RESUMEN
Vascular smooth muscle cell (VSMCs) is one of the important cell types in artery. VSMCs stiffening may regulate vascular stiffness and contribute to the development of vulnerable plaques. Thrombin, an enzyme in coagulation system, is involved in pathological processes of atherosclerosis. Inter-alpha-trypsin inhibitor heavy chain 4 (ITIH4) plays an important role in regulating inflammation and may have cardiovascular protective effect. Therefore, the elucidation of the mechanisms underlying ITIH4-mediated VSMCs stiffening helps to provide new ideas and potential targets for the diagnosis and treatment of atherosclerosis. In this study, we used specific ITIH4 expression vector and siRNA methods to transfect VSMCs. Our results found that ITIH4 expression increased VSMCs stiffness, meanwhile, ITIH4 siRNA decreased VSMCs stiffness. ITIH4 increased acetylated α-tubulin and inhibited ERK1/2 and JNK, but not P38 MAPK. ERK inhibitor (PD98059) or JNK inhibitor (SP600125) treatment increased acetylated α-tubulin expression and cell stiffness in VSMCs. ITIH4 was downregulated by thrombin treatment, ITIH4 partly reversed the effect of thrombin on acetylated α-tubulin and VSMCs stiffness. These results indicated that ITIH4 regulated acetylated α-tubulin expression in VSMCs and was against the effects of thrombin on VSMCs stiffness. JNK and ERK signaling pathways were proved to participate in this process.
Asunto(s)
Sistema de Señalización de MAP Quinasas , Músculo Liso Vascular , Trombina , Trombina/farmacología , Trombina/metabolismo , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/citología , Músculo Liso Vascular/efectos de los fármacos , Animales , Miocitos del Músculo Liso/metabolismo , Miocitos del Músculo Liso/efectos de los fármacos , Rigidez Vascular/efectos de los fármacos , Células Cultivadas , Ratas , Humanos , Ratas Sprague-Dawley , Hormonas Peptídicas/metabolismo , Hormonas Peptídicas/farmacología , Hormonas Peptídicas/genéticaRESUMEN
C-TERMINALLY ENCODED PEPTIDEs (CEPs) are a class of peptide hormones that have been shown in previous studies to play an important role in regulating the development and response to abiotic stress in model plants. However, their role in cotton is not well understood. In this study, we identified 54, 59, 34, and 35 CEP genes from Gossypium hirsutum (2n = 4x = 52, AD1), G. barbadense (AD2), G. arboreum (2n = 2X = 26, A2), and G. raimondii (2n = 2X = 26, D5), respectively. Sequence alignment and phylogenetic analyses indicate that cotton CEP proteins can be categorized into two subgroups based on the differentiation of their CEP domain. Chromosomal distribution and collinearity analyses show that most of the cotton CEP genes are situated in gene clusters, suggesting that segmental duplication may be a critical factor in CEP gene expansion. Expression pattern analyses showed that cotton CEP genes are widely expressed throughout the plant, with some genes exhibiting specific expression patterns. Ectopic expression of GhCEP46-D05 in Arabidopsis led to a significant reduction in both root length and seed size, resulting in a dwarf phenotype. Similarly, overexpression of GhCEP46-D05 in cotton resulted in reduced internode length and plant height. These findings provide a foundation for further investigation into the function of cotton CEP genes and their potential role in cotton breeding.
Asunto(s)
Regulación de la Expresión Génica de las Plantas , Gossypium , Familia de Multigenes , Filogenia , Proteínas de Plantas , Gossypium/genética , Gossypium/crecimiento & desarrollo , Gossypium/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Genoma de Planta , Cromosomas de las Plantas/genética , Arabidopsis/genética , Arabidopsis/crecimiento & desarrollo , Estudio de Asociación del Genoma Completo , Hormonas Peptídicas/genética , Hormonas Peptídicas/metabolismo , Desarrollo de la Planta/genética , Péptidos/genética , Péptidos/metabolismo , Mapeo Cromosómico , Genes de PlantasRESUMEN
C-terminally encoded peptides (CEPs) are peptide hormones that function as mobile signals coordinating crucial developmental programs in plants. Previous studies have revealed that CEPs exert negative regulation on root development through interaction with CEP receptors (CEPRs), CEP DOWNSTREAMs (CEPDs), the cytokinin receptor ARABIDOPSIS HISTIDINE KINASE (AHKs) and the transcriptional repressor Auxin/Indole-3-Acetic Acid (AUX/IAA). However, the precise molecular mechanisms underlying CEPs-mediated regulation of root development via auxin and cytokinin signaling pathways still necessitate further detailed investigation. In this study, we examined prior research and elucidated the underlying molecular mechanisms. The results showed that both synthetic AtCEPs and overexpression of AtCEP5 markedly supressed primary root elongation and lateral root (LR) formation in Arabidopsis. Molecular biology and genetics elucidated how CEPs inhibit root growth by suppressing auxin signaling while promoting cytokinin signaling. In summary, this study elucidated the inhibitory effects of AtCEPs on Arabidopsis root growth and provided insights into their potential molecular mechanisms, thus enhancing our comprehension of CEP-mediated regulation of plant growth and development.
