The Synthesis and Biological Activity of 3,3'-Dimethyl-L-Selenocystine,a New Selenocystine Derivative

Russian Journal of Bioorganic Chemistry - Using the known synthesis of L-selenocystine,3,3'-diseleno-bis (2-aminopropionic acid), from β?chloroalanine, a structural analog of natural...     

Melatonin,a toll-like receptor inhibitor: Current status and future perspectives

Toll-like receptors (TLRs) are crucial activators of inflammatory responses, they are considered immune receptors. TLRs are of fundamental importance in the pathophysiology of disorders related to inflammation including neurodegenerative diseases and cancer. Melatonin is a beneficial agent in the treatment of inflammatory and immune disorders. Melatonin is potent anti-inflammatory hormone that regulates various molecular pathways. Withal, limited studies have evaluated the inhibitory role of melatonin on TLRs. This review summarizes the current knowledge related to the effects of melatonin on TLRs in some common inflammatory and immunity disorders.     

Melatonin,a calpain inhibitor in the central nervous system: Current status and future perspectives

Dysregulation of neuronal Ca²⁺ and oxidative stress plays an important role in the activation of cysteine proteases including calpains and caspases that contribute to neuronal death. In neurodegenerative diseases, traumatic brain injury, stroke, and neuropathic pain calpain activities are markedly increased. Melatonin is a beneficial supplement in the treatment of central nervous system (CNS) disorders. Melatonin is a potent antioxidant and works as a free-radical scavenger to regulate a large number of molecular pathways, including oxidative stress, inflammation, apoptosis, and cell death under different pathological conditions. However, limited studies have evaluated the inhibitory effect of melatonin on calpains. This review summarizes the current knowledge related to the effects of melatonin on calpains in some of the common CNS disorders.     

Application of Nanoparticles and Melatonin for Cryopreservation of Gametes and Embryos

Cryopreservation of gametes and embryos, a technique widely applied in human infertility clinics and to preserve desirable genetic traits of livestock, has been developed over 30 years as a component of the artificial insemination process. A number of researchers have conducted studies to reduce cell toxicity during cryopreservation using adjuvants leading to higher gamete and embryo survival rates. Melatonin and Nanoparticles are novel cryoprotectants and recent studies have investigated their properties such as regulating oxidative stresses, lipid peroxidation, and DNA fragmentation in order to protect gametes and embryos during vitrification. This review presented the current status of cryoprotectants and highlights the novel biomaterials such as melatonin and nanoparticles that may improve the survivability of gametes and embryos during this process.     

Synthesis and Antiviral Activity of Betulonic Acid Amides and Conjugates with Amino Acids

Betulonic acid amides with aliphatic and heterocyclic amines and with L-amino acids were synthesized by the acid chloride method. Betulonic acid amide and L-methionine derivatives of betulonic acid and its 3-oxime effectively inhibit the influenza A virus. Betulonic acid octadecylamide is active against the herpes simplex Type 1 virus. The conjugate of betulonic acid 3-oxime with L-methionine is also active toward HIV-1. The tested compounds mainly show no activity toward the ECHO6 virus, which is devoid of a coat.     

褪黑素与维生素 E 对抗花萼海绵诱癌素毒性作用的差异

最近的研究发现,褪黑素对花萼海绵诱癌素 (calyculin A , CA) 引起的骨架蛋白神经细丝异常过度磷酸化有保护作用 . 为进一步探讨褪黑素对骨架蛋白τ异常过度磷酸化的保护作用及其机制,分别用 CA, CA+ 褪黑素或 CA+ 维生素 E 处理鼠野生型成神经瘤细胞 (N2awt) ,采用 MTT 法测定细胞存活率,用免疫印迹法测定τ蛋白磷酸化水平,用 ³²P- 特异底物标记技术检测 GSK-3 和 PP-2A 活性,并进一步测定了细胞内脂质过氧化产物丙二醛含量,细胞内过氧化氢酶、超氧化物歧化酶和谷胱甘肽过氧化物酶活性 . 结果显示：褪黑素不仅对 CA 引起的抗氧化酶活性降低和脂质过氧化的保护作用强于经典抗氧化剂维生素 E ,而且对τ蛋白磷酸化的保护作用也强于经典抗氧化剂维生素 E ;褪黑素可同时激活 PP-2A 又抑制 GSK-3 ,而维生素 E 同时抑制两种酶的活性 . 研究提示：褪黑素既通过抗氧化作用,也通过调节细胞内磷酸化平衡对抗 CA 对神经细胞的毒性作用 .     

