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Pyridazine, as a privileged scaffold, has been extensively utilized in drug development due to its multiple biological activities. Especially around its distinctive anticancer property, a massive number of pyridazine-containing compounds have been synthesized and evaluated that target a diverse array of biological processes involved in cancer onset and progression. These include glutaminase 1 (GLS1) inhibitors, tropomyosin receptor kinase (TRK) inhibitors, and bromodomain containing protein (BRD) inhibitors, targeting aberrant tumor metabolism, cell signal transduction and epigenetic modifications, respectively. Pyridazine moieties functioned as either core frameworks or warheads in the above agents, exhibiting promising potential in cancer treatment. Therefore, the review aims to summarize the recent contributions of pyridazine derivatives as potent anticancer agents between 2020 and 2024, focusing mainly on their structure-activity relationships (SARs) and development strategies, with a view to show that the application of the pyridazine scaffold by different medicinal chemists provides new insights into the rational design of anticancer drugs.
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Antineoplásicos , Piridazinas , Piridazinas/química , Piridazinas/farmacologia , Piridazinas/síntese química , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Humanos , Relação Estrutura-Atividade , Química Farmacêutica , Estrutura Molecular , Neoplasias/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos AntitumoraisRESUMO
BACKGROUND: Fragrant rice is increasingly popular with the public owing to its fresh aroma, and 2-acetyl-1-pyrroline (2-AP) is the main characteristic component of the aroma in fragrant rice. Rice-fish co-culture is an environmentally friendly practice in sustainable agriculture. However, the effect of rice-fish co-culture on 2-AP in grains has received little study. A conventional fragrant rice (Meixiangzhan 2) was used, and a related field experiment during three rice growing seasons was conducted to investigate the effects of rice-fish co-culture on 2-AP, as well as the rice quality, yield, plant nutrients, and precursors and enzyme activities of 2-AP biosynthesis in leaves. This study involved three fish stocking density treatments (i.e. 9000 (D1), 15 000 (D2), and 21 000 (D3) fish fries per hectare) and rice monocropping. RESULTS: Rice-fish co-culture increased the 2-AP content in grains by 2.5-49.4% over that of the monocropping, with significant increases in the early and late rice seasons of 2020. Rice-fish co-culture treatments significantly promoted seed-setting rates by 3.39-7.65%, and improved leaf nutrients and rice quality. Notably, the D2 treatment significantly increased leaf total nitrogen (TN), total phosphorus (TP), and total potassium (TK) contents and the head rice rate at maturity stage, while significantly decreased chalkiness degree. There was no significant difference in rice yield. CONCLUSION: Rice-fish co-culture had positive effects on 2-AP synthesis, rice quality, seed-setting rates, and plant nutrient contents. The better stocking density of field fish for rice-fish co-culture in this study was 15 000 fish ha-1 . © 2023 Society of Chemical Industry.
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Oryza , Animais , Oryza/química , Grão Comestível , Sementes , PirróisRESUMO
BACKGROUND: Sea cucumber (Stichopus japonicus) is easy to autolysis in response to a variety of environmental and mechanical factors. In the current study, collagen fibres were extracted from fresh sea cucumber body wall and then incubated with endogenous matrix metalloprotease (MMP) of sea cucumber. Scanning electron microscopy (SEM), differential scanning calorimetry (DSC), chemical analysis and sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE) analysis were utilized to demonstrate the changes in collagen fibres, collagen fibrils and collagen proteins. Moreover, a verification experiment was also carried out to confirm the contribution of MMP to the autolysis of sea cucumber. RESULTS: Endogenous MMP caused complete depolymerization of collagen fibres into smaller collagen fibril bundles and collagen fibrils due to the fracture of proteoglycan interfibrillar bridges. Meanwhile, endogenous MMP also caused partial degradation of collagen fibrils by releasing soluble hydroxyproline and pyridinium cross-links. Furthermore, the treatment with MMP inhibitor (1,10-phenanthroline) prevented the autolysis of tissue blocks from S. japonicus dermis. CONCLUSION: Endogenous MMP was the key enzyme in the autolysis of sea cucumber, while its action still focused on high-level structures of collagens especially collagen fibres. © 2019 Society of Chemical Industry.
