Diverse Biological Effects and Industry Applications of Squalene: From Ocean to Healthcare
Time：2023-11-24 Hits：312
Seebio’s Squalene(CAS: 111-02-4 or CAS: 7683-64-9) is a colorless oily liquid that becomes viscous when oxidized. It is an unsaturated triterpene compound consisting of six isoprene units and serves as a crucial intermediate in the human cholesterol metabolism pathway. Squalene exhibits potent antioxidant properties and acts as a scavenger of free radicals. Squalene is synthesized in the endoplasmic reticulum and stored in vesicles or transferred to the cell membrane through vesicles. It contains six isoprene double bonds and belongs to the terpene class of compounds.
Squalene
Squalene is widely present in the bodies of animals, plants, and microorganisms. Due to its strong biological activity, it finds extensive applications in industries such as food and cosmetics. Squalene has protective and nourishing effects on the skin. Its low solidification point (-72°C) makes it an excellent low-temperature lubricant. Many foods contain squalene, with shark liver oil having a particularly high content. Squalene is also relatively abundant in a few plant oils, such as olive oil and rice bran oil.
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Item
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Description
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Chemical formula
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C30H50
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Hydrophobicity
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Hydrophobic effect
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Stability
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Relatively stable under auto-oxidation conditions
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Density
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0.8584
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Boiling point
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About 330°C(at atmospheric pressure)
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Solubility
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Soluble in diethyl ether, petroleum ether, acetone, carbon tetrachloride and n-hexane; sparingly soluble in ethanol and acetic acid; insoluble in water
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Squalene possesses multiple bioactive effects, including enhancing hypoxia tolerance, inhibiting microbial growth, exhibiting antimicrobial and anti-inflammatory properties, and regulating cholesterol metabolism. Additionally, it has the ability to quench singlet oxygen, effectively protecting the skin from lipid peroxidation damage and preventing DNA oxidation damage to cells. This substance also demonstrates various crucial physiological functions, such as preventing cardiovascular diseases, enhancing immune response, and exhibiting anti-tumor properties.
(1) Oxygen Transport/Hypoxia Tolerance
The intake of squalene significantly enhances hypoxia tolerance, as demonstrated in mouse experiments where survival times were markedly extended under conditions of normobaric hypoxia and sodium nitrite poisoning. Research from the Fujian Provincial Center for Disease Control indicates that mice given squalene for 30 days showed a significant increase in survival and gasping time under conditions of sodium nitrite injection and acute cerebral ischemic hypoxic stress, with no toxic side effects. The absorption rate of dietary squalene can reach as high as 60% to 85%, making squalene an effective component widely used in hypoxia-resistant health foods.
(2) Moisturizing Antioxidant/Promoting Skin Health
Squalene possesses multiple skin care functions, including protection against ultraviolet radiation and antioxidant effects. It can improve skin texture, reduce pores and wrinkles, moisturize the skin without causing irritation. An experiment targeting women over 50 showed that squalene intake significantly reduced facial wrinkles, improved facial redness, and reduced pigment deposition. Moreover, squalene enhances skin antioxidant enzyme activity, surpassing the effects of vitamin E. Due to its outstanding moisturizing effects, some well-known cosmetic brands have incorporated squalene into skincare and haircare products, such as hydrating serums and skincare oils.
(3) Free Radical Scavenger, Immune Enhancement
Squalene has potent free radical scavenging abilities, playing a crucial role in promoting human metabolism. By activating metabolism, squalene helps improve the body's absorption and utilization efficiency of nutrients, thereby promoting health maintenance. As a functional food additive, squalene is applied in various health products, including nutritional supplements, health foods, and functional beverages. Research and applications of squalene continue to expand, providing people with more possibilities to obtain health benefits through food.
