目的:研究八角枫科八角枫属植物八角枫Alangium chinense(Lour.)Harms的化学成分.方法:采用各种柱色谱及半制备液相色谱分离纯化,经波谱数据鉴定化合物结构.结果:从八角枫根的正丁醇萃取物中分离得到21个化合物,其结构分别鉴定为(+)-异落叶松树脂醇-3α-O-β-D-吡喃葡萄糖苷(1)、(+)-南烛树脂醇-3α-O-β-D-吡喃葡萄糖苷(2)、(7S,8R)-川素馨木脂苷(3)、枇杷苷(4)、(6R,9R)-大柱香波龙烷-4-烯-9-醇-3-酮-O-β-D-(6′-O-β-D-呋喃芹糖基)吡喃葡萄糖苷(5)、马钱酸(6)、(1S,4S)-7-羟基去氢白菖烯(7)、(1R,4S)-7-羟基去氢白菖烯(8)、八角枫碱(9)、尿嘧啶(10)、尿苷(11)、胸苷(12)、5-羟基-2-羟甲基吡啶(13)、2,6-去氧果糖嗪(14)、3,4′-O-β-D-二甲基逆没食子酸(15)、3′-O-β-D-甲基-3,4-亚甲二氧基鞣花酸-4′-O-β-D-吡喃葡萄糖苷(16)、水杨醇(17)、香草醛(18)、没食子酸(19)、没食子酸甲酯(20)、没食子酸乙酯(21).结论:化合物1～6为首次在八角枫属中分离得到.

目的 探讨仿制药一致性评价时限取消前后我国药物一致性评价工作的进展.方法 采用描述性统计方法 分析Insight数据库、GBI Source数据库、国家药品监督管理局(NMPA)及其药品审评中心(CDE)官方网站搜集的一致性评价时限取消前后相关数据.结果 CDE 2018年共受理一致性评价612件,2019年共受理1038件,同比增长69.61％.截至2020年5月15日,"289目录"(含34个品规)中有83个品种通过一致性评价,通过率为28.72％;通过一致性评价企业不少于3家的有32个品种36个品规.结论 仿制药一致性评价时限取消后,药品生产企业申报一致性评价数量并未减少,一致性评价工作仍在稳步进行."289目录"药品一致性评价完成情况欠佳,提示我国药品生产企业仍需加快推进一致性评价进程.

Objectives Inflammation as well as oxygen metabolite play important roles in renal injury during pathogenesis of rhabdomyolysis induced myoglobinuric acute renal failure (ARF). The aim of this study was to investigate the protective effects of donepezil on immune responses in rats with glycerol-induced ARF. Methods Sixty male rats were randomly divided into six groups, the rats were given normal saline (10 ml/kg, i.m.), glycerol (50%, 10 ml/kg, i.m.), glycerol plus dexamethasone (0.1 mg/kg, i.g.), and glycerol plus donepezil (1, 5 and 10 mg/kg, i.g.) respectively. After two weeks of glycerol injections, the kidney tissues and blood samples were harvested for future biochemical and pathology analysis. The levels of creatinine (Cr) and urea nitrogen (BUN) in plasma, the content of malondialdehyde (MDA), glutathione (GSH), and superoxide dismutase (SOD) activity, total nitric oxide synthase (TNOS), inducible nitric oxide synthase (iNOS), endothelial NO synthase (eNOS) were evaluated in renal tissues. In addition, interleukin-6 (IL-6), tumor necrosis factors-alpha (TNF-alpha) in renal tissues were also determined. Results Donepezil treatment protected rats from renal dysfunction in a dose-dependent manner and through the cholinergic anti-inflammatory pathway. Additionally, donepezil significantly reduced tubular damages, prevented neutrophil infiltration and decreased productions of the IL-6, TNF-alpha, nitric oxide content and oxidative damage. Conclusions These data indicate that donepezil exerts a protective anti-inflammatory effect during ARF through the cholinergic pathway and Nitric oxide pathway. In addition, this study could provide an opportunity to overcome the effect of surgical cholinergic denervation during kidney transplantation and other injury.

