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1.
Plant J ; 2024 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-38981025

RESUMO

Mangroves grow in tropical/subtropical intertidal habitats with extremely high salt tolerance. Trehalose and trehalose-6-phosphate (T6P) have an alleviating function against abiotic stress. However, the roles of trehalose in the salt tolerance of salt-secreting mangrove Avicennia marina is not documented. Here, we found that trehalose was significantly accumulated in A. marina under salt treatment. Furthermore, exogenous trehalose can enhance salt tolerance by promoting the Na+ efflux from leaf salt gland and root to reduce the Na+ content in root and leaf. Subsequently, eighteen trehalose-6-phosphate synthase (AmTPS) and 11 trehalose-6-phosphate phosphatase (AmTPP) genes were identified from A. marina genome. Abscisic acid (ABA) responsive elements were predicted in AmTPS and AmTPP promoters by cis-acting elements analysis. We further identified AmTPS9A, as an important positive regulator, that increased the salt tolerance of AmTPS9A-overexpressing Arabidopsis thaliana by altering the expressions of ion transport genes and mediating Na+ efflux from the roots of transgenic A. thaliana under NaCl treatments. In addition, we also found that ABA could promote the accumulation of trehalose, and the application of exogenous trehalose significantly promoted the biosynthesis of ABA in both roots and leaves of A. marina. Ultimately, we confirmed that AmABF2 directly binds to the AmTPS9A promoter in vitro and in vivo. Taken together, we speculated that there was a positive feedback loop between trehalose and ABA in regulating the salt tolerance of A. marina. These findings provide new understanding to the salt tolerance of A. marina in adapting to high saline environment at trehalose and ABA aspects.

2.
Acta Pharmacol Sin ; 45(7): 1425-1437, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38839936

RESUMO

Cardiac fibrosis is a pathological scarring process that impairs cardiac function. N-acetyltransferase 10 (Nat10) is recently identified as the key enzyme for the N4-acetylcytidine (ac4C) modification of mRNAs. In this study, we investigated the role of Nat10 in cardiac fibrosis following myocardial infarction (MI) and the related mechanisms. MI was induced in mice by ligation of the left anterior descending coronary artery; cardiac function was assessed with echocardiography. We showed that both the mRNA and protein expression levels of Nat10 were significantly increased in the infarct zone and border zone 4 weeks post-MI, and the expression of Nat10 in cardiac fibroblasts was significantly higher compared with that in cardiomyocytes after MI. Fibroblast-specific overexpression of Nat10 promoted collagen deposition and induced cardiac systolic dysfunction post-MI in mice. Conversely, fibroblast-specific knockout of Nat10 markedly relieved cardiac function impairment and extracellular matrix remodeling following MI. We then conducted ac4C-RNA binding protein immunoprecipitation-sequencing (RIP-seq) in cardiac fibroblasts transfected with Nat10 siRNA, and revealed that angiomotin-like 1 (Amotl1), an upstream regulator of the Hippo signaling pathway, was the target gene of Nat10. We demonstrated that Nat10-mediated ac4C modification of Amotl1 increased its mRNA stability and translation in neonatal cardiac fibroblasts, thereby increasing the interaction of Amotl1 with yes-associated protein 1 (Yap) and facilitating Yap translocation into the nucleus. Intriguingly, silencing of Amotl1 or Yap, as well as treatment with verteporfin, a selective and potent Yap inhibitor, attenuated the Nat10 overexpression-induced proliferation of cardiac fibroblasts and prevented their differentiation into myofibroblasts in vitro. In conclusion, this study highlights Nat10 as a crucial regulator of myocardial fibrosis following MI injury through ac4C modification of upstream activators within the Hippo/Yap signaling pathway.


Assuntos
Fibrose , Camundongos Endogâmicos C57BL , Infarto do Miocárdio , Animais , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Camundongos , Masculino , Proteínas de Sinalização YAP/metabolismo , Fibroblastos/metabolismo , Citidina/análogos & derivados , Citidina/farmacologia , Camundongos Knockout , Proteínas de Membrana/metabolismo , Proteínas de Membrana/genética , Acetiltransferase N-Terminal E/metabolismo , Via de Sinalização Hippo , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Células Cultivadas , Transdução de Sinais , Acetiltransferases N-Terminal/metabolismo , Miocárdio/patologia , Miocárdio/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo
3.
Plant J ; 118(4): 1119-1135, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38308390