Synthesis,Biological Evaluation and Action Mechanism Study of New Mitochondria-Targeted Curcumin Derivative as Potential Antitumor Drugs

Mitochondria have emerged as important targets in cancer therapy due to their key role in regulating energy supply, maintaining redox homeostasis, and intrinsic apoptosis. Curcumin (CUR) has shown promise in inhibiting the proliferation and metastasis of cancer cells by inducing apoptosis and arresting cell cycle. However, the clinical application of CUR has been limited by its low stability and poor tumor selectivity. To address these issues, the novel mitochondria-targeted curcumin derivatives were synthesized through the unilateral coupling (CUR-T) or bilateral coupling (CUR-2T) of curcumin's phenolic hydroxy groups with triphenyl phosphorus via ester bond. The aim was to achieve better stability, higher tumor selectivity, and stronger curative efficacy. The results of stability and biological experiments indicated that both stability and cytotoxicity were arranged in descending order of CUR-2T>CUR-T>CUR. In ovarian cancer cells (A2780 cells), CUR-2T showed well-defined preferential selectivity towards cancer cells and exhibited efficient anticancer efficacy due to its superior mitochondria accumulation ability. Subsequently, the mitochondrial redox balance was disrupted, accompanied by increased ROS levels, decreased ATP levels, dissipated MMP, and increased G₀/G₁ phase arrest, leading to a higher apoptotic rate. In summary, the results of this study suggest that CUR-2T holds substantial promise for further development as a potential agent for the treatment of ovarian cancer.     

Older Poor-Sleeping Women Display a Smaller Evening Increase in Melatonin Secretion and Lower Values of Melatonin and Core Body Temperature Than Good Sleepers

Melatonin concentration and core body temperature (CBT) follow endogenous circadian biological rhythms. In the evening, melatonin level increases and CBT decreases. These changes are involved in the regulation of the sleep-wake cycle. Therefore, the authors hypothesized that age-related changes in these rhythms affect sleep quality in older people. In a cross-sectional study design, 11 older poor-sleeping women (aged 62–72 yrs) and 9 older good-sleeping women (60–82 yrs) were compared with 10 younger good-sleeping women (23–28 yrs). The older groups were matched by age and body mass index. Sleep quality was assessed by the Pittsburgh Sleep Quality Index questionnaire. As an indicator of CBT, oral temperature was measured at 1-h intervals from 17:00 to 24:00?h. At the same time points, saliva samples were collected for determining melatonin levels by enzyme-linked immunosorbent assay (ELISA). The dim light melatonin onset (DLMO), characterizing the onset of melatonin production, was calculated. Evening changes in melatonin and CBT levels were tested by the Friedman test. Group comparisons were performed with independent samples tests. Predictors of sleep-onset latency (SOL) were assessed by regression analysis. Results show that the mean CBT decreased in the evening from 17:00 to 24:00?h in both young women (from 36.57°C to 36.25°C, p < .001) and older women (from 36.58°C to 35.88°C, p < .001), being lowest in the older poor sleepers (p < .05). During the same time period, mean melatonin levels increased in young women (from 16.2 to 54.1 pg/mL, p < .001) and older women (from 10.0 to 23.5 pg/mL, p < .001), being lowest among the older poor sleepers (from 20:00 to 24:00?h, p < .05 vs. young women). Older poor sleepers also showed a smaller increase in melatonin level from 17:00 to 24:00?h than older good sleepers (mean?±?SD: 7.0?±?9.63 pg/mL vs. 15.6?±?24.1 pg/mL, p = .013). Accordingly, the DLMO occurred at similar times in young (20:10?h) and older (19:57?h) good-sleeping women, but was delayed ～50?min in older poor-sleeping women (20:47?h). Older poor sleepers showed a shorter phase angle between DLMO and sleep onset, but a longer phase angle between CBT peak and sleep onset than young good sleepers, whereas older good sleepers had intermediate phase angles (insignificant). Regression analysis showed that the DLMO was a significant predictor of SOL in the older women (R²?=?0.64, p < .001), but not in the younger women. This indicates that melatonin production started later in those older women who needed more time to fall asleep. In conclusion, changes in melatonin level and CBT were intact in older poor sleepers in that evening melatonin increased and CBT decreased. However, poor sleepers showed a weaker evening increase in melatonin level, and their DLMO was delayed compared with good sleepers, suggesting that it is not primarily the absolute level of endogenous melatonin, but rather the timing of the circadian rhythm in evening melatonin secretion that might be related to disturbances in the sleep-wake cycle in older people. (Author correspondence: mdittmar@zoologie.uni-kiel.de)     