BACKGROUND/AIMS:Obesity is associated with chronic inflammation and cognitive decline, and is considered a major risk factor for neurodegeneration. Meanwhile, neuroinflammation is important in the pathogenesis and progression of neurodegenerative diseases.METHODS:In this study, we tested the hypothesis that donepezil would attenuate central inflammation and oxidative damage and improve memory deficit in high-fat diet (HFD)-fed mice. After 16 weeks on a HFD, C57BL/6J mice were given either donepezil (3 mg/kg, i.p.) or saline for 4 weeks in parallel to a control diet (CD) group. Thereafter, the step-through test was used to assess learning and memory function.RESULTS:In the brain of HFD-fed mice, levels of the proinflammatory cytokines interleukin 16 and tumor necrosis factor α were reduced by donepezil treatment. Similarly, HFD-induced protein levels of advanced glycation end-products and oxidative stress in the brain were significantly decreased by donepezil treatment.CONCLUSION:Our results indicate that donepezil may reverse obesity-related central inflammation and oxidative damage and improve memory deficit in HFD-fed mice.

Oxidative stress and inflammation contributes to glycerol-induced acute renal failure (ARF), and they are inseparably linked as each one begets and amplifies the other. In this study, we have evaluated the potential use of donepezil in glycerol-induced ARF treatment in rat. Fifty male rats were randomly averagely divided into five groups: group 1 served as a control; group 2 was only given glycerol (50 %, 10 mL/kg, i.m.); the last three groups were given glycerol plus donepezil (5, 10 and 20 mg/kg, oral) respectively, starting at the same time as the glycerol injections. After a single glycerol injection, the i.g. administrations of donepezil were repeated every 24 h for two weeks. After two weeks of glycerol injections, the kidney tissues and blood samples were harvested for future biochemical and pathology analysis. The levels of creatinine and urea nitrogen in plasma, the content of malondialdehyde, glutathione, and superoxide dismutase activity were evaluated in renal tissues. In addition, the levels of interleukin-6, tumor necrosis factors-alpha in renal tissues were also determined. Renal morphological alterations were assessed by examination of Hematoxylin-Eosin staining. Importantly, the effects of donepezil on renal function may involve alleviating oxidative damage, inflammatory reaction, and morphological renal deterioration. These results indicate that donepezil might have potential in therapy against glycerol-induced ARF by inhibiting intrarenal oxidative stress and inflammation.

Chronic cerebral hypoperfusion, a mild ischemic condition, is associated with the cognitive deficits of Alzheimer's disease (AD). Luteolin, a polyphenolic compound found in foods of plant origin, belonging to the flavone subclass of flavonoids, has been shown to possess antioxidant, anti-inflammatory and antitumorigenic properties. In the present study, the effects of luteolin on chronic cerebral hypoperfusion-associated neurocognitive pathologies were investigated by using rats with permanent bilateral common carotid artery occlusion, a rat model of chronic cerebral hypoperfusion. As expected, we found that luteolin could attenuate cognitive dysfunction in chronic cerebral hypoperfused rats, as assessed using Morris water maze tests. Daily oral administration of luteolin (50, 100 and 200 mg/kg) significantly scavenged oxygen free radicals, enhanced antioxidant potential, decreased the lipid peroxide production and suppressed inflammatory reaction in the cerebral cortex and hippocampus induced by chronic cerebral hypoperfusion. Meanwhile, the results indicated that cerebral hypoperfusion activated nuclear factor-κB (NF-κB), increased the expression of β-site amyloid precursor protein cleaving enzyme (BACE1), as well as elevated amyloid beta (Aβ) levels in the cortex and hippocampus. However, long-term administration of luteolin significantly down-regulated the expression of NF-κB and BACE1, accompanied by diminishing the deposition of Aβ. Our results suggest a potential therapeutic use of luteolin for cerebral hypoperfusion associated cognitive dysfunction in AD.