RESUMO

Salicylic acid (SA) is known to enhance salt tolerance in plants. However, the mechanism of SA-mediated response to high salinity in halophyte remains unclear. Using electrophysiological and molecular biological methods, we investigated the role of SA in response to high salinity in mangrove species, Kandelia obovata, a typical halophyte. Exposure of K. obovata roots to high salinity resulted in a rapid increase in endogenous SA produced by phenylalanine ammonia lyase pathway. The application of exogenous SA improved the salt tolerance of K. obovata, which depended on the NADPH oxidase-mediated H2O2. Exogenous SA and H2O2 increased Na+ efflux and reduced K+ loss by regulating the transcription levels of Na+ and K+ transport-related genes, thus reducing the Na+/K+ ratio in the salt-treated K. obovata roots. In addition, exogenous SA-enhanced antioxidant enzyme activity and its transcripts, and the expressions of four genes related to AsA-GSH cycle as well, then alleviated oxidative damages in the salt-treated K. obovata roots. However, the above effects of SA could be reversed by diphenyleneiodonium chloride (the NADPH oxidase inhibitor) and paclobutrazol (a SA biosynthesis inhibitor). Collectively, our results demonstrated that SA-induced salt tolerance of K. obovata depends on NADPH oxidase-generated H2O2 that affects Na+/K+ and redox homeostasis in response to high salinity.


Assuntos
Homeostase , Peróxido de Hidrogênio , NADPH Oxidases , Oxirredução , Raízes de Plantas , Potássio , Ácido Salicílico , Tolerância ao Sal , Sódio , Peróxido de Hidrogênio/metabolismo , NADPH Oxidases/metabolismo , NADPH Oxidases/genética , Ácido Salicílico/metabolismo , Ácido Salicílico/farmacologia , Potássio/metabolismo , Tolerância ao Sal/genética , Sódio/metabolismo , Raízes de Plantas/genética , Raízes de Plantas/fisiologia , Raízes de Plantas/metabolismo , Plantas Tolerantes a Sal/genética , Plantas Tolerantes a Sal/metabolismo , Plantas Tolerantes a Sal/fisiologia , Regulação da Expressão Gênica de Plantas , Rhizophoraceae/fisiologia , Rhizophoraceae/genética , Rhizophoraceae/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo
4.
Plant Cell Environ ; 47(2): 511-526, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37869766

RESUMO

Brassinosteroid (BR) has been shown to modulate plant tolerance to various stresses. S-nitrosoglutathione reductase (GSNOR) is involved in the plant response to environment stress by fine-turning the level of nitric oxide (NO). However, whether GSNOR is involved in BR-regulated Na+ /K+ homeostasis to improve the salt tolerance in halophyte is unknown. Here, we firstly reported that high salinity increases the expression of BR-biosynthesis genes and the endogenous levels of BR in mangrove Kandelia obovata. Then, salt-induced BR triggers the activities and gene expressions of GSNOR and antioxidant enzymes, thereafter decrease the levels of malondialdehyde, hydrogen peroxide. Subsequently, BR-mediated GSNOR negatively regulates NO contributions to the reduction of reactive oxygen species generation and induction of the gene expression related to Na+ and K+ transport, leading to the decrease of Na+ /K+ ratio in the roots of K. obovata. Finally, the applications of exogenous BR, NO scavenger, BR biosynthetic inhibitor and GSNOR inhibitor further confirm the function of BR. Taken together, our result provides insight into the mechanism of BR in the response of mangrove K. obovata to high salinity via GSNOR and NO signaling pathway by reducing oxidative damage and modulating Na+ /K+ homeostasis.


Assuntos
Óxido Nítrico , Rhizophoraceae , Óxido Nítrico/metabolismo , Oxirredutases/metabolismo , Brassinosteroides/farmacologia , Brassinosteroides/metabolismo , Rhizophoraceae/genética , Rhizophoraceae/metabolismo , Tolerância ao Sal , Transdução de Sinais
5.
Tree Physiol ; 43(5): 817-831, 2023 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-36611000

RESUMO

Avicennia marina, a mangrove plant growing in coastal wetland habitats, is frequently affected by tidal salinity. To understand its salinity tolerance, the seedlings of A. marina were treated with 0, 200, 400 and 600 mM NaCl. We found the whole-plant dry weight and photosynthetic parameters increased at 200 mM NaCl but decreased over 400 mM NaCl. The maximum quantum yield of primary photochemistry (Fv/Fm) significantly decreased at 600 mM NaCl. Transmission electron microscopy observations showed high salinity caused the reduction in starch grain size, swelling of the thylakoids and separation of the granal stacks, and even destruction of the envelope. In addition, the dense protoplasm and abundant mitochondria in the secretory and stalk cells, and abundant plasmodesmata between salt gland cells were observed in the salt glands of the adaxial epidermis. At all salinities, Na+ content was higher in leaves than in stems and roots; however, Na+ content increased in the roots while it remained at a constant level in the leaves over 400 mM NaCl treatment, due to salt secretion from the salt glands. As a result, salt crystals on the leaf adaxial surface increased with salinity. On the other hand, salt treatment increased Na+ and K+ efflux and decreased H+ efflux from the salt glands by the non-invasive micro-test technology, although Na+ efflux reached the maximum at 400 mM NaCl. Further real-time quantitative PCR analysis indicated that the expression of Na+/H+ antiporter (SOS1 and NHX1), H+-ATPase (AHA1 and VHA-c1) and K+ channel (AKT1, HAK5 and GORK) were up-regulated, and only the only Na+ inward transporter (HKT1) was down-regulated in the salt glands enriched adaxial epidermis of the leaves under 400 mM NaCl treatment. In conclusion, salinity below 200 mM NaCl was beneficial to the growth of A. marina, and below 400 mM, the salt glands could excrete Na+ effectively, thus improving its salt tolerance.


