更新于：2023-10-01

Phytosphingosine hydrochloride

植物鞘氨醇

更新于：2023-10-01

概要

概要

基本信息

药物类型

小分子化药

别名

C18-phytosphingosine、4-D-Hydroxysphinganine、DS-phytosphingosine

+ [3]

靶点-

作用机制-

治疗领域

其他疾病

在研适应症-

非在研适应症

溃疡

原研机构

1 A Pharma GmbH

在研机构-

非在研机构

1 A Pharma GmbH

最高研发状态(全球)无进展临床1期

首次获批日期(全球)-

最高研发状态(中国)-

特殊审评-

结构

分子式C18H40ClNO3

InChIKeyGDKAAHDFPOWGQE-RXQQAGQTSA-N

CAS号154801-32-8

查看全部结构式(2)

关联

项与植物鞘氨醇相关的临床试验

RBR-7rmtzg / CompletedN/A

Effect of phytosphingosine associated with toothbrushing regarding color alteration, surface roughness and microhardness of dental enamel - an in vitro and in situ study.

开始日期2020-01-06

申办/合作机构-

NTR1879 / CompletedN/A

A phase I/II, double blind, cross-over design, placebo controlled, pilot study to assess the effect and tolerability of multiple oral doses of phytosphingosine in Sjögren’s patients.

开始日期2009-09-01

申办/合作机构-

NTR1287 / RecruitingN/A

The effect of dietary phytosphingosine on insulin resistance and cholesterol levels in patients with the metabolic syndrome

开始日期2008-04-01

申办/合作机构-

100 项与植物鞘氨醇相关的专利（医药）

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137

项与植物鞘氨醇相关的文献（医药）

2023-07-11·Veterinary dermatology

Evaluation of residual antibacterial effects on canine skin surface and hair following treatment with five commercial mousse products against Staphylococcus pseudintermedius.

Article

作者: Chi-Yen Wu ; Rebecca Parsiola ; Mark Mitchell ; Maria Mitchell ; Sara Ramos ; Ivan Ravera ; Cherie Pucheu-Haston

BACKGROUND:

Antibacterial effect studies of commercial antiseptics typically have evaluated hair and not the skin.

OBJECTIVES:

To evaluate the antibacterial effects of mousse products on both canine skin and hair.

ANIMALS:

Fifteen short-haired and eight long-haired dogs without skin disease.

MATERIALS AND METHODS:

Five mousses were applied once: (1) 2% chlorhexidine and 2% miconazole; (2) 0.05% phytosphingosine; (3) 2% salicylic acid and 10% ethyl lactate; (4) 3% chlorhexidine and 0.5% climbazole; and (5) 2% chlorhexidine and 1% ketoconazole. Skin swabs and hair were collected from application sites before treatment, and at 1 h and at Day (D)2, D4, D8, D10 and D14 post-treatment. Skin swabs and hair were placed on Mueller-Hinton plates inoculated with Staphylococcus pseudintermedius inoculum suspension. Inhibition zones were measured after incubation.

RESULTS:

Inhibition was not noted with mousses 2 and 3. In mousse 5, inhibition zone sizes produced by swabs from long- and short-haired dogs were not significantly different (p = 0.105), and all swabs and hair produced inhibition until D14, regardless of hair length. By contrast, in mousse 1, inhibition zones produced by swabs from long-haired dogs were smaller than those from short-haired dogs (p < 0.001), and swabs from long-haired dogs produced a shorter duration of bacterial inhibition than hair.

CONCLUSIONS AND CLINICAL RELEVANCE:

The antibacterial effects of mousse 5 were not affected by hair length. Hair may be acceptable for evaluating effects on the skin in short-haired dogs. However, long hair may interfere with product distribution and duration of bacterial inhibition. Therefore, the evaluation of hair alone may overestimate clinically relevant antibacterial effects.

2023-07-05·Microbial pathogenesis

Phytosphingosine alleviates Staphylococcus aureus-induced mastitis by inhibiting inflammatory responses and improving the blood-milk barrier in mice.