Asunto(s)
Proteínas de Arabidopsis , Arabidopsis , Citocininas , Regulación de la Expresión Génica de las Plantas , Ácidos Indolacéticos , Raíces de Plantas , Transducción de Señal , Arabidopsis/crecimiento & desarrollo , Arabidopsis/metabolismo , Arabidopsis/genética , Citocininas/metabolismo , Ácidos Indolacéticos/metabolismo , Raíces de Plantas/crecimiento & desarrollo , Raíces de Plantas/metabolismo , Proteínas de Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Reguladores del Crecimiento de las Plantas/metabolismo , Hormonas Peptídicas/metabolismo , Hormonas Peptídicas/genéticaRESUMEN
Unlike other poultry, parent pigeons produce "pigeon milk" in their crops to nurture their squabs, which is mainly controlled by prolactin (PRL). Exception for PRL, the pituitary gland may also release various other peptide and protein hormones. However, whether these hormones change during pigeon crop lactation and their potential physiological functions remain unclear. Here, to identify potential peptide or protein hormone genes that regulate crop lactation, we conducted transcriptome analysis of pigeon pituitary glands at 3 different breeding stages (the ceased stage-nonincubation and non-nurturing stage, the 11th d of the incubation, and the 1st d of the nurturing stage) using RNA sequencing (RNA-Seq). Our analysis identified a total of 15,191 mRNAs and screened out 297 differentially expressed genes (DEG), including PRL, VIP, etc. The expression abundance of PRL mRNA on the 1st d of the nurturing stage was respectively 4.93 and 3.62 folds higher when compared to the ceased stage and the 11th d of the incubation stage. Additionally, the expression abundance of VIP is higher in the 1st d of the nurturing stage than in the ceased stage. Protein-protein interaction (PPI) network and Molecular Complex Detection (MCODE) analysis identified several vital DEGs (e.g., GHRHR, VIP, etc.), being closely linked with hormone and enriched in neuropeptide signaling pathway and response to the hormone. Expression pattern analysis revealed that these DEGs exhibited 4 distinct expression patterns (profile 10, 16, 18, 19). Genes in profile 10 and 19 presented a trend with the highest expression level on 1st d of the nurturing stage, and functional enrichment analysis indicated that these genes are involved in neuropeptide hormone activity, receptor-ligand activity, and the extracellular matrix, etc. Taken together, being consistent with PRL, some genes encoding peptide and protein hormones (e.g., VIP) presented differentially expressed in different breeding stages. It suggests that these hormones may be involved in regulation of the crop lactation process or corresponding behavior in domestic pigeons. The results of this study help to gain new insights into the role of pituitary gland in regulating pigeon lactation.
Asunto(s)
Columbidae , Perfilación de la Expresión Génica , Hipófisis , Animales , Columbidae/genética , Columbidae/fisiología , Columbidae/metabolismo , Hipófisis/metabolismo , Perfilación de la Expresión Génica/veterinaria , Femenino , Proteínas Aviares/genética , Proteínas Aviares/metabolismo , Hormonas Peptídicas/genética , Hormonas Peptídicas/metabolismo , Transcriptoma , Lactancia/genética , Prolactina/genética , Prolactina/metabolismoRESUMEN
The corpus luteum (CL) is a temporary endocrine gland that synthesizes progesterone. The luteal progesterone plays a central role in the regulation of the estrous cycle as well as the implantation and maintenance of pregnancy. Our previous study showed the expression of adropin and its receptor, GPR19, in the luteal cells and its significant role in luteinization. The aim of the present study was to investigate the in vitro effect of adropin on hCG-induced ovarian functions in adult mice. We also evaluated the effect of exogenous treatment with adropin on ovarian steroidogenesis and anti-oxidant parameters, with special emphasis on CL function. Our results demonstrated that adropin acts synergistically with hCG to promote ovarian steroidogenesis and survival by increasing the expression of StAR, 3ß-HSD, and aromatase proteins and decreasing the BAX/BCL2 ratio. Exogenous adropin treatment increased progesterone production by increasing the expression of GPR19, StAR and 3ß-HSD enzymes in the mouse ovary. Also, adropin inhibited the luteal oxidative stress by increasing nuclear translocation of NRF-2 in CL, which resulted in increased HO-1 expression and SOD, catalase activity. Decreased oxidative stress might inhibit the translocation of NF-κB into the nucleus of luteal cells, resulting into increased survival and decreased apoptosis, as evident by decreased lipid peroxidation, BAX/BCL2 ratio, caspase 3, active caspase 3 expression, and TUNEL-positive cells in adropin treated mice. Our findings suggest that adropin can be a promising candidate that can enhance the survivability of the CL.
