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1.
Braz. j. biol ; 83: e250179, 2023. graf
Artigo em Inglês | LILACS, VETINDEX | ID: biblio-1339372

RESUMO

Abstract Diabetes mellitus (DM) is a non-communicable disease throughout the world in which there is persistently high blood glucose level from the normal range. The diabetes and insulin resistance are mainly responsible for the morbidities and mortalities of humans in the world. This disease is mainly regulated by various enzymes and hormones among which Glycogen synthase kinase-3 (GSK-3) is a principle enzyme and insulin is the key hormone regulating it. The GSK-3, that is the key enzyme is normally showing its actions by various mechanisms that include its phosphorylation, formation of protein complexes, and other cellular distribution and thus it control and directly affects cellular morphology, its growth, mobility and apoptosis of the cell. Disturbances in the action of GSK-3 enzyme may leads to various disease conditions that include insulin resistance leading to diabetes, neurological disease like Alzheimer's disease and cancer. Fluoroquinolones are the most common class of drugs that shows dysglycemic effects via interacting with GSK-3 enzyme. Therefore, it is the need of the day to properly understand functions and mechanisms of GSK-3, especially its role in glucose homeostasis via effects on glycogen synthase.


Resumo O diabetes mellitus (DM) é uma doença não transmissível em todo o mundo, na qual existe nível glicêmico persistentemente alto em relação à normalidade. O diabetes e a resistência à insulina são os principais responsáveis ​​pelas morbidades e mortalidades de humanos no mundo. Essa doença é regulada principalmente por várias enzimas e hormônios, entre os quais a glicogênio sintase quinase-3 (GSK-3) é uma enzima principal e a insulina é o principal hormônio que a regula. A GSK-3, que é a enzima-chave, normalmente mostra suas ações por vários mecanismos que incluem sua fosforilação, formação de complexos de proteínas e outras distribuições celulares e, portanto, controla e afeta diretamente a morfologia celular, seu crescimento, mobilidade e apoptose do célula. Perturbações na ação da enzima GSK-3 podem levar a várias condições de doença que incluem resistência à insulina que leva ao diabetes, doenças neurológicas como a doença de Alzheimer e câncer. As fluoroquinolonas são a classe mais comum de drogas que apresentam efeitos disglicêmicos por meio da interação com a enzima GSK-3. Portanto, é necessário hoje em dia compreender adequadamente as funções e mecanismos da GSK-3, principalmente seu papel na homeostase da glicose via efeitos na glicogênio sintase.


Assuntos
Humanos , Resistência à Insulina , Diabetes Mellitus , Quinase 3 da Glicogênio Sintase , Glucose , Homeostase
2.
Inflamm Bowel Dis ; 28(4): 639-648, 2022 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-34871402

RESUMO

Ulcerative colitis (UC), an etiologically complicated and relapsing gastrointestinal disease, is characterized by the damage of mucosal epithelium and destruction of the intestinal homeostasis, which has caused a huge social and economic burden on the health system all over the world. Its pathogenesis is multifactorial, including environmental factors, genetic susceptibility, epithelial barrier defect, symbiotic flora imbalance, and dysregulated immune response. Thus far, although immune cells have become the focus of most research, it is increasingly clear that intestinal epithelial cells play an important role in the pathogenesis and progression of UC. Notably, apoptosis is a vital catabolic process in cells, which is crucial to maintain the stability of intestinal environment and regulate intestinal ecology. In this review, the mechanism of apoptosis induced by reactive oxygen species and endoplasmic reticulum stress, as well as excessive apoptosis in intestinal epithelial dysfunction and gut microbiology imbalance are systematically and comprehensively summarized. Further understanding the role of apoptosis in the pathogenesis of UC may provide a novel strategy for its therapy in clinical practices and the development of new drugs.


Recently, the prevalence of ulcerative colitis (UC) has increased, but the pathogenesis of UC remains poorly understood. A better understanding of the role of apoptosis in the pathogenesis of UC may provide a promising prospect for UC treatment.


