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1.
Proc Natl Acad Sci U S A ; 121(4): e2309006120, 2024 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-38190516

RESUMO

Improving water use efficiency in crops is a significant challenge as it involves balancing water transpiration and CO2 uptake through stomatal pores. This study investigates the role of SlROP9, a tomato Rho of Plants protein, in guard cells and its impact on plant transpiration. The results reveal that SlROP9 null mutants exhibit reduced stomatal conductance while photosynthetic CO2 assimilation remains largely unaffected. Notably, there is a notable decrease in whole-plant transpiration in the rop9 mutants compared to the wild type, especially during noon hours when the water pressure deficit is high. The elevated stomatal closure observed in rop9 mutants is linked to an increase in reactive oxygen species formation. This is very likely dependent on the respiratory burst oxidase homolog (RBOH) NADPH oxidase and is not influenced by abscisic acid (ABA). Consistently, activated ROP9 can interact with RBOHB in both yeast and plants. In diverse tomato accessions, drought stress represses ROP9 expression, and in Arabidopsis stomatal guard cells, ABA suppresses ROP signaling. Therefore, the phenotype of the rop9 mutants may arise from a disruption in ROP9-regulated RBOH activity. Remarkably, large-scale field experiments demonstrate that the rop9 mutants display improved water use efficiency without compromising fruit yield. These findings provide insights into the role of ROPs in guard cells and their potential as targets for enhancing water use efficiency in crops.


Assuntos
Arabidopsis , Solanum lycopersicum , Solanum lycopersicum/genética , Produtos Agrícolas , Proteínas de Plantas/genética , Ácido Abscísico , Arabidopsis/genética
2.
Hum Mol Genet ; 33(15): 1328-1338, 2024 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-38692286

RESUMO

Syntaxin-binding protein 1 (STXBP1) is a presynaptic protein that plays important roles in synaptic vesicle docking and fusion. STXBP1 haploinsufficiency causes STXBP1 encephalopathy (STXBP1-E), which encompasses neurological disturbances including epilepsy, neurodevelopmental disorders, and movement disorders. Most patients with STXBP1-E present with regression and movement disorders in adulthood, highlighting the importance of a deeper understanding of the neurodegenerative aspects of STXBP1-E. An in vitro study proposed an interesting new role of STXBP1 as a molecular chaperone for α-Synuclein (αSyn), a key molecule in the pathogenesis of neurodegenerative disorders. However, no studies have shown αSyn pathology in model organisms or patients with STXBP1-E. In this study, we used Drosophila models to examine the effects of STXBP1 haploinsufficiency on αSyn-induced neurotoxicity in vivo. We demonstrated that haploinsufficiency of Ras opposite (Rop), the Drosophila ortholog of STXBP1, exacerbates compound eye degeneration, locomotor dysfunction, and dopaminergic neurodegeneration in αSyn-expressing flies. This phenotypic aggravation was associated with a significant increase in detergent-insoluble αSyn levels in the head. Furthermore, we tested whether trehalose, which has neuroprotective effects in various models of neurodegenerative disorders, mitigates αSyn-induced neurotoxicity exacerbated by Rop haploinsufficiency. In flies expressing αSyn and carrying a heterozygous Rop null variant, trehalose supplementation effectively alleviates neuronal phenotypes, accompanied by a decrease in detergent-insoluble αSyn in the head. In conclusion, this study revealed that Rop haploinsufficiency exacerbates αSyn-induced neurotoxicity by altering the αSyn aggregation propensity. This study not only contributes to understanding the mechanisms of neurodegeneration in STXBP1-E patients, but also provides new insights into the pathogenesis of α-synucleinopathies.


Assuntos
Modelos Animais de Doenças , Proteínas de Drosophila , Drosophila melanogaster , Haploinsuficiência , Proteínas Munc18 , alfa-Sinucleína , Animais , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismo , Haploinsuficiência/genética , Drosophila melanogaster/genética , Proteínas Munc18/genética , Proteínas Munc18/metabolismo , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Humanos , Sinucleinopatias/genética , Sinucleinopatias/patologia , Sinucleinopatias/metabolismo , Trealose/metabolismo , Encefalopatias/genética , Encefalopatias/patologia , Encefalopatias/metabolismo , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/patologia
3.
Development ; 149(22)2022 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-36314989