Synthesis and Biological Activity of Fatty Acid Derivatives of Quinine

Derivatives of quinine with fatty acids including polyunsaturated fatty acids were prepared. They showed moderate antimalarial activity as compared with quinine itself using Plasmodium falciparum. The activities were not dependent on whether the fatty acyl group was saturated or unsaturated. On the other hand, the derivatives showed significantly higher cytotoxicity against a mammary tumor cell line FM3A than quinine itself. Calculating from these data, an acetyl derivative of quinine with the shortest acyl group was found to give the highest selectivity.     

Synthesis of Some New Halogenated N-Thiazolyl Substituted Hydroxy Acid Amides and Their Use as Possible Fungicides

A large number of new N-thiazolyl, chloro-thiazolyl, brome-thiazolyl and iodothiazolyl amides of salicylic, hydroxy naphthoic acids, both halogenated and non-halogenated ones have been synthesised by condensing simple as well as halogenated thiazoles with different aromatic hydroxy acids, viz. salicylic, chloro- and bromo-salicylic, hydroxy naphthoic and bromo hydroxyl naphthoic acids. All these compounds are assayed for their fungicidal activity using Piricularia oryzae (Cav.), Helminthosporium oryzae and Carvularia lunata as the test fungi. An attempt has been made to establish a relationship between chemical structure and fungicidal activity.     

Synthesis and Biological Evaluation of Acyclic Phosphonic Acid Nucleoside Derivatives

As part of a project to generate a library of nucleosides as potential antiviral agents, a small subset of novel acyclic phosphonic acid nucleosides was prepared. Practical synthetic routes are described for three targets, which were then tested against HIV, hepatitis C virus (HCV), and Dengue virus.     

Synthesis,Biological Activity and Decomposition Studies of Amino Acid Phosphomonoester Amidates of Acyclovir

Abstract

Highly stable and water soluble amino acid phosphomonoester amidates of acyclovir (ACV) were synthesized and shown to function predominantly as prodrugs of AC V and not acyclovir monophosphate (AC V-MP) with activities within two fold of the amino acid prodrug of ACV, valaciclovir (VACV). Metabolism studies revealed that incubation of cell-free extracts of Vero cells with the L-leucine phosphomonoester amidate of ACV (3c), resulted in a burst of ACV-MP production followed by the rapid generation of ACV.     

Synthesis,Crystal Structure and Biological Activity of 2-Hydroxyethylammonium Salt of p-Aminobenzoic Acid

p-Aminobenzoic acid (pABA) plays important roles in a wide variety of metabolic processes. Herein we report the synthesis, theoretical calculations, crystallographic investigation, and in vitro determination of the biological activity and phytotoxicity of the pABA salt, 2-hydroxyethylammonium p-aminobenzoate (HEA-pABA). The ability of neutral and anionic forms of pABA to interact with TIR1 pocket was investigated by calculation of molecular electrostatic potential maps on the accessible surface area, docking experiments, Molecular Dynamics and Quantum Mechanics/Molecular Mechanics calculations. The docking study of the folate precursor pABA, its anionic form and natural auxin (indole-3-acetic acid, IAA) with the auxin receptor TIR1 revealed a similar binding mode in the active site. The phytotoxic evaluation of HEA-pABA, pABA and 2-hydroxyethylamine (HEA) was performed on the model plant Arabidopsis thaliana ecotype Col 0 at five different concentrations. HEA-pABA and pABA acted as potential auxin-like regulators of root development in Arabidopsis thaliana (0.1 and 0.2 mM) and displayed an agravitropic root response at high concentration (2 mM). This study suggests that HEA-pABA and pABA might be considered as potential new regulators of plant growth.     