Assuntos
Colite Ulcerativa , Apoptose , Colite Ulcerativa/tratamento farmacológico , Estresse do Retículo Endoplasmático , Homeostase , Humanos , Mucosa Intestinal/patologia , Espécies Reativas de Oxigênio/metabolismo
3.
Cell Biol Int ; 46(3): 475-487, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34939719

RESUMO

Mutations of PSEN1 have been reported in dilated cardiomyopathy pedigrees. Understanding the effects and mechanisms of PSEN1 in cardiomyocytes might have important implications for treatment of heart diseases. Here, we showed that PSEN1 was downregulated in ischemia-induced failing hearts. Functionally, cardiovascular specific PSEN1 deletion led to spontaneous death of the mice due to cardiomyopathy. At the age of 11 months, the ratio of the heart weight/body weight was slightly lower in the Sm22a-PSEN1-KO mice compared with that of the WT mice. Echocardiography showed that the percentage of ejection fraction and fractional shortening was significantly reduced in the Sm22a-PSEN1-KO group compared with the percent of these measures in the WT group, indicating that PSEN1-KO resulted in heart failure. The abnormally regulated genes resulted from PSEN1-KO were detected to be enriched in muscle development and dilated cardiomyopathy. Among them, several genes encode Ca2+ ion channels, promoting us to investigate the effects of PSEN1 KO on regulation of Ca2+ in isolated adult cardiomyocytes. Consistently, in isolated adult cardiomyocytes, PSEN1-KO increased the concentration of cytosolic Ca2+ and reduced Ca2+ concentration inside the sarcoplasmic reticulum (SR) lumen at the resting stage. Additionally, SR Ca2+ was decreased in the failing hearts of WT mice, but with the lowest levels observed in the failing hearts of PSEN1 knockout mice. These results indicate that the process of Ca2+ release from SR into cytoplasm was affected by PSEN1 KO. Therefore, the abnormalities in Ca2+ homeostasis resulted from downregulation of PSEN1 in failing hearts might contribute to aging-related cardiomyopathy, which might had important implications for the treatment of aging-related heart diseases.


Assuntos
Cálcio , Cardiomiopatia Dilatada , Animais , Cardiomiopatia Dilatada/genética , Homeostase , Camundongos , Camundongos Knockout , Miócitos Cardíacos/fisiologia , Retículo Sarcoplasmático
4.
Cell Biol Int ; 46(4): 660-670, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35066972

RESUMO

The predominance of cardiovascular diseases among men compared to premenopausal women has been attributed to testosterone, which is implicated in vascular remodeling. Molecular mechanisms underlying its role have not been clarified but oxidative stress-induced inflammation may be important. We therefore investigated in vitro the effects of testosterone and dihydrotestosterone, (a nonaromatized androgen), on redox homeostasis in absence (basal conditions) and after corticotropin-releasing hormone-induced pro-oxidant action in macroendothelial cells. More specifically, we explored their role on well-established antioxidant enzymes activity, namely endothelial nitric oxide synthase, superoxide dismutase, catalase, and glutathione. We observed that both androgens significantly increased the intracellular reactive oxygen species levels, endothelial nitric oxide synthase activity, nitric oxide concentration as well as superoxide dismutase activity and decreased catalase activity. These effects of Testosterone and DHT were reversed in the presence of the androgen receptor antagonist, flutamide. Moreover, testosterone and dihydrotestosterone similarly enhanced the stimulatory effect of corticotropin-releasing hormone on intracellular reactive oxygen species levels and superoxide dismutase activity but did not influence the inhibitory effect on endothelial nitric oxide synthase activity, nitric oxide release and catalase activity. Finally, androgens did not have a detectable effect on glutathione levels or the glutathione/glutathione plus glutathione disulfide ratio. Our results reveal that testosterone and DHT rise the intracellular redox threshold of the endothelial cell and increases NO synthesis. These findings suggest that the action of testosterone is affected by the redox status of the endothelium and help to explain its controversial effects on the cardiovascular system.


Assuntos
Di-Hidrotestosterona , Testosterona , Di-Hidrotestosterona/farmacologia , Endotélio , Endotélio Vascular , Feminino , Homeostase , Humanos , Masculino , Óxido Nítrico , Oxirredução , Testosterona/farmacologia
5.
Front Endocrinol (Lausanne) ; 13: 904754, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35909536

RESUMO

Ghrelin is considered one of the most potent orexigenic peptide hormones and one that promotes homeostatic and hedonic food intake. Research on ghrelin, however, has been conducted predominantly in males and particularly in male rodents. In female mammals the control of energy metabolism is complex and it involves the interaction between ovarian hormones like estrogen and progesterone, and metabolic hormones. In females, the role that ghrelin plays in promoting feeding and how this is impacted by ovarian hormones is not well understood. Basal ghrelin levels are higher in females than in males, and ghrelin sensitivity changes across the estrus cycle. Yet, responses to ghrelin are lower in female and seem dependent on circulating levels of ovarian hormones. In this review we discuss the role that ghrelin plays in regulating homeostatic and hedonic food intake in females, and how the effects of ghrelin interact with those of ovarian hormones to regulate feeding and energy balance.