Assuntos
Avicennia , Animais , Tolerância ao Sal , Glândula de Sal/metabolismo , Sódio/metabolismo , Cloreto de Sódio/farmacologia , Cloreto de Sódio/metabolismo , Homeostase , Folhas de Planta/metabolismo , Raízes de Plantas/metabolismo
6.
Eur J Med Chem ; 225: 113821, 2021 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-34517222

RESUMO

Histone deacetylase 6 (HDAC6) is a potential target for Alzheimer's disease (AD). In this study, a series of novel phenothiazine-, memantine-, and 1,2,3,4-tetrahydro-γ-carboline-based HDAC6 inhibitors with a variety of linker moieties were designed and synthesized. As a hydrochloride salt, the phenothiazine-based hydroxamic acid W5 with a pyridyl-containing linker motif was identified as a high potent and selective HDAC6 inhibitor. It inhibited HDAC6 with an IC50 of 2.54 nM and was more than 290- to 3300-fold selective over other HDAC isoforms. In SH-SY5Y cells, W5 dose-dependently increased the acetylated α-tubulin levels and reduced the hyperphosphorylated tau proteins at Ser396. As an effective metal chelator, W5 inhibited Cu2+-induced Aß1-42 aggregation and disaggregated Cu2+-Aß1-42 oligomers, and showed protective effects on the SH-SY5Y cells against Aß1-42- as well as Cu2+-Aß1-42 induced cell damages, serving as a potential ligand to target AD metal dyshomeostasis. Moreover, W5 promoted the differentiated neuronal neurite outgrowth, increased the mRNA expression of the recognized neurogenesis markers, GAP43, N-myc, and MAP-2. Therefore, W5 might be a good lead for the development of novel HDAC6 inhibitors targeting multi-facets of AD.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Desacetilase 6 de Histona/antagonistas & inibidores , Inibidores de Histona Desacetilases/farmacologia , Fármacos Neuroprotetores/farmacologia , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Cobre/metabolismo , Relação Dose-Resposta a Droga , Desacetilase 6 de Histona/metabolismo , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/química , Humanos , Estrutura Molecular , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Fragmentos de Peptídeos/antagonistas & inibidores , Fragmentos de Peptídeos/metabolismo , Relação Estrutura-Atividade , Células Tumorais Cultivadas
7.
Acta Pharmacol Sin ; 42(6): 921-931, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32839503

RESUMO

The neonatal heart possesses the ability to proliferate and the capacity to regenerate after injury; however, the mechanisms underlying these processes are not fully understood. Melatonin has been shown to protect the heart against myocardial injury through mitigating oxidative stress, reducing apoptosis, inhibiting mitochondrial fission, etc. In this study, we investigated whether melatonin regulated cardiomyocyte proliferation and promoted cardiac repair in mice with myocardial infarction (MI), which was induced by ligation of the left anterior descending coronary artery. We showed that melatonin administration significantly improved the cardiac functions accompanied by markedly enhanced cardiomyocyte proliferation in MI mice. In neonatal mouse cardiomyocytes, treatment with melatonin (1 µM) greatly suppressed miR-143-3p levels. Silencing of miR-143-3p stimulated cardiomyocytes to re-enter the cell cycle. On the contrary, overexpression of miR-143-3p inhibited the mitosis of cardiomyocytes and abrogated cardiomyocyte mitosis induced by exposure to melatonin. Moreover, Yap and Ctnnd1 were identified as the target genes of miR-143-3p. In cardiomyocytes, inhibition of miR-143-3p increased the protein expression of Yap and Ctnnd1. Melatonin treatment also enhanced Yap and Ctnnd1 protein levels. Furthermore, Yap siRNA and Ctnnd1 siRNA attenuated melatonin-induced cell cycle re-entry of cardiomyocytes. We showed that the effect of melatonin on cardiomyocyte proliferation and cardiac regeneration was impeded by the melatonin receptor inhibitor luzindole. Silencing miR-143-3p abrogated the inhibition of luzindole on cardiomyocyte proliferation. In addition, both MT1 and MT2 siRNA could cancel the beneficial effects of melatonin on cardiomyocyte proliferation. Collectively, the results suggest that melatonin induces cardiomyocyte proliferation and heart regeneration after MI by regulating the miR-143-3p/Yap/Ctnnd1 signaling pathway, providing a new therapeutic strategy for cardiac regeneration.