RESUMO

Rho of plant (ROP) proteins and the interactor of constitutively active ROP (ICR) family member ICR5/MIDD1 have been implicated to function as signaling modules that regulate metaxylem secondary cell wall patterning. Yet, loss-of-function mutants of ICR5 and its closest homologs have not been studied and, hence, the functions of these ICR family members are not fully established. Here, we studied the functions of ICR2 and its homolog ICR5. We show that ICR2 is a microtubule-associated protein that affects microtubule dynamics. Secondary cell wall pits in the metaxylem of Arabidopsis icr2 and icr5 single mutants and icr2 icr5 double mutants are smaller than those in wild-type Col-0 seedlings; however, they are remarkably denser, implying a complex function of ICRs in secondary cell wall patterning. ICR5 has a unique function in protoxylem secondary cell wall patterning, whereas icr2, but not icr5, mutants develop split root hairs, demonstrating functional diversification. Taken together, our results show that ICR2 and ICR5 have unique and cooperative functions as microtubule-associated proteins and as ROP effectors.


Assuntos
Proteínas de Arabidopsis , Arabidopsis , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Proteínas rho de Ligação ao GTP/metabolismo , Arabidopsis/metabolismo , Parede Celular/metabolismo , Microtúbulos/metabolismo , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Proteínas de Plantas/metabolismo
4.
Development ; 149(12)2022 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-35660859

RESUMO

A complete picture of how signaling pathways lead to multicellularity is largely unknown. Previously, we generated mutations in a protein prenylation enzyme, GGB, and showed that it is essential for maintaining multicellularity in the moss Physcomitrium patens. Here, we show that ROP GTPases act as downstream factors that are prenylated by GGB and themselves play an important role in the multicellularity of P. patens. We also show that the loss of multicellularity caused by the suppression of GGB or ROP GTPases is due to uncoordinated cell expansion, defects in cell wall integrity and the disturbance of the directional control of cell plate orientation. Expressing prenylatable ROP in the ggb mutant not only rescues multicellularity in protonemata but also results in development of gametophores. Although the prenylation of ROP is important for multicellularity, a higher threshold of active ROP is required for gametophore development. Thus, our results suggest that ROP activation via prenylation by GGB is a key process at both cell and tissue levels, facilitating the developmental transition from one dimension to two dimensions and to three dimensions in P. patens.


Assuntos
Bryopsida , GTP Fosfo-Hidrolases , Bryopsida/metabolismo , Parede Celular/metabolismo , GTP Fosfo-Hidrolases/metabolismo , Prenilação , Transdução de Sinais
5.
Proc Natl Acad Sci U S A ; 119(47): e2117803119, 2022 11 22.
Artigo em Inglês | MEDLINE | ID: mdl-36375069

RESUMO

The formation of cell polarity is essential for many developmental processes such as polar cell growth and spatial patterning of cell division. A plant-specific ROP (Rho-like GTPases from Plants) subfamily of conserved Rho GTPase plays a crucial role in the regulation of cell polarity. However, the functional study of ROPs in angiosperm is challenging because of their functional redundancy. The Marchantia polymorpha genome encodes a single ROP gene, MpROP, providing an excellent genetic system to study ROP-dependent signaling pathways. Mprop knockout mutants exhibited rhizoid growth defects, and MpROP was localized at the tip of elongating rhizoids, establishing a role for MpROP in the control of polar cell growth and its functional conservation in plants. Furthermore, the Mprop knockout mutant showed defects in the formation of meristem notches associated with disorganized cell division patterns. These results reveal a critical function of MpROP in the regulation of plant development. Interestingly, these phenotypes were complemented not only by MpROP but also Arabidopsis AtROP2, supporting the conservation of ROP's function among land plants. Our results demonstrate a great potential for M. polymorpha as a powerful genetic system for functional and mechanistic elucidation of ROP signaling pathways during plant development.


Assuntos
Proteínas de Arabidopsis , Arabidopsis , Marchantia , Meristema/genética , Meristema/metabolismo , Arabidopsis/metabolismo , Marchantia/genética , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Divisão Celular/genética , Plantas/metabolismo
6.
Plant J ; 116(3): 756-772, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37516999