Assuntos
Comportamento Alimentar , Grelina , Animais , Metabolismo Energético , Comportamento Alimentar/fisiologia , Feminino , Homeostase , Masculino , Mamíferos/metabolismo
6.
Proc Natl Acad Sci U S A ; 119(32): e2206869119, 2022 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-35914172

RESUMO

The phytohormone auxin, indole-3-acetic acid (IAA), plays a prominent role in plant development. Auxin homeostasis is coordinately regulated by auxin synthesis, transport, and inactivation; however, the physiological contribution of auxin inactivation to auxin homeostasis has not been determined. The GH3 IAA-amino acid conjugating enzymes play a central role in auxin inactivation. Chemical inhibition of GH3 proteins in planta is challenging because the inhibition of these enzymes leads to IAA overaccumulation that rapidly induces GH3 expression. Here, we report the characterization of a potent GH3 inhibitor, kakeimide, that selectively targets IAA-conjugating GH3 proteins. Chemical knockdown of the auxin inactivation pathway demonstrates that auxin turnover is very rapid (about 10 min) and indicates that both auxin biosynthesis and inactivation dynamically regulate auxin homeostasis.


Assuntos
Arabidopsis , Regulação da Expressão Gênica de Plantas , Homeostase , Ácidos Indolacéticos/metabolismo , Reguladores de Crescimento de Plantas/metabolismo
7.
Proc Natl Acad Sci U S A ; 119(32): e2201328119, 2022 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-35914175

RESUMO

Cellular quiescence is a state of reversible cell cycle arrest that is associated with tissue dormancy. Timely regulated entry into and exit from quiescence is important for processes such as tissue homeostasis, tissue repair, stem cell maintenance, developmental processes, and immunity. However, little is known about processes that control the mechanical adaption to cell behavior changes during the transition from quiescence to proliferation. Here, we show that quiescent human keratinocyte monolayers sustain an actinomyosin-based system that facilitates global cell sheet displacements upon serum-stimulated exit from quiescence. Mechanistically, exposure of quiescent cells to serum-borne mitogens leads to rapid amplification of preexisting contractile sites, leading to a burst in monolayer tension that subsequently drives large-scale displacements of otherwise motility-restricted monolayers. The stress level after quiescence exit correlates with the level of quiescence depth at the time of activation, and a critical stress magnitude must be reached to overcome the cell sheet displacement barrier. The study shows that static quiescent cell monolayers are mechanically poised for motility, and it identifies global stress amplification as a mechanism for overcoming motility restrictions in confined confluent cell monolayers.


Assuntos
Células-Tronco , Ciclo Celular/fisiologia , Divisão Celular , Proliferação de Células , Homeostase , Humanos , Células-Tronco/metabolismo
8.
Sci Adv ; 8(31): eabm5550, 2022 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-35921424

RESUMO

The mechanoelectrical transduction (MET) channel in auditory hair cells converts sound into electrical signals, enabling hearing. Transmembrane-like channel 1 and 2 (TMC1 and TMC2) are implicated in forming the pore of the MET channel. Here, we demonstrate that inhibition of MET channels, breakage of the tip links required for MET, or buffering of intracellular Ca... induces pronounced phosphatidylserine externalization, membrane blebbing, and ectosome release at the hair cell sensory organelle, culminating in the loss of TMC1. Membrane homeostasis triggered by MET channel inhibition requires Tmc1 but not Tmc2, and three deafness-causing mutations in Tmc1 cause constitutive phosphatidylserine externalization that correlates with deafness phenotype. Our results suggest that, in addition to forming the pore of the MET channel, TMC1 is a critical regulator of membrane homeostasis in hair cells, and that Tmc1-related hearing loss may involve alterations in membrane homeostasis.