Assuntos
Proliferação de Células/efeitos dos fármacos , Melatonina/uso terapêutico , Infarto do Miocárdio/tratamento farmacológico , Miócitos Cardíacos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Animais Recém-Nascidos , Cateninas/metabolismo , Ciclo Celular/efeitos dos fármacos , Células Cultivadas , Coração/efeitos dos fármacos , Camundongos Endogâmicos C57BL , MicroRNAs/metabolismo , Infarto do Miocárdio/metabolismo , Miocárdio/metabolismo , Receptor MT1 de Melatonina/metabolismo , Receptor MT2 de Melatonina/metabolismo , Regeneração/efeitos dos fármacos , Proteínas de Sinalização YAP , delta Catenina
8.
World J Clin Cases ; 8(14): 3122-3129, 2020 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-32775395

RESUMO

BACKGROUND: Hepatosplenic T-cell lymphoma (HSTCL) is a rare subtype of non-Hodgkin's lymphoma, which has an aggressive clinical course and an extremely poor prognosis. Chidamide is a novel, orally active, benzamide-type histone deacetylase (HDAC) inhibitor that has been used for peripheral T-cell lymphoma (PTCL) treatment. However, to date, there has been no report of the treatment and effect of the HDAC inhibitor chidamide in HSTCL, which is a special subtype of PTCL. CASE SUMMARY: A 45-year-old male patient was admitted with splenomegaly and slight bicytopenia. He was diagnosed with HSTCL via splenectomy. The patient was treated with fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with high-dose methotrexate and cytarabine regiment as inductive therapy. Unfortunately, the disease progressed rapidly during chemotherapy before a suitable allogeneic gene transplant donor was found. The chidamide-combined chemotherapy regimen and single-drug oral maintenance regimen achieved complete remission, duration of response of 9 mo, and overall survival of 15 mo. CONCLUSION: The novel agent chidamide can be used in HSTCL to achieve deep remission and improve the duration of response and overall survival.

9.
Clin Exp Pharmacol Physiol ; 47(5): 771-779, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31925815

RESUMO

Gallic acid (GA) has a protective effect on the cardiovascular system. To study its cardiac electrophysiological effects, voltage-gated Na+ channel currents (INa ) were recorded in rat cardiomyocytes using whole-cell patch clamp techniques. Moreover, the effects of GA on aconitine-induced arrhythmias were assessed using electrocardiograms in vivo. We found that the current-voltage characteristic curve (I-V curve) of INa significantly shifted in the presence of 1, 3, and 10 µmol/L of GA. The peak sodium current density (INa -Peak) was reduced from -84.02 ± 5.68 pA/pF to -65.78 ± 3.96 pA/pF with 1 µmol/L, -54.45 ± 5.18 pA/pF with 3 µmol/L, and -44.20 ± 4.35 pA/pF with 10 µmol/L, respectively. GA shifted the steady-state activation curve of INa and recovery curve to the right and the steady-state inactivation curve to the left. The observed inhibitory effect was comparable to that of amiodarone. GA pre-treatment significantly prolonged the onset of fatal ventricular fibrillation. Our results indicated that GA inhibited INa in rat ventricular myocytes and aconitine-induced arrhythmias in vivo. These results suggest the potential of GA for development as a novel anti-arrhythmic therapeutic.


Assuntos
Antiarrítmicos/farmacologia , Ácido Gálico/farmacologia , Frequência Cardíaca/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Fibrilação Ventricular/prevenção & controle , Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacologia , Canais de Sódio Disparados por Voltagem/efeitos dos fármacos , Aconitina , Potenciais de Ação/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Eletrocardiografia , Feminino , Masculino , Miócitos Cardíacos/metabolismo , Ratos Sprague-Dawley , Fatores de Tempo , Fibrilação Ventricular/induzido quimicamente , Fibrilação Ventricular/metabolismo , Fibrilação Ventricular/fisiopatologia , Canais de Sódio Disparados por Voltagem/metabolismo
10.
Medchemcomm ; 10(10): 1740-1754, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32055299