RESUMO

Cell differentiation and morphogenesis are crucial for the establishment of diverse cell types and organs in multicellular organisms. Trichome cells offer an excellent paradigm for dissecting the regulatory mechanisms of plant cell differentiation and morphogenesis due to their unique growth characteristics. Here, we report the isolation of an Arabidopsis mutant, aberrantly branched trichome 3-1 (abt3-1), with a reduced trichome branching phenotype. Positional cloning and molecular complementation experiments confirmed that abt3-1 is a new mutant allele of Auxin resistant 1 (AXR1), which encodes the N-terminal half of ubiquitin-activating enzyme E1 and functions in auxin signaling pathway. Meanwhile, we found that transgenic plants expressing constitutively active version of ROP2 (CA-ROP2) caused a reduction of trichome branches, resembling that of abt3-1. ROP2 is a member of Rho GTPase of plants (ROP) family, serving as versatile signaling switches involved in a range of cellular and developmental processes. Our genetic and biochemical analyses showed AXR1 genetically interacted with ROP2 and mediated ROP2 protein stability. The loss of AXR1 aggravated the trichome defects of CA-ROP2 and induced the accumulation of steady-state ROP2. Consistently, elevated AXR1 expression levels suppressed ROP2 expression and partially rescued trichome branching defects in CA-ROP2 plants. Together, our results presented a new mutant allele of AXR1, uncovered the effects of AXR1 and ROP2 during trichome development, and revealed a pathway of ROP2-mediated regulation of plant cell morphogenesis in Arabidopsis.


Assuntos
Proteínas de Arabidopsis , Arabidopsis , Proteínas de Arabidopsis/metabolismo , Tricomas/genética , Tricomas/metabolismo , Ácidos Indolacéticos , Alelos , Diferenciação Celular , Morfogênese/genética , Plantas Geneticamente Modificadas/genética , Mutação , Proteínas de Ligação ao GTP/genética , Proteínas de Ligação ao GTP/metabolismo
7.
Plant J ; 114(5): 1132-1148, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-36994639

RESUMO

Quiescence is a crucial survival attribute in which cell division is repressed in a reversible manner. Although quiescence has long been viewed as an inactive state, recent studies have shown that it is an actively monitored process that is influenced by environmental stimuli. Here, we provide a perspective of the quiescent state and discuss how this process is tuned by energy, nutrient and oxygen status, and the pathways that sense and transmit these signals. We not only highlight the governance of canonical regulators and signalling mechanisms that respond to changes in nutrient and energy status, but also consider the central significance of mitochondrial functions and cues as key regulators of nuclear gene expression. Furthermore, we discuss how reactive oxygen species and the associated redox processes, which are intrinsically linked to energy carbohydrate metabolism, also play a key role in the orchestration of quiescence.


Assuntos
Plantas , Transdução de Sinais , Plantas/genética , Plantas/metabolismo , Divisão Celular , Metabolismo dos Carboidratos
8.
New Phytol ; 241(6): 2523-2539, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38214469

RESUMO

The transcriptional regulation of Rho-related GTPase from plants (ROPs), which determine cell polarity formation and maintenance during plant development, still remains enigmatic. In this study, we elucidated the epigenetic mechanism of histone deacetylase HDA6 in transcriptional repression of ROP6 and its impact on cell polarity and morphogenesis in Arabidopsis leaf epidermal pavement cells (PCs). We found that the hda6 mutant axe1-4 exhibited impaired jigsaw-shaped PCs and convoluted leaves. This correlated with disruptions in the spatial organizations of cortical microtubules and filamentous actin, which is integral to PC indentation and lobe formation. Further transcriptional analyses and chromatin immunoprecipitation assay revealed that HDA6 specifically represses ROP6 expression through histone H3K9K14 deacetylation. Importantly, overexpression of dominant negative-rop6 in axe1-4 restored interdigitated cell morphology. Our study unveils HDA6 as a key regulator in Arabidopsis PC morphogenesis through epigenetic suppression of ROP6. It reveals the pivotal role of HDA6 in the transcriptional regulation of ROP6 and provides compelling evidence for the functional interplay between histone deacetylation and ROP6-mediated cytoskeletal arrangement in the development of interdigitated PCs.


Assuntos
Proteínas de Arabidopsis , Arabidopsis , Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Epigênese Genética , GTP Fosfo-Hidrolases/metabolismo , Histona Desacetilases/genética , Histona Desacetilases/metabolismo , Histonas/metabolismo , Morfogênese
9.
J Exp Bot ; 75(5): 1274-1288, 2024 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-37962515

RESUMO

ROPs (Rho of Plants) are plant specific small GTPases involved in many membrane patterning processes and play important roles in the establishment and communication of cell polarity. These small GTPases can produce a wide variety of patterns, ranging from a single cluster in tip-growing root hairs and pollen tubes to an oriented stripe pattern controlling protoxylem cell wall deposition. For an understanding of what controls these various patterns, models are indispensable. Consequently, many modelling studies on small GTPase patterning exist, often focusing on yeast or animal cells. Multiple patterns occurring in plants, however, require the stable co-existence of multiple active ROP clusters, which does not occur with the most common yeast/animal models. The possibility of such patterns critically depends on the precise model formulation. Additionally, different small GTPases are usually treated interchangeably in models, even though plants possess two types of ROPs with distinct molecular properties, one of which is unique to plants. Furthermore, the shape and even the type of ROP patterns may be affected by the cortical cytoskeleton, and cortex composition and anisotropy differ dramatically between plants and animals. Here, we review insights into ROP patterning from modelling efforts across kingdoms, as well as some outstanding questions arising from these models and recent experimental findings.


