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1.
Sci Transl Med ; 16(767): eadk5005, 2024 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-39356748

RESUMO

Acute kidney injury (AKI) is a frequent and challenging clinical condition associated with high morbidity and mortality and represents a common complication in critically ill patients with COVID-19. In AKI, renal tubular epithelial cells (TECs) are a primary site of damage, and recovery from AKI depends on TEC plasticity. However, the molecular mechanisms underlying adaptation and maladaptation of TECs in AKI remain largely unclear. Here, our study of an autopsy cohort of patients with COVID-19 provided evidence that injury of TECs by myoglobin, released as a consequence of rhabdomyolysis, is a major pathophysiological mechanism for AKI in severe COVID-19. Analyses of human kidney biopsies, mouse models of myoglobinuric and gentamicin-induced AKI, and mouse kidney tubuloids showed that TEC injury resulted in activation of the glucocorticoid receptor by endogenous glucocorticoids, which aggravated tubular damage. The detrimental effect of endogenous glucocorticoids on injured TECs was exacerbated by the administration of a widely clinically used synthetic glucocorticoid, dexamethasone, as indicated by experiments in mouse models of myoglobinuric- and folic acid-induced AKI, human and mouse kidney tubuloids, and human kidney slice cultures. Mechanistically, studies in mouse models of AKI, mouse tubuloids, and human kidney slice cultures demonstrated that glucocorticoid receptor signaling in injured TECs orchestrated a maladaptive transcriptional program to hinder DNA repair, amplify injury-induced DNA double-strand break formation, and dampen mTOR activity and mitochondrial bioenergetics. This study identifies glucocorticoid receptor activation as a mechanism of epithelial maladaptation, which is functionally important for AKI.


Assuntos
Injúria Renal Aguda , COVID-19 , Células Epiteliais , Glucocorticoides , Receptores de Glucocorticoides , Animais , Injúria Renal Aguda/metabolismo , Injúria Renal Aguda/patologia , Humanos , Glucocorticoides/efeitos adversos , Glucocorticoides/farmacologia , COVID-19/complicações , COVID-19/metabolismo , Camundongos , Células Epiteliais/metabolismo , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/patologia , Receptores de Glucocorticoides/metabolismo , Modelos Animais de Doenças , Masculino , Túbulos Renais/patologia , Túbulos Renais/metabolismo , Túbulos Renais/efeitos dos fármacos , Mioglobina/metabolismo , Dexametasona/farmacologia , Dexametasona/efeitos adversos , Estresse Fisiológico/efeitos dos fármacos , SARS-CoV-2 , Camundongos Endogâmicos C57BL , Feminino
2.
BMC Plant Biol ; 24(1): 850, 2024 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-39256706

RESUMO

This study evaluated the responses of sweet potatoes to Cadmium (Cd) stress through pot experiments to theoretically substantiate their comprehensive applications in Cd-polluted agricultural land. The experiments included a CK treatment and three Cd stress treatments with 3, 30, and 150 mg/kg concentrations, respectively. We analyzed specified indicators of sweet potato at different growth periods, such as the individual plant growth, photosynthesis, antioxidant capacity, and carbohydrate Cd accumulation distribution. On this basis, the characteristics of the plant carbon metabolism in response to Cd stress throughout the growth cycle were explored. The results showed that T2 and T3 treatments inhibited the vine growth, leaf area expansion, stem diameter elongation, and tuberous root growth of sweet potato; notably, T3 treatment significantly increased the number of sweet potato branches. Under Cd stress, the synthesis of chlorophyll in sweet potato was significantly suppressed, and the Rubisco activity experienced significant reductions. With the increasing Cd concentration, the function of PS II was also affected. The soluble sugar content underwent no significant change in low Cd concentration treatments. In contrast, it decreased significantly under high Cd concentrations. Additionally, the tuberous root starch content decreased significantly with the increase in Cd concentration. Throughout the plant growth, the activity levels of catalase, peroxidase, and superoxide dismutase increased significantly in T2 and T3 treatments. By comparison, the superoxide dismutase activity in T1 treatment was significantly lower than that of CK. With the increasing application of Cd, its accumulation accordingly increased in various sweet potato organs. The the highest bioconcentration factor was detected in absorbing roots, while the tuberous roots had a lower bioconcentration factor and Cd accumulation. Moreover, the transfer factor from stem to petiole was the highest of the potato organs. These results demonstrated that sweet potatoes had a high Cd tolerance and a restoration potential for Cd-contaminated farmland.


Assuntos
Cádmio , Ipomoea batatas , Fotossíntese , Ipomoea batatas/crescimento & desenvolvimento , Ipomoea batatas/efeitos dos fármacos , Ipomoea batatas/metabolismo , Ipomoea batatas/fisiologia , Cádmio/toxicidade , Cádmio/metabolismo , Fotossíntese/efeitos dos fármacos , Estresse Fisiológico/efeitos dos fármacos , Clorofila/metabolismo , Antioxidantes/metabolismo , Raízes de Plantas/crescimento & desenvolvimento , Raízes de Plantas/efeitos dos fármacos , Raízes de Plantas/metabolismo , Poluentes do Solo/metabolismo , Folhas de Planta/efeitos dos fármacos , Folhas de Planta/crescimento & desenvolvimento , Folhas de Planta/metabolismo
3.
Physiol Plant ; 176(5): e14524, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39266459