Article

作者: Yihong Zhao ; Jiawen Xu ; Caijun Zhao ; Lijuan Bao ; Keyi Wu ; Lianjun Feng ; Hao Sun ; Shan Shang ; Xiaoyu Hu ; Qingsong Sun ; Yunhe Fu

Mastitis is one of the common diseases in dairy cows which threatens the health of cows and impacts on economic benefits seriously. Recent studies have been showed that Subacute Ruminal Acidosis (SARA) increased the susceptibility of cow mastitis. SARA leads the disturbance of the rumen microbiota, and the rumen bacterial disordered community is an important endogenous factor of cow mastitis. That is to say, cows which suffer from SARA have a disordered rumen microbiota, a prolonged decline in ruminal PH and a high level of lipopolysaccharide (LPS) in the rumen, blood. Therefore, ruminal metabolism is closely related to the rumen microbiota. However, the specific mechanism of SARA and mastitis still not clear. We found an intestinal metabolite according to the metabonomics, which is correlated to inflammation. Phytophingosine (PS), a product from rumen fluid and milk of the cows which suffer from SARA and mastitis. It has the effect of killing bacteria and anti-inflammatory. Emerging evidences indicate that PS can alleviate inflammatory diseases. However, how PS affects mastitis is largely unknown. In this study, we explored the concrete role of PS on Staphylococcus aureus (S. aureus) -induced mastitis in mice. We found that PS obviously decreased the level of the proinflammatory cytokines. Meanwhile, PS also significantly relieved the mammary gland inflammation caused by S. aureus and restored the function of the blood-milk barrier. Here, we showed that PS increased the expression of the classic Tight-junctions (TJs) proteins including ZO-1, Occludin and Claudin-3. Moreover, PS improves S. aureus-induced mastitis by inhibiting the activation of the NF-κB and NLRP3 signaling pathways. These data indicated that PS relieved S. aureus-induced mastitis effectively. This also provides a reference for exploring the correlation between the intestinal metabolism and inflammation.

2023-03-29·Ecotoxicology and environmental safety

Phytosphingosine inhibits cell proliferation by damaging DNA in human cell lines.

Article

作者: Chunxiao Sun ; Xuexiu Chang ; Hugh J MacIsaac ; Jiayao Wen ; Lixing Zhao ; Zhi Dai ; Jiaojiao Li

Harmful cyanobacterial blooms have caused numerous biosecurity incidents owing to the production of hazardous secondary metabolites such as microcystin. Additionally, cyanobacteria also release many other components that have not been explored. We identified compounds of a toxic mixture exudated from a dominant, blooming species, Microcystis aeruginosa, and found that phytosphingosine (PHS) was one of the bioactive components. Since PHS exhibited toxicity and is deemed a hazardous substance by the European Chemicals Agency, we hypothesized that PHS is a potentially toxic compound in M. aeruginosa exudates. However, the mechanisms of PHS ecotoxicity remain unclear. We assessed the cytotoxicity of PHS using an in vitro cell model in eight human cell lines and observed that the nasopharyngeal carcinoma cell line CNE2 was the most sensitive. We exposed CNE2 cells to 0-25 µmol/L PHS for 24 hr to explore its toxicity and mechanism. PHS exposure resulted in abnormal nuclear morphology, micronuclei, and DNA damage. Moreover, PHS significantly inhibited cell proliferation and arrested cell cycle at S phase. The results of Western blot suggested that PHS increased the expression of DNA damage-related proteins (ATM, p-P53 and P21) and decreased the expression of S phase-related proteins (CDK2, CyclinA2 and CyclinE1), indicating the toxicological mechanism of PHS on CNE2 cells. These data provide evidence that PHS has genetic toxicity and inhibits cell proliferation by damaging DNA. Our study provides evidence that PHS inhibits cell proliferation by damaging DNA. While additional work is required, we propose that PHS been considered as a potentially toxic component in MaE in addition to other well-characterized secondary compounds.