RESUMO

Indoleamine 2,3-dioxygenase 1 (IDO1), an important immunoregulatory enzyme ubiquitously expressed in various tissues and cells, plays a key role in tryptophan metabolism via the kynurenine pathway and has emerged as an attractive therapeutic target for the treatment of cancer and other diseases, such as Alzheimer's disease and arthritis. IDO1 has diverse biological roles in immune suppression and tumor progression by tryptophan catabolism. In addition, IDO1-mediated immune tolerance assists tumor cells in escaping the immune surveillance. Recently, extensive and enormous investigations have been made in the discovery of IDO1 inhibitors in both academia and pharmaceutical companies. In this review, IDO1 inhibitors are grouped as tryptophan derivatives, inhibitors with an imidazole, 1,2,3-triazole or tetrazole scaffold, inhibitors with quinone or iminoquinone, N-hydroxyamidines and other derivatives, and their enzymatic inhibitory activity, selectivity and other biological activities are also introduced and summarized.

11.
J Interpers Violence ; 34(5): 980-999, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-27147274

RESUMO

Although a body of research has established the relationship between childhood maltreatment and bullying in Western culture backgrounds, few studies have examined the association between childhood maltreatment experiences and bullying in China. Moreover, to date, the relationship between multiple types of childhood maltreatment and cyber bullying is poorly understood. This study examined the association between multiple types of childhood maltreatment (physical abuse, emotional abuse, sexual abuse, physical neglect, and emotional neglect) and multiple forms of school bullying (physical, verbal, relational, and cyber). A cross-sectional study using three-stage random cluster-sampling approach was conducted in Tongling, Chuzhou, and Fuyang, in Anhui Province. Self-reported questionnaires were completed by 5,726 middle school students to assess their school bullying involvement and childhood maltreatment experiences. A multivariable logistic regression analysis was used to explore the relationship between each single type of childhood maltreatment and each single form of school bullying. Each type of childhood maltreatment was associated with increased risk for involvement in each form of bullying as bullies, victims, and bully-victims. Specifically, both childhood physical neglect and emotional neglect were associated with increased risk for involvement in each form of school bullying. Each type of childhood maltreatment was associated with involvement in cyber bullying. Students who experienced multiple types of childhood maltreatment seem to report more forms of school bullying. Furthermore, multiple forms of school bullying caused the co-occurrence of several forms of school bullying. Our results indicated a significant association between school bullying and childhood maltreatment among adolescents. Interventions to reduce school bullying encompassing prevention toward childhood maltreatment might get better results in China.

12.
Ying Yong Sheng Tai Xue Bao ; 29(9): 2797-2807, 2018 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-30411554

RESUMO

Soil nitrogen (N) cycling, one of the most important biogeochemical processes in forest ecosystems, has significant environmental effects. However, little is known about how it responds to N deposition and precipitation changes. Here, we examined the main effects of N deposition (NF), rainfall reduction (RR) and their interactive effect (RF) on soil N cycling by N addition and transparent V-shaped board interception in a broad-leaved Korean pine forest in Changbai Mountains. The responses of soil nitrification, denitrification, nitrifying functional genes (ammonia-oxidizing archaea AOA and ammonia-oxidizing bacteria AOB), denitrifying functional genes (nirK, nirS and nosZ) and N fixing function genes (nifH) to NF, RR and RF treatments were analyzed. We found significant positive correlations between nitrification and soil NH4+-N, denitrification and and NO3--N, respectively. Soil nitrification and denitrification were not significantly influenced by the three treatments, while denitrification showed an obvious seasonal dynamics. Long-term RR treatment inhibited soil net nitrification, while NF and RF treatments promoted soil net nitrification; nifH and nosZ genes of bacteria were strong resistant to stress, and their diversity was not susceptible to the changes of N and rainfall. Under drought condition, nirK gene of soil bacteria was more susceptible to N deposition. AOA had a higher sensitivity to drought, while AOB had higher sensitivity to NF and RF treatments. The three treatments affected soil net nitrification and altered the diversity of AOB, AOA and nirK-harboring denitrifier in varying degrees, which might affect the release of N-containing gas and ecosystem services.


Assuntos
Monitoramento Ambiental , Florestas , Nitrogênio/metabolismo , Microbiologia do Solo , Amônia , Archaea , China , Nitrificação , Nitrogênio/análise , Oxirredução , Solo/química
13.
Eur J Med Chem ; 143: 1406-1418, 2018 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-29133060

RESUMO

Histone deacetylase HDAC6, a member of the class IIb HDAC family, is unique among HDAC enzymes in having two active catalytic domains, and has unique physiological function. In addition to the modification of histone, HDAC6 targets specific substrates including α-tubulin and HSP90, and are involved in protein trafficking and degradation, cell shape and migration. Selective HDAC6 inhibitors are an emerging class of pharmaceuticals due to the involvement of HDAC6 in different pathways related to neurodegenerative diseases, cancer, and immunology. Therefore, extensive investigations have been made in the discovery of selective HDAC6 inhibitors. Based on their different zinc binding groups (ZBGs), in this review, HDAC6 inhibitors are grouped as hydroxamic acids, a sulfur containing ZBG based derivatives and other ZBG-derived compounds, and their enzymatic inhibitory activity, selectivity and other biological activities are introduced and summarized.