Asunto(s)
Antioxidantes , Péptidos y Proteínas de Señalización Intercelular , Ovario , Animales , Femenino , Ratones , Antioxidantes/metabolismo , Antioxidantes/farmacología , Apoptosis/efectos de los fármacos , Cuerpo Lúteo/metabolismo , Cuerpo Lúteo/efectos de los fármacos , Ovario/metabolismo , Ovario/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Hormonas Peptídicas/metabolismo , Hormonas Peptídicas/genética , Progesterona/metabolismo , Progesterona/farmacología , Péptidos y Proteínas de Señalización Intercelular/administración & dosificaciónRESUMEN
BACKGROUND: Coronary artery disease (CAD) is the leading cause of death worldwide despite advanced treatment and diagnosis strategies. Angiopoietin-like protein 8 (ANGPTL8) mainly functions in the lipid mechanism, which is a dysregulated mechanism during CAD pathogenesis. In this study, we aimed to determine the associations between an ANGPTL8 polymorphism rs2278426 and the severity, presence, and risk factors of CAD. METHODS: A total of 1367 unrelated Turkish individuals who underwent coronary angiography were recruited for the study and grouped as CAD (n = 736, ≥50 stenosis) and non-CAD (n = 549, ≤30 stenosis). Also, subjects were further divided into groups regarding type 2 diabetes mellitus (T2DM) status. Subjects were genotyped for rs2278426 (C/T) by quantitative real-time PCR. Secondary structure analyses of protein interactions were revealed using I-TASSER and PyMOL. RESULTS: Among CAD patients, T allele carriage frequency was lower in the T2DM group (p = 0.046). Moreover, in male non-CAD group, T allele carriage was more prevalent among T2DM patients than non-T2DM (p = 0.033). In logistic regression analysis adjusted for obesity, T allele carrier males had an increased risk for T2DM in non-CAD group (OR = 2.244, 95 % CI: 1.057-4.761, p = 0.035). Also, in T2DM group, stenosis (p = 0.002) and SYNTAX score (p = 0.040) were lower in T allele carrier males than in non-carriers. Analyzes of secondary structure showed that ANGPTL8 could not directly form complexes with ANGPTL3 or ANGPTL4. CONCLUSION: In conclusion, T allele carriage of ANGPTL8 rs2278426 has a protective effect on CAD in T2DM patients. Further research should be conducted to explore the association between ANGPTL8 polymorphism (rs2778426) and CAD.
Asunto(s)
Alelos , Proteína 8 Similar a la Angiopoyetina , Proteínas Similares a la Angiopoyetina , Enfermedad de la Arteria Coronaria , Diabetes Mellitus Tipo 2 , Polimorfismo de Nucleótido Simple , Humanos , Masculino , Femenino , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/complicaciones , Persona de Mediana Edad , Enfermedad de la Arteria Coronaria/genética , Proteínas Similares a la Angiopoyetina/genética , Anciano , Hormonas Peptídicas/genética , Predisposición Genética a la Enfermedad , Turquía , Angiografía Coronaria , Frecuencia de los Genes , Factores de RiesgoRESUMEN
The mechanism of fish gonadal sex differentiation is complex and regulated by multiple factors. It has been widely known that proper steroidogenesis in Leydig cells and sex-related genes in Sertoli cells play important roles in gonadal sex differentiation. In teleosts, the precise interaction of these signals during the sexual fate determination remains elusive, especially their effect on the bi-potential gonad during the critical stage of sexual fate determination. Recently, all-testis phenotypes have been observed in the cyp17a1-deficient zebrafish and common carp, as well as in cyp19a1a-deficient zebrafish. By mating cyp17a1-deficient fish with transgenic zebrafish Tg(piwil1:EGFP-nanos3UTR), germ cells in the gonads were labelled with enhanced green fluorescent protein (EGFP). We classified the cyp17a1-deficient zebrafish and their control siblings into primordial germ cell (PGC)-rich and -less groups according to the fluorescence area of the EGFP labelling. Intriguingly, the EGFP-labelled bi-potential gonads in cyp17a1+/+ fish from the PGC-rich group were significantly larger than those of the cyp17a1-/- fish at 23 days post-fertilization (dpf). Based on the transcriptome analysis, we observed that the cyp17a1-deficient fish of the PGC-rich group displayed a significantly upregulated expression of amh and gsdf compared to that of control fish. Likewise, the upregulated expressions of amh and gsdf were observed in cyp19a1a-deficient fish as examined at 23 dpf. This upregulation of amh and gsdf could be repressed by treatment with an exogenous supplement of estradiol. Moreover, tamoxifen, an effective antagonist of both estrogen receptor α and ß (ERα and Erß), upregulates the expression of amh and gsdf in wild-type (WT) fish. Using the cyp17a1- and cyp19a1a-deficient zebrafish, we provide evidence to show that the upregulated expression of amh and gsdf due to the compromised estrogen signaling probably determines their sexual fate towards testis differentiation. Collectively, our data suggest that estrogen signaling inhibits the expression of amh and gsdf during the critical time of sexual fate determination, which may broaden the scope of sex steroid hormones in regulating gonadal sex differentiation in fish.
