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1.
Biology (Basel) ; 10(11)2021 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-34827109

RESUMO

The efficient discovery of anticancer targets with minimal side effects is a major challenge in drug discovery and development. Early prediction of side effects is key for reducing development costs, increasing drug efficacy, and increasing drug safety. This study developed a fuzzy optimization framework for Identifying AntiCancer Targets (IACT) using constraint-based models. Four objectives were established to evaluate the mortality of treated cancer cells and to minimize side effects causing toxicity-induced tumorigenesis on normal cells and smaller metabolic perturbations. Fuzzy set theory was applied to evaluate potential side effects and investigate the magnitude of metabolic deviations in perturbed cells compared with their normal counterparts. The framework was applied to identify not only gene regulator targets but also metabolite- and reaction-centric targets. A nested hybrid differential evolution algorithm with a hierarchical fitness function was applied to solve multilevel IACT problems. The results show that the combination of a carbon metabolism target and any one-target gene that participates in the sphingolipid, glycerophospholipid, nucleotide, cholesterol biosynthesis, or pentose phosphate pathways is more effective for treatment than one-target inhibition is. A clinical antimetabolite drug 5-fluorouracil (5-FU) has been used to inhibit synthesis of deoxythymidine-5'-triphosphate for treatment of colorectal cancer. The computational results reveal that a two-target combination of 5-FU and a folate supplement can improve cell viability, reduce metabolic deviation, and reduce side effects of normal cells.

2.
Hear Res ; 411: 108368, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34678647

RESUMO

The Toll-like receptor (TLR) signaling pathway is the key regulator of the innate immune system in response to systemic infection. Several studies have reported that the systemic TLR4 agonist lipopolysaccharide exacerbates aminoglycoside ototoxicity, but the influence of virus-associated TLR7 and TLR9 signaling cascades on the cochlea is unclear. The present study aimed to investigate the auditory effects of systemic TLR7 and TLR9 agonists during chronic kanamycin treatment. CBA/CaJ mice received the TLR7 agonist gardiquimod or TLR9 agonist CpG oligodeoxynucleotides (ODN) one day before kanamycin injection and on the 5th and 10th days during a 14-day course of kanamycin treatment. We observed that systemic gardiquimod or CpG ODN alone did not affect the baseline auditory brainstem response (ABR) threshold. Three weeks after kanamycin treatment, gardiquimod did not significantly change ABR threshold shifts, whereas CpG ODN significantly increased kanamycin-induced ABR threshold shifts. Furthermore, outer hair cell (OHC) evaluation revealed that CpG ODN reduced distortion product otoacoustic emission amplitudes and increased kanamycin-induced OHC loss. CpG ODN significantly elevated cochlear Irf-7, Tnf-α, Il-1, and Il-6 transcript levels. In addition, an increased number of Iba-1+ cells, which represented activated macrophages, was observed in the cochlea treated with CpG ODN. Our results indicated that systemic CpG ODN exacerbated kanamycin-induced ototoxicity and increased cochlear inflammation. This study implies that patients with underlying virus infection may experience more severe aminoglycoside-induced hearing loss if it occurs.

3.
Antioxidants (Basel) ; 10(9)2021 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-34573026

RESUMO

Bone-forming cells build mineralized microstructure and couple with bone-resorbing cells, harmonizing bone mineral acquisition, and remodeling to maintain bone mass homeostasis. Mitochondrial glycolysis and oxidative phosphorylation pathways together with ROS generation meet the energy requirement for bone-forming cell growth and differentiation, respectively. Moderate mechanical stimulations, such as weight loading, physical activity, ultrasound, vibration, and electromagnetic field stimulation, etc., are advantageous to bone-forming cell activity, promoting bone anabolism to compromise osteoporosis development. A plethora of molecules, including ion channels, integrins, focal adhesion kinases, and myokines, are mechanosensitive and transduce mechanical stimuli into intercellular signaling, regulating growth, mineralized extracellular matrix biosynthesis, and resorption. Mechanical stimulation changes mitochondrial respiration, biogenesis, dynamics, calcium influx, and redox, whereas mechanical disuse induces mitochondrial dysfunction and oxidative stress, which aggravates bone-forming cell apoptosis, senescence, and dysfunction. The control of the mitochondrial biogenesis activator PGC-1α by NAD+-dependent deacetylase sirtuins or myokine FNDC/irisin or repression of oxidative stress by mitochondrial antioxidant Nrf2 modulates the biophysical stimulation for the promotion of bone integrity. This review sheds light onto the roles of mechanosensitive signaling, mitochondrial dynamics, and antioxidants in mediating the anabolic effects of biophysical stimulation to bone tissue and highlights the remedial potential of mitochondrial biogenesis regulators for osteoporosis.