RESUMO

The yield of Tartary buckwheat is significantly affected by continuous cropping. Melatonin plays a crucial role in plant defense mechanisms against abiotic stresses. However, the relationship between melatonin and continuous cropping tolerance remains unclear. This study aimed to analyze the physiological mechanism of melatonin in enhancing the continuous cropping tolerance (abiotic stress) of Tartary buckwheat. A field experiment was conducted on Tartary buckwheat cultivar Jinqiao 2 under continuous cropping with five melatonin application rates, 0 (Control), 10, 50, 100, and 200 µmol L-1, applied during the early budding stage. The chlorophyll content, antioxidant enzyme activity, osmolyte and auxin (IAA) contents, root activity, rhizosphere soil nutrient content, and agronomic traits of Tartary buckwheat initially increased and then decreased with an increase in the concentration of exogenous melatonin application, with the best effects observed at 100 µmol L-1. Compared with the Control treatment, the 100 µmol L-1 treatment decreased the contents of malondialdehyde, superoxide anion free radical, and abscisic acid (ABA) by an average of 28.79%, 27.08%, and 31.64%, respectively. Exogenous melatonin treatment significantly increased the yield of Tartary buckwheat under continuous cropping. Plants treated with 10, 50, 100, and 200 µM respectively had 1.88, 2.01, 2.20, and 1.78 times higher yield than those of the Control treatment. In summary, melatonin treatment, particularly 100 µmol L-1, enhanced the continuous cropping tolerance of Tartary buckwheat by increasing antioxidant capacity and osmotica content, coordinating endogenous ABA and IAA content levels, and delaying senescence, ultimately increasing yield.


Assuntos
Antioxidantes , Fagopyrum , Melatonina , Fagopyrum/efeitos dos fármacos , Fagopyrum/metabolismo , Fagopyrum/crescimento & desenvolvimento , Fagopyrum/fisiologia , Melatonina/farmacologia , Melatonina/metabolismo , Antioxidantes/metabolismo , Ácido Abscísico/metabolismo , Ácido Abscísico/farmacologia , Clorofila/metabolismo , Ácidos Indolacéticos/metabolismo , Malondialdeído/metabolismo , Estresse Fisiológico/efeitos dos fármacos , Raízes de Plantas/efeitos dos fármacos , Raízes de Plantas/metabolismo , Raízes de Plantas/crescimento & desenvolvimento
5.
BMC Plant Biol ; 24(1): 889, 2024 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-39343870

RESUMO

Plants are subjected to various biotic and abiotic stresses that significantly impact their growth and productivity. To achieve balanced crop growth and yield, including for leafy vegetables, the continuous application of micronutrient is crucial. This study investigates the effects of different concentrations of copper sulphate (0, 75, 125, and 175 ppm) on the morphological and biochemical features of Spinacia oleracea and Avena sativa. Morphological parameters such as plant height, leaf area, root length, and fresh and dry weights were optimized at a concentration of 75 ppm copper sulfate. At this concentration, chlorophyll a & b levels increased significantly in Spinacia oleracea (462.9 and 249.8 𝜇𝑔/𝑔), and Avena sativa (404.7 and 437.63𝜇𝑔/𝑔). However, carotenoid content and sugar levels in Spinacia oleracea were negatively affected, while sugar content in Avena sativa increased at 125 ppm (941.6 µg/ml). Protein content increased in Spinacia oleracea (75 ppm, 180.3 µg/ml) but decreased in Avena sativa. Phenol content peaked in both plants at 75 ppm (362.2 and 244.5 µg/ml). Higher concentrations (175 ppm) of copper sulfate reduced plant productivity and health. Plants exposed to control and optimal concentrations (75 and 125 ppm) of copper sulpate exhibited the best health and growth compared to those subjected to higher concentrations. Maximum plant height, leaf area, root length, fresh and dry weights were observed at lower concentrations (75 and 125 ppm) of copper sulfate, while higher concentrations caused toxicity. Optimal copper sulfate levels enhanced chlorophyll a, chlorophyll b, total chlorophyll, protein, and phenol contents but inhibited sugar and carotenoid contents in both Spinacia oleracea and Avena sativa. Overall, increased copper sulfate treatment adversely affected the growth parameters and biochemical profiles of these plants.


Assuntos
Avena , Clorofila , Sulfato de Cobre , Spinacia oleracea , Spinacia oleracea/efeitos dos fármacos , Spinacia oleracea/crescimento & desenvolvimento , Spinacia oleracea/metabolismo , Clorofila/metabolismo , Avena/efeitos dos fármacos , Avena/crescimento & desenvolvimento , Avena/metabolismo , Folhas de Planta/efeitos dos fármacos , Folhas de Planta/crescimento & desenvolvimento , Carotenoides/metabolismo , Estresse Fisiológico/efeitos dos fármacos , Clorofila A/metabolismo , Proteínas de Plantas/metabolismo
6.
BMC Plant Biol ; 24(1): 897, 2024 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-39343873

