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1.
Respir Res ; 24(1): 16, 2023 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-36647045

RESUMO

BACKGROUND: The level of linked N-acetylglucosamine (O-GlcNAc) has been proved to be a sensor of cell state, but its relationship with hyperoxia-induced alveolar type 2 epithelial cells injure and bronchopulmonary dysplasia (BPD) has not been clarified. In this study, we evaluated if these effects ultimately led to functional damage in hyperoxia-induced alveolar cells. METHODS: We treated RLE-6TN cells at 85% hyperoxia for 0, 24 and 48 h with Thiamet G (TG), an OGA inhibitor; OSMI-1 (OS), an OGT inhibitor; or with UDP-GlcNAc, which is involved in synthesis of O-GlcNAc as a donor. The metabolic rerouting, cell viability and apoptosis resulting from the changes in O-GlcNAc glycosyltransferase levels were evaluated in RLE-6TN cells after hyperoxia exposure. We constructed rat Park2 overexpression and knockdown plasmmids for in vitro verification and Co-immunoprecipitation corroborated the binding of Parkin and O-GlcNAc. Finally, we assessed morphological detection in neonatal BPD rats with TG and OS treatment. RESULTS: We found a decrease in O-GlcNAc content and levels of its metabolic enzymes in RLE-6TN cells under hyperoxia. However, the inhibition of OGT function with OSMI-1 ameliorated hyperoxia-induced lung epithelial cell injury, enhanced cell metabolism and viability, reduced apoptosis, and accelerated the cell proliferation. Mitochondrial homeostasis was affected by O-GlcNAc and regulated Parkin. CONCLUSION: The results revealed that the decreased O-GlcNAc levels and increased O-GlcNAcylation of Parkin might cause hyperoxia-induced alveolar type II cells injurys.


Assuntos
Hiperóxia , Ubiquitina-Proteína Ligases , Animais , Ratos , Acetilglucosamina/metabolismo , Células Epiteliais Alveolares/metabolismo , Homeostase , Hiperóxia/genética , Hiperóxia/metabolismo , Mitofagia , Ubiquitina-Proteína Ligases/genética
2.
J Transl Med ; 21(1): 27, 2023 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-36647167

RESUMO

Mitochondria determine the physiological status of most eukaryotes. Mitochondrial dynamics plays an important role in maintaining mitochondrial homeostasis, and the disorder in mitochondrial dynamics could affect cellular energy metabolism leading to tumorigenesis. In recent years, disrupted mitochondrial dynamics has been found to influence the biological behaviors of gastrointestinal cancer with the potential to be a novel target for its individualized therapy. This review systematically introduced the role of mitochondrial dynamics in maintaining mitochondrial homeostasis, and further elaborated the effects of disrupted mitochondrial dynamics on the cellular biological behaviors of gastrointestinal cancer as well as its association with cancer progression. We aim to provide clues for elucidating the etiology and pathogenesis of gastrointestinal cancer from the perspective of mitochondrial homeostasis and disorder.


Assuntos
Neoplasias Gastrointestinais , Mitocôndrias , Humanos , Mitocôndrias/metabolismo , Dinâmica Mitocondrial , Neoplasias Gastrointestinais/metabolismo , Neoplasias Gastrointestinais/patologia , Homeostase , Carcinogênese/patologia
3.
Commun Biol ; 6(1): 97, 2023 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-36694005

RESUMO

The spatially organized gene expression program within the liver specifies hepatocyte functions according to their relative distances to the bloodstream (i.e., zonation), contributing to liver homeostasis. Despite the knowledge that solid cancers remotely disrupt liver homeostasis, it remains unexplored whether solid cancers affect liver zonation. Here, using spatial transcriptomics, we thoroughly investigate the abundance and zonation of hepatic genes in cancer-bearing mice. We find that breast cancers affect liver zonation in various distinct manners depending on biological pathways. Aspartate metabolism and triglyceride catabolic processes retain relatively intact zonation patterns, but the zonation of xenobiotic catabolic process genes exhibits a strong disruption. The acute phase response is induced in zonated manners. Furthermore, we demonstrate that breast cancers activate innate immune cells in particular neutrophils in distinct zonated manners, rather than in a uniform fashion within the liver. Collectively, breast cancers disorganize hepatic transcriptomes in zonated manners, thereby disrupting zonated functions of the liver.