Assuntos
Proteínas Monoméricas de Ligação ao GTP , Saccharomyces cerevisiae , Animais , Plantas/genética , Modelos Teóricos
10.
J Exp Bot ; 75(12): 3685-3699, 2024 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-38683617

RESUMO

Every cell constantly receives signals from its neighbours or the environment. In plants, most signals are perceived by RECEPTOR-LIKE KINASEs (RLKs) and then transmitted into the cell. The molecular switches RHO OF PLANTS (ROP) are critical proteins for polar signal transduction and regulate multiple cell polarity processes downstream of RLKs. Many ROP-regulating proteins and scaffold proteins of the ROP complex are known. However, the spatiotemporal ROP signalling complex composition is not yet understood. Moreover, how specificity is achieved in different ROP signalling pathways within one cell still needs to be determined. This review gives an overview of recent advances in ROP signalling and how specificity by downstream scaffold proteins can be achieved. The composition of the ROP signalling complexes is discussed, focusing on the possibility of the simultaneous presence of ROP activators and inactivators within the same complex to balance ROP activity. Furthermore, this review highlights the function of plant-specific ROP GUANINE NUCLEOTIDE EXCHANGE FACTORS polarizing ROP signalling and defining the specificity of the initiated ROP signalling pathway.


Assuntos
Fatores de Troca do Nucleotídeo Guanina , Proteínas de Plantas , Plantas , Transdução de Sinais , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Proteínas de Plantas/metabolismo , Proteínas de Plantas/genética , Plantas/metabolismo
11.
Exp Eye Res ; 239: 109773, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38171476

RESUMO

The retinopathy of prematurity (ROP) can cause serious clinical consequences and, fortunately, it is remediable while the time window for treatment is relatively narrow. Therefore, it is urgent to screen all premature infants and diagnose ROP degree timely, which has become a large workload for pediatric ophthalmologists. We developed a retinal image-free procedure using small amount of blood samples based on the plasma Raman spectrum with the machine learning model to automatically classify ROP cases before medical intervention was performed. Statistical differences in infrared Raman spectra of plasma samples were found among the control, mild (ZIIIS1), moderate (ZIIIS2 & ZIIS1), and advanced (ZIIS2) ROP groups. With the different wave points of Raman spectra as the inputs, the outputs of our support vector machine showed that the area under the curves in the receiver operating characteristic (AUC) were 0.763 for the pair comparisons of the control with the mild groups, 0.821 between moderate and advanced groups (ZIIS2), while more than 90% in comparisons of the other four pairs: control vs. moderate (0.981), control vs. advanced (0.963), mild vs. moderate (0.936), and mild vs. advanced (0.953), respectively. Our study could advance principally the ROP diagnosis in two dimensions: the moderate ROPs have been classified remarkably from the mild ones, which leaves more time for the medical treatments, and the procedure of Raman spectrum with a machine learning model based on blood samples can be conveniently promoted to those hospitals lacking of the pediatric ophthalmologists with experience in reading retinal images.


Assuntos
Retinopatia da Prematuridade , Telemedicina , Recém-Nascido , Lactente , Humanos , Criança , Retinopatia da Prematuridade/diagnóstico , Retinopatia da Prematuridade/terapia , Sensibilidade e Especificidade , Telemedicina/métodos , Algoritmos , Aprendizado de Máquina , Idade Gestacional
12.
Ann Hematol ; 103(7): 2299-2310, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38438627