Assuntos
Descoberta de Drogas/métodos , Desacetilase 6 de Histona/metabolismo , Inibidores de Histona Desacetilases/farmacologia , Animais , Inibidores de Histona Desacetilases/química , Inibidores de Histona Desacetilases/metabolismo , Humanos , Ácidos Hidroxâmicos/química , Ácidos Hidroxâmicos/metabolismo , Ácidos Hidroxâmicos/farmacologia , Enxofre/química , Zinco/metabolismo
14.
Curr Genet ; 61(2): 143-52, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25417093

RESUMO

Conidiation promotes fungal dispersal and survival in the environment, and is a determinant for the biocontrol potential of Beauveria bassiana. The SNF1/AMPK protein kinases function as an important regulator of fungal development and energy metabolism, and play a crucial role in conidiation of the filamentous fungi. In previous study, it has been established that the B. bassiana homolog (BbSNF1) controls conidial production. This study showed that the ΔBbSNF1 mutants displayed a delayed development of mycelia and conidia, but the conidiophore morphogenesis was not significantly changed in the mutants. Ablation of BbSNF1 significantly changed the metabolic homeostasis of intracellular amino acids during conidiation, and caused a notable reduction in the contents of seven amino acids (i.e., arginine, alanine, valine, phenylalanine, lysine, leucine, and glutamic acid). All above amino acids could recover conidiation of the mutants in different extents (ranging from 43.3 to 300 %). Transcriptomic analysis revealed many putative target genes regulated by BbSNF1 and associated with conidial development, and these genes were primarily involved in metabolism, cell rescue, and transport. Particularly, four categories related to the amino acid degradation were over-represented in the up-regulated genes, and three categories related to the amino acid biosynthesis were over-represented in the down-regulated genes. Moreover, the ΔBbSNF1 mutants displayed reduced expression level of the upstream and central regulators of conidiation, as well as the other regulator and cytoskeleton genes. Our data indicate that SNF1 kinase contributes to B. bassiana conidiation by regulating the metabolism and the central regulators of conidiation.


Assuntos
Beauveria/genética , Proteínas Serina-Treonina Quinases/genética , Esporos Fúngicos/genética , Transcriptoma/genética , Beauveria/crescimento & desenvolvimento , Beauveria/metabolismo , Proteínas Fúngicas/biossíntese , Regulação da Expressão Gênica no Desenvolvimento , Regulação Fúngica da Expressão Gênica , Micélio/genética , Micélio/crescimento & desenvolvimento , Proteínas Serina-Treonina Quinases/metabolismo , Análise de Sequência de RNA , Esporos Fúngicos/crescimento & desenvolvimento
15.
Appl Microbiol Biotechnol ; 98(20): 8657-73, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25016341

RESUMO

SNF1/AMPK protein kinase plays important roles in fungal development and activation of catabolite-repressed genes. In this study, we characterized the role of the Beauveria bassiana SNF1 ortholog. The vegetative growth of the ΔBbSNF1 mutant was reduced by 16 to 50 % on diverse carbon/nitrogen sources. Transcriptional analysis revealed a collection of proteases and chitinases that were not induced when the mutant was grown on complex carbon/nitrogen sources. BbSNF1 also contributes to extracellular acidification. The ΔBbSNF1 mutant had enhanced production of lactic, pyruvic, and citric acid, but oxalic acid production was partially repressed. Transcriptional analysis showed that a set of genes involved in acid biosynthesis and secretion was changed in the disruption mutant, indicating that BbSNF1 controls the production of different organic acids with different mechanisms. Deletion of BbSNF1 resulted in a significant reduction in conidiation (57-75 %) and blastospore yield (80-95 %) in the mutant. Additionally, BbSNF1 regulates the morphology of blastospore-forming structures and the in vitro blastospore size. Insect bioassays revealed that the ΔBbSNF1 strain exhibited an approximately doubled median lethal time in topical bioassays, but the decreased virulence in intrahemocoel assays (~20 % change) was not as great as in the topical bioassays. These data suggest that BbSNF1 is important in penetration through the host cuticle. Moreover, a series of genes regulated by BbSNF1 and associated with blastospore formation were primarily involved in metabolism, cell cycle, and transportation. In conclusion, the SNF1/AMPK kinase contributes to the biocontrol potential of B. bassiana by mediating cellular differentiation and utilization of carbon/nitrogen sources.