4.
Int J Mol Sci ; 22(17)2021 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-34502056

RESUMO

Skeletal tissue involves systemic adipose tissue metabolism and energy expenditure. MicroRNA signaling controls high-fat diet (HFD)-induced bone and fat homeostasis dysregulation remains uncertain. This study revealed that transgenic overexpression of miR-29a under control of osteocalcin promoter in osteoblasts (miR-29aTg) attenuated HFD-mediated body overweight, hyperglycemia, and hypercholesterolemia. HFD-fed miR-29aTg mice showed less bone mass loss, fatty marrow, and visceral fat mass together with increased subscapular brown fat mass than HFD-fed wild-type mice. HFD-induced O2 underconsumption, respiratory quotient repression, and heat underproduction were attenuated in miR-29aTg mice. In vitro, miR-29a overexpression repressed transcriptomic landscapes of the adipocytokine signaling pathway, fatty acid metabolism, and lipid transport, etc., of bone marrow mesenchymal progenitor cells. Forced miR-29a expression promoted osteogenic differentiation but inhibited adipocyte formation. miR-29a signaling promoted brown/beige adipocyte markers Ucp-1, Pgc-1α, P2rx5, and Pat2 expression and inhibited white adipocyte markers Tcf21 and Hoxc9 expression. The microRNA also reduced peroxisome formation and leptin expression during adipocyte formation and downregulated HFD-induced leptin expression in bone tissue. Taken together, miR-29a controlled leptin signaling and brown/beige adipocyte formation of osteogenic progenitor cells to preserve bone anabolism, which reversed HFD-induced energy underutilization and visceral fat overproduction. This study sheds light on a new molecular mechanism by which bone integrity counteracts HFD-induced whole-body fat overproduction.


Assuntos
Gordura Intra-Abdominal/metabolismo , Leptina/genética , MicroRNAs/metabolismo , Osteoblastos/metabolismo , Osteoporose/metabolismo , Adipócitos/citologia , Adipócitos/metabolismo , Sistemas de Transporte de Aminoácidos Neutros/genética , Sistemas de Transporte de Aminoácidos Neutros/metabolismo , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Linhagem Celular , Dieta Hiperlipídica/efeitos adversos , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Leptina/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Osteoblastos/citologia , Osteoporose/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Peroxissomos/metabolismo , Receptores Purinérgicos P2X5/genética , Receptores Purinérgicos P2X5/metabolismo , Simportadores/genética , Simportadores/metabolismo , Termogênese , Proteína Desacopladora 1/genética , Proteína Desacopladora 1/metabolismo
5.
Int J Mol Sci ; 22(17)2021 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-34502380

RESUMO

Biophysical stimulation alters bone-forming cell activity, bone formation and remodeling. The effect of piezoelectric microvibration stimulation (PMVS) intervention on osteoporosis development remains uncertain. We investigated whether 60 Hz, 120 Hz, and 180 Hz PMVS (0.05 g, 20 min/stimulation, 3 stimulations/week for 4 consecutive weeks) intervention affected bone integrity in ovariectomized (OVX) mice or osteoblastic activity. PMVS (120 Hz)-treated OVX mice developed fewer osteoporosis conditions, including bone mineral density loss and trabecular microstructure deterioration together with decreased serum resorption marker CTX-1 levels, as compared to control OVX animals. The biomechanical strength of skeletal tissue was improved upon 120 Hz PMVS intervention. This intervention compromised OVX-induced sparse trabecular bone morphology, osteoblast loss, osteoclast overburden, and osteoclast-promoting cytokine RANKL immunostaining and reversed osteoclast inhibitor OPG immunoreactivity. Osteoblasts in OVX mice upon PMVS intervention showed strong Wnt3a immunoreaction and weak Wnt inhibitor Dkk1 immunostaining. In vitro, PMVS reversed OVX-induced loss in von Kossa-stained mineralized nodule formation, Runx2, and osteocalcin expression in primary bone-marrow stromal cells. PMVS also promoted mechanoreceptor Piezo1 expression together with increased microRNA-29a and Wnt3a expression, whereas Dkk1 rather than SOST expression was repressed in MC3T3-E1 osteoblasts. Taken together, PMVS intervention promoted Piezo1, miR-29a, and Wnt signaling to upregulate osteogenic activity and repressed osteoclastic bone resorption, delaying estrogen deficiency-induced loss in bone mass and microstructure. This study highlights a new biophysical remedy for osteoporosis.