Assuntos
Neoplasias , Transcriptoma , Camundongos , Animais , Fígado/metabolismo , Hepatócitos/metabolismo , Perfilação da Expressão Gênica , Homeostase , Neoplasias/patologia
4.
Pediatr Surg Int ; 39(1): 75, 2023 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-36617603

RESUMO

PURPOSE: This study aimed to examine the diagnostic value of IL-6, thiol-disulfide homeostasis, complete blood count and inflammatory biomarkers in the prediction of acute appendicitis in children. METHODS: The study was designed as a prospective and controlled study in children-the study was conducted at a tertiary referential university hospital between May 2020 and April 2021. Patients were divided between study groups and one control group (CG): 1: confirmed acute appendicitis group (AAP); 2: perforated appendicitis group (PAP); and 3: non-specified abdominal pain (NAP). The age and gender of the patients were determined. The following listed laboratory parameters were compared between groups: TOS: total oxidative status, TAS: total antioxidant status, OSI: oxidative stress index, TT: total thiol, NT (µmol/L): native thiol, DIS: disulfide, IL-6: interleukin 6, TNF-a: tumor necrosis factor-alpha, WBC: white blood cell, NEU: neutrophil, NEU%: neutrophil percentage, LY: lymphocyte, LY%: lymphocyte percentage, PLT: platelet, MPV: mean platelet volume NLR: neutrophil lymphocyte ratio, CRP: C-reactive protein, LCR: lymphocyte CRP ratio, and serum lactate. RESULTS: The TOS level of the PAP group was found to be significantly higher than that in the AAP, NAP and control groups (p = 0.006, < 0.001 and p < 0.001). TAS, TT, and NT levels in the PAP group were significantly lower than those in the AAP, NAP and control groups. OSI was significantly higher in the PAP group than in the other groups. The TT and NT levels of the NAP group were both similar to those of the control group. Serum DIS level was similar between the AAP and PAP groups, AAP and NAP groups, and NAP and control groups. Serum IL-6 and TNF-α levels were found to be significantly higher in the PAP group compared to those in all groups. The WBC, NEU, and NEU% values were found to be significantly higher in the PAP group than those in the NAP and control groups, while LY and LY% values were found to be significantly lower. PAP and AAP groups were found to be similar in terms of WBC, NEU, LYM, NEU%, and LYM% values. PLT and MPV values and serum lactate values did not show a significant difference between the groups. NLR was similar in the AAP and PAP groups. A significant increase in CRP versus a decrease in LCR was detected in the PAP group compared to that in the AAP group. Multivariate analysis demonstrated that only IL-6 has significant estimated accuracy rates as 80% for the control group, 78.8% for AAP, 96.9% for PAP, and 81.6% for NAP. CONCLUSION: Rather than AAP, PAP caused significantly higher oxidative stress (increased TOS and OSI), and lower antioxidation capacity (decreased TT and NT). IL-6 levels can provide a significant stratification. Nevertheless, simply detecting WBC or CRP is not enough to distinguish the specific pathology in acute appendicitis and related conditions.


Assuntos
Apendicite , Interleucina-6 , Humanos , Criança , Apendicite/diagnóstico , Dissulfetos , Compostos de Sulfidrila , Estudos Prospectivos , Biomarcadores , Antioxidantes , Homeostase , Lactatos
5.
Neural Plast ; 2023: 1455634, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36647544