项与植物鞘氨醇相关的新闻（医药）

2023-05-26

·生物谷

Cell：李佳学/李晓淳等解析Spns2介导的磷酸鞘氨醇转运机制

这项研究通过结构和功能分析阐明了Spns2的工作机制，为理解 S1P代谢和信号传导提供了重要的分子基础。淋巴细胞的迁入和迁出对于维持淋巴组织的稳态和免疫功能的发挥是至关重要的。磷酸鞘氨醇（S1P）是一种重要的溶血脂类信号分子，在淋巴细胞迁出中扮演着关键作用。然而，S1P信号异常升高时会引起外周淋巴细胞过度活跃，导致自身免疫疾病，例如多发性硬化症（MS）。S1P分子在细胞内合成，但必须经跨膜转运进入循环系统，与细胞表面的GPCR受体S1PR1~5结合才能执行其信号传递功能。芬戈莫德（fingolimod）是一种靶向S1PR1的药物，已进入临床用于治疗发性硬化症（MS）。多发性硬化症（MS）是一种自身免疫性疾病，主要攻击中枢神经系统（脑、脊髓和视神经）。该疾病的特点是炎性脱髓鞘，即免疫系统攻击了神经纤维的髓鞘，导致电信号传递障碍和神经系统功能障碍，表现为感觉异常、肌肉无力、共济失调、语言障碍等症状。作为S1PR1的激动剂，芬戈莫德作用于淋巴细胞使其表面的S1PR1脱敏，导致这些淋巴细胞不能从淋巴结迁移进入输出淋巴管，从而缓解MS的症状。然而，芬戈莫德同样也会作用于内皮细胞和心肌细胞表面的S1PR1受体，引起严重的副作用，包括黄斑水肿和心动过缓。 S1P的跨膜转运主要通过特定的次级转运蛋白完成，目前已鉴定出的两种转运蛋白包括Spns2和Mfsd2b。淋巴液中的S1P主要来源于Spns2的转运，而血液中的S1P则主要来自于红细胞和血小板中的另一转运蛋白Mfsd2b。那么特异性抑制Spns2从而减少淋巴液中的S1P将有可能避免芬戈莫德这类S1PR1激动剂引起的副作用。此外，在小鼠模型的实验显示Spns2的功能缺陷能够减少癌细胞转移对肺部的侵袭。因此，Spns2是一个用于治疗自身免疫疾病和癌细胞转移的极具潜力的靶点，其结构和功能的研究对揭示S1P的转运机制和小分子抑制机制具有重要意义。 2023年5月23日，美国圣裘德儿童研究医院李佳学课题组和德克萨斯大学西南医学研究中心李晓淳课题组合作，在 Cell 期刊发表了题为：Structural and Functional insight into Spns2-mediated transport of sphingosine-1-phosphate 的研究论文。该研究解析了淋巴管/血管内皮细胞中由Spns2介导的磷酸鞘氨醇的转运机制，为开发更先进的Spns2抑制剂奠定基础，有助于癌症、炎症和免疫疾病的治疗。为了研究Spns2如何特异性的识别底物S1P，以及如何通过构象转变将S1P从细胞膜内侧运输到外侧，研究团队利用冷冻电镜技术解析了人源Spns2四种不同构象的结构，包括分别结合底物S1P和小分子抑制剂16d的向内开放状态、不结合底物的部分阻塞状态和向外开放状态（图1）。结合计算生物学和细胞功能实验，这些结构展示了Spns2介导S1P跨膜转运的完整循环过程，为理解该蛋白家族转运溶血脂类的工作机制奠定了基础，也为优化开发新型小分子抑制剂提供了依据。图1. 不同构象的Spns2结构 Spns2的整体结构属于典型的MFS折叠构型，包含12个跨膜螺旋，分为N端和C端两个相对伪对称的结构域。值得注意的是，在所有构象中只有向内开放状态下的Spns2结合有S1P，说明在这一构象的Spns2对S1P有较高的亲和力。在循环转运过程中，Tyr246/Gly333、Tyr246/Asp445、Asp220/Arg456等成对的氨基酸像开关一样控制脂质转运通道的开放与闭合，以及底物结合口袋的形状变化。例如，在向内开放状态下，Tyr246和Gly333形成的氢键会阻塞脂质转运通道；当进入状态2时，这两个氨基酸残基之间不再存在氢键，而TM4的Asp220和TM11的Arg456之间形成盐桥，这两个跨膜螺旋近膜内端之间的距离随之缩短，从而使得内向开口关闭。对这些结构分析直接展示了在相同实验条件下多个状态之间的分子转变。去年，有研究报道了首个Spns2特异性小分子抑制剂16d。为了研究该抑制剂的工作机制，研究人员还解析了结合16d的Spns2结构。当Spns2结合16d时，只有一种构象，即向内开放状态的结构被捕捉并解析。16d与S1P结合在Spns2相似的位置。与结合S1P的构象相比，Trp440发生了明显的构象变化，并远离结合位点，表明Trp440对16d的特异性结合起重要作用。该结构表明，16d通过直接与S1P竞争同一位点，并将转运蛋白锁定在向内开放状态以阻止其转运活性。 Spns2转运S1P需要偶联质子的跨膜转运（proton-coupled），还是仅仅依靠S1P的顺浓度梯度仍存在争议。研究人员利用细胞实验，证明了Spns2转运S1P并不依赖细胞膜内外两侧的质子浓度（即pH）和Na+离子浓度。此外，当细胞外的S1P浓度足够高时，Spns2还能将S1P转运至细胞内。这些实验表明，Spns2是一个S1P的协助扩散转运蛋白（facilitated-diffusion uniporter）（图2）。图2. Spns2转运S1P的工作模型总的来说，这项研究通过结构和功能分析阐明了Spns2的工作机制，为理解 S1P代谢和信号传导提供了重要的分子基础。