteasomal activity and it is a promising therapeutic target to treat DCM.


Assuntos
Apoptose/efeitos dos fármacos , Cardiomiopatias Diabéticas/prevenção & controle , Proteínas Musculares/farmacologia , Miócitos Cardíacos/efeitos dos fármacos , Complexo de Endopeptidases do Proteassoma/metabolismo , Fatores de Transcrição/farmacologia , Animais , Células Cultivadas , Proteínas Quinases Dependentes de GMP Cíclico/metabolismo , Cardiomiopatias Diabéticas/enzimologia , Cardiomiopatias Diabéticas/patologia , Modelos Animais de Doenças , Proteína Forkhead Box O1/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Miócitos Cardíacos/enzimologia , Miócitos Cardíacos/patologia , Fosforilação , Estudo de Prova de Conceito , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Proteínas Recombinantes/farmacologia , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
17.
Ultrason Sonochem ; 76: 105652, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34182317

RESUMO

The effects of the different combined manner of ultrasound and covalent reaction between polyphenol and myofibrillar protein (MP) from chicken were studied. More so, antioxidant activities, digestive properties, and potential mechanism of ultrasound-assisted oxidation system of hydrophilic ((-)-Epicatechin gallate, ECG) and hydrophobic (Baicalein, BN) polyphenols was also analyzed in this study. Among all the combined treatments, surface hydrophobicity (SUH), active sulfhydryl contents (ASC), and specific surface area (SSA) of ultrasonic assisted ECG oxidation group (T6) was relatively apparent, indicating that a more unfolding MP structure was obtained. Furthermore, ultrasonic assisted ECG oxidation group showed the highest antioxidant activities compared with other combined treatments on the basis of the results of DPPH free radical scavenging activities, metal ion chelating activities, and hydroxyl radicals (OH·) scavenging activities. The results of simulated digestion system and kinetic analysis also verified that ultrasonic assisted ECG oxidation had higher MP bio-accessibility than the control group. In contrast, a lower digestibility was displayed in ultrasonic assisted BN oxidation group. In summary, the ultrasound-assisted covalent reaction of MP and ECG might be a desirable approach for industrial production of MP from chicken with better antioxidant activities and digestive properties.


Assuntos
Proteínas Musculares/química , Proteínas Musculares/metabolismo , Ondas Ultrassônicas , Animais , Interações Hidrofóbicas e Hidrofílicas , Cinética , Oxirredução
18.
Clin Immunol ; 229: 108775, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34116211

RESUMO

The pathogenesis of recurrent tonsillitis is to be further investigated. B cell-derived interleukin (IL)-10 plays a critical role in immune regulation. Ras activation plays an important role in cancer and many immune disorders. This study aims to investigate the role of Ras activation in down regulating IL-10 expression in tonsillar B cells. Surgically removed tonsil tissues were collected from patients with recurrent acute tonsillar inflammation; B cells were isolated from the tonsillar tissues by flow cytometry sorting to be analyzed by the Ras-specific enzyme-linked immunosorbent assay and pertinent immunological approaches. We found that, compared to peripheral B cells (pBC), B cells isolated from the tonsillar tissues with recurrent inflammation (tBC) showed higher Ras activation, lower IL-10 expression and higher Bcl2L12 expression. Bcl2L12 formed a complex with GAP (GTPase activating protein) to prevent Ras from deactivating. The Ras activation triggered the MAPK/Sp1 pathway to promote the Bcl2L12 expression in B cells. Bcl2L12 prevented the IL-10 expression in tBCs, that was counteracted by inhibition of Ras or the Ras signal transduction pathway. In conclusion, Bcl2L12 interacts with Ras activation to compromise immune tolerance in the tonsils by inhibiting the IL-10 expression in tBCs. Inhibition of Bcl2L12 can restore the IL-10 expression in tBCs.


