Introduction/Overview
Natural products, as an important source of drug discovery, play an indispensable role in the long struggle between humans and diseases. Among the numerous bioactive lipid molecules, phytosphingosine (PS) has attracted widespread attention in the fields of pharmacology, dermatology, and metabolic disease research in recent years due to its unique chemical structure and extensive pharmacological activity. Plant sphingosine, chemically known as (2S, 3S, 4R) -2-amino-1,3,4-octanetriol, is a naturally occurring sphingolipid compound. Unlike sphingosine commonly found in mammals, plant sphingosine contains an additional hydroxyl group at the C4 position, which endows it with unique physicochemical properties and biological functions.
Plant sphingosine was initially discovered in plants, yeast, and certain mammalian tissues, and is a key intermediate in the sphingolipid metabolism network. In living organisms, it is not only an important component that constitutes the cell membrane and participates in maintaining the barrier function of the skin's stratum corneum, but also a signaling molecule with multiple pharmacological activities. Research has shown that plant sphingosine has significant anti-inflammatory, antibacterial, and anticancer activities, and can inhibit tumor cell proliferation by inducing apoptosis. In addition, it is also an immunomodulatory agent that plays an important role in the pathological and physiological processes of inflammatory skin diseases such as atopic dermatitis and psoriasis.
In recent years, with the deepening of research on the sphingolipid signaling pathway, new functions of plant sphingolipids have been continuously revealed. Of particular note, research has found that plant sphingosine is an activator of G protein coupled receptor 120 (GPR120), with a half maximal inhibitory concentration (IC50) of 33.4 μ M. GPR120 is a long-chain fatty acid receptor, which plays a key role in regulating insulin sensitivity, controlling appetite and anti-inflammatory reaction, which makes plant sphingosine show potential application value in the treatment of type 2 diabetes and related metabolic disorders. This review aims to systematically review the chemical properties, sources, pharmacological activities, mechanisms of action, and pharmacological evaluation of plant sphingosine, and explore its clinical application prospects in the fields of skin barrier repair, inflammatory diseases, and metabolic diseases.
Chemical structure and physicochemical properties
The chemical structure of plant sphingosine is the basis of its biological function. Its system is named (2S, 3S, 4R) -2-amino-1,3,4-octanetriol, with a molecular formula of C18H39NO3 and a molecular weight of 317.5140 g/mol. Structurally, plant sphingosine is composed of a long-chain (C18) aliphatic skeleton with an amino group (- NH2) at the C2 position and a hydroxyl group (- OH) at each of the C1, C3, and C4 positions. Among them, the chiral centers at positions C2, C3, and C4 are in the S, S, and R configurations, respectively. Compared with mammalian sphingosine (which only has hydroxyl groups at the C1 and C3 positions and a double bond at the C4 position), the additional hydroxyl group at the C4 position is the most significant structural feature of plant sphingosine, which directly affects its intermolecular hydrogen bonding network and interaction mode with proteins.
In terms of physicochemical properties, plant sphingosine exhibits typical amphiphilic characteristics. Its long-chain alkyl tail (C5-C18) has hydrophobicity, while the polar head (C1-C4 hydroxyl and amino) has hydrophilicity. This amphiphilicity allows it to be inserted into the phospholipid bilayer of biological membranes, affecting the fluidity and stability of the membrane. The calculated lipid water partition coefficient (LogP) is 3.4159, indicating that it has a certain degree of lipid solubility, which is beneficial for its penetration into the stratum corneum and cell membrane. Its topological polar surface area (TPSA) is 86.71 Å ², mainly contributed by three hydroxyl groups and one amino group, indicating its certain water solubility (calculated water solubility is 0.1433 mg/mL). It is worth noting that under physiological pH conditions, the amino group of plant sphingosine can undergo protonation, forming positively charged ammonium ions, which are crucial for its interaction with negatively charged cell membranes or bacterial cell walls.
In addition, the stability of plant sphingosine is affected by pH and temperature. Under acidic or alkaline conditions, its amino and hydroxyl groups may undergo hydrolysis or oxidation reactions. In living organisms, plant sphingosine is mainly phosphorylated (producing plant sphingosine-1-phosphate) or acylated (producing ceramide) through the sphingolipid metabolism pathway, and is rapidly metabolized or converted into other active molecules. These physical and chemical properties determine its formulation strategy in pharmaceutical preparations, for example, it is usually required to wrap it in liposomes or nano lotion to improve stability and bioavailability.
Plant sources and extraction methods
Plant sphingosine was initially isolated and identified from plants, hence its name. It is widely distributed in nature, not only in the plant kingdom, but also in yeast, fungi, and the stratum corneum of mammalian skin. In plants, phytosphingosine is the core component of sphingolipids such as plant ceramides and glycosylated ceramides, mainly present in cell membranes and wax layers. Natural sources rich in plant sphingosine include wheat germ, rice, corn, soybeans, and certain medicinal plants such as centella asiatica and purple grass. Among them, wheat germ oil and rice bran oil are the main raw materials for industrial extraction of plant sphingolipids and their derivatives (such as plant ceramides).