Assuntos
Surdez , Mecanotransdução Celular , Audição/fisiologia , Homeostase , Humanos , Mecanotransdução Celular/fisiologia , Proteínas de Membrana/metabolismo , Fosfatidilserinas
9.
Signal Transduct Target Ther ; 7(1): 265, 2022 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-35918332

RESUMO

Disturbed cholesterol homeostasis plays critical roles in the development of multiple diseases, such as cardiovascular diseases (CVD), neurodegenerative diseases and cancers, particularly the CVD in which the accumulation of lipids (mainly the cholesteryl esters) within macrophage/foam cells underneath the endothelial layer drives the formation of atherosclerotic lesions eventually. More and more studies have shown that lowering cholesterol level, especially low-density lipoprotein cholesterol level, protects cardiovascular system and prevents cardiovascular events effectively. Maintaining cholesterol homeostasis is determined by cholesterol biosynthesis, uptake, efflux, transport, storage, utilization, and/or excretion. All the processes should be precisely controlled by the multiple regulatory pathways. Based on the regulation of cholesterol homeostasis, many interventions have been developed to lower cholesterol by inhibiting cholesterol biosynthesis and uptake or enhancing cholesterol utilization and excretion. Herein, we summarize the historical review and research events, the current understandings of the molecular pathways playing key roles in regulating cholesterol homeostasis, and the cholesterol-lowering interventions in clinics or in preclinical studies as well as new cholesterol-lowering targets and their clinical advances. More importantly, we review and discuss the benefits of those interventions for the treatment of multiple diseases including atherosclerotic cardiovascular diseases, obesity, diabetes, nonalcoholic fatty liver disease, cancer, neurodegenerative diseases, osteoporosis and virus infection.


Assuntos
Aterosclerose , Doenças Cardiovasculares , Aterosclerose/tratamento farmacológico , Aterosclerose/genética , Aterosclerose/metabolismo , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/metabolismo , Colesterol , Células Espumosas/metabolismo , Células Espumosas/patologia , Homeostase , Humanos
10.
Front Immunol ; 13: 963444, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35911776

RESUMO

Cardiac mast cells (CMCs) are multifarious immune cells with complex roles both in cardiac physiological and pathological conditions, especially in cardiac fibrosis. Little is known about the physiological importance of CMCs in cardiac homeostasis and inflammatory process. Therefore, the present review will summarize the recent progress of CMCs on origin, development and replenishment in the heart, including their effects on cardiac development, function and ageing under physiological conditions as well as the roles of CMCs in inflammatory progression and resolution. The present review will shed a light on scientists to understand cardioimmunology and to develop immune treatments targeting on CMCs following cardiac injury.


Assuntos
Coração , Mastócitos , Contagem de Células , Células Cultivadas , Homeostase , Mastócitos/fisiologia
11.
Cell Death Dis ; 13(8): 674, 2022 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-35927240

RESUMO

Transmembrane of coiled-coil domains 1 (TMCO1) plays an important role in maintaining homeostasis of calcium (Ca2+) stores in the endoplasmic reticulum (ER). TMCO1-defect syndrome shares multiple features with human cerebro-facio-thoracic (CFT) dysplasia, including abnormal corpus callosum (CC). Here, we report that TMCO1 is required for the normal development of CC through sustaining Ca2+ homeostasis. Tmco1-/- mice exhibit severe agenesis of CC with stalled white matter fiber bundles failing to pass across the midline. Mechanistically, the excessive Ca2+ signals caused by TMCO1 deficiency result in upregulation of FGFs and over-activation of ERK, leading to an excess of glial cell migration and overpopulated midline glia cells in the indusium griseum which secretes Slit2 to repulse extension of the neural fiber bundles before crossing the midline. Supportingly, using the clinical MEK inhibitors to attenuate the over-activated FGF/ERK signaling can significantly improve the CC formation in Tmco1-/- brains. Our findings not only unravel the underlying mechanism of abnormal CC in TMCO1 defect syndrome, but also offer an attractive prevention strategy to relieve the related agenesis of CC in patients.