RESUMO

Heavy metal toxicity adversely affects plants by changing physiological, biochemical, and molecular mechanisms. Lead (Pb) is one of the most common heavy metal pollutants. Hence this study investigated changes caused by exogenous methyl jasmonate (MeJA; 20 and 100 µM) and salicylic acid (SA; 2 and 20 mM) elicitors in local Karacadag rice exposed to Pb stress (0, 100, and 400 ppm). The effects of elicitors on photosynthetic pigment content (chlorophyll a, chlorophyll b, and total carotenoid), proline, malondialdehyde (MDA), total phenolic and flavonoid, Pb, and total protein contents in stressed plants were evaluated. All parameters studied increased and decreased at varying rates in the treatment groups compared to the Pb-free group (control), indicating that rice plants were affected by Pb stress. The elicitors (MeJA, SA, and MeJA + SA) were applied by foliar spraying. The elicitor treatments increased photosynthetic pigment content, total protein, proline, total flavonoid, and phenolic contents depending on the elicitor type and concentration. MDA and Pb contents, increasing with Pb toxicity, decreased with elicitor treatments, and the stress degree was reduced. When the elicitors were compared, SA was more effective than MeJA in total flavonoid content at 400 ppm Pb toxicity. However, MeJA was more effective in photosynthetic pigment contents, MDA, total protein, Pb, total phenolic, and proline contents. The best results for all parameters examined in rice plants exposed to Pb toxicity were obtained from the 400 ppm Pb + 2 mM SA + 20 µM MeJA treatment group. In conclusion, this study showed that the combined application of MeJA + SA alleviated the harmful effects of Pb by reducing MDA and increasing photosynthetic pigments, total protein, proline, and secondary metabolites, especially at high Pb concentrations. Consequently, this study demonstrated that the combined use of MeJA and SA in rice plants eliminated the negative effects of stress quite effectively, even at high Pb concentrations. Therefore, future studies should focus on the synergistic application of different elicitors to better understand the effects of heavy metal toxicity on plant growth and development.


Assuntos
Acetatos , Clorofila , Ciclopentanos , Chumbo , Oryza , Oxilipinas , Ácido Salicílico , Oryza/efeitos dos fármacos , Oryza/metabolismo , Oryza/crescimento & desenvolvimento , Chumbo/toxicidade , Oxilipinas/farmacologia , Ciclopentanos/farmacologia , Ácido Salicílico/farmacologia , Acetatos/farmacologia , Clorofila/metabolismo , Estresse Fisiológico/efeitos dos fármacos , Fotossíntese/efeitos dos fármacos , Reguladores de Crescimento de Plantas/farmacologia , Reguladores de Crescimento de Plantas/metabolismo , Prolina/metabolismo , Flavonoides , Carotenoides/metabolismo , Malondialdeído/metabolismo , Proteínas de Plantas/metabolismo
7.
Physiol Plant ; 176(5): e14532, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39291463

RESUMO

Glyphosate (GLY), the most widely used herbicide, has been regarded as an emergent environmental contaminant due to its constant and cumulative use, with potential harm to non-target organisms, such as crops, disrupting cells' redox balance. Therefore, plants need to fine-tune their antioxidant (AOX) mechanisms to thrive under GLY-contaminated environments. Proline overaccumulation is a common response in plants exposed to GLY, yet its role in GLY-induced toxicity remains unclear. Thus, this study explores whether Pro overaccumulation in response to GLY is perceived as a downstream tolerance mechanism or an early-warning stress signal. To investigate this, Arabidopsis thaliana T-DNA mutant lines for Pro biosynthetic (P5CS1) and catabolic genes (ProDH) were used and screened for their GLY susceptibility. Upon seedlings' exposure to GLY (0.75 mg L-1) for 14 days, the herbicide led to reduced biomass in all genotypes, accompanied by Pro overaccumulation. Mutants with heightened Pro levels (prodh) exhibited the greatest biomass reduction, increased lipid peroxidation (LP), and hydrogen peroxide (H2O2) levels, accompanied by a compromised performance of the AOX system. Conversely, p5cs1-4, mutants with lower Pro levels, demonstrated an enhanced AOX system activation, not only with increased levels of glutathione (GSH) and ascorbate (AsA), but also with increased activity of both ascorbate peroxidase (APX) and catalase (CAT). These findings suggest that Pro overaccumulation under GLY exposure is associated with stress sensitivity rather than tolerance, highlighting its potential as an early-warning signal for GLY toxicity in non-target plants and for detecting weed resistance.


Assuntos
Arabidopsis , Glicina , Glifosato , Herbicidas , Prolina , Glicina/análogos & derivados , Glicina/farmacologia , Glicina/toxicidade , Prolina/metabolismo , Arabidopsis/genética , Arabidopsis/efeitos dos fármacos , Arabidopsis/metabolismo , Arabidopsis/fisiologia , Herbicidas/toxicidade , Herbicidas/farmacologia , Peroxidação de Lipídeos/efeitos dos fármacos , Antioxidantes/metabolismo , Peróxido de Hidrogênio/metabolismo , Estresse Fisiológico/efeitos dos fármacos , Estresse Fisiológico/genética , Proteínas de Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Regulação da Expressão Gênica de Plantas/efeitos dos fármacos , Plântula/efeitos dos fármacos , Plântula/genética , Plântula/fisiologia , Plântula/metabolismo
8.
Aquat Toxicol ; 275: 107075, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39244834