RESUMO

Interferon-based therapies, such as ropeginterferon alfa-2b have emerged as promising disease-modifying agents for myeloproliferative neoplasms (MPNs), including essential thrombocythemia (ET). Current ET treatments aim to normalize hematological parameters and reduce the thrombotic risk, but they do not modify the natural history of the disease and hence, have no impact on disease progression. Ropeginterferon alfa-2b (trade name BESREMi®), a novel, monopegylated interferon alfa-2b with an extended administration interval, has demonstrated a robust and sustained efficacy in polycythemia vera (PV) patients. Given the similarities in disease pathophysiology and treatment goals, ropeginterferon alfa-2b holds promise as a treatment option for ET. The ROP-ET trial is a prospective, multicenter, single-arm phase III study that includes patients with ET who are intolerant or resistant to, and/or are ineligible for current therapies, such as hydroxyurea (HU), anagrelide (ANA), busulfan (BUS) and pipobroman, leaving these patients with limited treatment options. The primary endpoint is a composite response of hematologic parameters and disease-related symptoms, according to modified European LeukemiaNet (ELN) criteria. Secondary endpoints include improvements in symptoms and quality of life, molecular response and the safety profile of ropeginterferon alfa-2b. Over a 3-year period the trial assesses longer term outcomes, particularly the effects on allele burden and clinical outcomes, such as disease-related symptoms, vascular events and disease progression. No prospective clinical trial data exist for ropeginterferon alfa-2b in the planned ET study population and this study will provide new findings that may contribute to advancing the treatment landscape for ET patients with limited alternatives. TRIAL REGISTRATION: EU Clinical Trials Register; EudraCT, 2023-505160-12-00; Registered on October 30, 2023.


Assuntos
Interferon alfa-2 , Interferon-alfa , Polietilenoglicóis , Proteínas Recombinantes , Trombocitemia Essencial , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Interferon alfa-2/uso terapêutico , Interferon alfa-2/efeitos adversos , Interferon-alfa/uso terapêutico , Interferon-alfa/efeitos adversos , Polietilenoglicóis/uso terapêutico , Polietilenoglicóis/efeitos adversos , Polietilenoglicóis/administração & dosagem , Estudos Prospectivos , Proteínas Recombinantes/uso terapêutico , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/administração & dosagem , Trombocitemia Essencial/tratamento farmacológico , Resultado do Tratamento , Estudos Multicêntricos como Assunto , Ensaios Clínicos Fase III como Assunto
13.
Parasite Immunol ; 46(2): e13023, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38372452

RESUMO

Toxoplasmosis is one of the most dangerous zoonotic diseases, causing serious economic losses worldwide due to abortion and reproductive problems. Vaccination is the best way to prevent disease; thus, it is imperative to develop a candidate vaccine for toxoplasmosis. BAG1 and ROP8 have the potential to become vaccine candidates. In this study, rTgBAG1, rTgROP8, and rTgBAG1-rTgROP8 were used to evaluate the immune effect of vaccines in each group by detecting the humoral and cellular immune response levels of BABL/c mice after immunization and the ability to resist acute and chronic infection with Toxoplasma gondii (T. gondii). We divided the mice into vaccine groups with different proteins, and the mice were immunized on days 0, 14, and 28. The protective effects of different proteins against T. gondii were analysed by measuring the cytokines, serum antibodies, splenocyte proliferation assay results, survival time, and number and diameter of brain cysts of mice after infection. The vaccine groups exhibited substantially higher IgG, IgG1, and IgG2a levels and effectively stimulated lymphocyte proliferation. The levels of IFN-γ and IL-2 in the vaccine group were significantly increased. The survival time of the mice in each vaccine group was prolonged and the diameter of the cysts in the vaccine group was smaller; rTgBAG1-rTgROP8 had a better protection. Our study showed that the rTgBAG1, rTgROP8, and rTgBAG1-rTgROP8 recombinant protein vaccines are partial but effective approaches against acute or chronic T. gondii infection. They are potential candidates for a toxoplasmosis vaccine.


Assuntos
Vacinas Protozoárias , Toxoplasmose , Animais , Camundongos , Anticorpos Antiprotozoários , Antígenos de Protozoários/genética , Imunidade Celular , Imunização , Imunoglobulina G , Camundongos Endogâmicos BALB C , Proteínas de Protozoários , Vacinas Protozoárias/imunologia , Proteínas Recombinantes/genética , Toxoplasma , Toxoplasmose/prevenção & controle , Vacinação
14.
Macromol Rapid Commun ; 45(14): e2400091, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38690992