Asunto(s)
Hormonas Peptídicas , Procesos de Determinación del Sexo , Pez Cebra , Animales , Femenino , Masculino , Hormona Antimülleriana/genética , Hormona Antimülleriana/metabolismo , Estrógenos/metabolismo , Regulación del Desarrollo de la Expresión Génica , Gónadas/metabolismo , Ovario/metabolismo , Hormonas Peptídicas/genética , Testículo/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Pez Cebra/genética , Pez Cebra/crecimiento & desarrollo , Proteínas de Pez Cebra/genética , Proteínas de Pez Cebra/metabolismoRESUMEN
BACKGROUND: Angiopoietin-like protein 8 (ANGPTL8) is an important regulator of lipid metabolism. We aimed to investigate the difference of ANGPTL8 expression in different depots of adipose tissues between individuals with and without obesity, and its correlation with various metabolic parameters. METHODS: Subcutaneous (SAT) and visceral adipose tissue (VAT) samples were collected from patients who underwent bariatric or intra-abdominal surgery. Expression levels of ANGPTL8, monoglyceride lipase (MGL), monocyte chemoattractant protein-1 (MCP-1), leptin and adiponectin (APM1) were determined using real-time quantitative polymerase chain reaction. The correlation of ANGPTL8 expression with various metabolic parameters and other gene expression levels was analyzed using Person's correlation analysis. Logistic regression was used to establish a prediction model of obesity. RESULTS: Totally 330 subjects (obese: 281, non-obese: 49) were recruited. ANGPTL8 expression in VAT was significantly higher in the obesity group than in the non-obesity group (P = 0.0096). ANGPTL8 expression in VAT was positively correlated with body mass index (BMI) (r = 0.1169, P < 0.05) and was independently associated with obesity (O.R., 1.246; 95 % C.I. 1.013-21.533, P = 0.038). We also found the gene expression of ANGPTL8 in SAT and VAT was negatively correlated with APM1 expression in respective SAT and VAT. CONCLUSION: ANGPTL8 expression levels in VAT were higher in subjects with obesity, and positively correlated with BMI. This suggests a role of ANGPTL8 in the pathophysiology of obesity and may pave the way for novel treatment target of obesity.
Asunto(s)
Proteína 8 Similar a la Angiopoyetina , Proteínas Similares a la Angiopoyetina , Índice de Masa Corporal , Grasa Intraabdominal , Obesidad , Hormonas Peptídicas , Humanos , Grasa Intraabdominal/metabolismo , Masculino , Femenino , Proteínas Similares a la Angiopoyetina/genética , Proteínas Similares a la Angiopoyetina/metabolismo , Persona de Mediana Edad , Adulto , Obesidad/metabolismo , Obesidad/genética , Hormonas Peptídicas/genética , Hormonas Peptídicas/metabolismo , Modelos Logísticos , Adiponectina/genética , Adiponectina/metabolismo , Leptina/metabolismo , Leptina/genética , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Grasa Subcutánea/metabolismoRESUMEN
Hepcidin, a peptide hormone that negatively regulates iron metabolism, is expressed by bone morphogenetic protein (BMP) signaling. Erythroferrone (ERFE) is an extracellular protein that binds and inhibits BMP ligands, thus positively regulating iron import by indirectly suppressing hepcidin. This allows for rapid erythrocyte regeneration after blood loss. ERFE belongs to the C1Q/TNF-related protein family and is suggested to adopt multiple oligomeric forms: a trimer, a hexamer, and a high molecular weight species. The molecular basis for how ERFE binds BMP ligands and how the different oligomeric states impact BMP inhibition are poorly understood. In this study, we demonstrated that ERFE activity is dependent on the presence of stable dimeric or trimeric ERFE and that larger species are dispensable for BMP inhibition. Additionally, we used an in silico approach to identify a helix, termed the ligand-binding domain, that was predicted to bind BMPs and occlude the type I receptor pocket. We provide evidence that the ligand-binding domain is crucial for activity through luciferase assays and surface plasmon resonance analysis. Our findings provide new insight into how ERFE oligomerization impacts BMP inhibition, while identifying critical molecular features of ERFE essential for binding BMP ligands.