(4) Pharmaceutical Delivery Carrier/Vaccine Adjuvant
As a natural lipid, squalene is widely used as a biocompatible drug carrier for controlled drug release. Emulsion drugs containing squalene can prolong the half-life of drugs. Squalene-based vaccine adjuvants such as MF59, AS03, and AF03 have been registered for influenza vaccines and have shown significant efficacy in the development of COVID-19 vaccines. Squalene also plays a role in the development of intranasal vaccine delivery, generating antibodies against COVID-19 and making progress in vaccine research against the Zika virus.
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Product
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CAS
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Chemical Formula
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Grade
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Specification
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Squalene
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111-02-4
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C30H50
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Cosmetic
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25kg/barrel
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111-02-4
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C30H50
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Pharmaceutical
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25kg/barrel
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7683-64-9
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C30H50
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Cosmetic
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25kg/barrel
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7683-64-9
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C30H50
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Pharmaceutical
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25kg/barrel
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Medical Aesthetics Industry Applications
Plant-derived squalene finds widespread application in cosmetics, particularly olive oil squalene. Research has focused on its effectiveness in moisturizers, its impact on skin irritation and hydration, as well as its metabolism and inflammatory responses under solar ultraviolet radiation. Analyses indicate potential benefits of squalene in preventing skin diseases, providing crucial information for a deeper understanding of the application of plant-derived squalene in cosmetics and skin health.
Squalene and its hydrogenated products are popular due to their extensive use in cosmetics. Plant-derived squalene, especially extracted from olive oil, is a preferred choice in the cosmetics industry. It not only meets the preference for plant-based ingredients but also avoids the unethical collection of protected marine species.
Effectiveness of Squalene in Moisturizers: The evaluation of the effects of plant stem cells, squalene, and alkyl polyglucoside emulsifiers in moisturizers, with a particular focus on olive oil squalene's impact on skin irritation and hydration. A study involving 76 volunteers measured skin parameters in two phases, demonstrating that these ingredients, combined with a novel stabilizer, can safely be used in moisturizers for normal and dry skin. Olive oil squalene performed well in treating sensitive skin without causing significant irritation. The research supports the safety and effectiveness of these active ingredients in cosmetics, providing valuable information for the development of customized moisturizers.
Inflammatory Responses to Squalene Photooxidation Products: Investigating the metabolism and inflammatory responses of human corneocytes under solar ultraviolet radiation (UVA+UVB) and analyzing endogenous lipid mediators. Using physiologically relevant doses of simulated solar UVA+UVB on the surface skin lipids (SSL) or normal human epidermal keratinocytes (NHEK), the study analyzed the depletion of photosensitive lipophilic components in SSL, including α-tocopherol, squalene (Sq), and cholesterol, and quantitatively separated squalene photooxidation products (SqPx) in irradiated SSL. In experiments simulating UVA+UVB exposure, squalene photooxidation products induced UVA+UVB-specific metabolic and inflammatory responses through AhR, EGFR, and G2A receptors. This research provides important insights into understanding the biological response of human corneocytes to UV radiation, especially in deciphering the regulatory mechanisms of squalene photooxidation products.
Regulating Squalene Oxidation for Skin Disease Prevention: Squalene, a terpenoid compound found in human skin surface lipids (SSLs), has beneficial effects. Due to the potential complications arising from squalene oxidation, understanding its oxidation mechanism is essential. This study aims to analyze squalene monohydroperoxide (SQOOH) isomers, revealing that squalene in human SSLs is primarily oxidized by singlet oxygen, while squalene in sebum lipids (SLO) is mainly oxidized by free radicals. The study proposes a method to estimate the oxidation mechanism by analyzing squalene monohydroperoxide isomers. This approach not only provides a new perspective on understanding the oxidation process of squalene but also establishes a foundation for preventing skin diseases by regulating squalene oxidation.
Medical Industry Applications
Squalene has demonstrated multiple potential applications in medical research. In HepG2 cells, squalene has been explored for its ability to inhibit cell proliferation and increase LDLR expression, potentially contributing to cholesterol reduction. Molecular docking studies suggest squalene may play a role in skin cancer treatment. Additionally, when encapsulated in PLGA NPs, it enhances cellular uptake in olive oil, showcasing potential in maintaining cell health and combating oxidative stress.