The epidemic and experimental studies have confirmed that the obesity can lead to neuroinflammation, neurodegenerative diseases and adversely affect cognition. Despite the numerous elucidations on the impact of obesity on cognition decline, the contributors to the impairments in obesity remain unclear. Male C57BL/6J mice were fed either a control or high-fat diet (HFD) for 16 weeks and then randomized into four groups treated with their respective diets for 4 weeks including control diet (CD); control diet+luteolin (CDL); high-fat diet (HFD), high-fat diet+luteolin (HFDL). The dose of luteolin was 10mg/kg, oral. We showed that adding luteolin in high-fat diet can significantly reduce body weight gain, food intake and plasma cytokines as well as improving glucose metabolism of mice on HFD. Importantly, we showed that luteolin treatment had the effects of alleviating neuroinflammation, oxidative stress and neuronal insulin resistance in the mouse brain, restored blood adipocytokines level to normal. Furthermore, luteolin increased the level of brain-derived neurotrophic factor (BDNF), the action of synapsin I (SYP) and postsynaptic density protein 95 (PSD-95) in the cortex and hippocampus as to that the behavioral performance in Morris water maze (MWM) and step-through task were significantly improved. These results indicate a previously unrecognized potential of luteolin in alleviating obesity-induced cognitive impairment for type-2 diabetes mellitus and Alzheimer disease (AD).

Ropivacaine hydrochloride was synthesized from 2-pipecolic acid by successive reaction with SOCl2 and 2,6-dimethylaniline at 40°C under ultrasonic irradiation to give (S)-N-(2,6-dimethylphenyl)-piperidin-2-carboxamide (4), and 4 was reacted with 1-bromopropane at 50°C for 1 h under ultrasonic irradiation. The effect of reaction solvent, temperature and time under ultrasonic irradiation were investigated. Compared with conventional methods, the main advantages of the present procedure are milder conditions, shorter reaction time and higher yields. The total yield was 63.1%, [α]25 D= – 6.7°(c = 2, H2O).

Tea polyphenols (TPs), which are the natural compounds extracted from tea leaves, possess a number of beneficial properties, such as reducing the risks of cancer and heart diseases, alleviating cognitive impairments and showing antidepressant-like activity in the forced swim test (FST) and tail suspension test (TST). The present study was designed to investigate the protective effect of TPs on the chronic unpredictable mild stress (CUMS)-induced depression model in mice and to elucidate the related underlying mechanisms. With the daily exposure to stressor for 5 consecutive weeks, TPs were administered in mice at a daily dose of 25 mg/kg or 50 mg/kg by gavage for 3 consecutive weeks from the 3rd week. Our results showed that CUMS significantly decreased the levels of serum serotonin (5-HT) and norepinephrine (NE) in the hippocampus, the prefrontal cortex and serum, and the activities of superoxide dismutase (SOD) and catalase (CAT), with an increase in lipid peroxidation level as well as a reduction in glutathione (GSH) level and an elevation in the production of malondialdehyde (MDA) in the hippocampus and the prefrontal cortex. CUMS also reduced open-field activity, sucrose consumption, as well as increased immobility duration in FST and TST. TPs administration could effectively reverse the alterations in the concentrations of 5-HT and NE, elevate the activities of SOD and CAT as well as the level of GSH, reduce the MDA level and inhibit lipid peroxidation. Moreover, TPs could effectively reverse alterations in immobility duration, sucrose consumption and open-field activity. In conclusion, TPs administration has exhibited significant antidepressant-like effects in mice with CUMS-induced depression. The antidepressant activity of TPs might be related to the alteration of monoaminergic responses and antioxidant defenses.

There is an increasing evidence that oxidative stress plays an important role in the pathogenesis of rhabdomyolysis-induced acute renal failure (ARF). In this study, protective effects of L-citrulline on glycerol-induced ARF in rats were investigated. Six groups of rats were employed in this study: group 1 served as a control; group 2 was only given glycerol (50%, 10 mL/kg, i.m.); group 3 was given glycerol plus dexamethasone (0.1 mg/kg, i.g.) as positive reference drug, starting at the same time as the glycerol injections; the last three groups were given glycerol plus L-citrulline (300, 600, and 900 mg/kg, i.g.) respectively, starting at the same time as the glycerol injections. The injections of glycerol were only once, and after glycerol injections the i.g. administrations of dexamethasone and L-citrulline were repeated every 24 h for 7 days. After 7 days of glycerol injections, the blood samples and kidney tissues were harvested for future biochemical and pathology analyses. The levels of creatinine (Cr) and urea nitrogen (BUN) in plasma, the content of malondialdehyde (MDA), glutathione (GSH), nitric oxide (NO), the activity of total nitric oxide synthase (TNOS), inducible nitric oxide synthase (iNOS), endothelial NO synthase (eNOS), and superoxide dismutase (SOD) were evaluated in kidney tissues. Consequently, administrations of L-citrulline improved an impaired intrarenal oxygenation and kidney function compared with the glycerol group, and prevented the renal oxidative stress damage as well as severe functional and morphological renal deterioration. Therefore, L-citrulline might have potential application in the amelioration of glycerol-induced ARF.