Extracting plant sphingolipids from natural products usually involves the following steps: raw material pretreatment, total lipid extraction, sphingolipid enrichment, hydrolysis, and purification. Firstly, plant materials rich in sphingolipids (such as rice bran or wheat germ) are dried and crushed, and then total lipids are extracted using organic solvents (such as chloroform methanol mixture, n-hexane isopropanol, etc.). After concentration of the extract, complex sphingolipids (such as ceramides and sphingolipids) are hydrolyzed through alkaline hydrolysis or enzymatic hydrolysis, releasing free plant sphingolipids. The hydrolysis product is then separated and purified by liquid-liquid extraction, column chromatography (such as silica gel column, reverse phase C18 column) or high performance liquid chromatography (HPLC) to obtain high-purity plant sphingosine.
In addition to natural extraction, chemical synthesis is also an important way to obtain plant sphingolipids. Due to the high cost, low yield, and limited raw material supply of natural extraction, chemical synthesis methods (such as stereoselective synthesis using D-glucose or L-serine as chiral raw materials) can provide structurally clear and high-purity products. In addition, biological fermentation methods (such as metabolic engineering using yeast strains) have gradually become a green and sustainable production method. In laboratory research, commercialized plant sphingosine is usually provided in the form of hydrochloride salt to enhance its water solubility and stability.
Pharmacological activity research
The pharmacological activity spectrum of plant sphingosine is very broad, covering multiple aspects such as anti-inflammatory, antibacterial, anticancer, and metabolic regulation, making it a candidate molecule for multi-target drug development.
1. Anti inflammatory activity and immune regulation
Plant sphingosine is a potent immunomodulatory agent. In the skin inflammation model, plant sphingosine can inhibit the production of pro-inflammatory cytokines (such as TNF - α, IL-1 β, IL-6) in keratinocytes and immune cells. The mechanism is partially attributed to the inhibition of the NF - κ B signaling pathway. In addition, plant sphingosine can regulate the activation and proliferation of T cells, inhibit the maturation of dendritic cells, and thus play a therapeutic role in Th1/Th2 inflammatory skin diseases such as atopic dermatitis and psoriasis. This immunomodulatory effect makes it a potential candidate drug for treating chronic inflammatory diseases.
2. Antibacterial activity
Plant sphingosine has broad-spectrum antibacterial activity, especially showing strong inhibitory effects on Gram positive bacteria (such as Staphylococcus aureus, Propionibacterium acnes) and certain fungi (such as Candida albicans). Its antibacterial mechanism mainly depends on its cationic amphiphilic structure. Positively charged plant sphingosine molecules can adsorb onto negatively charged bacterial cell membranes through electrostatic interactions, and then insert into lipid bilayers, disrupting membrane integrity and leading to leakage of cell contents and bacterial death. This physical membrane disruption mechanism makes it difficult for bacteria to develop drug resistance, therefore plant sphingosine has unique advantages in developing new antibiotics, especially against drug-resistant strains.
3. Anti cancer activity and induction of apoptosis
A large number of in vitro and in vivo studies have shown that plant sphingosine has significant cytotoxic effects on a variety of cancer cell lines (such as melanoma, colon cancer, liver cancer, breast cancer, etc.). The core mechanism is to induce cell apoptosis. Plant sphingosine can activate the apoptotic cascade through two pathways: endogenous (mitochondrial) and exogenous (death receptor). Specifically, it can upregulate the expression of pro apoptotic proteins (such as Bax and Bad) and downregulate the expression of anti apoptotic proteins (such as Bcl-2), leading to loss of mitochondrial membrane potential, release of cytochrome c, and activation of Caspase-9 and Caspase-3. In addition, plant sphingosine can promote cell death by activating the JNK and p38 MAPK signaling pathways, as well as inhibiting the PI3K/Akt survival pathway. It is worth noting that plant sphingosine has relatively low toxicity to normal cells and exhibits certain selective anti-tumor activity.
4. Metabolic regulation effect
In recent years, breakthroughs have been made in the research of plant sphingolipids in the field of metabolic diseases. Research has found that plant sphingosine is an agonist of the GPR120 receptor. GPR120 is a G protein coupled receptor highly expressed in the intestine, adipose tissue, and macrophages, involved in regulating fatty acid uptake, inflammatory response, and insulin sensitivity. After activation of GPR120 by plant sphingosine, it can promote the secretion of glucagon like peptide-1 (GLP-1), enhance insulin sensitivity, and inhibit macrophage mediated inflammatory response. These effects are of great significance for improving blood glucose control and reducing insulin resistance in patients with type 2 diabetes. In addition, plant sphingosine may also demonstrate potential in the treatment of non-alcoholic fatty liver disease (NAFLD) by regulating lipid metabolism and reducing liver fat accumulation.