Assuntos
Beauveria/fisiologia , Ácidos Carboxílicos/metabolismo , Regulação Fúngica da Expressão Gênica , Proteínas Serina-Treonina Quinases/metabolismo , Animais , Beauveria/genética , Beauveria/crescimento & desenvolvimento , Beauveria/metabolismo , Bioensaio , Carbono/metabolismo , Deleção de Genes , Perfilação da Expressão Gênica , Insetos/microbiologia , Nitrogênio/metabolismo , Proteínas Serina-Treonina Quinases/genética , Esporos Fúngicos/crescimento & desenvolvimento , Análise de Sobrevida , Virulência
16.
Environ Microbiol ; 16(6): 1879-97, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24612420

RESUMO

Multiprotein bridging factors (MBFs) are evolutionarily highly conserved cofactors that link TATA-binding protein and the associated basal transcription machinery to transcription factors. The filamentous fungus, Beauveria bassiana, has a multipotential lifestyle capable of growing as a saprophyte, plant endophyte and insect pathogen. Deletion of the single B. bassiana MBF homologue (BbMBF1) affected fungal growth and hyphal morphogenesis, stress response and virulence. Compared with wild type, the ΔBbMBF1 strain displayed increased sensitivity to UV-irradiation and to oxidative, osmotic and heat stress, and decreased virulence in both topical and intrahaemocoel injection bioassays using the greater wax moth, Galleria mellonella larvae. Although only minor radial growth effects were seen for the ΔBbMBF1 strain, aberrant hyphal morphogenesis was observed, which could be rescued by growth in rich broth media. Transcriptional analysis during stress response showed altered gene expression in ΔBbMBF1 during growth under osmotic, oxidative and thermal stress conditions. Genome-wide expression analyses during growth under unstressed and thermal stress conditions revealed global gene expression changes and a set of putative targets for MBF1 mediated gene expression control. Our data indicate that BbMBF1 acts as a key regulatory cofactor controlling stress responses and virulence and that MBF1 dependent and independent pathways control proper hyphal morphogenesis.


Assuntos
Beauveria/crescimento & desenvolvimento , Proteínas Fúngicas/genética , Hifas/crescimento & desenvolvimento , Transativadores/genética , Adaptação Fisiológica , Animais , Beauveria/patogenicidade , Proteínas Fúngicas/metabolismo , Regulação Fúngica da Expressão Gênica , Técnicas de Inativação de Genes , Hifas/patogenicidade , Larva/microbiologia , Morfogênese , Mariposas/microbiologia , Estresse Fisiológico , Transativadores/metabolismo , Virulência
17.
Res Microbiol ; 164(5): 480-9, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23499939

RESUMO

Carbohydrate transporters are critical players mediating nutrient uptake during saprophytic and pathogenic growth for most filamentous fungi. For entomopathogenic fungi, such as Beauveria bassiana, assimilation of α-glucosides, in particular, trehalose, the major carbohydrate constituent of the insect haemolymph, has been hypothesized to represent an important ability for infectious growth within the insect hemocoel. In this study, a B. bassiana α-glucoside transporter homolog was identified and genetically characterized via generation of a targeted gene disruption mutant. Trehalose utilization was compromised in the mutant strain. In addition, inactivation of the α-glucoside transporter resulted in decreased conidial germination, growth, and yield on various carbohydrates (α-glucosides, monosaccharides and polyols) as compared to the wild-type strain. Insect bioassays revealed decreased mean lethal mortality time using both topical and intrahemocoel injection assays, although final mortality levels were comparable in both the mutant and wild type. Gene expression profiles showed altered expression of other putative transporters in the knockout mutant as compared to the wild type. These results highlighted complex sugar utilization and responsiveness in B. bassiana and the potential role for trehalose assimilation during fungal pathogenesis of insects.