Asunto(s)
Proteínas Morfogenéticas Óseas , Hormonas Peptídicas , Proteínas Morfogenéticas Óseas/antagonistas & inhibidores , Proteínas Morfogenéticas Óseas/metabolismo , Ligandos , Transducción de Señal/efectos de los fármacos , Línea Celular , Hormonas Peptídicas/genética , Hormonas Peptídicas/aislamiento & purificación , Hormonas Peptídicas/farmacología , Multimerización de Proteína/genética , Mutación , Proteínas Recombinantes/genética , Proteínas Recombinantes/farmacología , Dominios Proteicos , HumanosRESUMEN
BACKGROUND: Angiopoietin-like protein 8 (ANGPTL8) is known to regulate lipid metabolism and inflammation. It interacts with ANGPTL3 and ANGPTL4 to regulate lipoprotein lipase (LPL) activity and with IKK to modulate NF-κB activity. Further, a single nucleotide polymorphism (SNP) leading to the ANGPTL8 R59W variant associates with reduced low-density lipoprotein/high-density lipoprotein (LDL/HDL) and increased fasting blood glucose (FBG) in Hispanic and Arab individuals, respectively. In this study, we investigate the impact of the R59W variant on the inflammatory activity of ANGPTL8. METHODS: The ANGPTL8 R59W variant was genotyped in a discovery cohort of 867 Arab individuals from Kuwait. Plasma levels of ANGPTL8 and inflammatory markers were measured and tested for associations with the genotype; the associations were tested for replication in an independent cohort of 278 Arab individuals. Impact of the ANGPTL8 R59W variant on NF-κB activity was examined using approaches including overexpression, luciferase assay, and structural modeling of binding dynamics. RESULTS: The ANGPTL8 R59W variant was associated with increased circulatory levels of tumor necrosis factor alpha (TNFα) and interleukin 7 (IL7). Our in vitro studies using HepG2 cells revealed an increased phosphorylation of key inflammatory proteins of the NF-κB pathway in individuals with the R59W variant as compared to those with the wild type, and TNFα stimulation further elevated it. This finding was substantiated by increased luciferase activity of NF-κB p65 with the R59W variant. Modeled structural and binding variation due to R59W change in ANGPTL8 agreed with the observed increase in NF-κB activity. CONCLUSION: ANGPTL8 R59W is associated with increased circulatory TNFα, IL7, and NF-κB p65 activity. Weak transient binding of the ANGPTL8 R59W variant explains its regulatory role on the NF-κB pathway and inflammation.
Asunto(s)
Proteína 8 Similar a la Angiopoyetina , Hormonas Peptídicas , Humanos , FN-kappa B/metabolismo , Factor de Necrosis Tumoral alfa , Proteínas Similares a la Angiopoyetina/genética , Proteínas Similares a la Angiopoyetina/metabolismo , Interleucina-7 , Inflamación/genética , Transducción de Señal , Luciferasas/metabolismo , Proteína 3 Similar a la Angiopoyetina , Hormonas Peptídicas/genética , Hormonas Peptídicas/metabolismoRESUMEN
Iron delivery to the plasma is closely coupled to erythropoiesis, the production of red blood cells, as this process consumes most of the circulating plasma iron. In response to hemorrhage and other erythropoietic stresses, increased erythropoietin stimulates the production of the hormone erythroferrone (ERFE) by erythrocyte precursors (erythroblasts) developing in erythropoietic tissues. ERFE acts on the liver to inhibit bone morphogenetic protein (BMP) signaling and thereby decrease hepcidin production. Decreased circulating hepcidin concentrations then allow the release of iron from stores and increase iron absorption from the diet. Guided by evolutionary analysis and Alphafold2 protein complex modeling, we used targeted ERFE mutations, deletions, and synthetic ERFE segments together with cell-based bioassays and surface plasmon resonance to probe the structural features required for bioactivity and BMP binding. We define the ERFE active domain and multiple structural features that act together to entrap BMP ligands. In particular, the hydrophobic helical segment 81 to 86 and specifically the highly conserved tryptophan W82 in the N-terminal region are essential for ERFE bioactivity and Alphafold2 modeling places W82 between two tryptophans in its ligands BMP2, BMP6, and the BMP2/6 heterodimer, an interaction similar to those that bind BMPs to their cognate receptors. Finally, we identify the cationic region 96-107 and the globular TNFα-like domain 186-354 as structural determinants of ERFE multimerization that increase the avidity of ERFE for BMP ligands. Collectively, our results provide further insight into the ERFE-mediated inhibition of BMP signaling in response to erythropoietic stress.
Asunto(s)
Hepcidinas , Hierro , Hormonas Peptídicas , Dominios Proteicos , Proteínas Morfogenéticas Óseas/metabolismo , Eritropoyesis , Hepcidinas/genética , Hepcidinas/metabolismo , Hierro/metabolismo , Hígado/metabolismo , Humanos , Línea Celular , Hormonas Peptídicas/química , Hormonas Peptídicas/genética , Hormonas Peptídicas/metabolismo , Secuencia de Aminoácidos , Estructura Terciaria de Proteína , Modelos Moleculares , Unión Proteica , Multimerización de Proteína , Estrés FisiológicoRESUMEN
Peptide hormones influence diverse aspects of plant development through highly coordinated cell-cell signaling pathways. Many peptide hormone families play key roles in stem cell maintenance across land plants. In this review, we focus on recent work in two conserved peptide hormone families, CLAVATA3/EMBRYO-SURROUNDING REGION (CLEs) and ROOT MERISTEM GROWTH FACTOR (RGFs), and their roles in regulating plant stem cells. We discuss recent work establishing downstream crosstalk between peptide hormones and other conserved signaling mechanisms in meristem maintenance as well as highlight advances in peptide hormone gene identification that provide important context for CLE/RGF family evolution across diverse plant lineages. CLE and RGF gene families have greatly expanded in angiosperms, contributing to the complex genetic regulation of stem cell homeostasis observed in model systems over the last 30 years. Peptide hormone duplications have resulted in genetic compensation mechanisms that ensure robust development through the function of paralogous genes. Broad conservation of genetic compensation across angiosperms highlights the importance of these mechanisms in developmental signaling and understanding their regulation could inform broader understanding of morphological diversity and evolutionary innovation.