RESUMO

Depression is a highly prevalent and heterogeneous disorder that requires new strategies to overcome depression. In this study, we aimed to investigate whether leonurine modulated hippocampal nerve regeneration in chronic and unpredictable mild stress (CUMS) rats through the SHH/GLI signaling pathway and restoring gut microbiota and microbial metabolic homeostasis. The CUMS rat model was constructed and treated with leonurine. The body weight of rats was recorded, and a series of tests were performed. Western blot was utilized to measure the expression of BDNF and 5-HT in the hippocampus. Then the expression of SHH, GLI, PTCH, and SMO were measured by qRT-PCR and western blot. The colocalization of BrdU+DCX and BrdU+NeuN was evaluated by IF. 16S rDNA high-throughput sequencing was applied to detect the composition and distribution of gut microbiota. The differential metabolites were analyzed by untargeted metabolomics. The correlation between gut microbiota and microbial metabolites was analyzed by Pearson correlation coefficient. After CUMS modeling, the body weight of rats was decreased, and the expression of BDNF and 5-HT were decreased, while the body weight was recovered, and the expression of BDNF and 5-HT were increased after leonurine treatment. Leonurine reversed the reduction in the colocalization of BrdU+DCX and BrdU+NeuN and the reduction in the levels of SHH, GLI, PTCH, and SMO induced by CUMS modeling. Leonurine also restored gut microbiota and microbial metabolites homeostasis in CUMS rats. Furthermore, Prevotellaceae_Ga6A1_group was negatively correlated with 3-Oxocholic acid, nutriacholic acid, and cholic acid. Collectively, leonurine regulated hippocampal nerve regeneration in CUMS rats by activating the SHH/GLI signaling pathway and restoring gut microbiota and microbial metabolic homeostasis.


Assuntos
Depressão , Microbioma Gastrointestinal , Ratos , Animais , Depressão/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Serotonina/metabolismo , Bromodesoxiuridina/metabolismo , Regeneração Nervosa , Homeostase , Transdução de Sinais , Hipocampo/metabolismo , Peso Corporal , Estresse Psicológico/metabolismo , Modelos Animais de Doenças
6.
Oral Health Prev Dent ; 21(1): 1-6, 2023 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-36651310

RESUMO

PURPOSE: This study aimed to compare insulin status and dysglycemia (prediabetes/diabetes) of patients with chronic (stage III, grade B) or aggressive periodontitis (stage III, grade C) to that of a healthy population. MATERIALS AND METHODS: Patients with chronic (CP, n = 16) or aggressive periodontitis (AP, n = 15) and periodontally healthy controls (n = 32) were recruited. Body mass index was calculated. Glycemia, plasma insulin, glycated hemoglobin, C-reactive protein, and lipid levels were measured in fasting. The Homeostasis Model Assessment was used to calculate the insulin sensitivity (HOMA-%S), the beta-cell function (HOMA-%B), and their hyperbolic product (HOMA-%BxS). RESULTS: The CP group showed statistically significantly insulin resistance with a lower HOMA-%S (p = 0.0003) and a reduced HOMA-%BxS (p = 0.049) despite a higher insulin level (p = 0.01) vs the control group, even after BMI adjustment. There was also a trend to dysglycemia (prediabetes/diabetes) in the chronic group. In patients with AP, no abnormalities in insulin status were observed and glycemic levels were comparable with controls. Additionally, patients in both AP and CP groups presented significantly higher CRP levels compared to those of the control group (p = 0.02). CONCLUSION: Patients with CP showed reduced insulin sensitivity, increased insulin levels but a reduced %BxS product and a trend to dysglycemia. These abnormalities were not observed in AP.


Assuntos
Periodontite Agressiva , Diabetes Mellitus Tipo 2 , Resistência à Insulina , Estado Pré-Diabético , Humanos , Insulina , Projetos Piloto , Diabetes Mellitus Tipo 2/metabolismo , Glicemia/metabolismo , Homeostase
7.
PLoS One ; 18(1): e0279028, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36662875