RESUMO

Within bioplastics, natural poly(3-hydroxybutyrate) (PHB) stands out as fully biocompatible and biodegradable, even in marine environments; however, its high isotacticity and crystallinity limits its mechanical properties and hence its applications. PHB can also be synthesized with different tacticities via a catalytic ring-opening polymerization (ROP) of rac-ß-butyrolactone (BBL), paving the way to PHB with better thermomechanical and processability properties. In this work, the catalyst family is extended based on aluminum phenoxy-imine methyl catalyst [AlMeL2], that reveals efficient in the ROP of BBL, to the halogeno analogous complex [AlClL2]. As well, the impact on the ROP mechanism of different initiators is further explored with a particular focus in dimethylaminopyridine (DMAP), a hardly studied initiator for the ROP of BBL. A thorough mechanistic study is performed that evidences the presence of two concomitant DMAP-mediated mechanisms, that lead to either a DMAP or a crotonate end-capping group. Besides, in order to increase the possibilities of PHB post-polymerization functionalization, the introduction of a side-chain functionality is explored, establishing the copolymerization of BBL with ß-allyloxymethylene propiolactone (BPLOAll), resulting in well-defined P(BBL-co-BPLOAll) copolymers.


Assuntos
4-Butirolactona , Alumínio , Poli-Hidroxialcanoatos , Polimerização , Catálise , 4-Butirolactona/química , 4-Butirolactona/análogos & derivados , Poli-Hidroxialcanoatos/química , Alumínio/química , Estrutura Molecular , Hidroxibutiratos/química , Poli-Hidroxibutiratos
15.
Kidney Blood Press Res ; 49(1): 69-80, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38185105

RESUMO

INTRODUCTION: Renal fibrosis is a critical event in the development and progression of chronic kidney disease (CKD), and it is considered the final common pathway for all types of CKD. The prevalence of CKD is higher in females; however, males have a greater prevalence of end-stage renal disease. In addition, low birth weight and low nephron number are associated with increased risk for CKD. This study examined the development and severity of unilateral ureter obstruction (UUO)-induced renal fibrosis in male and female wild-type (ROP +/+) and mutant (ROP Os/+) mice, a mouse model of low nephron number. METHODS: Male and female ROP +/+ and ROP Os/+ mice were subjected to UUO, and kidney tissue was collected at the end of the 10-day experimental period. Kidney histological analysis and mRNA expression determined renal fibrosis, tubular injury, collagen deposition, extracellular matrix proteins, and immune cell infiltration. RESULTS: Male and female UUO mice demonstrated marked renal injury, kidney fibrosis, and renal extracellular matrix production. Renal fibrosis and α-smooth muscle actin were increased to a similar degree in ROP +/+ and ROP Os/+ mice with UUO of either sex. There were also no sex differences in renal tubular cast formation or renal infiltration of macrophage in ROP +/+ and ROP Os/+ UUO mice. Interestingly, renal fibrosis and α-smooth muscle actin were 1.5-3-fold greater in UUO-ROP +/+ compared to UUO-ROP Os/+ mice. Renal inflammation phenotypes following UUO were also 30-45% greater in ROP +/+ compared to ROP Os/+ mice. Likewise, expression of extracellular matrix and renal fibrotic genes was greater in UUO-ROP +/+ mice compared to UUO-ROP Os/+ mice. In contrast to these findings, ROP Os/+ mice with UUO demonstrated glomerular hypertrophy with 50% greater glomerular tuft area compared to ROP +/+ with UUO. Glomerular hypertrophy was not sex-dependent in any of the genotypes of ROP mice. These findings provide evidence that low nephron number contributes to UUO-induced glomerular hypertrophy in ROP Os/+ mice but does not enhance renal fibrosis, inflammation, and renal tubular injury. CONCLUSION: Taken together, we demonstrate that low nephron number contributes to enhanced glomerular hypertrophy but not kidney fibrosis and tubular injury. We also demonstrate that none of the changes caused by UUO was affected by sex in any of the ROP mice genotypes.


Assuntos
Insuficiência Renal Crônica , Obstrução Ureteral , Feminino , Masculino , Animais , Camundongos , Obstrução Ureteral/complicações , Obstrução Ureteral/metabolismo , Actinas/metabolismo , Caracteres Sexuais , Rim/patologia , Insuficiência Renal Crônica/complicações , Inflamação/patologia , Fibrose , Hipertrofia/patologia , Camundongos Endogâmicos C57BL , Modelos Animais de Doenças
16.
Eur J Pediatr ; 183(6): 2671-2682, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38509232