Assuntos
Corpo Caloso , Deficiência Intelectual , Animais , Canais de Cálcio/metabolismo , Corpo Caloso/metabolismo , Retículo Endoplasmático/metabolismo , Homeostase , Humanos , Camundongos , Neurogênese
12.
BMC Genomics ; 23(1): 556, 2022 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-35927609

RESUMO

BACKGROUND: There is a need to investigate mechanisms of phenotypic plasticity in marine invertebrates as negative effects of climate change, like ocean acidification, are experienced by coastal ecosystems. Environmentally-induced changes to the methylome may regulate gene expression, but methylome responses can be species- and tissue-specific. Tissue-specificity has implications for gonad tissue, as gonad-specific methylation patterns may be inherited by offspring. We used the Pacific oyster (Crassostrea gigas) - a model for understanding pH impacts on bivalve molecular physiology due to its genomic resources and importance in global aquaculture- to assess how low pH could impact the gonad methylome. Oysters were exposed to either low pH (7.31 ± 0.02) or ambient pH (7.82 ± 0.02) conditions for 7 weeks. Whole genome bisulfite sequencing was used to identify methylated regions in female oyster gonad samples. C- > T single nucleotide polymorphisms were identified and removed to ensure accurate methylation characterization. RESULTS: Analysis of gonad methylomes revealed a total of 1284 differentially methylated loci (DML) found primarily in genes, with several genes containing multiple DML. Gene ontologies for genes containing DML were involved in development and stress response, suggesting methylation may promote gonad growth homeostasis in low pH conditions. Additionally, several of these genes were associated with cytoskeletal structure regulation, metabolism, and protein ubiquitination - commonly-observed responses to ocean acidification. Comparison of these DML with other Crassostrea spp. exposed to ocean acidification demonstrates that similar pathways, but not identical genes, are impacted by methylation. CONCLUSIONS: Our work suggests DNA methylation may have a regulatory role in gonad and larval development, which would shape adult and offspring responses to low pH stress. Combined with existing molluscan methylome research, our work further supports the need for tissue- and species-specific studies to understand the potential regulatory role of DNA methylation.


Assuntos
Crassostrea , Metilação de DNA , Animais , Crassostrea/metabolismo , DNA/metabolismo , Ecossistema , Feminino , Homeostase , Concentração de Íons de Hidrogênio , Oceanos e Mares , Água do Mar/química
13.
Front Immunol ; 13: 898138, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35784325

RESUMO

Sex bias in autoimmune disease (AID) prevalence is known, but the role of estrogen in disease progression is more complex. Estrogen can even be protective in some AIDs; but in systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and systemic sclerosis (SSc), estrogen, its metabolites, and its receptors have been demonstrated to play critical, localized inflammatory roles. Estrogen is instrumental to the fibrosis seen in RA, SLE, SSc and other disease states, including breast cancer and uterine leiomyomas. Fibrotic diseases tend to share a common pattern in which lymphocyte-monocyte interactions generate cytokines which stimulate the deposition of fibrogenic connective tissue. RA, SLE, SSc and thyroid eye disease (TED) have very similar inflammatory and fibrotic patterns-from pathways to tissue type. The thorough investigations that demonstrated estrogen's role in the pathology of RA, SLE, and SSc could, and possibly should, be carried out in TED. One might even expect to find an even greater role for estrogen, and sex steroid homeostasis in TED, given that TED is typically sequalae to Graves' disease (GD), or Hashimoto's disease (HD), and these are endocrine disorders that can create considerable sex steroid hormone dysregulation. This paper highlights the pathophysiology similarities in 4 AIDs, examines the evidence of sex steroid mediated pathology across 3 AIDs and offers a case study and speculation on how this may be germane to TED.


Assuntos
Síndrome de Imunodeficiência Adquirida , Artrite Reumatoide , Doenças Autoimunes , Doença de Graves , Oftalmopatia de Graves , Lúpus Eritematoso Sistêmico , Escleroderma Sistêmico , Estrogênios , Hormônios Esteroides Gonadais , Homeostase , Humanos , Esteroides
14.
Front Immunol ; 13: 876029, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35784368

RESUMO

Group 2 innate lymphoid cells (ILC2s) were initially identified as a new type of lymphocytes that produce vigorous amounts of type 2 cytokines in adipose tissue. Subsequent studies revealed that ILC2s are present not only in adipose tissue but also in various other tissues such as lung and skin. ILC2s are generally recognized as tissue-resident immune cells that regulate tissue homeostasis. ILC2s express receptors for various humoral factors and thus can change their functions or distribution depending on the environment and circumstances. In this review, we will outline our recent understanding of ILC2 biology and discuss future directions for ILC2 research, particularly in adipose tissue and metabolic homeostasis.