RESUMO

This study investigated the toxicological effects and mechanisms of cadmium (Cd) (5 and 50 µg/L) and selenium (Se) (3 and 30 µg/L) at environmentally relevant concentrations on the gills and digestive glands of clams Ruditapes philippinarum. Results indicated that Cd and Se could tissue-specifically impact osmoregulation, energy metabolism, and synaptic transmission in the gills and digestive glands of clams. After exposure to 50 µg/L Cd, the digestive glands of clams up-regulated the expression of methionine-gamma-lyase and metallothionein for detoxification. Clam digestive glands exposed to 3 µg/L Se up-regulated the expression of catalase and glutathione peroxidase to alleviate oxidative stress, and down-regulated the expression of selenide-water dikinase to reduce the conversion of inorganic Se. Additionally, the interaction mode between Cd and Se largely depended on their molar ratio, with a ratio of 11.71 (50 µg/L Cd + 3 µg/L Se) demonstrated to be particularly harmful, as manifested by significantly more lesions, oxidative stress, and detoxification demand in clams than those exposed to Cd or Se alone. Collectively, this study revealed the complex interaction patterns and mechanisms of Cd and Se on clams, providing a reference for exploring their single and combined toxicity.


Assuntos
Bivalves , Cádmio , Estresse Oxidativo , Selênio , Poluentes Químicos da Água , Animais , Cádmio/toxicidade , Bivalves/efeitos dos fármacos , Poluentes Químicos da Água/toxicidade , Selênio/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Transmissão Sináptica/efeitos dos fármacos , Brânquias/efeitos dos fármacos , Brânquias/metabolismo , Inativação Metabólica , Estresse Fisiológico/efeitos dos fármacos
9.
Biomolecules ; 14(9)2024 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-39334943

RESUMO

Abiotic stresses, such as drought, salinity, and extreme temperatures, limit plant growth and development, reducing crop yields. Therefore, a more comprehensive understanding of the signaling mechanisms and responses of plants to changing environmental conditions is crucial for improving sustainable agricultural productivity. Chemical screening was conducted to find novel small compounds that act as regulators of the abiotic stress signaling pathway using the ABA-inducible transgenic reporter line. Small molecules called stress response regulators (SRRs) were isolated by screening a synthetic library composed of 14,400 small compounds, affecting phenotypes such as seed germination, root growth, and gene expression in response to multiple abiotic stresses. Seeds pretreated with SRR compounds positively affected the germination rate and radicle emergence of Arabidopsis and tomato plants under abiotic stress conditions. The SRR-priming treatment enhanced the transcriptional responses of abiotic stress-responsive genes in response to subsequent salt stress. The isolation of the novel molecules SRR1 and SRR2 will provide a tool to elucidate the complex molecular networks underlying the plant stress-tolerant responses.


Assuntos
Arabidopsis , Regulação da Expressão Gênica de Plantas , Germinação , Transdução de Sinais , Estresse Fisiológico , Estresse Fisiológico/efeitos dos fármacos , Arabidopsis/genética , Arabidopsis/efeitos dos fármacos , Arabidopsis/metabolismo , Transdução de Sinais/efeitos dos fármacos , Regulação da Expressão Gênica de Plantas/efeitos dos fármacos , Germinação/efeitos dos fármacos , Solanum lycopersicum/efeitos dos fármacos , Solanum lycopersicum/genética , Solanum lycopersicum/metabolismo , Solanum lycopersicum/crescimento & desenvolvimento , Bibliotecas de Moléculas Pequenas/farmacologia , Sementes/efeitos dos fármacos , Sementes/crescimento & desenvolvimento , Sementes/genética , Sementes/metabolismo
10.
Genes (Basel) ; 15(9)2024 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-39336824

RESUMO

Background: Climate change is leading to severe and long-term droughts in European forest ecosystems. can have profound effects on various physiological processes, including photosynthesis, gene expression patterns, and nutrient uptake at the developmental stage of young trees. Objectives: Our study aimed to test the hypothesis that the application of silica (SiO2) influences photosynthetic efficiency and gene expression in 1- to 2-year-old Fagus sylvatica (L.) seedlings. Additionally, we aimed to assess whether silicon application positively influences the structural properties of leaves and roots. To determine whether the plant physiological responses are genotype-specific, seedlings of four geographically different provenances were subjected to a one-year evaluation under greenhouse conditions. Methods: We used the Kruskal-Wallis test followed by Wilcoxon's test to evaluate the differences in silicon content and ANOVA followed by Tukey's test to evaluate the physiological responses of seedlings depending on treatment and provenance. Results: Our results showed a significantly higher Si content in the roots compared with the leaves, regardless of provenance and treatment. The most significant differences in photosynthetic performance were found in trees exposed to Si treatment, but the physiological responses were generally nuanced and provenance-dependent. Expression of hsp70 and hsp90 was also increased in leaf tissues of all provenances. These results provide practical insights that Si can improve the overall health and resilience of beech seedlings in nursery and forest ecosystems, with possible differences in the beneficial role of silicon application arising from the large differences in wild populations of forest tree species.