RESUMO

To describe the variability in carotenoid content of human milk (HM) in mothers of very to extremely low birth weight preterm infants throughout lactation and to explore the relationship between lutein in HM and the occurrence of retinopathy of prematurity (ROP) in preterm infants. We recruited healthy mothers along with their preterm infants that were born at gestational age 24 + 2 to 29 + 6 weeks or with a birth weight under 1500 g and were exclusively breastfed HM. Each participant provided up to 7 HM samples (2-10 ml) on day 0-3 and once a week until 6 weeks. Additionally, when possible, a blood sample was collected from the infant at week 6. Concentrations of the major carotenoids (lutein, zeaxanthin, beta-carotene, and lycopene) in all HM and blood samples were assessed and compared. Thirty-nine mother-infant dyads were included and 184 HM samples and 21 plasma samples were provided. Mean lutein, zeaxanthin, beta-carotene, and lycopene concentration decreased as lactation progressed, being at their highest in colostrum samples (156.9 vs. 66.9 vs. 363.9 vs. 426.8 ng/ml, respectively). Lycopene (41%) and beta-carotene (36%) were the predominant carotenoids in colostrum and up to 2 weeks post-delivery. Inversely, the proportion of lutein and zeaxanthin increased with lactation duration to account for 45% of the carotenoids in mature HM. Lutein accounted for 58% of the carotenoids in infant plasma and only 28% in HM. Lutein content of transition and mature HM did not differ between mothers of ROP and non-ROP infants.Conclusion Carotenoid content of HM was dynamic and varied between mothers and as lactation progressed. Infant plasma displayed a distinct distribution of carotenoids from HM.


Assuntos
Carotenoides , Leite Humano , Humanos , Leite Humano/química , Feminino , Carotenoides/análise , Carotenoides/sangue , Recém-Nascido , Adulto , Estudos Longitudinais , Retinopatia da Prematuridade/sangue , Recém-Nascido Prematuro , Masculino , Lactação/metabolismo , Colostro/química , Aleitamento Materno , Luteína/análise , Luteína/sangue
17.
BMC Ophthalmol ; 24(1): 180, 2024 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-38641774

RESUMO

BACKGROUND: Retinopathy of prematurity (ROP) is a major cause of visual impairment in premature infants, often requiring surgical interventions in advanced stages. This retrospective case series study investigates non-surgical management for Stage 4A ROP, specifically the use of combined laser therapy and intravitreal anti-vascular endothelial growth factor (VEGF) injections. METHODS: Ten eyes from five infants with Stage 4A ROP were treated with a combined laser and anti-VEGF approach. Comprehensive follow-up examinations were conducted to evaluate the treatment outcomes. RESULTS: The study demonstrated successful retinal attachment without complications, showcasing the efficacy and safety of this non-surgical method. A comparison with surgical interventions highlighted the potential benefits in terms of reduced adverse effects. DISCUSSION: This combined treatment emerges as a promising first-choice option for Stage 4A ROP, offering rapid regression without surgical intervention, particularly in early stages. However, larger randomized clinical trials are necessary to validate these findings and establish definitive guidelines for managing this complex condition. CONCLUSION: Combined laser and anti-VEGF therapy proved to be an effective and safe non-surgical approach for Stage 4A ROP, with the potential to reduce the need for surgery, especially in its early presentation. Further research is required to confirm these findings and provide comprehensive recommendations for clinical practice.


Assuntos
Inibidores da Angiogênese , Retinopatia da Prematuridade , Recém-Nascido , Lactente , Humanos , Inibidores da Angiogênese/uso terapêutico , Retinopatia da Prematuridade/cirurgia , Retinopatia da Prematuridade/tratamento farmacológico , Fator A de Crescimento do Endotélio Vascular , Estudos Retrospectivos , Fotocoagulação a Laser/métodos , Recém-Nascido Prematuro , Injeções Intravítreas , Idade Gestacional
18.
BMC Ophthalmol ; 24(1): 364, 2024 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-39180010

RESUMO

BACKGROUND: Retinopathy of prematurity (ROP), is a preventable leading cause of blindness in infants and is a condition in which the immature retina experiences abnormal blood vessel growth. The development of ROP is multifactorial; nevertheless, the risk factors are controversial. This study aimed to identify risk factors of time to development of ROP in Iran. METHODS: This historical cohort study utilized data from the hospital records of all newborns referred to the ROP department of Farabi Hospital (from 2017 to 2021) and the NICU records of infants referred from Mahdieh Hospital to Farabi Hospital. Preterm infants with birth weight (BW) ≤ 2000 g or gestational age (GA) < 34 wk, as well as selected infants with an unstable clinical course, as determined by their pediatricians or neonatologists, with BW > 2000 g or GA ≥ 34 wk. The outcome variable was the time to development of ROP (in weeks). Random survival forest was used to analyze the data. RESULTS: A total of 338 cases, including 676 eyes, were evaluated. The mean GA and BW of the study group were 31.59 ± 2.39 weeks and 1656.72 ± 453.80 g, respectively. According to the criteria of minimal depth and variable importance, the most significant predictors of the time to development of ROP were duration of ventilation, GA, duration of oxygen supplementation, bilirubin levels, duration of antibiotic administration, duration of Total Parenteral Nutrition (TPN), mother age, birth order, number of surfactant administration, and on time screening. The concordance index for predicting survival of the fitted model was 0.878. CONCLUSION: Our findings indicated that the duration of ventilation, GA, duration of oxygen supplementation, bilirubin levels, duration of antibiotic administration, duration of TPN, mother age, birth order, number of surfactant administrations, and on time screening are potential risk factors of prognosis of ROP. The associations between identified risk factors were mostly nonlinear. Therefore, it is recommended to consider the nature of these relationships in managing treatment and designing early interventions.