Assuntos
Imunidade Inata , Linfócitos , Tecido Adiposo , Citocinas/metabolismo , Homeostase
15.
Proc Natl Acad Sci U S A ; 119(28): e2203114119, 2022 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-35787040

RESUMO

Most Actinobacteria encode a small transmembrane protein, whose gene lies immediately downstream of the housekeeping sortase coding for a transpeptidase that anchors many extracellular proteins to the Gram-positive bacterial cell wall. Here, we uncover the hitherto unknown function of this class of conserved proteins, which we name SafA, as a topological modulator of sortase in the oral Actinobacterium Actinomyces oris. Genetic deletion of safA induces cleavage and excretion of the otherwise predominantly membrane-bound SrtA in wild-type cells. Strikingly, the safA mutant, although viable, exhibits severe abnormalities in cell morphology, pilus assembly, surface protein localization, and polymicrobial interactions-the phenotypes that are mirrored by srtA depletion. The pleiotropic defect of the safA mutant is rescued by ectopic expression of safA from not only A. oris, but also Corynebacterium diphtheriae or Corynebacterium matruchotii. Importantly, the SrtA N terminus harbors a tripartite-domain feature typical of a bacterial signal peptide, including a cleavage motif AXA, mutations in which prevent SrtA cleavage mediated by the signal peptidase LepB2. Bacterial two-hybrid analysis demonstrates that SafA and SrtA directly interact. This interaction involves a conserved motif FPW within the exoplasmic face of SafA, since mutations of this motif abrogate SafA-SrtA interaction and induce SrtA cleavage and excretion as observed in the safA mutant. Evidently, SafA is a membrane-imbedded antagonist of signal peptidase that safeguards and maintains membrane homeostasis of the housekeeping sortase SrtA, a central player of cell surface assembly.


Assuntos
Actinobacteria/metabolismo , Aminoaciltransferases , Aminoaciltransferases/genética , Aminoaciltransferases/metabolismo , Proteínas de Bactérias/metabolismo , Cisteína Endopeptidases/genética , Cisteína Endopeptidases/metabolismo , Homeostase , Proteínas de Membrana , Morfogênese , Serina Endopeptidases
16.
Curr Opin Hematol ; 29(4): 188-193, 2022 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-35787547

RESUMO

PURPOSE OF REVIEW: Hematopoietic stem cells (HSCs) are endowed with high regenerative potential to supply mature blood cells throughout life, under steady state or stress conditions. HSCs are thought to rely on glycolysis when in a quiescent state and to switch to oxidative phosphorylation to meet their metabolic needs during activation. Recently, a series of important studies reveals a higher degree of complexity that goes well beyond the dichotomy between glycolysis and oxidative phosphorylation. The purpose of this review is to summarize the recent findings highlighting the multifaceted metabolic requirements of HSC homeostasis. RECENT FINDINGS: Emerging evidence points to the importance of lysosomal catabolic activity and noncanonical retinoic acid pathway in maintaining HSC quiescence and stemness. HSC activation into cycle seems to be accompanied by a switch to glycolysis-mitochondrial coupling and to anabolic pathways, including Myc, aspartate-mediated purine synthesis. SUMMARY: Knowledge of metabolism of HSCs has dramatically increased in the past 2 years and reveals unexpected needs of HSCs during both their quiescent and activated state. Understanding how HSCs use metabolism for their functions will offer new opportunity for HSC-based therapies.


Assuntos
Células-Tronco Hematopoéticas , Mitocôndrias , Células-Tronco Hematopoéticas/metabolismo , Homeostase , Humanos , Mitocôndrias/metabolismo
17.
Nan Fang Yi Ke Da Xue Xue Bao ; 42(6): 785-793, 2022 Jun 20.
Artigo em Chinês | MEDLINE | ID: mdl-35790428