RESUMO

Nod-Like Receptor Pyrin domain-containing protein 6 (NLRP6), a member of the Nucleotide-oligomerization domain-Like Receptor (NLR) family of proteins, assembles together with the ASC protein to form an inflammasome upon stimulation by bacterial lipoteichoic acid and double-stranded DNA. Besides its expression in myeloid cells, NLRP6 is also expressed in intestinal epithelial cells where it may contribute to the maintenance of gut homeostasis and negatively controls colorectal tumorigenesis. Here, we report that NLRP6 is very faintly expressed in several colon cancer cell lines, detected only in cytoplasmic small dots were it colocalizes with ASC. Consequently, it is very hardly detected by standard western-blotting techniques by several presently available commercial antibodies which, in contrast, highly cross-react with a protein of 90kDa that we demonstrate to be unrelated to NLRP6. We report here these results to caution the community not to confuse the 90kDa protein with the endogenous human NLRP6.


Assuntos
Inflamassomos , Neoplasias , Humanos , Inflamassomos/metabolismo , Homeostase , Células Epiteliais/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular
8.
Cell ; 186(2): 238-240, 2023 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-36669471

RESUMO

Body temperature maintenance is an important regulator of glucose homeostasis. In this issue of Cell, Meng et al. discover a regulatory axis in which light activation of photoreceptive retinal ganglia stimulates the supraoptic nucleus (SON) to inhibit brown adipose tissue (BAT) thermogenesis and impair glucose homeostasis. This could explain the impact of constant light exposure on metabolism.


Assuntos
Glucose , Núcleo Supraóptico , Glucose/metabolismo , Núcleo Supraóptico/metabolismo , Termogênese/fisiologia , Homeostase , Tecido Adiposo Marrom/metabolismo , Metabolismo Energético
9.
Nat Commun ; 14(1): 344, 2023 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-36670126

RESUMO

Mesenchymal stem cells (MSCs) reside in microenvironments, referred to as niches, which provide structural support and molecular signals. Sensory nerves are niche components in the homeostasis of tissues such as skin, bone marrow and hematopoietic system. However, how the sensory nerve affects the behavior of MSCs remains largely unknown. Here we show that the sensory nerve is vital for mesenchymal tissue homeostasis and maintenance of MSCs in the continuously growing adult mouse incisor. Loss of sensory innervation leads to mesenchymal disorder and a decrease in MSCs. Mechanistically, FGF1 from the sensory nerve directly acts on MSCs by binding to FGFR1 and activates the mTOR/autophagy axis to sustain MSCs. Modulation of mTOR/autophagy restores the MSCs and rescues the mesenchymal tissue disorder of Fgfr1 mutant mice. Collectively, our study provides insights into the role of sensory nerves in the regulation of MSC homeostasis and the mechanism governing it.


Assuntos
Células-Tronco Mesenquimais , Camundongos , Animais , Células-Tronco Mesenquimais/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Autofagia/fisiologia , Medula Óssea/metabolismo , Homeostase , Nicho de Células-Tronco
10.
J Transl Med ; 21(1): 36, 2023 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-36670507

RESUMO

MOTS-c is a peptide encoded by the short open reading frame of the mitochondrial 12S rRNA gene. It is significantly expressed in response to stress or exercise and translocated to the nucleus, where it regulates the expression of stress adaptation-related genes with antioxidant response elements (ARE). MOTS-c mainly acts through the Folate-AICAR-AMPK pathway, thereby influencing energy metabolism, insulin resistance, inflammatory response, exercise, aging and aging-related pathologies. Because of the potential role of MOTS-c in maintaining energy and stress homeostasis to promote healthy aging, especially in view of the increasing aging of the global population, it is highly pertinent to summarize the relevant studies. This review summarizes the retrograde signaling of MOTS-c toward the nucleus, the regulation of energy metabolism, stress homeostasis, and aging-related pathological processes, as well as the underlying molecular mechanisms.