Assuntos
Beauveria/crescimento & desenvolvimento , Beauveria/metabolismo , Insetos/microbiologia , Proteínas de Membrana Transportadoras/genética , Proteínas de Membrana Transportadoras/metabolismo , Esporos Fúngicos/crescimento & desenvolvimento , Trealose/metabolismo , Animais , Beauveria/genética , Beauveria/patogenicidade , Bioensaio , Análise por Conglomerados , DNA Fúngico/química , DNA Fúngico/genética , Técnicas de Inativação de Genes , Genes Fúngicos , Insetos/fisiologia , Dados de Sequência Molecular , Filogenia , Análise de Sequência de DNA , Homologia de Sequência de Aminoácidos , Análise de Sobrevida
18.
PLoS One ; 5(12): e15134, 2010 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-21151897

RESUMO

Knowledge of soil respiration and photosynthesis under elevated CO(2) is crucial for exactly understanding and predicting the carbon balance in forest ecosystems in a rapid CO(2)-enriched world. Quercus mongolica Fischer ex Ledebour seedlings were planted in open-top chambers exposed to elevated CO(2) (EC = 500 µmol mol(-1)) and ambient CO(2) (AC = 370 µmol mol(-1)) from 2005 to 2008. Daily, seasonal and inter-annual variations in soil respiration and photosynthetic assimilation were measured during 2007 and 2008 growing seasons. EC significantly stimulated the daytime soil respiration by 24.5% (322.4 at EC vs. 259.0 mg CO(2) m(-2) hr(-1) at AC) in 2007 and 21.0% (281.2 at EC vs. 232.6 mg CO(2) m(-2) hr(-1) at AC) in 2008, and increased the daytime CO(2) assimilation by 28.8% (624.1 at EC vs. 484.6 mg CO(2) m(-2) hr(-1) at AC) across the two growing seasons. The temporal variation in soil respiration was positively correlated with the aboveground photosynthesis, soil temperature, and soil water content at both EC and AC. EC did not affect the temperature sensitivity of soil respiration. The increased daytime soil respiration at EC resulted mainly from the increased aboveground photosynthesis. The present study indicates that increases in CO(2) fixation of plants in a CO(2)-rich world will rapidly return to the atmosphere by increased soil respiration.


Assuntos
Dióxido de Carbono/química , Respiração Celular , Quercus/fisiologia , Árvores/fisiologia , Ecossistema , Fotossíntese , Folhas de Planta/fisiologia , Fenômenos Fisiológicos Vegetais , Raízes de Plantas/metabolismo , Estações do Ano , Plântula , Solo , Temperatura
19.
Zhongguo Zhong Xi Yi Jie He Za Zhi ; 30(2): 161-6, 2010 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-20462044

RESUMO

OBJECTIVE: To investigate the functional and metabolic alterations in cultured insulin resistant ovary model in vitro, and to observe the effect of berberine (Ber, a Chinese medical monomer) in improving insulin resistance (IR). METHODS: Ovary of mouse was cultured in vitro and treated by dexamethasone (Dex) to induce IR for establishing IR model ovary. The functional alteration in model ovary was assessed through detecting glucose and hormone levels in medium using RT-PCR, meanwhile, the expression of key molecules in insulin signal and steroid synthetic pathway were detected, and condition of IR improved by berberine was evaluated also. RESULTS: (1) The model ovary was made by Dex in dose- and acting time-dependent manner. After being treated by 300 nmol/L Dex for 48 h, the glucose uptake of ovary reduced from 9.05 +/- 0.75 mg/g to 2.48 +/- 0.29 mg/g (P < 0.05); it further decreased (from 9.59 +/- 1.74 mg/g to 1.94 +/- 0.19 mg/g, P < 0.01) under the stimulation of insulin, which proved that the IR model ovary was made successfully. Berberine significantly increased the glucose uptake of model ovaries (1.89 +/- 0.33 mg/g to 13.95 +/- 3.30 mg/g, P < 0.05). (2) As compared with control group, levels of testosterone (T) and androstenedione (A2) were higher, and levels of progesterone (P) and 17-hydroxyprogesterone (17-OHP) were lower significantly in the model. Berberine reversed the alternations of T, A2 and 17-OHP levels, but did not influence the level of P. (3) RT-PCR showed that the mRNA expressions of cytochrome 17-hydroxylase (CYP17) and mini-chromosome maintenance protein-2 (MCM-2) elevated, but extracellular regulated protein-1 (ERK-1), protein kinase B (AKT-2) and glycogen synthase kinase-3 (GSK-3beta) lowered in the medium after Dex inducing. Berberine treatment restored these molecular index obviously. CONCLUSIONS: (1) Dex could induce IR in mouse ovary, which might enhance the androgenic synthesis. (2) Berberine could alleviate the degree of IR and the androgen synthesis, indicating that the Chinese sensitizing agents has favorable therapeutic effect for the treatment of polycystic ovaries.


Assuntos
Berberina/farmacologia , Resistência à Insulina , Ovário/efeitos dos fármacos , Ovário/metabolismo , 17-alfa-Hidroxiprogesterona/metabolismo , Androstenodiona/biossíntese , Animais , Feminino , Técnicas In Vitro , Insulina/metabolismo , Camundongos , Camundongos Endogâmicos , Síndrome do Ovário Policístico , Progesterona/biossíntese , Testosterona/biossíntese
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