RESUMO

OBJECTIVE: To explore the mechanism by which inositol-requiring enzyme-1α (IRE1α) regulates autophagy function of chondrocytes through calcium homeostasis endoplasmic reticulum protein (CHERP). METHODS: Cultured human chondrocytes (C28/I2 cells) were treated with tunicamycin, 4µ8c, rapamycin, or both 4µ8c and rapamycin, and the expressions of endoplasmic reticulum (ER) stress- and autophagy-related proteins were detected with Western blotting. Primary chondrocytes from ERN1 knockout (ERN1 CKO) mice and wild-type mice were examined for ATG5 and ATG7 mRNA expressions, IRE1α and p-IRE1α protein expressions, and intracellular calcium ion content using qPCR, Western blotting and flow cytometry. The effect of bafilomycin A1 treatment on LC3 Ⅱ/LC3 Ⅰ ratio in the isolated chondrocytes was assessed with Western blotting. Changes in autophagic flux of the chondrocytes in response to rapamycin treatment were detected using autophagy dual fluorescent virus. The changes in autophagy level in C28/I2 cells overexpressing CHERP and IRE1α were detected using immunofluorescence assay. RESULTS: Tunicamycin treatment significantly up-regulated ER stress-related proteins and LC3 Ⅱ/LC3 Ⅰ ratio and down-regulated the expression of p62 in C28/I2 cells (P < 0.05). Rapamycin obviously up-regulated LC3 Ⅱ/LC3 Ⅰ ratio (P < 0.001) in C28/I2 cells, but this effect was significantly attenuated by co-treatment with 4µ8c (P < 0.05). Compared with the cells from the wild-type mice, the primary chondrocytes from ERN1 knockout mice showed significantly down-regulated mRNA levels of ERN1 (P < 0.01), ATG5 (P < 0.001) and ATG7 (P < 0.001), lowered or even lost expressions of IRE1α and p-IRE1α proteins (PP < 0.01), and increased expression of CHERP (P < 0.05) and intracellular calcium ion content (P < 0.001). Bafilomycin A1 treatment obviously increased LC3 Ⅱ/ LC3 Ⅰ ratio in the chondrocytes from both wild-type and ERN1 knockout mice (P < 0.01 or 0.05), but the increment was more obvious in the wild-type chondrocytes (P < 0.05). Treatment with autophagy dual-fluorescence virus resulted in a significantly greater fluorescence intensity of LC3-GFP in rapamycin-treated ERN1 CKO chondrocytes than in wild-type chondrocytes (P < 0.05). In C28/I2 cells, overexpression of CHERP obviously decreased the fluorescence intensity of LC3, and overexpression of IRE1α enhanced the fluorescence intensity and partially rescued the fluorescence reduction of LC3 caused by CHERP. CONCLUSION: IRE1α deficiency impairs autophagy in chondrocytes by upregulating CHERP and increasing intracellular calcium ion content.


Assuntos
Condrócitos , Endorribonucleases , Animais , Autofagia , Cálcio/metabolismo , Retículo Endoplasmático/metabolismo , Endorribonucleases/metabolismo , Endorribonucleases/farmacologia , Homeostase , Inositol , Camundongos , Camundongos Knockout , Proteínas Serina-Treonina Quinases , RNA Mensageiro/metabolismo , Sirolimo/farmacologia , Tunicamicina/metabolismo , Tunicamicina/farmacologia
18.
NPJ Biofilms Microbiomes ; 8(1): 53, 2022 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-35794154

RESUMO

Microbial pathogens employ signaling systems through cyclic (di-) nucleotide monophosphates serving as second messengers to increase fitness during pathogenesis. However, signaling schemes via second messengers in Porphyromonas gingivalis, a key Gram-negative anaerobic oral pathogen, remain unknown. Here, we report that among various ubiquitous second messengers, P. gingivalis strains predominantly synthesize bis-(3',5')-cyclic di-adenosine monophosphate (c-di-AMP), which is essential for their growth and survival. Our findings demonstrate an unusual regulation of c-di-AMP synthesis in P. gingivalis. P. gingivalis c-di-AMP phosphodiesterase (PDE) gene (pdepg) positively regulates c-di-AMP synthesis and impedes a decrease in c-di-AMP concentration despite encoding conserved amino acid motifs for phosphodiesterase activity. Instead, the predicted regulator gene cdaR, unrelated to the c-di-AMP PDE genes, serves as a potent negative regulator of c-di-AMP synthesis in this anaerobe. Further, our findings reveal that pdepg and cdaR are required to regulate the incorporation of ATP into c-di-AMP upon pyruvate utilization, leading to enhanced biofilm formation. We show that shifts in c-di-AMP signaling change the integrity and homeostasis of cell envelope, importantly, the structure and immunoreactivity of the lipopolysaccharide layer. Additionally, microbe-microbe interactions and the virulence potential of P. gingivalis were modulated by c-di-AMP. These studies provide the first glimpse into the scheme of second messenger signaling in P. gingivalis and perhaps other Bacteroidetes. Further, our findings indicate that c-di-AMP signaling promotes the fitness of the residents of the oral cavity and the development of a pathogenic community.