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Autólise , Metaloproteases/metabolismo , Stichopus/enzimologia , Stichopus/fisiologia , Animais , Colágeno/metabolismo , Colágeno/ultraestrutura , Hidroxiprolina/metabolismo , Metaloproteases/genética , Microscopia Eletrônica de Varredura , Stichopus/ultraestruturaRESUMO
It has always been a challenge to combine research progress with undergraduate laboratory teaching. Herein we designed a comprehensive experiment to compare classical Mendelian segregation and non-Mendelian distorted segregation by utilizing a rice material (DSSL) containing F1 hybrid male sterility locus S23 constructed previously in our research project. Using the four SSR markers located on two chromosomes of rice, the genotypes of the F2 population and the two parents were analyzed, and the phenotypes of the pollen fertility of the two parents and their F1 plants were investigated. The results not only verified segregation law at the molecular level, but also fully demonstrated the distorted segregation in both genotypes and phenotypes, thus deepening students' understandings of plant genetics and the relationship between genotypes and phenotypes, inspiring students' interests in genetics experiments, and enhancing students' consciousness and enthusiasm for experimental learning. On the basis of this, a sustainable development idea of transforming scientific research progress into teaching applications was conceived to promote the reform and innovation of genetics laboratory teaching.
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Segregação de Cromossomos , Genética/educação , Aprendizagem , Oryza/genética , Marcadores Genéticos , Genótipo , Repetições de Microssatélites , Infertilidade das Plantas/genética , Pólen , EstudantesRESUMO
Optogenetics is a cell-type specific and high spatial-temporal resolution method that combines genetic encoding of light-sensitive proteins and optical manipulation techniques. Optogenetics technology provides a novel approach for research on cardiac arrhythmia treatment, including pacing, recovering the conduction system, and achieving cardiac resynchronization with precise and low-energy optical control. Photosensitive proteins, which usually act as ion channels, pumps, or receptors, are delivered to target cells, where they respond to light pulses of specific wavelengths, evoke transient flows of transmembrane ion currents, and induce signal transmission. With the development of gene technology, the in vivo efficiency of optogenetics in cardiology has been trialed, and in vitro experiments have been performed to test its potential in cardiac electrophysiology. Challenges for applying optogenetics in large animals and humans include the effectiveness, safety, and long-term expression of photosensitive proteins, unscattered and unattenuated exogenous light stimulation, and the need for implantable miniature light stimulators. Photosensitive proteins, genetic engineering technology, and light equipment are essential for experiments in cardiac optogenetics. Optogenetics may provide an alternative method for evaluating the mechanism of cardiac arrhythmias, testing hypotheses, and treating cardiovascular diseases.
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Arritmias Cardíacas , Optogenética/métodos , Animais , Arritmias Cardíacas/genética , Arritmias Cardíacas/terapia , Eletrofisiologia Cardíaca/métodos , Eletrofisiologia Cardíaca/tendências , HumanosRESUMO
IMPORTANCE: Phage therapy is gaining traction as an alternative to antibiotics due to the rise of multi-drug-resistant (MDR) bacteria. This study assessed the pharmacokinetics and safety of PA_LZ7, a phage targeting MDR Pseudomonas aeruginosa, in mice. After intravenous administration, the phage showed an exponential decay in plasma and its concentration dropped significantly within 24 h for all dosage groups. Although there was a temporary increase in certain plasma cytokines and spleen weight at higher dosages, no significant toxicity was observed. Therefore, PA_LZ7 shows potential as an effective and safe candidate for future phage therapy against MDR P. aeruginosa infections.