Melatonin: a possible link between the presence of artificial light at night and reductions in biological fitness

The mechanisms underpinning the ecological impacts of the presence of artificial night lighting remain elusive. One suspected underlying cause is that the presence of light at night (LAN) supresses nocturnal production of melatonin, a key driver of biological rhythm and a potent antioxidant with a proposed role in immune function. Here, we briefly review the evidence for melatonin as the link between LAN and changes in behaviour and physiology. We then present preliminary data supporting the potential for melatonin to act as a recovery agent mitigating the negative effects of LAN in an invertebrate. Adult crickets (Teleogryllus commodus), exposed to constant illumination, were provided with dietary melatonin (concentrations: 0, 10 or 100 µg ml⁻¹) in their drinking water. We then compared survival, lifetime fecundity and, over a 4-week period, immune function (haemocyte concentration, lysozyme-like and phenoloxidase (PO) activity). Melatonin supplementation was able only partially to mitigate the detrimental effects of LAN: it did not improve survival or fecundity or PO activity, but it had a largely dose-dependent positive effect on haemocyte concentration and lysozyme-like activity. We discuss the implications of these relationships, as well as the usefulness of invertebrates as model species for future studies that explore the effects of LAN.     

Synthesis of a Fluorobenzoxazine Derivative and Its Analogues

Syntheses of a fluorobenzoxazine derivative, fluorobenzothiazine derivative and fluoroquinoxaline derivative are described. These compounds were synthesized by reductive cyclization of the corresponding fluorodinitrobenzene derivatives. The fluorobenzoxazine derivative and its analogues are useful intermediates for agro-chemicals.     

Effects of Artificial Dawn and Morning Blue Light on Daytime Cognitive Performance,Well-being,Cortisol and Melatonin Levels

Light exposure elicits numerous effects on human physiology and behavior, such as better cognitive performance and mood. Here we investigated the role of morning light exposure as a countermeasure for impaired cognitive performance and mood under sleep restriction (SR). Seventeen participants took part of a 48h laboratory protocol, during which three different light settings (separated by 2?wks) were administered each morning after two 6-h sleep restriction nights: a blue monochromatic LED (light-emitting diode) light condition (BL; 100?lux at 470?nm for 20?min) starting 2?h after scheduled wake-up time, a dawn-simulating light (DsL) starting 30?min before and ending 20?min after scheduled wake-up time (polychromatic light gradually increasing from 0 to 250?lux), and a dim light (DL) condition for 2?h beginning upon scheduled wake time (<8?lux). Cognitive tasks were performed every 2?h during scheduled wakefulness, and questionnaires were administered hourly to assess subjective sleepiness, mood, and well-being. Salivary melatonin and cortisol were collected throughout scheduled wakefulness in regular intervals, and the effects on melatonin were measured after only one light pulse. Following the first SR, analysis of the time course of cognitive performance during scheduled wakefulness indicated a decrease following DL, whereas it remained stable following BL and significantly improved after DsL. Cognitive performance levels during the second day after SR were not significantly affected by the different light conditions. However, after both SR nights, mood and well-being were significantly enhanced after exposure to morning DsL compared with DL and BL. Melatonin onset occurred earlier after morning BL exposure, than after morning DsL and DL, whereas salivary cortisol levels were higher at wake-up time after DsL compared with BL and DL. Our data indicate that exposure to an artificial morning dawn simulation light improves subjective well-being, mood, and cognitive performance, as compared with DL and BL, with minimal impact on circadian phase. Thus, DsL may provide an effective strategy for enhancing cognitive performance, well-being, and mood under mild sleep restriction.     