Assuntos
Linfócitos B/imunologia , Linfócitos B/metabolismo , Interleucina-10/metabolismo , Proteínas Musculares/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteínas ras/metabolismo , Adolescente , Adulto , Linfócitos B/patologia , Criança , Regulação para Baixo , Feminino , Proteínas Ativadoras de GTPase/metabolismo , Técnicas de Silenciamento de Genes , Humanos , Tolerância Imunológica , Interleucina-10/genética , Masculino , Proteínas Musculares/antagonistas & inibidores , Proteínas Musculares/genética , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-bcl-2/genética , Recidiva , Fatores de Troca de Nucleotídeo Guanina Rho/genética , Fatores de Troca de Nucleotídeo Guanina Rho/metabolismo , Transdução de Sinais , Fator de Transcrição Sp1/antagonistas & inibidores , Fator de Transcrição Sp1/genética , Fator de Transcrição Sp1/metabolismo , Tonsilite/imunologia , Tonsilite/metabolismo , Tonsilite/patologia , Regulação para Cima , Adulto Jovem
19.
Nat Commun ; 12(1): 3258, 2021 05 31.
Artigo em Inglês | MEDLINE | ID: mdl-34059679

RESUMO

Autophagy can selectively target protein aggregates, pathogens, and dysfunctional organelles for the lysosomal degradation. Aberrant regulation of autophagy promotes tumorigenesis, while it is far less clear whether and how tumor-specific alterations result in autophagic aberrance. To form a link between aberrant autophagy selectivity and human cancer, we establish a computational pipeline and prioritize 222 potential LIR (LC3-interacting region) motif-associated mutations (LAMs) in 148 proteins. We validate LAMs in multiple proteins including ATG4B, STBD1, EHMT2 and BRAF that impair their interactions with LC3 and autophagy activities. Using a combination of transcriptomic, metabolomic and additional experimental assays, we show that STBD1, a poorly-characterized protein, inhibits tumor growth via modulating glycogen autophagy, while a patient-derived W203C mutation on LIR abolishes its cancer inhibitory function. This work suggests that altered autophagy selectivity is a frequently-used mechanism by cancer cells to survive during various stresses, and provides a framework to discover additional autophagy-related pathways that influence carcinogenesis.


Assuntos
Carcinogênese/genética , Macroautofagia/genética , Proteínas de Membrana/genética , Modelos Genéticos , Proteínas Musculares/genética , Neoplasias/genética , Algoritmos , Animais , Carcinogênese/patologia , Linhagem Celular Tumoral , Simulação por Computador , Análise Mutacional de DNA , Conjuntos de Dados como Assunto , Técnicas de Silenciamento de Genes , Glicogênio/metabolismo , Humanos , Estimativa de Kaplan-Meier , Proteínas de Membrana/metabolismo , Camundongos , Proteínas Associadas aos Microtúbulos/metabolismo , Proteínas Musculares/metabolismo , Mutação , Neoplasias/mortalidade , Neoplasias/patologia , Via de Pentose Fosfato/genética , Domínios e Motivos de Interação entre Proteínas/genética , Proteoma/genética , RNA-Seq , Análise Serial de Tecidos , Efeito Warburg em Oncologia , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Food Chem ; 362: 130189, 2021 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-34087710

RESUMO

Structural changes of cytochrome c and its relationship with apoptosis and protein degradation of bovine muscle during postmortem aging were investigated. Results from amide I and amide II ~ VI showed that the π* orbital d electron decreased, the π electron density increased, and the frequency of the C-N stretching vibration increased. The distance between heme Fe and N atoms of the porphyrin decreased, the bond length decreased, and the heme core size decreased. Besides, Fe ligand vibration related Raman bands of cytochrome c had red (right) shift gradually with the extension of aging. The apoptotic rate and the degradation products of desmin and troponin-T were increased (P < 0.05). Correlation analysis results suggested that Fe ligand vibration, not amide I ~ VI related Raman bands were correlated with cytochrome c mediated apoptosis and degradation of myofibrillar protein of bovine muscle during aging.


Assuntos
Citocromos c/química , Músculo Esquelético/metabolismo , Amidas/química , Animais , Apoptose/fisiologia , Bovinos , Desmina/química , Desmina/metabolismo , Heme/química , Masculino , Proteínas Musculares/química , Proteínas Musculares/metabolismo , Músculo Esquelético/patologia , Porfirinas/química , Proteólise , Análise Espectral Raman/métodos , Fatores de Tempo , Troponina T/química , Troponina T/metabolismo
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