Assuntos
AMP Cíclico , Porphyromonas gingivalis , Monofosfato de Adenosina , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , AMP Cíclico/metabolismo , Fosfatos de Dinucleosídeos/metabolismo , Homeostase , Diester Fosfórico Hidrolases/genética , Porphyromonas gingivalis/genética , Porphyromonas gingivalis/metabolismo , Virulência
19.
Int J Mol Med ; 50(3)2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35796003

RESUMO

Non­alcoholic fatty liver disease (NAFLD) is a clinically progressive illness that can advance from simple fatty liver to non-alcoholic hepatitis and liver fibrosis. Cirrhosis and hepatocellular carcinoma are two of the most common diseases caused by NAFLD. As there are no early disease biomarkers and no US Food and Drug Administration­approved medications, treatment for NAFLD is still focused on altering lifestyle and dietary habits, which makes it difficult to treat effectively. As a result, a novel treatment is urgently needed to prevent NAFLD progression. Calcium (Ca2+) channels regulate intracellular Ca2+ homeostasis via the mediation of Ca2+ flow. Previous studies have reported that Ca2+ channel expression varies throughout the development and progression of NAFLD, which results in the dysregulation of intracellular Ca2+ homeostasis, endoplasmic reticulum stress, mitochondrial dysfunction and autophagy suppression, all of which contribute to NAFLD progression. Several types of Ca2+ channels (including two­pore segment channel 2, transient receptor potential, inositol triphosphate receptor, voltage­dependent anion channel 1, store­operated Ca2+ entry, purinergic receptor X7 and potassium Ca2+­activated channel subfamily N member 4) have been identified as potential targets for preventing NAFLD development and controlling intracellular Ca2+ homeostasis. To achieve this, these channels can be blocked or activated, which exerts anti­steatotic, anti­inflammatory, anti­fibrotic and other effects, which ultimately prevents the development of NAFLD. In the present review NAFLD therapeutics and the treatments that target Ca2+ channels that are currently being developed were examined.


Assuntos
Neoplasias Hepáticas , Hepatopatia Gordurosa não Alcoólica , Homeostase , Humanos , Receptores de Inositol 1,4,5-Trifosfato , Cirrose Hepática , Estados Unidos
20.
Endocrinol Metab (Seoul) ; 37(3): 408-414, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35798547

RESUMO

Skeletal muscle is now regarded as an endocrine organ based on its secretion of myokines and exerkines, which, in response to metabolic stimuli, regulate the crosstalk between the skeletal muscle and other metabolic organs in terms of systemic energy homeostasis. This conceptual basis of skeletal muscle as a metabolically active organ has provided insights into the potential role of physical inactivity and conditions altering muscle quality and quantity in the development of multiple metabolic disorders, including insulin resistance, obesity, and diabetes. Therefore, it is important to understand human muscle physiology more deeply in relation to the pathophysiology of metabolic diseases. Since monolayer cell lines or animal models used in conventional research differ from the pathophysiological features of the human body, there is increasing need for more physiologically relevant in vitro models of human skeletal muscle. Here, we introduce recent studies on in vitro models of human skeletal muscle generated from adult myogenic progenitors or pluripotent stem cells and summarize recent progress in the development of three-dimensional (3D) bioartificial muscle, which mimics the physiological complexity of native skeletal muscle tissue in terms of maturation and functionality. We then discuss the future of skeletal muscle 3D-organoid culture technology in the field of metabolic research for studying pathological mechanisms and developing personalized therapeutic strategies.


Assuntos
Resistência à Insulina , Músculo Esquelético , Animais , Linhagem Celular , Homeostase/fisiologia , Humanos , Resistência à Insulina/fisiologia , Músculo Esquelético/metabolismo , Obesidade/metabolismo
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