褪黑素UPLC-MS/MS检测方法优化及其对干旱和盐胁迫下葡萄幼苗褪黑素含量的分析

褪黑素是一种吲哚类激素,对植物的生理活动和抗逆性起到显著的调节作用。该研究建立了褪黑素超高效液相色谱-串联质谱(UPLC-MS/MS)检测方法,并分别对干旱胁迫和盐胁迫条件下‘赤霞珠’葡萄幼苗根系和叶片中褪黑素含量的变化进行分析,以探讨葡萄中褪黑素的生理功能及其响应逆境胁迫的调控机制。结果显示:(1)褪黑素UPLC-MS/MS检测方法的优化条件为:采用超声波破碎法提取葡萄组织中的褪黑素;色谱条件为:色谱柱为Agilent Eclipse XDB-C18(1.8μm,3.0×50mm),流动相A为0.1%(v/v)的甲酸水溶液,流动相B为纯甲醇,梯度洗脱,柱温42℃,进样量1μL,流速0.2mL/min;质谱条件为:电喷雾正离子模式(ESI+)电离,多反应监测模式(MRM)检测,检测离子对为m/z 233→174。该方法测量结果的相对标准偏差(RSD)低于7%,最低检测限(LOD)和最低定量限(LOQ)分别为0.04ng/mL和0.12ng/mL。(2)干旱胁迫和盐胁迫下葡萄幼苗根系和叶片中褪黑素含量较对照组均显著增加,且胁迫程度越强增幅越大;用120mmol/L的NaCl溶液处理幼苗以后,幼苗根系和叶片中褪黑素含量分别达到627.25和3 220.42pg/g,大约都是相应对照组幼苗根系和叶片中褪黑素含量的7倍;10%PEG6000处理植株后其根系和叶片中褪黑素含量也远远高于对照组。研究表明,超高效液相色谱串联质谱法可作为一种准确、高效、简便易操作且具有较高的灵敏度和精确度的植物内源褪黑素含量检测方法;葡萄中褪黑素的合成是其对逆境胁迫的一种应激响应,暗示着褪黑素在缓解逆境胁迫方面具有重要作用。     

Effects of Melatonin on Growth,Physiology and Gene Expression in Rice Seedlings Under Cadmium Stress

Melatonin (MLT) is a hormonal substance found in many organisms and can improve plant stress resistance. In this study, the japonica rice variety Y32 and indica rice variety NJ6 were cultivated in hydroponics under different concentrations of CdCl₂ at the two-leaf stage. The growth, physiological and biochemical responses of the seedlings and the expression of cadmium (Cd)-related genes under exogenous melatonin (MLT) treatment were assessed. The results indicated that Cd stress destroyed the dynamic balance between reactive oxygen species (ROS) production and removal, resulting in ROS accumulation, membrane lipid peroxidation, and impaired growth and development. Following the application of exogenous MLT to rice seedlings, increases in plant biomass including both underground and above-ground areas were observed. MLT also scavenged the inhibition of superoxide dismutase (SOD) and peroxidase (POD) in a concentration dependent manner in response to Cd stress. Catalase (CAT) activity and malondialdehyde (MDA) expression also decreased following MLT treatment. Amongst the six Cd-related genes assessed, five genes were down-regulated and one was up-regulated in response to MLT treatment. Taken together, these data demonstrate that MLT improves the resilience of rice seedlings at the biochemical, physiological, and molecular levels, and diminishes the damage caused by Cd stress.     

Synthesis and Biological Evaluation of a Series of Novel Celastrol Derivatives with Amino Acid Chain

The synthesis of celastrol analogues containing amino acid ester at the C(29) position and their evaluation for cytotoxic activities in vitro were reported. The MTT test showed that a set of derivatives with lower IC₅₀ values than that of the positive control group cisplatin and the parent compound celastrol, which exhibited greater antiproliferative activities. The most potent title compounds 2a and 2e exhibited cytotoxic activities in vitro against HeLa and A549 cell lines with IC₅₀ values of 0.371 and 0.237 μm , 0.235 and 0.109 μm , respectively. The apoptosis assay demonstrated that 2a and 2e can induces of A549 cell apoptosis in low concentrations. These results showed that 2a and 2e may be promising for further research as antitumor agents.