Assuntos
Osteoblastos/metabolismo , Osteoporose/terapia , Terapia por Ultrassom/métodos , Animais , Fenômenos Biomecânicos , Densidade Óssea/efeitos dos fármacos , Reabsorção Óssea/metabolismo , Osso e Ossos/metabolismo , Calcificação Fisiológica , Diferenciação Celular/efeitos dos fármacos , Estrogênios/metabolismo , Feminino , Canais Iônicos/metabolismo , Canais Iônicos/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/genética , MicroRNAs/metabolismo , Osteoblastos/fisiologia , Osteoclastos/metabolismo , Osteogênese/efeitos dos fármacos , Osteoporose/metabolismo , Ovariectomia , Transdução de Sinais , Ondas Ultrassônicas , Proteína Wnt3A/metabolismo
6.
Antioxidants (Basel) ; 10(8)2021 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-34439496

RESUMO

Senescent osteoblast overburden accelerates bone mass loss. Little is understood about microRNA control of oxidative stress and osteoblast senescence in osteoporosis. We revealed an association between microRNA-29a (miR-29a) loss, oxidative stress marker 8-hydroxydeoxyguanosine (8-OHdG), DNA hypermethylation marker 5-methylcystosine (5mC), and osteoblast senescence in human osteoporosis. miR-29a knockout mice showed low bone mass, sparse trabecular microstructure, and osteoblast senescence. miR-29a deletion exacerbated bone loss in old mice. Old miR-29a transgenic mice showed fewer osteoporosis signs, less 5mC, and less 8-OHdG formation than age-matched wild-type mice. miR-29a overexpression reversed age-induced senescence and osteogenesis loss in bone-marrow stromal cells. miR-29a promoted transcriptomic landscapes of redox reaction and forkhead box O (FoxO) pathways, preserving oxidation resistance protein-1 (Oxr1) and FoxO3 in old mice. In vitro, miR-29a interrupted DNA methyltransferase 3b (Dnmt3b)-mediated FoxO3 promoter methylation and senescence-associated ß-galactosidase activity in aged osteoblasts. Dnmt3b inhibitor 5'-azacytosine, antioxidant N-acetylcysteine, or Oxr1 recombinant protein attenuated loss in miR-29a and FoxO3 to mitigate oxidative stress, senescence, and mineralization matrix underproduction. Taken together, miR-29a promotes Oxr1, compromising oxidative stress and FoxO3 loss to delay osteoblast aging and bone loss. This study sheds light on a new antioxidation mechanism by which miR-29a protects against osteoblast aging and highlights the remedial effects of miR-29a on osteoporosis.

7.
Int J Mol Sci ; 22(13)2021 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-34281226

RESUMO

Patients with Rett syndrome (RTT) show severe difficulties with communication, social withdrawl, and learning. Music-based interventions improve social interaction, communication skills, eye contact, and physical skills and reduce seizure frequency in patients with RTT. This study aimed to investigate the mechanism by which music-based interventions compromise sociability impairments in mecp2 null/y mice as an experimental RTT model. Male mecp2 null/y mice and wild-type mice (24 days old) were randomly divided into control, noise, and music-based intervention groups. Mice were exposed to music or noise for 6 h/day for 3 consecutive weeks. Behavioral patterns, including anxiety, spontaneous exploration, and sociability, were characterized using open-field and three-chamber tests. BDNF, TrkB receptor motif, and FNDC5 expression in the prefrontal cortex (PFC), hippocampus, basal ganglia, and amygdala were probed using RT-PCR or immunoblotting. mecp2 null/y mice showed less locomotion in an open field than wild-type mice. The social novelty rather than the sociability of these animals increased following a music-based intervention, suggesting that music influenced the mecp2-deletion-induced social interaction repression rather than motor deficit. Mechanically, the loss of BDNF signaling in the prefrontal cortex and hippocampal regions, but not in the basal ganglia and amygdala, was compromised following the music-based intervention in mecp2 null/y mice, whereas TrkB signaling was not significantly changed in either region. FNDC5 expression in the prefrontal cortex region in mecp2 null/y mice also increased following the music-based intervention. Collective evidence reveals that music-based interventions improve mecp2-loss-induced social dysfunction. BDNF and FNDC5 signaling in the prefrontal cortex region mediates the music-based-intervention promotion of social interactions. This study gives new insight into the mechanisms underlying the improvement of social behaviors in mice suffering from experimental Rett syndrome following a music-based intervention.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Glicoproteínas de Membrana/metabolismo , Musicoterapia , Córtex Pré-Frontal/metabolismo , Receptor trkB/metabolismo , Síndrome de Rett/terapia , Animais , Modelos Animais de Doenças , Masculino , Camundongos , Síndrome de Rett/metabolismo , Síndrome de Rett/psicologia , Comportamento Social
8.
Front Mol Neurosci ; 14: 697440, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34305527