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Bacteriófagos , Infecções por Pseudomonas , Fagos de Pseudomonas , Animais , Camundongos , Fagos de Pseudomonas/genética , Antibacterianos/uso terapêutico , Antibacterianos/farmacologia , Infecções por Pseudomonas/terapia , Infecções por Pseudomonas/microbiologia , Pseudomonas aeruginosaRESUMO
Chinese fir in China are generally inefficient plantations with single species, unreasonable stand density, and low productivity. The introduction of broadleaved species is usually adopted as a strategy to improve Chinese fir plantations. Taking the pure forests and mixed forests of the Guanshan Forest Farm in Jiangxi Province as example, we quantified the intrinsic water-use efficiency (iWUE) of trees based on the stable isotope carbon method, as well as its response to meteorological factors, and investigated the improvement of stand quality after introducing Phoebe zhennan into Chinese fir plantation. The results showed that the basal area increment was 0.23 cm2 in pure forest, being higher than that of 0.19 cm2 in mixed forest. The δ13C and iWUE of pure forest were -27.4 and 52.9%, respectively, being lower than those of -26.7 and 62.8% in the mixed forest. Tree δ13C in pure forest was more sensitive to changes in mean annual precipitation and mean annual relative humidity, while that in mixed forest was not significantly correlated with meteorological factors. Pure forest iWUE was positively correlated with mean annual temperature, mean annual atmospheric CO2 concentration, and mean annual maximum temperature, and negatively correlated with mean annual precipitation and mean annual relative humidity, while mixed forest iWUE was positively correlated with mean annual atmospheric CO2 concentration only. Our results indicated that pure forests was more sensitive to climate than mixed forests.
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Cunninghamia , Água , Dióxido de Carbono , Clima , Florestas , Árvores , TemperaturaRESUMO
Older individuals with macular diseases, such as age-related macular degeneration, experience central vision loss (CVL) due to degeneration of their photoreceptors and retinal cells. Patients with CVL may experience various vision impairments, including of visual acuity, fixation stability, contrast sensitivity, and stereoacuity. After CVL, most patients develop a preferred retinal locus outside the affected macular region, which serves as a new visual reference. In this review, we provide an overview of the visual function and impairment in individuals with CVL. In addition, the important role of biofeedback training on the visual function and activity of individuals with CVL is also reviewed. Accordingly, the location and development of the preferred retinal loci are discussed. Finally, this review discusses how to conduct biofeedback training to treat individuals with CVL.
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The process of plant water use is complex and changeable, which is affected by various factors. Exploring the sources and influencing factors of plant water use can provide reference for clarifying the mechanisms of forest water adaptation under climate change. We chosen the typical forest communities in the hilly region of Sou-thern China, Pinus massoniana and Quercus acutissima mixed forest as the research object. By analyzing water sources of plants in different seasons, the factors affecting the changes of water sources were explored in combination with soil water, precipitation, and plant roots. The results showed that water use characteristics of P. massoniana and Q. acutissima were similar and both mainly utilized 0-40 cm soil water during the dry season, with proportions of 60.0% and 66.6%. During the rainy season, as soil water content of deep layers increased, the main water sources of both gradually shifted towards deep soil. The similarity proportion indices of P. massoniana and Q. acutissima were above 60%, indicating that there was an obvious water competition between them. Root system of Q. acutissima had plasticity in water absorption, and played a dominant role in absorbing shallow water during the dry season. Water was the main driving factor for water source transformation of Q. acutissima and P. massoniana during the rainy season. Compared with P. massoniana, Q. acutissima was more sensitive to the changes of water sources. Under the background of future warming and drying, the competition between the two species for shallow water sources might be intensified. Those two species should be sparsely planted or thinned to optimize forest structure to cope with water stress.
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Pinus , Quercus , Aclimatação , China , SoloRESUMO
IMPORTANCE: Salmonella infection is a significant threat to global public health, and the increasing prevalence of antibiotic resistance exacerbates the situation. Therefore, finding new and effective ways to combat this pathogen is essential. Phages are natural predators of bacteria and can be used as an alternative to antibiotics to kill specific bacteria, including drug-resistant strains. One significant limitation of using phages as antimicrobial agents is their low cellular uptake, which limits their effectiveness against intracellular bacterial infections. Therefore, finding ways to enhance phage uptake is crucial. Our study provides a straightforward strategy for displaying cell-penetrating peptides on non-model phages, offering a promising novel and effective therapeutic approach for treating intracellular and drug-resistant bacteria. This approach has the potential to address the global challenge of antibiotic resistance and improve public health outcomes.