Assuntos
Resistência à Insulina , Mitocôndrias , Humanos , Mitocôndrias/metabolismo , Peptídeos/metabolismo , Envelhecimento , Homeostase , Resistência à Insulina/fisiologia , Fatores de Transcrição/metabolismo , Proteínas Mitocondriais/genética
11.
Cells ; 12(2)2023 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-36672169

RESUMO

The term moonlighting proteins refers to those proteins that present alternative functions performed by a single polypeptide chain acquired throughout evolution (called canonical and moonlighting, respectively). Over 78% of moonlighting proteins are involved in human diseases, 48% are targeted by current drugs, and over 25% of them are involved in the virulence of pathogenic microorganisms. These facts encouraged us to study the link between the functions of moonlighting proteins and disease. We found a large number of moonlighting functions activated by pathological conditions that are highly involved in disease development and progression. The factors that activate some moonlighting functions take place only in pathological conditions, such as specific cellular translocations or changes in protein structure. Some moonlighting functions are involved in disease promotion while others are involved in curbing it. The disease-impairing moonlighting functions attempt to restore the homeostasis, or to reduce the damage linked to the imbalance caused by the disease. The disease-promoting moonlighting functions primarily involve the immune system, mesenchyme cross-talk, or excessive tissue proliferation. We often find moonlighting functions linked to the canonical function in a pathological context. Moonlighting functions are especially coordinated in inflammation and cancer. Wound healing and epithelial to mesenchymal transition are very representative. They involve multiple moonlighting proteins with a different role in each phase of the process, contributing to the current-phase phenotype or promoting a phase switch, mitigating the damage or intensifying the remodeling. All of this implies a new level of complexity in the study of pathology genesis, progression, and treatment. The specific protein function involved in a patient's progress or that is affected by a drug must be elucidated for the correct treatment of diseases.


Assuntos
Transição Epitelial-Mesenquimal , Proteínas , Humanos , Proteínas/metabolismo , Homeostase , Movimento Celular , Progressão da Doença
12.
J Reprod Immunol ; 155: 103787, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36603465

RESUMO

Embryo implantation is a key step in human reproduction, and the endometrium plays a key role in this process. Changes in the receptive state of the endometrium are one of the main reasons for embryo implantation failure. However, the mechanism underlying the altered endometrial receptivity remains unclear. In this study, we recruited 140 women undergoing assisted reproductive technology and divided them into a shifting group and a normal group based on their embryo implantation window results. Endometrial transcriptome data suggested that changes in the remodeling process of decidual spiral arterioles and changes in the immune environment might be important mechanisms of implantation window shift. The functional enrichment analysis results also suggested that the changes in microbiota had an important role in the changes in endometrial status. The endometrial functionally active microbial profiles were obtained based on previously validated metatranscriptomic analysis pipelines. Combining host gene expression information, immune cell abundance information and functionally active microbial abundance and activity information, we found that Treponema succinifaciens, Fusobacterium sp. oral taxon 203 and other potentially harmful species may over-activate Eicosapentaenoic acid (EPA) biosynthesis Thus, the balance of the immune environment of the endometrium is disrupted, resulting in the shift of the implantation window and the failure of embryo implantation.


Assuntos
Ácido Eicosapentaenoico , Endométrio , Feminino , Humanos , Ácido Eicosapentaenoico/metabolismo , Implantação do Embrião , Homeostase , Transcriptoma
13.
Nat Commun ; 14(1): 1, 2023 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-36596776

RESUMO

Pancreatic cancer is characterized by abundant desmoplasia, a dense stroma composed of extra-cellular and cellular components, with cancer associated fibroblasts (CAFs) being the major cellular component. However, the tissue(s) of origin for CAFs remains controversial. Here we determine the tissue origin of pancreatic CAFs through comprehensive lineage tracing studies in mice. We find that the splanchnic mesenchyme, the fetal cell layer surrounding the endoderm from which the pancreatic epithelium originates, gives rise to the majority of resident fibroblasts in the normal pancreas. In a genetic mouse model of pancreatic cancer, resident fibroblasts expand and constitute the bulk of CAFs. Single cell RNA profiling identifies gene expression signatures that are shared among the fetal splanchnic mesenchyme, adult fibroblasts and CAFs, suggesting a persistent transcriptional program underlies splanchnic lineage differentiation. Together, this study defines the phylogeny of the mesenchymal component of the pancreas and provides insights into pancreatic morphogenesis and tumorigenesis.