Mechanism of action and molecular targets
The pharmacological activity of plant sphingosine originates from its interactions with various molecular targets. Its mechanism of action is complex, involving signal transduction, gene expression regulation, and changes in cell membrane physical properties.
1. Regulation of sphingolipid metabolism enzymes
Plant sphingosine is a core node in the sphingolipid metabolism network. As a substrate, it can be phosphorylated by sphingosine kinases (SPHK1 and SPHK2) to produce phytosingosine-1-phosphate (Phyto-S1P) in plants. Phyto-S1P is an important signaling molecule that exerts various biological effects by binding to the S1P receptor (S1PR1-5), such as regulating cell migration, angiogenesis, and immune cell transport. In addition, plant sphingosine can also be acylated by ceramide synthases (CERAS, CERS1, CERS3, etc.) to produce phytoceramide, which is a key lipid that forms the skin's stratum corneum barrier. Therefore, plant sphingosine indirectly affects downstream signaling pathways and cellular functions by regulating the activity of SPHK and CERS.
2. GPR120 receptor activation
Plant sphingosine, as an agonist of GPR120, is a key mechanism for its metabolic regulation. GPR120 is a long-chain fatty acid receptor belonging to the GPCR family. When plant sphingosine binds to GPR120, the receptor conformation changes, coupling with Gq/11 protein and activating downstream phospholipase C (PLC) and protein kinase C (PKC) signaling pathways. In intestinal L cells, this leads to an increase in GLP-1 secretion; In macrophages, TLR4 mediated inflammatory response is inhibited, reducing the release of pro-inflammatory cytokines. This mechanism provides a molecular basis for the treatment of type 2 diabetes and obesity related inflammation with plant sphingosine.
3. Cell membrane disturbance and signal transduction
The amphiphilic nature of plant sphingosine allows it to directly insert into cell membranes, altering membrane fluidity, lipid raft structure, and permeability. This physical action can non specifically affect the function of membrane proteins, such as receptors and ion channels. For example, plant sphingosine can inhibit the activity of protein kinase C (PKC), activate the mitogen activated protein kinase (MAPK) pathway (such as p38, JNK), and induce endoplasmic reticulum stress (ER stress). The activation of these signaling pathways ultimately leads to cell cycle arrest, apoptosis, or autophagy. Especially in cancer cells, plant sphingosine induced membrane damage and signal disruption are important mechanisms for its selective killing effect.
4. Targets related to skin barrier repair
In skin biology, plant sphingosine is a precursor for the synthesis of plant ceramides. Ceramides are the main component of intercellular lipids in the stratum corneum and are crucial for maintaining skin barrier function. Plant sphingosine is acylated by enzymes such as CERS1 and CERS3 to generate plant ceramides with long-chain fatty acids. These ceramides can fill the gaps between keratinocytes, forming a dense lipid bilayer to prevent water loss and invasion of external stimuli. In addition, plant sphingosine itself can directly stimulate the differentiation and lipid synthesis of keratinocytes, upregulate the expression of barrier related proteins such as filaggrin and Loricrin. Therefore, plant sphingosine promotes skin barrier repair through two ways: supplementing precursor substances and directly regulating gene expression.
Evaluation of drug properties and pharmacokinetics
Developing plant sphingosine as a clinical drug requires a systematic evaluation of its pharmacological properties. Based on the provided parameters and literature data, its pharmacological characteristics are as follows:
1. Physical and chemical properties and drug like properties
The molecular weight of plant sphingosine is 317.5 Da, which falls within the typical range of small molecule drugs (<500 Da). Its LogP is 3.42, which is within the ideal range of lipid solubility (2-4) and is conducive to transmembrane absorption. The TPSA is 86.71 Å ², which is lower than 140 Å ², indicating its good oral absorption potential. The low water solubility (0.1433 mg/mL) is considered a low solubility drug, which may be one of the main reasons for its limited oral bioavailability. In the development of formulations, solubilization techniques such as liposomes, cyclodextrin inclusion complexes, and solid dispersions need to be used to improve their solubility.
2. Security assessment
The key toxicological prediction results show that the inhibitory risk of plant sphingosine on hERG potassium channels is "no", indicating a low risk of causing QT interval prolongation and arrhythmia in the heart. The Ames test result is 0.0, indicating no significant genetic toxicity or mutagenicity. These data provide preliminary assurance for the safety of plant sphingosine. However, as a lipid molecule with membrane activity, high concentrations of plant sphingosine may cause cytotoxicity or hemolysis, so strict dosage control is required in in vivo applications.