There is increasing evidence indicating that oxidative stress plays an important role in the pathogenesis of rhabdomyolysis-induced myoglobinuric acute renal failure (ARF). In this study, protective effects of L-citrulline on glycerol-induced acute renal failure (ARF) in rats were investigated. Six groups of rats were employed in this study, after seven days of glycerol injections, the blood samples and kiney tissues were harvested for future biochemical and pathology analysis. The levels of creatinine (Cr) and urea nitrogen (BUN) in plasma, the content of malondialdehyde (MDA), glutathione (GSH), nitric oxide (NO), the activity of total nitric oxide synthase (TNOS), inducible nitric oxide synthase (iNOS), endothelial NO synthase (eNOS) and superoxide dismutase (SOD) were evaluated in kiney tissues. Consequently, treatment with L-citrulline improved an impaired intrarenal oxygenation and kidney function compare with the glycerol group, and prevented the renal oxidative stress damage as well as severe functional and morphological renal deterioration.

In the present study, the effects of theanine on hepatic and renal injury in mice exposed to unpredictable chronic mild stress (UCMS) were investigated. Mice were subjected to the exposure to unpredictable stressor daily for 5 consecutive weeks, with theanine administered (2 and 4 mg/kg, i.g.) for consecutive 3 weeks from the 3rd week. Our experiment showed hepatic and renal indices were sensitive to UCMS except the renal functional indices. However, theanine (2 and 4 mg/kg) decreased the malondialdehyde (MDA) content, meanwhile, increased the glutathione (GSH) content and the activities of superoxide dismutase (SOD) and catalase (CAT) in the liver and kidneys. Moreover, theanine treatment significantly ameliorated the hepatic function, also, decreased the tumour necrosis factor-alpha (TNF-alpha) levels in the liver and the kidneys. These findings suggested that theanine possesses the effect against the UCMS-induced hepatic and renal impairment and the underlying mechanism is related to its antioxidative and antiinflammatory properties.

目的 探讨木犀草素对慢性不可预知性温和应激抑郁模型(CUMS)所致小鼠脑组织氧化应激损伤的改善作用.方法 建立小鼠慢性不可预知性温和应激抑郁模型；用经典的糖水消耗实验检测小鼠快感缺失；旷场实验、悬尾实验和强迫游泳实验检测小鼠的活动能力和绝望程度；采用分光光度法测定小鼠脑组织超氧物歧化酶(SOD)和谷胱甘肽(GSH)活性及丙二醛(MDA)含量.结果 与模型组相比,木犀草素能明显改善小鼠抑郁样行为,提高SOD和GSH活性,降低小鼠脑组织MDA含量.结论 木犀草素对CUMS小鼠的抑郁样行为有改善作用,作用机制可能与其增强小鼠脑组织的抗氧化活性,改善氧化/抗氧化平衡有关.

To observe the protective effects of L-citrulline on the renal I/R injury and elucidate the mechanisms involved, 48 rats were randomized into eight groups: Group 1: sham operated; Group 2: I/R (45 min renal ischaemia and 24 h reperfusion); Group 3: I/R + L-citrulline (300 mg/kg, i.g.); Group 4: I/R + L-citrulline (600 mg/kg, i.g.); Group 5: I/R + L-citrulline (900 mg/kg, i.g.); Group 6: I/R + normal saline (NS, i.g.); Group 7: I/R + N sup ω nitro-L-arginine ester (L-NAME, 20 mg/kg, i.p.); Group 8: I/R + L-citrulline (900 mg/kg, i.g.) + L-NAME (20 mg/ kg, i.p.). At the end of the reperfusion period, serum was collected and the kidneys underwent histological and biochemical examinations. Our results showed that pre-treatment with L-citrulline (300, 600, and 900 mg/kg) significantly ameliorated the renal injury caused by I/R. Moreover, L-citrulline prevented induction of lipid peroxidation and increased the activity of superoxide dismutase and the levels of glutathione and nitric oxide. The I/R-induced decreases in total nitric oxide synthase activity, inducible nitric oxide activity, constitutive nitric oxide activity and endothelial nitric oxide protein expression in the renal cortex were significantly prevented. However, the L-citrulline-mediated protection was significantly antagonized by co-administration of L-NAME. These results suggested that L-citrulline administration exhibited significant protection against renal I/R injury. This protective effect, at least in part, via up-regulation of the endothelial nitric oxide protein expression and constitutive nitric oxide synthase activity, maintained production of nitric oxide at the basal level.