Assuntos
Pâncreas , Neoplasias Pancreáticas , Camundongos , Animais , Pâncreas/metabolismo , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Fibroblastos/metabolismo , Carcinogênese/genética , Carcinogênese/metabolismo , Transformação Celular Neoplásica/metabolismo , Mesoderma/metabolismo , Homeostase
14.
NPJ Biofilms Microbiomes ; 9(1): 1, 2023 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-36596826

RESUMO

Tibial dyschondroplasia (TD) with multiple incentives is a metabolic skeletal disease that occurs in fast-growing broilers. Perturbations in the gut microbiota (GM) have been shown to affect bone homoeostasis, but the mechanisms by which GM modulates bone metabolism in TD broilers remain unknown. Here, using a broiler model of TD, we noted elevated blood glucose (GLU) levels in TD broilers, accompanied by alterations in the pancreatic structure and secretory function and damaged intestinal barrier function. Importantly, faecal microbiota transplantation (FMT) of gut microbes from normal donors rehabilitated the GM and decreased the elevated GLU levels in TD broilers. A high GLU level is a predisposing factor to bone disease, suggesting that GM dysbiosis-mediated hyperglycaemia might be involved in bone regulation. 16S rRNA gene sequencing and short-chain fatty acid analysis revealed that the significantly increased level of the metabolite butyric acid derived from the genera Blautia and Coprococcus regulated GLU levels in TD broilers by binding to GPR109A in the pancreas. Tibial studies showed reduced expression of vascular regulatory factors (including PI3K, AKT and VEFGA) based on transcriptomics analysis and reduced vascular distribution, contributing to nonvascularization of cartilage in the proximal tibial growth plate of TD broilers with elevated GLU levels. Additionally, treatment with the total flavonoids from Rhizoma drynariae further validated the improvement in bone homoeostasis in TD broilers by regulating GLU levels through the regulation of GM to subsequently improve intestinal and pancreatic function. These findings clarify the critical role of GM-mediated changes in GLU levels via the gut-pancreas axis in bone homoeostasis in TD chickens.


Assuntos
Microbioma Gastrointestinal , Osteocondrodisplasias , Animais , Osteocondrodisplasias/terapia , Osteocondrodisplasias/veterinária , Osteocondrodisplasias/metabolismo , Tiram , Galinhas , RNA Ribossômico 16S , Homeostase , Glucose
15.
Proc Natl Acad Sci U S A ; 120(2): e2212644120, 2023 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-36595688

RESUMO

Iron homeostasis is critical for cellular and organismal function and is tightly regulated to prevent toxicity or anemia due to iron excess or deficiency, respectively. However, subcellular regulatory mechanisms of iron remain largely unexplored. Here, we report that SEL1L-HRD1 protein complex of endoplasmic reticulum (ER)-associated degradation (ERAD) in hepatocytes controls systemic iron homeostasis in a ceruloplasmin (CP)-dependent, and ER stress-independent, manner. Mice with hepatocyte-specific Sel1L deficiency exhibit altered basal iron homeostasis and are sensitized to iron deficiency while resistant to iron overload. Proteomics screening for a factor linking ERAD deficiency to altered iron homeostasis identifies CP, a key ferroxidase involved in systemic iron distribution by catalyzing iron oxidation and efflux from tissues. Indeed, CP is highly unstable and a bona fide substrate of SEL1L-HRD1 ERAD. In the absence of ERAD, CP protein accumulates in the ER and is shunted to refolding, leading to elevated secretion. Providing clinical relevance of these findings, SEL1L-HRD1 ERAD is responsible for the degradation of a subset of disease-causing CP mutants, thereby attenuating their pathogenicity. Together, this study uncovers the role of SEL1L-HRD1 ERAD in systemic iron homeostasis and provides insights into protein misfolding-associated proteotoxicity.