Assuntos
Idade Gestacional , Recém-Nascido Prematuro , Aprendizado de Máquina , Retinopatia da Prematuridade , Humanos , Retinopatia da Prematuridade/epidemiologia , Retinopatia da Prematuridade/diagnóstico , Recém-Nascido , Fatores de Risco , Irã (Geográfico)/epidemiologia , Masculino , Feminino , Peso ao Nascer , Estudos Retrospectivos , Fatores de Tempo , Lactente
19.
BMC Pediatr ; 24(1): 579, 2024 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-39272051

RESUMO

BACKGROUND: Preterm infants are at risk of complications due to their prematurity and Retinopathy of Prematurity (ROP) is one of them. To discover and treat ROP the preterm infants regularly undergo eye examinations. Nurses are responsible for the infants' care during this painful and stressful procedure. AIM: The aim of this study was to explore nurses' perceptions of preterm infants' eye examinations. METHODS: Data were collected through semi-structured interviews with 10 nurses experienced in participating in preterm infants' eye examinations. Data were analysed using a phenomenographic approach. RESULTS: The results showed several perceptions of the eye examinations, and the analysis resulted in four descriptive categories: Infants are affected by the eye examination; Nurses have comprehensive overall responsibility for the infants; Parents are important to their infants, but they need support to fulfil their parental role, and Collaboration is important for the examination's favourable outcome. The category Nurses have comprehensive overall responsibility for the infants was regarded as the most comprehensive, covering all the other categories. CONCLUSIONS: Nurses felt a great responsibility during a painful and stressful procedure for preterm infants. Infants' well-being could be better protected by interprofessional collaboration, improved nursing care and involved parents.


Assuntos
Atitude do Pessoal de Saúde , Recém-Nascido Prematuro , Retinopatia da Prematuridade , Humanos , Recém-Nascido , Feminino , Retinopatia da Prematuridade/diagnóstico , Retinopatia da Prematuridade/enfermagem , Masculino , Adulto , Papel do Profissional de Enfermagem , Pesquisa Qualitativa , Entrevistas como Assunto , Enfermagem Neonatal , Pais/psicologia , Exame Físico
20.
Int J Mol Sci ; 25(14)2024 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-39063242

RESUMO

The promoter of the RECEPTOR-LIKE CYTOPLASMIC KINASE VI_A2 (RLCK VI_A2) gene contains nine binding sites for the REPLUMLESS (RPL) transcription factor. In agreement, the expression of the kinase gene was strongly downregulated in the rpl-4 mutant. Comparing phenotypes of loss-of-function mutants, it was revealed that both genes are involved in stem growth, phyllotaxis, organization of the vascular tissues, and the replum, highlighting potential functional interactions. The expression of the RLCKVI_A2 gene from the constitutive 35S promoter could not complement the rpl-4 phenotypes but exhibited a dominant positive effect on stem growth and affected vascular differentiation and organization. The results also indicated that the number of vascular bundles is regulated independently from stem thickness. Although our study cannot demonstrate a direct link between the RPL and RLVKVI_A2 genes, it highlights the significance of the proper developmental regulation of the RLCKVI_A2 promoter for balanced stem development.


Assuntos
Proteínas de Arabidopsis , Arabidopsis , Frutas , Regulação da Expressão Gênica de Plantas , Regiões Promotoras Genéticas , Fatores de Transcrição , Arabidopsis/genética , Arabidopsis/crescimento & desenvolvimento , Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Frutas/genética , Frutas/crescimento & desenvolvimento , Frutas/metabolismo , Brotos de Planta/crescimento & desenvolvimento , Brotos de Planta/genética , Brotos de Planta/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
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