RESUMO

Parkinson disease (PD) is the second most common neurodegenerative disease without known disease modification therapy to slow down disease progression. This disease has pathological features of Lewy bodies with α-synuclein aggregation being the major component and selective dopaminergic neuronal loss over the substantia nigra. Although the exact etiology is still unknown, mitochondrial dysfunction has been shown to be central in PD pathophysiology. Type 2 diabetes mellitus has recently been connected to PD, and anti-diabetic drugs, such as glucagon-like peptide-1 receptor agonists (GLP-1RAs), have been shown to possess neuroprotective effects in PD animal models. The GLP-1RA liraglutide is currently under a phase 2 clinical trial to measure its effect on motor and non-motor symptoms in PD patients. In this study, we used an acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD to test the possible mechanism of the GLP-1RA liraglutide in the pathogenesis of PD. We show that the neurobehavioral and motor dysfunction caused by the mitochondrial complex I inhibitor, MPTP, can be partially reversed by liraglutide. The GLP-1RA can protect mice from apoptosis of substantia nigra neurons induced by MPTP. MPTP treatment led to imbalanced mitochondrial fusion and fission dynamics, altered mitochondrial morphology, impeded autophagy flux, increased α-synuclein accumulation, and elevated oxidative stress. Specifically, the normalizing of mitochondrial fusion-fission dynamic-related proteins and enhancement of autophagy flux after administration of liraglutide is associated with improving neuronal survival. This suggests that GLP-1RAs may provide potential beneficial effects for PD caused by mitochondrial dysfunction through improvement of mitochondrial morphology balance and enhancing damaged organelle degradation.

9.
FEBS Open Bio ; 2021 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-34137202

RESUMO

Cancer cell dysregulations result in the abnormal regulation of cellular metabolic pathways. By simulating this metabolic reprogramming using constraint-based modeling approaches, oncogenes can be predicted, and this knowledge can be used in prognosis and treatment. We introduced a trilevel optimization problem describing metabolic reprogramming for inferring oncogenes. First, this study used RNA-Seq expression data of lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) samples and their healthy counterparts to reconstruct tissue-specific genome-scale metabolic models and subsequently build the flux distribution pattern that provided a measure for the oncogene inference optimization problem for determining tumorigenesis. The platform detected 45 genes for LUAD and 84 genes for LUSC that lead to tumorigenesis. A high level of differentially expressed genes was not an essential factor for determining tumorigenesis. The platform indicated that pyruvate kinase (PKM), a well-known oncogene with a low level of differential gene expression in LUAD and LUSC, had the highest fitness among the predicted oncogenes based on computation. By contrast, pyruvate kinase L/R (PKLR), an isozyme of PKM, had a high level of differential gene expression in both cancers. Phosphatidylserine synthase 1 (PTDSS1), an oncogene in LUAD, was inferred to have a low level of differential gene expression, and overexpression could significantly reduce survival probability. According to the factor analysis, PTDSS1 characteristics were close to those of the template, but they were unobvious in LUSC. Angiotensin-converting enzyme 2 (ACE2) has recently garnered widespread interest as the SARS-CoV-2 virus receptor. Moreover, we determined that ACE2 is an oncogene of LUSC but not of LUAD. The platform developed in this study can identify oncogenes with low levels of differential expression and be used to identify potential therapeutic targets for cancer treatment.

10.
Int J Mol Sci ; 21(20)2020 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-33066038

RESUMO

Noise-induced hearing loss is one of the major causes of acquired sensorineural hearing loss in modern society. While people with excessive exposure to noise are frequently the population with a lifestyle of irregular circadian rhythms, the effects of circadian dysregulation on the auditory system are still little known. Here, we disturbed the circadian clock in the cochlea of male CBA/CaJ mice by constant light (LL) or constant dark. LL significantly repressed circadian rhythmicity of circadian clock genes Per1, Per2, Rev-erbα, Bmal1, and Clock in the cochlea, whereas the auditory brainstem response thresholds were unaffected. After exposure to low-intensity (92 dB) noise, mice under LL condition initially showed similar temporary threshold shifts to mice under normal light-dark cycle, and mice under both conditions returned to normal thresholds after 3 weeks. However, LL augmented high-intensity (106 dB) noise-induced permanent threshold shifts, particularly at 32 kHz. The loss of outer hair cells (OHCs) and the reduction of synaptic ribbons were also higher in mice under LL after noise exposure. Additionally, LL enhanced high-intensity noise-induced 4-hydroxynonenal in the OHCs. Our findings convey new insight into the deleterious effect of an irregular biological clock on the auditory system.