Asunto(s)
Magnoliopsida , Hormonas Peptídicas , Hormonas Peptídicas/genética , Transducción de Señal/genética , Células Madre , Células Vegetales , Reguladores del Crecimiento de las Plantas , Tallos de la PlantaRESUMEN
Nonalcoholic fatty liver disease (NAFLD) is a prevalent chronic liver disease with a global prevalence, and modulation of ANGPTL8 expression has emerged as a promising predictor of NAFLD susceptibility. This research was conducted to scrutinize ANGPTL8 protein expression in NAFLD patients and elucidate the interplay between ANGPTL8 gene polymorphisms and their lipid profiles, thus shedding new light on the pathophysiology of this complex disease. The study comprised 423 unrelated participants, including 222 healthy controls and 201 individuals with NAFLD, screened using FibroScan/ultrasonography and laboratory tests. The main goal focused on the genotype and allele frequency distribution in the ANGPTL8 gene, specifically analyzing two genetic variations: rs737337 (T/C) and rs2278426 (C/T). The participants diagnosed with NAFLD were slightly younger (P ≥ 0.05) and had a higher body mass index (BMI) than the individuals in the control group. Notably, there was a significant difference in the occurrence of the rs737337 polymorphism between the NAFLD and control groups, with a lower frequency observed in the NAFLD group. Our results indicated that individuals with the TC + CC genotype and C allele of rs737337 (T/C) had a decreased risk of higher levels of ALT and AST. Conversely, those with the CT, CT + TT genotype, and T allele of rs2278426 (C/T) exhibited an increased risk of higher levels of ALT and AST. The results imply that the rs2278426 (C/T) variant of the ANGPTL8 gene is more strongly linked to an increased risk of NAFLD compared to the rs737337 polymorphism. However, additional research is needed to understand the specific molecular mechanisms responsible for the upregulation of ANGPTL8 in individuals with NAFLD.
Asunto(s)
Enfermedad del Hígado Graso no Alcohólico , Hormonas Peptídicas , Humanos , Adulto , Predisposición Genética a la Enfermedad , Enfermedad del Hígado Graso no Alcohólico/genética , Irán , Genotipo , Alelos , Proteína 8 Similar a la Angiopoyetina , Hormonas Peptídicas/genéticaRESUMEN
Asprosin, encoded by penultimate two exons (exon 65 and exon 66) of the gene Fibrillin 1 (FBN1), has been recently discovered to be a novel hormone secreted by white adipose tissues during fasting. The glucose metabolism disorders are often accompanied by increased asprosin level. Previous research suggests that asprosin may contribute to the development of diabetes by regulating glucose homeostasis, appetite, insulin secretion, and insulin sensitivity. In this review, we summarize the recent findings from studies on asprosin and its association with Type 2 diabetes mellitus, and discusses its mechanisms from various aspects, so as to provide clinical diagnosis and treatment ideas for T2DM.
Asunto(s)
Diabetes Mellitus Tipo 2 , Resistencia a la Insulina , Hormonas Peptídicas , Humanos , Adipoquinas , Hormonas Peptídicas/genética , Glucosa/metabolismoRESUMEN
Neuropeptides and peptide hormones are ancient, widespread signaling molecules that underpin almost all brain functions. They constitute a broad ligand-receptor network, mainly by binding to G protein-coupled receptors (GPCRs). However, the organization of the peptidergic network and roles of many peptides remain elusive, as our insight into peptide-receptor interactions is limited and many peptide GPCRs are still orphan receptors. Here we report a genome-wide peptide-GPCR interaction map in Caenorhabditis elegans. By reverse pharmacology screening of over 55,384 possible interactions, we identify 461 cognate peptide-GPCR couples that uncover a broad signaling network with specific and complex combinatorial interactions encoded across and within single peptidergic genes. These interactions provide insights into peptide functions and evolution. Combining our dataset with phylogenetic analysis supports peptide-receptor co-evolution and conservation of at least 14 bilaterian peptidergic systems in C. elegans. This resource lays a foundation for system-wide analysis of the peptidergic network.