Assuntos
Ceruloplasmina , Degradação Associada com o Retículo Endoplasmático , Camundongos , Animais , Ceruloplasmina/genética , Ubiquitina-Proteína Ligases/metabolismo , Retículo Endoplasmático/metabolismo , Proteínas/metabolismo , Homeostase , Ferro/metabolismo
16.
Int J Mol Sci ; 24(1)2023 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-36614256

RESUMO

Pancreatic ß-cells synthesize and secrete insulin. A key feature of diabetes mellitus is the loss of these cells. A decrease in the number of ß-cells results in decreased biosynthesis of insulin. Increasing the number of ß-cells should restore adequate insulin biosynthesis leading to adequate insulin secretion. Therefore, identifying proteins that regulate the number of ß-cells is a high priority in diabetes research. In this review article, we summerize the results of three sophisticated transgenic mouse models showing that the transcription factors Elk-1 and Egr-1 and the Ca2+/calmodulin-regulated protein phosphatase calcineurin control the formation of sufficiently large pancreatic islets. Impairment of the biological activity of Egr-1 and Elk-1 in pancreatic ß-cells leads to glucose intolerance and dysregulation of glucose homeostasis, the process that maintains glucose concentration in the blood within a narrow range. Transgenic mice expressing an activated calcineurin mutant also had smaller islets and showed hyperglycemia. Calcineurin induces dephosphorylation of Elk-1 which subsequently impairs Egr-1 biosynthesis and the biological functions of Elk-1 and Egr-1 to regulate islet size and glucose homeostasis.


Assuntos
Calcineurina , Ilhotas Pancreáticas , Camundongos , Animais , Calcineurina/genética , Calcineurina/metabolismo , Ilhotas Pancreáticas/metabolismo , Insulina/metabolismo , Camundongos Transgênicos , Glucose/metabolismo , Homeostase
17.
Int J Mol Sci ; 24(1)2023 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-36614315

RESUMO

The glymphatic system, a fluid-clearance pathway involved in brain waste clearance, is known to be impaired in neurological disorders, including Alzheimer's disease (AD). For this reason, it is important to understand the specific mechanisms and factors controlling glymphatic function. This pathway enables the flow of cerebrospinal fluid (CSF) into the brain and subsequently the brain interstitium, supported by aquaporins (AQPs). Continuous CSF transport through the brain parenchyma is critical for the effective transport and drainage of waste solutes, such as toxic proteins, through the glymphatic system. However, a balance between CSF production and secretion from the choroid plexus, through AQP regulation, is also needed. Thus, any condition that affects CSF homeostasis will also interfere with effective waste removal through the clearance glymphatic pathway and the subsequent processes of neurodegeneration. In this review, we highlight the role of AQPs in the choroid plexus in the modulation of CSF homeostasis and, consequently, the glymphatic clearance pathway, with a special focus on AD.


Assuntos
Doença de Alzheimer , Aquaporinas , Sistema Glinfático , Humanos , Sistema Glinfático/metabolismo , Doença de Alzheimer/metabolismo , Plexo Corióideo/metabolismo , Encéfalo/metabolismo , Homeostase , Aquaporinas/metabolismo
18.
FASEB J ; 37(2): e22772, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36645117

RESUMO

Circadian disruption (CD) is the consequence of a mismatch between endogenous circadian rhythms and behavior, and frequently occurs in shift workers. CD has often been linked to impairment of glucose and lipid homeostasis. It is, however, unknown if these effects are sex dependent. Here, we subjected male and female C57BL/6J mice to 6-h light phase advancements every 3 days to induce CD and assessed glucose and lipid homeostasis. Within this model, we studied the involvement of gonadal sex hormones by injecting mice with gonadotropin-releasing hormone-antagonist degarelix. We demonstrate that CD has sex-specific effects on glucose homeostasis, as CD elevated fasting insulin levels in male mice while increasing fasting glucose levels in female mice, which appeared to be independent of behavior, food intake, and energy expenditure. Absence of gonadal sex hormones lowered plasma insulin levels in male mice subjected to CD while it delayed glucose clearance in female mice subjected to CD. CD elevated plasma triglyceride (TG) levels and delayed plasma clearance of TG-rich lipoproteins in both sexes, coinciding with reduced TG-derived FA uptake by adipose tissues. Absence of gonadal sex hormones did not notably alter the effects of CD on lipid metabolism. We conclude that CD causes sex-dependent effects on glucose metabolism, as aggravated by male gonadal sex hormones and partly rescued by female gonadal sex hormones. Future studies on CD should consider the inclusion of both sexes, which may eventually contribute to personalized advice for shift workers.