Assuntos
Limiar Auditivo/efeitos da radiação , Relógios Circadianos/efeitos da radiação , Cóclea/efeitos da radiação , Perda Auditiva Provocada por Ruído/fisiopatologia , Luz , Fatores de Transcrição ARNTL/genética , Fatores de Transcrição ARNTL/metabolismo , Animais , Proteínas CLOCK/genética , Proteínas CLOCK/metabolismo , Cóclea/metabolismo , Cóclea/fisiopatologia , Potenciais Evocados Auditivos do Tronco Encefálico , Perda Auditiva Provocada por Ruído/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos CBA , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/genética , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/metabolismo , Proteínas Circadianas Period/genética , Proteínas Circadianas Period/metabolismo
11.
Int J Mol Sci ; 21(18)2020 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-32961796

RESUMO

MicroRNA-29a (miR-29a) has been shown to ameliorate hepatocellular damage, such as in the context of non-alcoholic fatty liver disease (NAFLD), steatohepatitis (NASH), and cholestatic injury. However, the mechanism mediating the hepatoprotective effect of miR-29a in diet-induced NASH remains elusive. In the present study, C57BL/6 mice of wild-type (WT) or miR-29a overexpression were fed with methionine-choline sufficient (MCS) or methionine-choline-deficient (MCD) diet for four weeks. The C57BL/6 mice harboring miR-29a overexpression presented reduced plasma AST, hepatic CD36, steatosis, and fibrosis induced by MCD. The TargetScan Release7.2-based bioinformatic analysis, KEGG pathway analysis, and luciferase reporter assay confirmed that miR-29a targets 3'UTR of glycogen synthase kinase 3 beta (Gsk3b) mRNA in the HepG2 hepatocyte cell line. Furthermore, miR-29a overexpression in the MCD-fed group resulted in inhibition of Gsk3b mRNA and GSK3ß protein levels in the liver. GSK3ß was notably expressed jointly with the extent of aggregated protein, which was then identified to be associated with mitochondrial unfolded protein response (UPRmt), but not with endoplasmic reticulum UPR (UPRER). Additionally, in silico analysis of protein-protein interaction, in vivo, and in vitro correlation analyses of protein expression demonstrated that GSK3ß closely associated with sirtuin 1(SIRT1). Finally, the implication of SIRT1-mediated mitochondrial biogenesis in the perturbation of proteostasis was observed. We herein provide novel insight into a hepatoprotective pathway, whereby miR-29a inhibits GSK3ß to repress SIRT1-mediated mitochondrial biogenesis, leading to alleviation of mitochondrial proteostatic stress and UPRmt in the context of NASH. miR-29a, GSK3ß, and SIRT1 could thus serve as possible therapeutic targets to improve the treatment of NAFLD/NASH.


Assuntos
Glicogênio Sintase Quinase 3 beta/metabolismo , MicroRNAs/biossíntese , Mitocôndrias Hepáticas/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Proteostase , Sirtuína 1/metabolismo , Animais , Glicogênio Sintase Quinase 3 beta/genética , Camundongos , Camundongos Transgênicos , MicroRNAs/genética , Mitocôndrias Hepáticas/genética , Mitocôndrias Hepáticas/patologia , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/patologia , Sirtuína 1/genética , Resposta a Proteínas não Dobradas
12.
Antioxidants (Basel) ; 9(9)2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32882839

RESUMO

Compromised autophagy and mitochondrial dysfunction downregulate chondrocytic activity, accelerating the development of osteoarthritis (OA). Irisin, a cleaved form of fibronectin type III domain containing 5 (FNDC5), regulates bone turnover and muscle homeostasis. Little is known about the effect of Irisin on chondrocytes and the development of osteoarthritis. This study revealed that human osteoarthritic articular chondrocytes express decreased level of FNDC5 and autophagosome marker LC3-II but upregulated levels of oxidative DNA damage marker 8-hydroxydeoxyguanosine (8-OHdG) and apoptosis. Intra-articular administration of Irisin further alleviated symptoms of medial meniscus destabilization, like cartilage erosion and synovitis, while improved the gait profiles of the injured legs. Irisin treatment upregulated autophagy, 8-OHdG and apoptosis in chondrocytes of the injured cartilage. In vitro, Irisin improved IL-1ß-mediated growth inhibition, loss of specific cartilage markers and glycosaminoglycan production by chondrocytes. Irisin also reversed Sirt3 and UCP-1 pathways, thereby improving mitochondrial membrane potential, ATP production, and catalase to attenuated IL-1ß-mediated reactive oxygen radical production, mitochondrial fusion, mitophagy, and autophagosome formation. Taken together, FNDC5 loss in chondrocytes is correlated with human knee OA. Irisin repressed inflammation-mediated oxidative stress and extracellular matrix underproduction through retaining mitochondrial biogenesis, dynamics and autophagic program. Our analyses shed new light on the chondroprotective actions of this myokine, and highlight the remedial effects of Irisin on OA development.