Cholesterol Reduction Mechanism: Investigation into the impact of squalene on LDLR expression in HepG2 cells and its mechanism for lowering cholesterol. Results indicate a concentration-dependent inhibition of HepG2 cell proliferation and increased LDLR expression. FRET technology detected squalene's potential mechanism in upregulating LDLR expression through the modulation of key proteins SCAP and Insig2 in the SCAP/SREBP signaling pathway. This suggests potential pharmacological value for squalene in cholesterol reduction.
Skin Cancer Treatment Research: Molecular docking studies involving TGF-beta, MIA, and Raf explore the therapeutic effects of squalene from quinoa grains on skin cancer. Squalene, possibly acting as an enzyme inhibitor, shows potential in anti-cancer screening. Results suggest that squalene from quinoa grains has therapeutic potential in preventing skin cancer, with interactions with BRAF, TGF-beta, and MIA proteins being more effective than Vemurafenib. This establishes squalene as a potential drug, with nutritional products from quinoa being a potential dietary therapy for skin cancer treatment.
Cell Health Maintenance and Oxidative Stress Resistance: Olive oil, a major fat source in the Mediterranean diet, contains natural antioxidant squalene. Despite squalene's low bioavailability due to its hydrophobic nature, successful encapsulation in PLGA NPs increases cellular uptake efficiency in mouse liver cells and TXNDC5-deficient cell lines. Experimental results show squalene significantly enhances cell survival by regulating oxidative stress and endoplasmic reticulum stress-related signaling pathways. This highlights the potential role of squalene in maintaining cell health and resisting oxidative stress, especially in its crucial interaction with TXNDC5.
Food Industry Applications
Squalene as a functional food additive is extensively studied for its potential in preventing various diseases, including cardiovascular diseases and cancer. Adding squalene capsules significantly improves the quality of cakes, exhibiting excellent oxidation stability and microbial quality. Subacute toxicity tests show that squalene has no adverse effects on the body and no toxic side effects.
Prevention of Cardiovascular Diseases as a Functional Food: Squalene, a highly regarded natural product, is widely studied for its potential in preventing cardiovascular diseases and cancers. Originally found in shark liver oil, squalene plays a role as a precursor in cholesterol biosynthesis in animals. Due to its unique physical properties and diverse physiological functions, such as anticancer and antihypercholesterolemia effects, squalene becomes an attractive resource for functional foods, supplements, and even drugs. Its antioxidant and oxygen-carrying properties suggest its potential in preventing cardiovascular diseases.
Quality Improvement in Cakes: Research indicates that adding encapsulated squalene significantly improves the quality of cakes. Nutritional analysis reveals that the prepared cakes have a caloric value ranging from 480.78 to 501.61 kcal. Cakes with encapsulated squalene exhibit lower baking loss and higher breadcrumb moisture content. Color kinetics studies show that the crust browning index is high in cakes rich in encapsulated squalene. Texture studies confirm that cakes containing squalene capsules have excellent stickiness, elasticity, and chewiness. Furthermore, squalene-rich foods demonstrate outstanding oxidation stability and microbial quality, suggesting potential antimicrobial effects. The study suggests that encapsulated squalene is a high-quality ready-to-eat functional food ingredient.
Subchronic Toxicity Test of Squalene: Experimental animals were randomly divided into three different dose groups and a solvent control group based on body weight and orally administered the test substance for 30 consecutive days. Results show that there are no statistically significant differences in various aspects, including body weight, weight gain, food intake, food utilization rate, and organ-to-body ratio, among the dose groups of rats and the control group. Blood indicators, including hemoglobin content, red blood cell count, white blood cell count, and white blood cell classification, are within normal ranges. Biochemical indicators such as serum alanine aminotransferase, aspartate aminotransferase, urea, creatinine, total cholesterol, triglycerides, blood glucose, total protein, and albumin are also within normal ranges. No adverse effects on the body are observed, and there are no toxic side effects.