In the present study, the protective effects of luteolin were investigated against psychological stress-induced cognitive impairment. To emulate the psychological stress, mice received restraint stress for six hours daily, between 9:00 and 15:00 hours, for 21 consecutive days. The results of step-through test, open-field test and Morris Water Maze test demonstrated that psychological stress treatment could result in cognitive impairments in mice. This cognition dysfunction was improved by treatment with low- and medium-dose luteolin. In addition, psychological stress induced an increased serum corticosterone concentration with a decreased serum norepinephrine and dopamine concentration. These alterations were attenuated by treatment with luteolin. Also, psychological stress significantly decreased the glutathione (GSH) concentrations and superoxide dismutase (SOD) activities in prefrontal cortex and hippocampus, while the malondialdehyde (MDA) concentrations were enhanced. However, these oxidative alterations in prefrontal cortex and hippocampus induced by psychological stress were significantly reversed by treatment of luteolin. Further, the current study indicated a decline of catalase (CAT) activities in the hippocampus of the ST group, which was significantly prevented by low, medium and high dose of luteolin. On the other hand, there was no significance in CAT activities of the prefrontal cortex among the six groups. Collectively, the present results suggest that luteolin treatment serves as a key role in improving the psychological stress-induced cognitive impairments.

Context: Rutin, a flavonoid commonly present in onions, apples and tea, has been suggested to have a variety of pharmacological activities, including immunomodulator, anti-inflammatory and antioxidant activities.Objectives: The present study was to examine the protective effects of rutin on gastric mucosal damage induced by gastric ischemia-reperfusion (I/R) in rats.Materials and methods: Rutin (50, 100, 200 mg/kg) was administered intragastrically for five consecutive days before ischemia. Sixty minutes after the last administration of rutin, under anesthesia, the celiac artery was clamped for 30 min, and then the clamp was removed for 60 min reperfusion. After reperfusion, the stomach was removed for biochemical and histological examinations.Results: As compared with the I/R group (116.7 ± 21.5), administration of rutin at doses of 50, 100 and 200 mg/kg significantly prevented the increase of gastric mucosal injury index induced by gastric I/R (73.4 ± 14.8, 65.9 ± 9.6 and 26.9 ± 5.7, respectively). ED50 value was 138.7 mg/kg. Moreover, rutin at doses of 50, 100 and 200 mg/kg showed an inhibition on the increased myeloperoxidase (24.6, 41.3 and 53.1% reduction) activity and malondialdehyde levels (27.4, 40.3 and 50.7% reduction) in gastric mucosa. Also, the elevation of inducible NO synthase (iNOS) activity as well as the decrease of constitutive NO synthase (cNOS) in the gastric mucosa were significantly prevented by rutin pretreatment.Conclusion: These results suggested that rutin has a protective effect against gastric mucosal injury induced by gastric I/R and that the gastroprotection was related to the NOS/NO pathway and its antioxidant activity.