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Neuropéptidos , Hormonas Peptídicas , Animales , Caenorhabditis elegans/metabolismo , Filogenia , Neuropéptidos/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Hormonas Peptídicas/genéticaRESUMEN
Apelin and Elabela (Ela) are peptides encoded by APLN and APELA, respectively, which act on their receptor APJ and play crucial roles in the body. Recent research has shown that they not only have important effects on the endocrine system, but also promote vascular development and maintain the homeostasis of myocardial cells. From a molecular biology perspective, we explored the roles of Ela and apelin in the cardiovascular system and summarized the mechanisms of apelin-APJ signaling in the progression of myocardial infarction, ischemia-reperfusion injury, atherosclerosis, pulmonary arterial hypertension, preeclampsia, and congenital heart disease. Evidences indicated that apelin and Ela play important roles in cardiovascular diseases, and there are many studies focused on developing apelin, Ela, and their analogues for clinical treatments. However, the literature on the therapeutic potential of apelin, Ela and their analogues and other APJ agonists in the cardiovascular system is still limited. This review summarized the regulatory pathways of apelin/ELA-APJ axis in cardiovascular function and cardiovascular-related diseases, and the therapeutic effects of their analogues in cardiovascular diseases were also included.
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Enfermedades Cardiovasculares , Sistema Cardiovascular , Femenino , Humanos , Embarazo , Apelina/genética , Apelina/metabolismo , Receptores de Apelina/genética , Receptores de Apelina/metabolismo , Enfermedades Cardiovasculares/tratamiento farmacológico , Enfermedades Cardiovasculares/genética , Enfermedades Cardiovasculares/metabolismo , Sistema Cardiovascular/metabolismo , Hormonas Peptídicas/genética , Hormonas Peptídicas/metabolismo , Hormonas Peptídicas/farmacología , Hormonas Peptídicas/uso terapéutico , Transducción de SeñalRESUMEN
Angiopoietin-like proteins (ANGPTL) constitute a family of eight proteins (1-8) which play a pivotal role in the regulation of various pathophysiological processes. The current study sought to identify high-risk, "non-synonymous, single-nucleotide polymorphisms" (nsSNPs) in both ANGPTL3 and ANGPTL8 to evaluate the role that these nsSNPs play in various types of cancer. We retrieved a total of 301 nsSNPs from various databases; 79 of these candidates constitute high-risk nsSNPs. Moreover, we identified eleven high-risk nsSNPs that cause various types of cancer: seven candidates for ANGPTL3 (L57H, F295L, L309F, K329M, R332L, S348C, and G409R) and four candidates for ANGPTL8 (P23L, R85W, R138S, and E148D). Protein-protein interaction analysis revealed a strong association of ANGPTL proteins with several tumor-suppressor proteins such as ITGB3, ITGAV, and RASSF5. 'Gene-expression profiling interactive analysis' (GEPIA) showed that expression of ANGPTL3 is significantly downregulated in five cancers: sarcoma (SARC); cholangio carcinoma (CHOL); kidney chromophobe carcinoma (KICH); kidney renal clear cell carcinoma (KIRC); and kidney renal papillary cell carcinoma (KIRP). GEPIA also showed that expression of ANGPTL8 remains downregulated in three cancers: CHOL; glioblastoma (GBM); and breast invasive carcinoma (BRCA). Survival rate analysis indicated that both upregulation and downregulation of ANGPTL3 and ANGPTL8 leads to low survival rates in various types of cancer. Overall, the current study revealed that both ANGPTL3 and ANGPTL8 constitute potential prognostic biomarkers for cancer; moreover, nsSNPs in these proteins might lead to the progression of cancer. However, further in vivo investigation will be helpful to validate the role of these proteins in the biology of cancer.
Asunto(s)
Neoplasias de la Mama , Carcinoma de Células Renales , Carcinoma , Neoplasias Renales , Hormonas Peptídicas , Humanos , Femenino , Proteínas Similares a la Angiopoyetina/genética , Polimorfismo de Nucleótido Simple , Proteína 3 Similar a la Angiopoyetina , Proteína 8 Similar a la Angiopoyetina , Carcinoma de Células Renales/genética , Hormonas Peptídicas/genéticaRESUMEN
Rationale: Ischemia-reperfusion injury (I/R) is a common cause of acute kidney injury (AKI). Post-ischemic recovery of renal blood supply plays an important role in attenuating injury. Exogenous application of elabela (ELA) peptides has been demonstrated by us and others to alleviate AKI, partly through its receptor APJ. However, the endogenous role of ELA in renal I/R remains unclear. Methods: Renal tubule specific ELA knockout (ApelaKsp KO) mice challenged with bilateral or unilateral I/R were used to investigate the role of endogenous ELA in renal I/R. RNA-sequencing analysis was performed to unbiasedly investigate altered genes in kidneys of ApelaKsp KO mice. Injured mice were treated with ELA32 peptide, Nω-hydroxy-nor-L-arginine (nor-NOHA), prostaglandin E2 (PGE2), Paricalcitol, ML221 or respective vehicles, individually or in combination. Results: ELA is mostly expressed in renal tubules. Aggravated pathological injury and further reduction of renal microvascular blood flow were observed in ApelaKsp KO mice during AKI and the following transition to chronic kidney disease (AKI-CKD). RNA-seq analysis suggested that two blood flow regulators, arginine metabolizing enzyme arginase 2 (ARG2) and PGE2 metabolizing enzyme carbonyl reductases 1 and 3 (CBR1/3), were altered in injured ApelaKsp KO mice. Notably, combination application of an ARG2 inhibitor nor-NOHA, and Paricalcitol, a clinically used activator for PGE2 synthesis, alleviated injury-induced AKI/AKI-CKD stages and eliminated the worst outcomes observed in ApelaKsp KO mice. Moreover, while the APJ inhibitor ML221 blocked the beneficial effects of ELA32 peptide on AKI, it showed no effect on combination treatment of nor-NOHA and Paricalcitol. Conclusions: An endogenous tubular ELA-APJ axis regulates renal microvascular blood flow that plays a pivotal role in I/R-induced AKI. Furthermore, improving renal blood flow by inhibiting ARG2 and activating PGE2 is an effective treatment for AKI and prevents the subsequent AKI-CKD transition.