Assuntos
Secas , Fagus , Regulação da Expressão Gênica de Plantas , Fotossíntese , Plântula , Silício , Fagus/genética , Fagus/efeitos dos fármacos , Fagus/metabolismo , Fotossíntese/efeitos dos fármacos , Fotossíntese/genética , Plântula/genética , Plântula/efeitos dos fármacos , Plântula/crescimento & desenvolvimento , Plântula/metabolismo , Silício/farmacologia , Silício/metabolismo , Regulação da Expressão Gênica de Plantas/efeitos dos fármacos , Folhas de Planta/genética , Folhas de Planta/efeitos dos fármacos , Folhas de Planta/metabolismo , Folhas de Planta/crescimento & desenvolvimento , Raízes de Plantas/genética , Raízes de Plantas/efeitos dos fármacos , Raízes de Plantas/crescimento & desenvolvimento , Raízes de Plantas/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Estresse Fisiológico/genética , Estresse Fisiológico/efeitos dos fármacos , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/metabolismo , Proteínas de Choque Térmico HSP70/genética , Proteínas de Choque Térmico HSP70/metabolismo
11.
PLoS One ; 19(9): e0311078, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39325792

RESUMO

This study investigates the immunological and growth effects of Vitamin C and Zinc supplementation on Nile tilapia (Oreochromis niloticus) subjected to cold water stress. Nile tilapia fingerlings were housed in eight 20-gallon tanks at Purdue University, acclimated to 26 ± 2°C water conditions before the experiment. The tilapia was divided into groups with varying water temperatures and feed supplements: control fish in warm water, and experimental groups in cold water with increased levels of Vitamin C and Zinc. Stress was induced by lowering the water temperature to 15 ± 2°C in four tanks, while the remaining tanks were kept at the optimal growth temperature. Results demonstrated that Vitamin C and Zinc supplementation significantly enhanced immune response and muscle regeneration in cold-stressed tilapia, allowing them to achieve growth rates comparable to those of control fish in optimal warm water conditions. These findings highlight the potential benefits of combined Vitamin C and Zinc supplementation in improving the immune response and growth performance of tilapia under suboptimal temperature conditions.


Assuntos
Ácido Ascórbico , Ciclídeos , Suplementos Nutricionais , Zinco , Animais , Zinco/farmacologia , Ácido Ascórbico/farmacologia , Ciclídeos/imunologia , Ciclídeos/crescimento & desenvolvimento , Temperatura Baixa , Tilápia/crescimento & desenvolvimento , Tilápia/imunologia , Tilápia/fisiologia , Estresse Fisiológico/efeitos dos fármacos , Água
12.
Elife ; 122024 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-39287504

RESUMO

The integrated stress response (ISR) is a conserved pathway in eukaryotic cells that is activated in response to multiple sources of cellular stress. Although acute activation of this pathway restores cellular homeostasis, intense or prolonged ISR activation perturbs cell function and may contribute to neurodegeneration. DNL343 is an investigational CNS-penetrant small-molecule ISR inhibitor designed to activate the eukaryotic initiation factor 2B (eIF2B) and suppress aberrant ISR activation. DNL343 reduced CNS ISR activity and neurodegeneration in a dose-dependent manner in two established in vivo models - the optic nerve crush injury and an eIF2B loss of function (LOF) mutant - demonstrating neuroprotection in both and preventing motor dysfunction in the LOF mutant mouse. Treatment with DNL343 at a late stage of disease in the LOF model reversed elevation in plasma biomarkers of neuroinflammation and neurodegeneration and prevented premature mortality. Several proteins and metabolites that are dysregulated in the LOF mouse brains were normalized by DNL343 treatment, and this response is detectable in human biofluids. Several of these biomarkers show differential levels in CSF and plasma from patients with vanishing white matter disease (VWMD), a neurodegenerative disease that is driven by eIF2B LOF and chronic ISR activation, supporting their potential translational relevance. This study demonstrates that DNL343 is a brain-penetrant ISR inhibitor capable of attenuating neurodegeneration in mouse models and identifies several biomarker candidates that may be used to assess treatment responses in the clinic.


Assuntos
Fator de Iniciação 2B em Eucariotos , Animais , Camundongos , Fator de Iniciação 2B em Eucariotos/metabolismo , Fator de Iniciação 2B em Eucariotos/genética , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/prevenção & controle , Estresse Fisiológico/efeitos dos fármacos , Modelos Animais de Doenças , Masculino , Humanos , Fármacos Neuroprotetores/farmacologia , Camundongos Endogâmicos C57BL , Feminino , Acetamidas , Cicloexilaminas
13.
Sci Rep ; 14(1): 21948, 2024 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-39304700

RESUMO

Contamination of agricultural products with Cadmium (Cd) is a global problem that should be considered for minimizing the risks to human health. Considering the potential effects of SiNPs in decreasing abiotic stress, a study was conducted to investigate the effect of SiNPs in the reduction of Cd stress on Solanum lycopersicum. SiNPs was used at 0, 25, 50 and 100 mg/l and CdCl2 at 0, 100 and 200 µM concentrations. The results showed that Cd stress caused a significant decrease in dry weight, content of GSH, ASA, significently increasing the activity of GR, APX, GST, SOD, as well as content of H2O2, MDA, proline, and GABA in shoots and roots compared to the control. SiNPs significantly increased shoot and root dry weight compared to the control. As a coenzyme, SiNPs induced the activity of antioxidant enzymes and significantly increased GST and GR gene expression compared to the control. SiNPs also caused a substantial increase in the content of ASA, GSH, proline and GABA compared to the control. By inducing the activity of antioxidant enzymes and metabolites of the ascorbate-glutathione (ASA-GSH) cycle, SiNPs removed a large content of H2O2 and significantly reduced the MDA content, and as a result led to the stability of cell membrane under Cd stress. Induction of ASA-GSH, GABA and SOD cycle by SiNPs clearly showed that SiNPs could be a potential tool to alleviate Cd stress in plants cultivated in areas contaminated with this heavy metal.