Assuntos
Hormônios Esteroides Gonadais , Insulinas , Camundongos , Masculino , Feminino , Animais , Camundongos Endogâmicos C57BL , Homeostase , Glucose/metabolismo , Ritmo Circadiano , Insulinas/farmacologia
19.
Sci Rep ; 13(1): 601, 2023 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-36635409

RESUMO

Linagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor used for the treatment of type 2 diabetes, with additional beneficial effects for the kidney. Treatment of mice with linagliptin revealed increased storage of cobalamin (Cbl, Vitamin B12) in organs if a standard Cbl diet (30 µg Cbl/kg chow) is given. In order to translate these findings to humans, we determined methylmalonic acid (MMA), a surrogate marker of functional Cbl homeostasis, in human plasma and urine samples (n = 1092) from baseline and end of trial (6 months after baseline) of the previously completed MARLINA-T2D clinical trial. We found that individuals with medium Cbl levels (MMA between 50 and 270 nmol/L for plasma, 0.4 and 3.5 µmol/mmol creatinine for urine, at baseline and end of trial) exhibited higher MMA values at the end of study in placebo compared with linagliptin. Linagliptin might inhibit the N-terminal degradation of the transcobalamin receptor CD320, which is necessary for uptake of Cbl into endothelial cells. Because we demonstrate that linagliptin led to increased organ levels of Cbl in mice, sustained constant medium MMA levels in humans, and inhibited CD320 processing by DPP-4 in-vitro, we speculate that linagliptin promotes intra-cellular uptake of Cbl by prolonging half-life of CD320.


Assuntos
Diabetes Mellitus Tipo 2 , Inibidores da Dipeptidil Peptidase IV , Humanos , Animais , Camundongos , Linagliptina/farmacologia , Linagliptina/uso terapêutico , Vitamina B 12/farmacologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Células Endoteliais , Inibidores da Dipeptidil Peptidase IV/farmacologia , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Hipoglicemiantes/uso terapêutico , Homeostase
20.
BMC Plant Biol ; 23(1): 20, 2023 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-36627574

RESUMO

Although the interaction between P and Zn has long been recognized in plants, the physiological and molecular mechanisms underlying P and Zn interactions are poorly understood. We show here that P supply decreases the Zn concentration in maize shoots and roots. Compared to +P + Zn (addition of both P and Zn), +P-Zn reduced and -P-Zn increased the total length of 1° lateral roots (LRs). Under +P + Zn, both P and Zn concentrations were lower in the sl1 mutant roots than in wild-type (WT) maize roots, and P accumulation did not reduce the Zn concentration in ll1 mutant roots. Transcriptome profiling showed that the auxin signaling pathway contributed to P-mediated Zn homeostasis in maize. Auxin production and distribution were altered by changes in P and Zn supply. Cytosolic Zn co-localized with auxin accumulation under +P + Zn. Exogenous application of 1-NAA and L-Kyn altered the P-mediated root system architecture (RSA) under Zn deficiency. -P-Zn repressed the expression of miR167. Overexpression of ZmMIR167b increased the lengths of 1° LRs and the concentrations of P and Zn in maize. These results indicate that auxin-dependent RSA is important for P-mediated Zn homeostasis in maize.HighlightAuxin-dependent RSA is important for P-mediated Zn homeostasis in maize.


Assuntos
Fósforo , Zea mays , Fósforo/metabolismo , Zea mays/metabolismo , Raízes de Plantas/metabolismo , Ácidos Indolacéticos/metabolismo , Homeostase , Zinco/metabolismo , Transdução de Sinais
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