13.
Int J Mol Sci ; 21(14)2020 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-32664681

RESUMO

Bone turnover is sophisticatedly balanced by a dynamic coupling of bone formation and resorption at various rates. The orchestration of this continuous remodeling of the skeleton further affects other skeletal tissues through organ crosstalk. Chronic excessive bone resorption compromises bone mass and its porous microstructure as well as proper biomechanics. This accelerates the development of osteoporotic disorders, a leading cause of skeletal degeneration-associated disability and premature death. Bone-forming cells play important roles in maintaining bone deposit and osteoclastic resorption. A poor organelle machinery, such as mitochondrial dysfunction, endoplasmic reticulum stress, and defective autophagy, etc., dysregulates growth factor secretion, mineralization matrix production, or osteoclast-regulatory capacity in osteoblastic cells. A plethora of epigenetic pathways regulate bone formation, skeletal integrity, and the development of osteoporosis. MicroRNAs inhibit protein translation by binding the 3'-untranslated region of mRNAs or promote translation through post-transcriptional pathways. DNA methylation and post-translational modification of histones alter the chromatin structure, hindering histone enrichment in promoter regions. MicroRNA-processing enzymes and DNA as well as histone modification enzymes catalyze these modifying reactions. Gain and loss of these epigenetic modifiers in bone-forming cells affect their epigenetic landscapes, influencing bone homeostasis, microarchitectural integrity, and osteoporotic changes. This article conveys productive insights into biological roles of DNA methylation, microRNA, and histone modification and highlights their interactions during skeletal development and bone loss under physiological and pathological conditions.


Assuntos
Remodelação Óssea/genética , Epigênese Genética , Osteoporose/genética , Adipogenia , Animais , Autofagia , Reabsorção Óssea/genética , Metilação de DNA , Modelos Animais de Doenças , Endorribonucleases/fisiologia , Código das Histonas , Histona Desacetilases/fisiologia , Histona Metiltransferases/fisiologia , Homeostase , Humanos , Camundongos , MicroRNAs/sangue , MicroRNAs/genética , Mitofagia , Organelas/fisiologia , Osteoblastos/fisiologia , Osteoblastos/ultraestrutura , Osteoporose/metabolismo , Polimorfismo de Nucleotídeo Único
14.
Int J Mol Sci ; 21(12)2020 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-32560314

RESUMO

Psoriatic arthritis (PsA) is a destructive joint disease mediated by osteoclasts. MicroRNAs (miRNAs) regulate several important pathways in osteoclastogenesis. We profiled the expression of miRNAs in CD14+ monocytes from PsA patients and investigated how candidate microRNAs regulate the pathophysiology in osteoclastogenesis. The RNA from circulatory CD14+ monocytes was isolated from PsA patients, psoriasis patients without arthritis (PsO), and healthy controls (HCs). The miRNAs were initially profiled by next-generation sequencing (NGS). The candidate miRNAs revealed by NGS were validated by PCR in 40 PsA patients, 40 PsO patients, and 40 HCs. The osteoclast differentiation and its functional resorption activity were measured with or without RNA interference against the candidate miRNA. The microRNA-941 was selectively upregulated in CD14+ monocytes from PsA patients. Osteoclast development and resorption ability were increased in CD14+ monocytes from PsA patients. Inhibition of miR-941 abrogated the osteoclast development and function while increased the expression of WNT16. After successful treatment, the increased miR-941 expression in CD14+ monocytes from PsA patients was revoked. The expression of miR-941 in CD14+ monocytes is associated with PsA disease activity. MiR-941 enhances osteoclastogenesis in PsA via WNT16 repression. The miR-941 could be a potential biomarker and treatment target for PsA.


Assuntos
Artrite Psoriásica/etiologia , Artrite Psoriásica/metabolismo , Regulação da Expressão Gênica , MicroRNAs/genética , Monócitos/metabolismo , Osteoclastos/metabolismo , Proteínas Wnt/metabolismo , Adulto , Idoso , Artrite Psoriásica/diagnóstico , Reabsorção Óssea/genética , Suscetibilidade a Doenças , Feminino , Perfilação da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Receptores de Lipopolissacarídeos/metabolismo , Masculino , Pessoa de Meia-Idade , Curva ROC , Máquina de Vetores de Suporte
15.
Cells ; 9(6)2020 06 19.
Artigo em Inglês | MEDLINE | ID: mdl-32575577