Assuntos
Cádmio , Glutationa , Silício , Solanum lycopersicum , Estresse Fisiológico , Ácido gama-Aminobutírico , Glutationa/metabolismo , Cádmio/toxicidade , Cádmio/metabolismo , Solanum lycopersicum/metabolismo , Solanum lycopersicum/efeitos dos fármacos , Ácido gama-Aminobutírico/metabolismo , Silício/farmacologia , Silício/metabolismo , Estresse Fisiológico/efeitos dos fármacos , Superóxido Dismutase/metabolismo , Antioxidantes/metabolismo , Nanopartículas/química , Peróxido de Hidrogênio/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ácido Ascórbico/metabolismo , Raízes de Plantas/metabolismo , Raízes de Plantas/efeitos dos fármacos
14.
Nat Commun ; 15(1): 8404, 2024 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-39333141

RESUMO

Cancer cells rely on high ribosome production to sustain their proliferation rate. Many chemotherapies impede ribosome production which is perceived by cells as "nucleolar stress" (NS), triggering p53-dependent and independent pathways leading to cell cycle arrest and/or apoptosis. The 5S ribonucleoprotein (RNP) particle, a sub-ribosomal particle, is instrumental to NS response. Upon ribosome assembly defects, the 5S RNP accumulates as free form. This free form is able to sequester and inhibit MDM2, thus promoting p53 stabilization. To investigate how cancer cells can resist to NS, here we purify free 5S RNP and uncover an interaction partner, SURF2. Functional characterization of SURF2 shows that its depletion increases cellular sensitivity to NS, while its overexpression promotes their resistance to it. Consistently, SURF2 is overexpressed in many cancers and its expression level is an independent marker of prognosis for adrenocortical cancer. Our data demonstrate that SURF2 buffers free 5S RNP particles, and can modulate their activity, paving the way for the research of new molecules that can finely tune the response to nucleolar stress in the framework of cancer therapies.


Assuntos
Nucléolo Celular , Proteínas Proto-Oncogênicas c-mdm2 , Proteína Supressora de Tumor p53 , Humanos , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-mdm2/genética , Nucléolo Celular/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Proteína Supressora de Tumor p53/genética , Linhagem Celular Tumoral , Estresse Fisiológico/efeitos dos fármacos , Ribossomos/metabolismo , Apoptose/efeitos dos fármacos
15.
Ecotoxicol Environ Saf ; 284: 117001, 2024 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-39236654

RESUMO

It is estimated that up to 50 % of arable lands worldwide are acidic, and most crops are severely inhibited due to the high active aluminum (Al). Trifolium repens is an excellent legume forage with a certain acid tolerance, although it is affected by Al toxicity in acidic soil. In this study, physiological and transcriptomic responses of different white clover varieties were analyzed when exposed to a high-level of Al stress. The results revealed that Trifolium repens had a high level of Al toxicity tolerance, and accumulated nearly 70 % of Al3+ in its roots. Al toxicity significantly inhibited the root length and root activity, decreased the chlorophyll (Chl) content and photosynthetic pigments, while significantly increased the intercellular CO2 concentration (Ci). The content of malondialdehyde (MDA), electrolyte leakage (EL), proline and reactive oxygen species (ROS) were significantly accumulated under Al stress. Furthermore, a total of 27,480 differentially expressed genes (DEGs) were identified after the treatment. Gene ontology (GO) and Kyoto encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that most Al-responsive genes enriched to chloroplast thylakoid membrane, chloroplast stroma and photosynthesis in Haifa leaf while in MAG leaf highly enriched in response to regulation of defense response, which could induce the different tolerance of the two cultivars to Al stress. Besides, pectin methylesterase (PME), glycosyl transferases (GT1) and chalcone synthase genes associated with cell wall biosynthesis may improve the Al accumulation and enhance tolerance of Al toxicity. The results established here would help to understand the morphological structure, physiological and biochemical response, and molecular mechanism of white clover under Al tolerance.


Assuntos
Alumínio , Perfilação da Expressão Gênica , Poluentes do Solo , Trifolium , Trifolium/efeitos dos fármacos , Trifolium/genética , Alumínio/toxicidade , Poluentes do Solo/toxicidade , Raízes de Plantas/efeitos dos fármacos , Fotossíntese/efeitos dos fármacos , Transcriptoma/efeitos dos fármacos , Regulação da Expressão Gênica de Plantas/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Clorofila/metabolismo , Folhas de Planta/efeitos dos fármacos , Estresse Fisiológico/efeitos dos fármacos
16.
Ecotoxicol Environ Saf ; 284: 116999, 2024 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-39244879