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Infecções Bacterianas , Bacteriófagos , Peptídeos Penetradores de Células , Humanos , Infecções Bacterianas/terapia , Resistência Microbiana a Medicamentos , Antibacterianos/farmacologiaRESUMO
Apoptosis plays a critical role in sea cucumber autolysis. To investigate the ultraviolet (UV)-induced apoptosis, sea cucumbers with and without injection of BAPTA-AM (cytosolic calcium chelator) were exposed to UV (15 W/m2) for 30 min. The results showed that UV irradiation caused several changes in sea cucumber coelomocytes, including calcium imbalance, abnormal morphology of endoplasmic reticulum, upregulation of pro-apoptotic proteins CRT, CHOP, and caspases 9 and 3, and downregulation of anti-apoptotic protein Bcl-2. A comparison between the two groups showed that injection of the calcium chelator into sea cucumbers helped maintain coelomocyte intracellular calcium homeostasis and suppressed other abnormal changes caused by ER stress, indicating apoptosis in sea cucumbers is mediated by calcium imbalance and follows the activation of the ER stress pathway. Therefore, this study broadens understanding of the apoptotic mechanism involved in sea cucumber autolysis, which is helpful in developing preservative agents for sea cucumbers.
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Pepinos-do-Mar , Stichopus , Animais , Autólise , Cálcio , HomeostaseRESUMO
In the areas with seasonal drought, water is the key factor affecting plant growth and development. Based on long-term continuous observation data, it is of great significance to explore plant water use patterns for vegetation construction in areas with seasonal drought. Taking Platycladus orientalis in Beijing mountainous area as the research object, stable hydrogen and oxygen isotope technique was applied to measure the isotopic composition of water from the soil, plant branches, and precipitation from 2012 to 2017. The relative contribution of soil water from different soil layers to P. orientalis was quantified by the MixSIAR model. The results showed that soil water in the deep layer (40-100 cm) was more stable than that in the shallow layer (0-40 cm). The variation of soil water content and water isotope values in the shallow layer were more obvious due to the effects of evaporation and precipitation. P. orientalis mainly absorbed stable deep soil water, with a relative contribution rate of 55.7%. In the dry season, with the decreases of soil water content, the absorption depth of plants to soil water gradually shifted to the shallow layer. Under conditions of moist, natural condition, mild drought and moderate drought, the relative contribution rates of deep soil water were 59.8%, 57.9%, 54.6%, 52.7%, respectively. To maintain higher transpiration in the wet season, P. orientalis relied more on deep soil water under mild and moderate drought conditions than in the dry season. Under the conditions of moist, natural condition, mild drought and moderate drought, the relative contribution rates of deep soil water were 58.9%, 57.6%, 56.4%, and 57.1%, respectively. The adaptive characteristic of P. orientalis, which adjusts the depth of root water absorption according to soil moisture condition, is of great significance for tree species selection in ecological afforestation and long-term management planning in areas with seasonal drought.
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Secas , Árvores , Pequim , Estações do Ano , Solo , ÁguaRESUMO
Protein oxidation is considered as an important factor affecting the texture quality of surimi. In this work, the myofibrillar protein (MP) from shrimp (Penaeus vannamei) was subjected to a hydroxyl radical generating system at various concentrations of H2O2, to simulate the oxidative environment during surimi processing. After the hydroxyl radical oxidation, it was found that the carbonyl content, surface hydrophobicity, and MP aggregation increased. Meanwhile, the a-helix decreased, but ß-sheet increased after oxidation. The moderate oxidation led to a dense network microstructure, increased water holding capacity (WHC) and decreased water mobility, which ultimately enhanced textural (hardness and springiness increased by 0.51- and 0.06-fold, respectively) and rheological properties of MP gel (MPG). However, excessive oxidation could reduce the mechanical properties of MPG. The microstructure, WHC and water distribution played a key role in the mechanical properties of MPG. This study can provide a theoretical basis for processing of shrimp surimi products.