RESUMO

Glucocorticoid provokes bone mass loss and fatty marrow, accelerating osteoporosis development. Bromodomain protein BRD4, an acetyl-histone-binding chromatin reader, regulates stem cell and tissue homeostasis. We uncovered that glucocorticoid inhibited acetyl Lys-9 at the histone 3 (H3K9ac)-binding Runx2 promoter and decreased osteogenic differentiation, whereas bromodomain protein 4 (BRD4) and adipocyte formation were upregulated in bone-marrow mesenchymal progenitor cells. BRD4 knockdown improved H3K9ac occupation at the Runx2 promoter and osteogenesis, but attenuated glucocorticoid-mediated adipocyte formation together with the unaffected H3K9ac-binding PPARγ2 promoter. BRD4 regulated epigenome related to fatty acid metabolism and the forkhead box P1 (Foxp1) pathway, which occupied the PPARγ2 promoter to modulate glucocorticoid-induced adipocytic activity. In vivo, BRD4 inhibitor JQ-1 treatment mitigated methylprednisolone-induced suppression of bone mass, trabecular microstructure, mineral acquisition, and osteogenic differentiation. Foxp1 signaling, marrow fat, and adipocyte formation in glucocorticoid-treated skeleton were reversed upon JQ-1 treatment. Taken together, glucocorticoid-induced H3K9 hypoacetylation augmented BRD4 action to Foxp1, which steered mesenchymal progenitor cells toward adipocytes at the cost of osteogenic differentiation in osteoporotic skeletons. BRD4 inhibition slowed bone mass loss and marrow adiposity. Collective investigations convey a new epigenetic insight into acetyl histone reader BRD4 control of osteogenesis and adipogenesis in skeleton, and highlight the remedial effects of the BRD4 inhibitor on glucocorticoid-induced osteoporosis.


Assuntos
Adipogenia/fisiologia , Medula Óssea/metabolismo , Proteínas de Ciclo Celular/metabolismo , Glucocorticoides/metabolismo , Fatores de Transcrição/metabolismo , Diferenciação Celular/efeitos dos fármacos , Glucocorticoides/farmacologia , Humanos , Células-Tronco Mesenquimais/metabolismo , Osteoblastos/efeitos dos fármacos , Osteogênese/fisiologia
16.
Int J Mol Sci ; 21(10)2020 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-32455716

RESUMO

Recent studies have found that microRNA-29a (miR-29a) levels are significantly lower in fibrotic livers, as shown with human liver cirrhosis. Such downregulation influences the activation of hepatic stellate cells (HSC). Phosphoinositide 3-kinase p85 alpha (PI3KP85α) is implicated in the regulation of proteostasis mitochondrial integrity and unfolded protein response (UPR) and apoptosis in hepatocytes. This study aimed to investigate the potential therapeutic role of miR-29a in a murine bile duct ligation (BDL)-cholestatic injury and liver fibrosis model. Mice were assigned to four groups: sham, BDL, BDL + scramble miRs, and BDL + miR-29a-mimic. Liver fibrosis and inflammation were assessed by histological staining and mRNA/protein expression of representative markers. Exogenous therapeutics of miR-29a in BDL-stressed mice significantly attenuated glutamic oxaloacetic transaminase (GOT)/glutamic-pyruvic transaminase (GPT) and liver fibrosis, and caused a significant downregulation in markers related to inflammation (IL-1ß), fibrogenesis (TGF-ß1, α-SMA, and COL1α1), autophagy (p62 and LC3B II), mitochondrial unfolded protein response (UPRmt; C/EBP homologous protein (CHOP), heat shock protein 60 (HSP60), and Lon protease-1 (LONP1, a mitochondrial protease), and PI3KP85α within the liver tissue. An in vitro luciferase reporter assay further confirmed that miR-29a mimic directly targets mRNA 3' untranslated region (UTR) of PI3KP85α to suppress its expression in HepG2 cell line. Our data provide new insights that therapeutic miR-29a improves cholestasis-induced hepatic inflammation and fibrosis and proteotstasis via blocking PI3KP85α, highlighting the potential of miR-29a targeted therapy for liver injury.


Assuntos
Colestase/terapia , Classe Ia de Fosfatidilinositol 3-Quinase/genética , Cirrose Hepática/terapia , MicroRNAs/metabolismo , Terapêutica com RNAi/métodos , Proteases Dependentes de ATP/genética , Proteases Dependentes de ATP/metabolismo , Alanina Transaminase/metabolismo , Animais , Aspartato Aminotransferases/metabolismo , Chaperonina 60/genética , Chaperonina 60/metabolismo , Classe Ia de Fosfatidilinositol 3-Quinase/metabolismo , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Células Hep G2 , Humanos , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Fígado/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Fator de Transcrição CHOP/genética , Fator de Transcrição CHOP/metabolismo , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismo
17.
Front Pediatr ; 8: 129, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32309269

RESUMO

Kawasaki disease (KD) is a common systemic vasculitides in children younger than 5 years of age. Activated macrophages are key drivers of vascular inflammation in KD. The aim of this study was to examine differences in M1 and M2 macrophage marker expression in patients with KD. Blood samples were obtained from 18 healthy controls and 18 patients with KD at 24 h prior and 21 days after to intravenous immunoglobulin therapy. GeneChip Human Transcriptome Array 2.0 and Illumina HumanMethylation450 BeadChip were used to examined the mRNA expression and corresponding CpG site methylation ratios of 10 M1 surface markers and 15 M2 surface markers. Of the markers examined 2 M1 markers (TLR2, IL2RA) and 8 M2 markers (ARG1, CCR2, TLR1, TLR8, TLR5, MS4A6A, CD36, and MS4A4A) showed increased mRNA expression in the acute phase of KD which decreased after IVIG therapy (P < 0.05). Corresponding CpG sites in the promoter regions these markers were hypomethylated in the acute phase of KD and significantly increased after IVIG therapy. In conclusion, both M1 and M2 markers showed increased mRNA expression in the acute phase of KD. CpG site methylation may be one of the mechanisms governing macrophage polarization in KD.