RESUMO

Chloro-haloacetonitrile (Cl-HAN), belongs to a group of nitrogenous disinfection by-products (N-DBPs) found in surface water, and are known to pose a major risk to the safety of human drinking water. However, the exact biological toxicity mechanism and the extent of the stress response caused by Cl-HAN remain unclear, resulting in a lack of effective measures to control its presence. Thus, the quantitative toxicological genomics and bioinformatics methods were applied to explore the effects of three chloro-haloacetonitriles (Cl-HANs) on the transcription of fusion genes under varying concentrations of stress in E. coli over 2-hour period. The initial stress response and their toxic mechanism were analyzed. The study also identified the molecular toxicity endpoint, and the core genes that are responsible for the specific toxicity of different Cl-HANs. Cl-HANs exhibited concentration-dependent characteristics of toxic effects, and caused changes in gene expression related oxidative and membrane stress. The stress response results showed that dichloroacetonitrile (dCAN) still caused significant DNA damage under the lowest concentration stress. Chloroacetonitrile (CAN) and trichloroacetonitrile (tCAN) exhibited lower genetic toxicity levels at 513 µg/L and 10.7 µg/L, respectively. The toxic effects of tCAN were widespread. And there was a good correlation between the molecular endpoint (EC-TELI1.5) and the phenotypic endpoint (LD50) with rp=-0.8634 (P=0.0593). In all concentrations of stress in CAN, dCAN, and tCAN, the number of overexpressed genes shared was 15, 2, and 14, respectively. Furthermore, bioinformatics analysis demonstrated that Cl-HANs affected genes associated with general stress pathways, such as cell biochemistry and physical homeostasis, resulting in changes in biological processes. And for CAN-induced DNA damage, polA played a dominant role, while katG, oxyR, and ahpC were the core genes involved in oxidative stress induced by dCAN and tCAN, respectively. These findings provide valuable data for the toxic effect of Cl-HANs.


Assuntos
Acetonitrilas , Dano ao DNA , Escherichia coli , Poluentes Químicos da Água , Acetonitrilas/toxicidade , Escherichia coli/efeitos dos fármacos , Escherichia coli/genética , Poluentes Químicos da Água/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Estresse Fisiológico/efeitos dos fármacos , Desinfetantes/toxicidade
17.
Sci Rep ; 14(1): 22315, 2024 09 27.
Artigo em Inglês | MEDLINE | ID: mdl-39333228

RESUMO

Lanthanum (La(III)) is recognized for its ability to mitigate heavy metal stress in plants. However, the inorganic La(III) salts and lanthanum oxide nanoparticles (La2O3 NPs) extensively used in agriculture are prone to soil immobilization, thereby compromising their bioavailability and posing environmental risks. This study synthesized and characterized the lanthanum(III)-amino acid chelate (La(III)-AA) from soybean protein isolate (SPI) hydrolysates. Maximum chelating rate (94.95%) was achieved under the conditions of mole ratio 1:1.5, pH 8.0, 50 ℃ and 5 h. Glu, Asp and Pro represent the primary La(III)-binding ligands. UV-vis and FTIR demonstrated that amino nitrogen and carboxyl oxygen participate in metal-ligand recognition. Scanning and Transmission electron microscopy showed that La(III) chelates with amino acids in a core-shell structure of uniform size. Consequently, a proposed chemical structure for the La(III)-AA complex was presented. A concentration of 20 mg/L La(III)-AA outperforms inorganic La salts in growth promotion and Cu detoxification. La(III)-AA significantly reduces the content of Cu (II) in rice tissues and enhances seedling tolerance to Cu (II) stress. This study provides a novel La(III)-based candidate for crop protection and furthers our understanding of rare earth element-induced mitigation of heavy metal stress.


Assuntos
Aminoácidos , Quelantes , Cobre , Lantânio , Oryza , Lantânio/química , Lantânio/farmacologia , Oryza/metabolismo , Oryza/efeitos dos fármacos , Cobre/química , Quelantes/química , Quelantes/farmacologia , Aminoácidos/química , Aminoácidos/metabolismo , Estresse Fisiológico/efeitos dos fármacos
18.
Int J Mol Sci ; 25(17)2024 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-39273130

RESUMO

Aluminum toxicity is a major abiotic stress on acidic soils, leading to restricted root growth and reduced plant yield. Long non-coding RNAs are crucial signaling molecules regulating the expression of downstream genes, particularly under abiotic stress conditions. However, the extent to which lncRNAs participate in the response to aluminum (Al) stress in barley remains largely unknown. Here, we conducted RNA sequencing of root samples under aluminum stress and compared the lncRNA transcriptomes of two Tibetan wild barley genotypes, XZ16 (Al-tolerant) and XZ61 (Al-sensitive), as well as the aluminum-tolerant cultivar Dayton. In total, 268 lncRNAs were identified as aluminum-responsive genes on the basis of their differential expression profiles under aluminum treatment. Through target gene prediction analysis, we identified 938 candidate lncRNA-messenger RNA (mRNA) pairs that function in a cis-acting manner. Subsequently, enrichment analysis showed that the genes targeted by aluminum-responsive lncRNAs were involved in diterpenoid biosynthesis, peroxisome function, and starch/sucrose metabolism. Further analysis of genotype differences in the transcriptome led to the identification of 15 aluminum-responsive lncRNAs specifically altered by aluminum stress in XZ16. The RNA sequencing data were further validated by RT-qPCR. The functional roles of lncRNA-mRNA interactions demonstrated that these lncRNAs are involved in the signal transduction of secondary messengers, and a disease resistance protein, such as RPP13-like protein 4, is probably involved in aluminum tolerance in XZ16. The current findings significantly contribute to our understanding of the regulatory roles of lncRNAs in aluminum tolerance and extend our knowledge of their importance in plant responses to aluminum stress.