3. Pharmacokinetic characteristics
The pharmacokinetic study of plant sphingosine is not yet sufficient, but reasonable speculation can be made based on its structure. Its blood-brain barrier (BBB) penetration ability has been evaluated as' low ', which limits its application in central nervous system diseases. However, for peripheral targets such as skin, liver, and adipose tissue, this may actually be an advantage, reducing central side effects. After oral administration, plant sphingosine may be absorbed through the lymphatic system and undergo first pass metabolism. In the body, it is rapidly metabolized into plant sphingosine-1-phosphate or ceramide, and its half-life may be short. Local administration (such as topical application on the skin) is its most advantageous route of administration, as its lipophilicity facilitates penetration through the stratum corneum and directly acts on epidermal cells.
4. Formulation strategy
Due to its low water solubility and membrane activity, the development of plant sphingosine formulations faces challenges. In the field of dermatology, it has been successfully used in a variety of cosmetics and cosmetics formulations, usually in the form of liposomes, nano lotion or microcapsules, to improve stability and skin permeability. For systemic administration (such as oral or injection), it is necessary to design prodrugs (such as phosphorylated derivatives) or use nanocarrier systems (such as lipid nanoparticles, polymer micelles) to improve their bioavailability and targeting.
Clinical application prospects and prospects
Based on its unique pharmacological activity, plant sphingosine has shown broad application prospects in multiple therapeutic fields.
1. Skin barrier repair and inflammatory skin diseases
This is currently the most mature application field of plant sphingosine. As an important component of natural skin lipids, plant sphingosine and its derivatives (such as plant ceramides) have been widely added to moisturizers, repair creams, and anti-aging products. Clinical studies have confirmed that formulations containing plant sphingosine can significantly improve skin barrier function in patients with atopic dermatitis and psoriasis, reduce transcutaneous water loss (TEWL), and alleviate itching and erythema. In the future, developing targeted delivery systems (such as microneedles and nanoemulsions) for specific inflammatory skin diseases (such as acne and rosacea) will be an important direction.
2. Metabolic disorders
Plant sphingosine, as a GPR120 agonist, provides a new idea for the treatment of type 2 diabetes and obesity. Compared with traditional GPR120 agonists such as omega-3 fatty acids, plant sphingosine has higher affinity and selectivity. Future research needs to validate its hypoglycemic, weight reducing, and anti-inflammatory effects in animal models and clinical trials. In addition, exploring its synergistic effects with existing drugs such as metformin and GLP-1 receptor agonists may lead to the development of more effective combination therapies.
3. Anti infection treatment
Given the increasing severity of antibiotic resistance, plant sphingosine, as a natural antibacterial agent with membrane disrupting properties, has the potential to be developed into a new type of antibacterial drug. Its broad antibacterial spectrum and resistance to drugs make it advantageous in treating acne, skin infections, and oral infections. Future research should focus on optimizing its antibacterial activity while reducing toxicity to host cells, such as through structural modifications or in combination with existing antibiotics.
4. Cancer treatment
The induction of apoptosis and anti proliferative activity of plant sphingosine make it a potential anti-cancer adjuvant drug. However, its non-specific membrane activity may lead to systemic toxicity. Therefore, future research directions should focus on the development of tumor targeted delivery systems, such as folate modified liposomes and pH sensitive nanoparticles, to achieve selective killing of tumor tissues. In addition, exploring the combined use of plant sphingosine and chemotherapy drugs (such as cisplatin and paclitaxel) may improve efficacy and reduce drug resistance through synergistic effects.
5. Future research directions
Despite the bright prospects, the clinical translation of plant sphingosine still faces many challenges. Firstly, its mechanism of action still needs further clarification, especially its exact role in the complex metabolic network in the body. Secondly, it is necessary to conduct systematic pharmacokinetic and toxicological studies to determine the optimal dosing regimen and safe dosage range. Finally, developing plant sphingosine analogs with stronger activity, higher selectivity, and better pharmacokinetic properties through structure-activity relationship (SAR) research will be the key to promoting the development of this field.
Conclusion
Plant sphingosine, as an ancient and novel natural lipid molecule, is transitioning from a traditional skin care ingredient to a multifunctional drug candidate molecule. Its unique chemical structure endows it with multiple pharmacological activities such as anti-inflammatory, antibacterial, anticancer, and metabolic regulation. By acting on sphingolipid metabolic enzyme, GPR120 receptor and cell membrane itself, plant sphingosine shows great potential in skin barrier repair, type 2 diabetes, infectious diseases and cancer treatment. Although there are still challenges such as poor water solubility and fast metabolism in drug development, these problems are expected to be solved through advanced formulation technology and structural modification. With the continuous deepening of research on sphingolipid biology and GPCR signaling pathways, plant sphingolipids and their derivatives are expected to become important drugs for treating inflammation, metabolic disorders, and tumors in the future, contributing to human health.