18.
Cells ; 9(4)2020 04 22.
Artigo em Inglês | MEDLINE | ID: mdl-32331364

RESUMO

Non-alcoholic fatty liver disease (NAFLD) is a common cause of chronic liver disease and ranges from steatosis to steatohepatitis and to liver fibrosis. Lipotoxicity in hepatocytes, elevated oxidative stress and the activation of proinflammatory mediators of Kupffer cells, and fibrogenic pathways of activated hepatic stellate cells can contribute to the development of NAFLD. MicroRNAs (miRs) play a crucial role in the dysregulated metabolism and inflammatory signaling connected with NAFLD and its progression towards more severe stages. Of note, the protective effect of non-coding miR-29a on liver damage and its versatile action on epigenetic activity, mitochondrial homeostasis and immunomodulation may improve our perception of the pathogenesis of NAFLD. Herein, we review the biological functions of critical miRs in NAFLD, as well as highlight the emerging role of miR-29a in therapeutic application and the recent advances in molecular mechanisms underlying its liver protective effect.


Assuntos
Inflamação/genética , Inflamação/patologia , MicroRNAs/metabolismo , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/patologia , Estresse Oxidativo/genética , Epigênese Genética , Pleiotropia Genética , Humanos , MicroRNAs/genética
19.
R Soc Open Sci ; 7(3): 191241, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32269785

RESUMO

Cancer cells are known to exhibit unusual metabolic activity, and yet few metabolic cancer driver genes are known. Genetic alterations and epigenetic modifications of cancer cells result in the abnormal regulation of cellular metabolic pathways that are different when compared with normal cells. Such a metabolic reprogramming can be simulated using constraint-based modelling approaches towards predicting oncogenes. We introduced the tri-level optimization problem to use the metabolic reprogramming towards inferring oncogenes. The algorithm incorporated Recon 2.2 network with the Human Protein Atlas to reconstruct genome-scale metabolic network models of the tissue-specific cells at normal and cancer states, respectively. Such reconstructed models were applied to build the templates of the metabolic reprogramming between normal and cancer cell metabolism. The inference optimization problem was formulated to use the templates as a measure towards predicting oncogenes. The nested hybrid differential evolution algorithm was applied to solve the problem to overcome solving difficulty for transferring the inner optimization problem into the single one. Head and neck squamous cells were applied as a case study to evaluate the algorithm. We detected 13 of the top-ranked one-hit dysregulations and 17 of the top-ranked two-hit oncogenes with high similarity ratios to the templates. According to the literature survey, most inferred oncogenes are consistent with the observation in various tissues. Furthermore, the inferred oncogenes were highly connected with the TP53/AKT/IGF/MTOR signalling pathway through PTEN, which is one of the most frequently detected tumour suppressor genes in human cancer.

20.
Metabolites ; 10(1)2019 Dec 25.
Artigo em Inglês | MEDLINE | ID: mdl-31881674

RESUMO

Although cancer has historically been regarded as a cell proliferation disorder, it has recently been considered a metabolic disease. The first discovery of metabolic alterations in cancer cells refers to Otto Warburg's observations. Cancer metabolism results in alterations in metabolic fluxes that are evident in cancer cells compared with most normal tissue cells. This study applied protein expressions of normal and cancer cells to reconstruct two tissue-specific genome-scale metabolic models. Both models were employed in a tri-level optimization framework to infer oncogenes. Moreover, this study also introduced enzyme pseudo-coding numbers in the gene association expression to avoid performing posterior decision-making that is necessary for the reaction-based method. Colorectal cancer (CRC) was the topic of this case study, and 20 top-ranked oncogenes were determined. Notably, these dysregulated genes were involved in various metabolic subsystems and compartments. We found that the average similarity ratio for each dysregulation is higher than 98%, and the extent of similarity for flux changes is higher than 93%. On the basis of surveys of PubMed and GeneCards, these oncogenes were also investigated in various carcinomas and diseases. Most dysregulated genes connect to catalase that acts as a hub and connects protein signaling pathways, such as those involving TP53, mTOR, AKT1, MAPK1, EGFR, MYC, CDK8, and RAS family.

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