Assuntos
Alumínio , Perfilação da Expressão Gênica , Regulação da Expressão Gênica de Plantas , Hordeum , RNA Longo não Codificante , Estresse Fisiológico , Transcriptoma , RNA Longo não Codificante/genética , Alumínio/toxicidade , Hordeum/genética , Hordeum/efeitos dos fármacos , Hordeum/metabolismo , Hordeum/crescimento & desenvolvimento , Regulação da Expressão Gênica de Plantas/efeitos dos fármacos , Estresse Fisiológico/genética , Estresse Fisiológico/efeitos dos fármacos , Transcriptoma/efeitos dos fármacos , Raízes de Plantas/genética , Raízes de Plantas/efeitos dos fármacos , Raízes de Plantas/metabolismo , Raízes de Plantas/crescimento & desenvolvimento , Genótipo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
19.
Endocrinology ; 165(10)2024 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-39240718

RESUMO

Biological sex affects the activity of the hypothalamus-pituitary-adrenal (HPA) axis. However, how androgen deprivation affects this axis remains largely unknown. In this study, we investigated the effect of androgen status on different components of the HPA axis in male mice. Two weeks of androgen deprivation did not affect total plasma corticosterone levels but led to increased pituitary ACTH levels. Stress-induced total plasma corticosterone levels were increased, whereas the suppression of corticosterone after dexamethasone treatment under basal conditions was attenuated. Androgen-deprived mice displayed a 2-fold increase in plasma levels of corticosteroid binding globulin (CBG). A similar increase in CBG was observed in global androgen receptor knock-out animals, compared to wild-type littermates. Androgen deprivation was associated with a 6-fold increase in CBG mRNA in the liver and enhanced transcriptional activity at CBG regulatory regions, as evidenced by increased H3K27 acetylation. We propose that the induction of CBG as a consequence of androgen deprivation, together with the unaltered total corticosterone levels, results in lower free corticosterone levels in plasma. This is further supported by mRNA levels of androgen-independent GR target genes in the liver. The reduction in negative feedback on the HPA axis under basal condition would suffice to explain the enhanced stress reactivity after androgen deprivation. Overall, our data demonstrate that, in mice, tonic androgen receptor activation affects CBG levels in conjunction with effects on gene expression and HPA-axis reactivity.


Assuntos
Androgênios , Corticosterona , Sistema Hipotálamo-Hipofisário , Camundongos Knockout , Sistema Hipófise-Suprarrenal , Transcortina , Animais , Masculino , Transcortina/metabolismo , Transcortina/genética , Camundongos , Corticosterona/sangue , Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Androgênios/sangue , Sistema Hipófise-Suprarrenal/metabolismo , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Estresse Fisiológico/efeitos dos fármacos , Receptores Androgênicos/metabolismo , Receptores Androgênicos/genética , Camundongos Endogâmicos C57BL , Fígado/metabolismo , Fígado/efeitos dos fármacos , Hormônio Adrenocorticotrópico/sangue , Dexametasona/farmacologia
20.
Plant Signal Behav ; 19(1): 2400451, 2024 Dec 31.
Artigo em Inglês | MEDLINE | ID: mdl-39235999

RESUMO

Lead is one of the major environmental pollutants which is highly toxic to plants and living beings. The current investigation thoroughly evaluated the synergistic effects of oxalic acid (OA) and salicylic acid (SA) on Zea mays L. plants subjected to varying durations (15, 30, 30, and 45 days) of lead (Pb) stress. Besides, the effects of oxalic acid (OA) combined with salicylic acid (SA) for different amino acids at various periods of Pb stress were also investigated on Zea mays L. The soil was treated with lead nitrate Pb (NO3)2 (0.5 mM) to induce Pb stress while the stressed plants were further treated using oxalic acid (25 mg/L), salicylic acid (25 mg/L), and their combination OA + SA (25 mg/L each). Measurements of protein content, malondialdehyde (MDA) levels, guaiacol peroxidase (GPOX) activity, catalase (CAT) activity, GSH content, and Pb concentration in maize leaves were done during this study. MDA levels increased by 71% under Pb stress, while protein content decreased by 56%, GSH content by 35%, and CAT activity by 46%. After treatment with SA, OA, and OA+SA, there was a significant reversal of these damages, with the OA+SA combination showing the highest improvement. Specifically, OA+SA treatment led to a 45% increase in protein content and a 39% reduction in MDA levels compared to Pb treatment alone. Moreover, amino acid concentrations increased by 68% under the Pb+OA+SA treatment, reflecting the most significant recovery (p < 0.0001).


Assuntos
Aminoácidos , Chumbo , Malondialdeído , Ácido Oxálico , Ácido Salicílico , Estresse Fisiológico , Zea mays , Zea mays/efeitos dos fármacos , Zea mays/metabolismo , Chumbo/toxicidade , Ácido Oxálico/metabolismo , Ácido Oxálico/farmacologia , Ácido Salicílico/farmacologia , Aminoácidos/metabolismo , Malondialdeído/metabolismo , Estresse Fisiológico/efeitos dos fármacos , Catalase/metabolismo , Peroxidase/metabolismo , Glutationa/metabolismo , Folhas de Planta/efeitos dos fármacos , Folhas de Planta/metabolismo , Sinergismo Farmacológico , Proteínas de Plantas/metabolismo
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