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Anostraca , Fenômenos Químicos , Radical Hidroxila/química , Proteínas Musculares/química , Animais , Géis , Interações Hidrofóbicas e Hidrofílicas , Oxirredução , Reologia , Alimentos Marinhos , Água/químicaRESUMO
Texture deterioration occurs in adductor muscle of scallop (Argopecten irradians) (AMS) after 5 d of cold storage. Principal component analysis indicated the texture deterioration resulted in significant decrease of hardness, springiness, adhesiveness and chewiness, but significantly increased cohesiveness. Endogenous proteases degraded structural proteins, among which cysteine proteases were mainly responsible for myofibrillar proteins (MPs) degradation, while serine proteases degraded both MPs and connective tissue proteins. Pearson coefficient analysis showed that texture indicators significantly correlated with structural protein indicators in AMS. To be more specific, the hardness, springiness, adhesiveness and chewiness negatively correlated with myofibrillar fragmentation index, soluble hydroxyproline (Hyp) and soluble glycosaminoglycans, but positively correlated with solubility of MPs and water holding capacity. Meanwhile, the cohesiveness positively correlated with soluble Hyp. The Taylor diagram and Hierarchical cluster analysis confirmed that the inhibitors of cysteine and serine proteases could effectively retard textural deterioration of AMS during 5 d of cold storage.
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Live sea cucumbers (Stichopus japonicus) were stored in a solution containing oxalic acid and tea polyphenols as natural metal ion chelators. The inhibitory effects of these chelators on the autolysis phenomenon and the underlying mechanism of action were investigated for the first time by using scanning electron microscopy, differential scanning calorimetry, low-field nuclear magnetic resonance and confocal laser scanning microscopy. External stimuli cause autolysis through the release of calcium ions (Ca2+) from cells into the extracellular connective tissue, initiating activity of the matrix metalloprotease (MMP) in the sea cucumber body wall (SCBW). MMP subsequently degrades the microfibrillar networks, that support the interconnecting collagen fibres and the interfibrillar proteoglycan bridges linking the collagen fibrils, to release the water restricted within the interspaces between collagen fibres and collagen fibrils, ultimately causing mucoid degeneration of SCBW. The natural metal ion chelators significantly inhibited the activation of MMP by chelating Ca2+, consequently effectively preventing the autolysis of SCBW.
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Pepinos-do-Mar , Stichopus , Animais , Autólise , Quelantes , ColágenoRESUMO
The effects of endogenous proteolysis and oxidation on mechanical properties of sea cucumber (Stichopus japonicus) during thermal processing and storage and their control were investigated. The lactic acid (LA) + tea polyphenols (TP)-treated sea cucumbers showed relatively higher values in texture and rheological indicators than the blank control group after thermal processing. By contrast, the (LA + TP)-treated sea cucumbers also had lower values in water-soluble hydroxyproline, glycosaminoglycans and proteins, trichloroacetic acid-soluble peptide content, and more orderly secondary structure of proteins, indicating that the additives affected the mechanical properties of thermally processed sea cucumbers by preventing the proteolysis of proteins. All texture and rheological indicators of thermally processed sea cucumbers decreased time-dependently during chilled storage. The additives (LA + TP) significantly prevented the progressive deterioration in mechanical properties by retarding the changes in microstructure as well as phase state and distribution of water through preventing protein oxidation.
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Pepinos-do-Mar/química , Animais , Temperatura Alta , Hidroxiprolina/química , Oxirredução , ProteóliseRESUMO
The impact of protein oxidation and degradation on texture deterioration of ready-to-eat (RTE) shrimps during storage was investigated. The deterioration in texture during storage was manifested by decreased instrumental hardness, elasticity, chewiness, and recoverability. The occurrence of protein oxidation was revealed by a significant increase in the contents of free radicals and carbonyls. The increases in trichloroacetic acid-soluble peptide (TCA-soluble peptide) content and myofibril fragmentation index (MFI) were also observed, suggesting the degradation of protein. Pearson correlation analysis showed that the decreased instrumental texture parameters were negatively correlated with the increased carbonyl content, TCA-soluble peptide, MFI, porosity, and pore size as well as the decreased water-holding capacity (WHC), thus, it was hypothesized that protein oxidation and degradation were responsible for changes in the microstructure and reduction of WHC, which ultimately resulted in texture deterioration of RTE shrimps.