目的 研究姜黄素对慢性不可预知性刺激诱发小鼠肾损伤的保护作用及机制.方法 采用慢性不可预知性刺激诱发小鼠肾损伤模型,经5周慢性不可预知性刺激诱发小鼠肾损伤,检测小鼠血清肌酐(Scr)、血清尿素氮(BUN)的含量、肾组织中超氧化物歧化酶(SOD)、过氧化氢酶(CAT)的活性,谷胱甘肽(GSH)、丙二醛(MDA)的含量,观察肾病理组织形态学变化.结果 与慢性不可预知性刺激诱发小鼠肾损伤模型组相比,姜黄素组可明显降低小鼠血清中Scr和BUN的含量,降低肾组织中MDA的含量,提高肾组织中SOD和CAT的活性、提高GSH的含量.同时光镜发现模型组小鼠肾小管损伤明显,肾小球体积增大,内皮细胞肿胀脱落,间质炎性浸润,给予姜黄素后肾组织损伤明显降低.结论 姜黄素对慢性不可预知性刺激诱发的小鼠肾损伤具有保护作用,其作用机制可能部分来自于清除自由基和抑制脂质过氧化过程.

The antidepressant effects of tea polyphenols on the chronic stress-induced depression in mice and the possible underlying mechanism were investigated in this paper.The antidepressant model of chronic unpredictable mild stress mice(CUMS) was established.The activities of the mice exposed to various stress were tested in the open-field,the immobility duration of the forced swimming test and tail suspension t est were measured.Meanwhile,the contents of the 5-HT and the NE in the brain tissue were determined,and the activities of superoxide dismutase(SOD),GSH-Px and the content of malondialdehyde(MDA) in the brain tissue were estimated by spectrophotometry.The CUMS-induced depressive mice exhibited significant decrease in the activities in the open-field test as compared with the control group(#P0.05,△P0.001),while the immobility duration in the forced swimming test and tail suspension test were significantly increased,and the latency period(#P0.05,△P0.001.#P0.05,△P0.05) were shortened.However,tea polyphenols ameliorated the defecits of the behavior of the mice.Moreover,tea polyphenols increased the activities of SOD,GSH-Px,and the content of 5-HT,NE,and decreased the contents of MDA in the brain tissue.The depressive status can be attenuated by the administration of tea polyphenols,the underlying mechanism might be attributed to their antioxidative property and enhancement of serotonergic functions.

The present study was designed to investigate the protective effects of luteolin, a flavonoid, against acute immobilization-induced liver damage in mice. Mice were immobilized for a period of 6 h daily for three consecutive weeks. Luteolin (25 or 100 mg/kg, i.g.) was administered 30 min before subjecting the animals to restraint stress (RS). Our experiment showed that RS could induce liver damage, with an increase in glutamic-pyruvic transaminase (GPT) and glutamic-oxaloacetic transaminase (GOT) in the liver tissue. Furthermore, the changes of anti-oxidative capacity in liver tissue were also measured. The changes of malondialdehyde (MDA), glutathione (GSH), superoxide dismutase (SOD) and catalase activities (CAT) of stress group were significantly different from those in the control group. However, these changes in stress low and high-doses of luteolin modulation group were improved. These results demonstrated that luteolin has a protective effect against RS-induced liver damage through scavenging both free radicals activity and lipid peroxidation inhibitory effect.

Naproxen is poorly water-soluble and has an increased risk of serious gastrointestinal adverse events. In our study, a new oil-in-water (o/w) microemulsion delivery system has been successfully developed, with improved solubility and lessened adverse reactions to the gastric mucosa. Pseudo-ternary phase diagrams were constructed to obtain the phase regions of o/w microemulsion and the effects of different co-surfactants and mass ratios of surfactant to co-surfactant (K-m) on the phase regions were also assessed. Suitable compositions of naproxen-loaded microemulsion were screened via viscosity studies and microemulsion droplet size tests. In vivo histological changes of gastric mucosa were also evaluated with oral administration of naproxen-loaded microemulsion. The optimal formulation of naproxen-loaded microemulsion consists of naproxen 1.0 %, oil (MCT) 5.0 %, surfactant (polysorbate 80) 233 %, co-surfactant (PEG 400) 11.7 % and water 60.0 %, with the average particle size at approximately 6831 urn. Transmission electron microscopy (TEM) revealed the spherical nature and size homogeneity of the microemulsion droplets. No significant variations (droplet size and naproxen content) in microemulsion were observed over a period of 14 days at 4 and 25 degrees C, respectively. The results of in vivo histological procedure of gastric tissue showed significant ameliorant in the gastric mucosal damage compared with its tablet formulation. The developed microemulsion revealed great potential as a possible alternative to conventional oral formulations of naproxen.