Asunto(s)
Lesión Renal Aguda , Hormonas Peptídicas , Insuficiencia Renal Crónica , Daño por Reperfusión , Ratones , Animales , Microcirculación , Dinoprostona/farmacología , Riñón/patología , Lesión Renal Aguda/patología , Insuficiencia Renal Crónica/etiología , Daño por Reperfusión/patología , Isquemia/patología , Hormonas Peptídicas/efectos adversos , Hormonas Peptídicas/genética , Reperfusión/efectos adversosRESUMEN
Angiopoietin-like protein 8 (ANGPTL8) plays important roles in lipid metabolism, glucose metabolism, inflammation, and cell proliferation and migration. Clinical studies have indicated that circulating ANGPTL8 levels are increased in patients with thoracic aortic dissection (TAD). TAD shares several risk factors with abdominal aortic aneurysm (AAA). However, the role of ANGPTL8 in AAA pathogenesis has never been investigated. Here, we investigated the effect of ANGPTL8 knockout on AAA in ApoE-/- mice. ApoE-/-ANGPTL8-/- mice were generated by crossing ANGPTL8-/- and ApoE-/- mice. AAA was induced in ApoE-/- using perfusion of angiotensin II (AngII). ANGPTL8 was significantly up-regulated in AAA tissues of human and experimental mice. Knockout of ANGPTL8 significantly reduced AngII-induced AAA formation, elastin breaks, aortic inflammatory cytokines, matrix metalloproteinase expression, and smooth muscle cell apoptosis in ApoE-/- mice. Similarly, ANGPTL8 sh-RNA significantly reduced AngII-induced AAA formation in ApoE-/- mice. ANGPTL8 deficiency inhibited AAA formation, and ANGPTL8 may therefore be a potential therapeutic target for AAA.
Asunto(s)
Aneurisma de la Aorta Abdominal , Hormonas Peptídicas , Humanos , Ratones , Animales , Proteína 8 Similar a la Angiopoyetina , Ratones Noqueados para ApoE , Aneurisma de la Aorta Abdominal/inducido químicamente , Aneurisma de la Aorta Abdominal/genética , Aneurisma de la Aorta Abdominal/prevención & control , Aorta/patología , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Angiotensina II/metabolismo , Ratones Noqueados , Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , Aorta Abdominal/patología , Hormonas Peptídicas/genética , Hormonas Peptídicas/efectos adversos , Hormonas Peptídicas/metabolismoRESUMEN
OBJECTIVES: The present study sought to examine the relationship of betatrophin with certain key enzymes, namely lactate dehydrogenase-5 (LDH5), citrate synthase (CS), and acetyl-CoA carboxylase-1 (ACC1), in insulin-resistant mice. METHODS: Eight-week-old male C57BL6/J mice were used in this study (experimental group n=10 and control group n=10). S961 was administered using an osmotic pump to induce insulin resistance in the mice. The betatrophin, LDH5, CS, and ACC1 expression levels were determined from the livers of the mice using the real-time polymerase chain reaction (RT-PCR) method. Moreover, biochemical parameters such as the serum betatrophin, fasting glucose, insulin, triglyceride, total cholesterol, and high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol levels were analyzed. RESULTS: The betatrophin expression and serum betatrophin (p=0.000), fasting glucose, insulin, triglyceride (p≤0.001), and total cholesterol (p=0.013) levels were increased in the experimental group. In addition, the CS gene expression level was statistically significantly decreased in the experimental group (p=0.01). Although strong correlation was found between the expression and serum betatrophin and triglyceride levels, no correlation was found between the betatrophin gene expression and the LDH5, ACC1, and CS gene expression levels. CONCLUSIONS: The betatrophin level appears to play an important role in the regulation of triglyceride metabolism, while insulin resistance increases both the betatrophin gene expression and serum levels and decreases the CS expression level. The findings suggest that betatrophin may not regulate carbohydrate metabolism through CS and LDH5 or lipid metabolism directly through the ACC1 enzyme.