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Proteínas de Artrópodes/química , Palaemonidae/química , Frutos do Mar/análise , Animais , Fast Foods/análise , Armazenamento de Alimentos , Radicais Livres/análise , Dureza , Miofibrilas/química , Oxirredução , Água/análiseRESUMO
The autolysis of sea cucumber is caused by depolymerisation of collagen fibres and unfolding of fibrils. In order to highlight the role of collagenase in sea cucumber autolysis, collagen fibres from sea cucumber were hydrolysed with collagenase type I. Electron microscopy (EM) results indicated the collagenase caused partial depolymerisation of collagen fibres into fibrils due to the fracture of proteoglycan interfibrillar bridges, as well as uncoiling of collagen fibrils. Chemical analysis and SDS-PAGE both indicated collagenase induced a time-dependent release of glycosaminoglycans (GAGs) and soluble proteins, which further demonstrated the degradation of proteoglycan interfibrillar bridges. Collagenase also degraded collagens by releasing soluble hydroxyproline (Hpy), with the dissolution rate of Hyp reaching 11.11% after 72â¯h. Fourier transform infrared analysis showed that collagenase caused the reduction of intermolecular interactions and structural order of collagen. Hence, collagenase participated in the autolysis of sea cucumber by deteriorating both macromolecular and monomeric collagens.
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Colágeno/química , Colagenases/química , Stichopus/química , Animais , Autólise , Colágeno/metabolismo , Colagenases/metabolismo , Eletroforese em Gel de Poliacrilamida , Glicosaminoglicanos/metabolismo , Hidrólise , Hidroxiprolina/metabolismo , Microscopia Eletrônica de Varredura , Microscopia Eletrônica de Transmissão , Proteoglicanas/química , Proteoglicanas/metabolismo , Espectroscopia de Infravermelho com Transformada de Fourier , Stichopus/anatomia & histologiaRESUMO
Water use efficiency (WUE) is an important index to evaluate plant drought resistance. Studying the dynamics of WUE and its influencing factors can provide reference for the vegetation restoration in Beijing mountainous area. We measured WUE of Platycladus orientalis in growing season and investigated the influence of meteorological factors, soil factors, and atmospheric CO2 concentration on WUE, based on the stable carbon isotope techniques. The results showed that: 1) The short-term WUE decreased and then increased in the growing season, with minimum value (2.69 mmol·mol-1) in July and maximum value (13.88 mmol·mol-1) in October. 2) The vapor pressure deficit (VPD) had the most significant impacts on WUE, followed by air temperature (Ta), soil moisture (Ms), relative humidity (RH), and atmospheric CO2 concentration (Ca), explaining 89.7% of the total variance. Solar radiation (Ra) and wind speed (Ws) had no impacts on WUE. 3) VPD and Ta are the most two important factors influencing short-term WUE, explaining 53.9% of the total variance. The effects of VPD on short-term WUE was higher than that of Ta. Ms and RH were the second important factors of the short-term WUE, explaining 25.4% of the total variance. The effects of Ms on short-term WUE was higher than that of RH. Ca had little effect on the short-term WUE and could explain 10.3% of the total variance.
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Solo , Água , Pequim , TemperaturaRESUMO
Change in quality of mussels (Mytilus edulis) meat when stored at 4⯰C was evaluated by determining volatile basic nitrogen (TVB-N), peroxide value (POV), thiobarbituric acid reactive substance (TBARS), total oxidation (TOTOX), lipid class, fatty acid (FA), phosphatidylcholine (PC) and phosphatidylcholine (PE) content, and glycerophospholipid (GP) molecular species. After 4â¯days of storage, the percentages of triacylglycerol and polar lipid as well as the contents of PC, PE and major GP molecular species significantly decreased (Pâ¯<â¯0.05), while the percentages of free FA and monoacylglycerol significantly increased (Pâ¯<â¯0.05), indicating the hydrolysis of lipids. The increase in activities of phospholipase and lipase during storage suggests that they may contribute to the hydrolysis of lipids. The cold storage also resulted in significantly increased POV, TBARS and TOTOX as well as lipoxygenase activity (Pâ¯<â¯0.05) but slightly decreased percentage of polyunsaturated FA (PUFA), indicating the occurrence of lipid oxidation.