Applications in Agriculture
Squalene has significant effects on productivity and immune regulation in agricultural animal husbandry. In male broiler chickens, dietary squalene supplementation significantly increased semen volume and egg fertilization rate in a natural mating model. In boars, high-dose squalene feeding significantly improved reproductive performance, including shortened mating time, increased semen volume and litter size. Additionally, as an immunomodulator, squalene activated the Wnt/β-catenin signaling pathway in rock bream, enhancing immunity and disease resistance. These studies provide empirical basis for applying squalene in livestock and aquaculture.
Promoting Reproductive Performance in Chickens: A study examined the effects of squalene on the reproductive performance of 72-week old male broiler breeders (6.0 ± 0.5 kg). Birds were divided into 4 groups representing two mating types - artificial insemination (AI) and natural mating (NM) - with control and squalene treatment (10 mg/kg/day for 45 days) subgroups in each. Results showed that the squalene treatment significantly increased semen volume (p<0.001) compared to control. In the NM model, the fertilization rate was also markedly higher in the treatment group (p<0.001), along with elevated serum testosterone (p<0.05). This demonstrates squalene’s promotional effects on male broiler breeder fertility.
Enhancing Reproductive Performance in Boars: A study investigated the effects of squalene supplementation on the reproductive performance of 12-month old boars (130±5 kg). Boars were randomly allotted to four groups receiving basal diet or diets with different doses of squalene for 60 days. Results displayed no significant improvements with 10 mg/kg/day squalene. Remarkably, 20 or 40 mg/kg/day squalene markedly enhanced reproductive performance, including shortened mating time, increased semen volume and viability, and greater litter size. High-dose squalene decreased serum leptin and increased testosterone levels. This suggests potential benefits of dietary squalene for elevating swine reproductive capacity.
Improving Immunity in Rock Bream: Squalene was observed to potentially modulate rock bream immunity via the Wnt/β-catenin signaling pathway, but the mechanism is unclear. Using intraperitoneal injections of PBS, squalene (Sq), Sq+pathway activator TWS119, and Sq+inhibitor IWR-1 to interfere with this pathway and downstream signals, Sq and Sq+TWS119 markedly increased rock bream survival rate and antioxidant abilities against Vibrio harveyi infection, while Sq+IWR-1 decreased survival. Sq and Sq+TWS119 activated PI3K-Akt and Wnt/β-catenin pathways and upregulated NF-κB signaling anti-inflammatory factors; conversely, Sq+IWR-1 inhibited these pathways. In summary, squalene enhances rock bream immunity and disease resistance by modulating the Wnt/β-catenin pathway, providing new potential for immunoprotection in aquaculture.
Applications as Vaccine Adjuvant
Squalene-based adjuvants have shown significant potential in vaccines. AddaVaxTM successfully enhanced epithelial ovarian cancer and COVID-19 vaccine efficacy, demonstrating good immunogenicity and safety profiles in mice EOC and rhesus macaque/hamster models. Additionally, as a novel adjuvant in inactivated vaccine preparation, squalene promoted antibody titer and cellular immunity, showcasing the broad application prospects of squalene-based adjuvants across vaccine areas.
Enhancing Ovarian Cancer Vaccine Efficacy: Epithelial ovarian cancer (EOC) is one of the most lethal gynecological malignancies. Previous studies reported an anti-Müllerian hormone receptor 2 extracellular domain (AMHR2-ED) vaccine using complete Freund’s adjuvant (CFA) that induced AMHR2-ED-specific immune responses and achieved EOC prevention/therapy in female mice. In this study, the squalene-based adjuvant AddaVaxTM was used as a replacement for clinical trial assessment. Results displayed that the AMHR2-ED vaccine with AddaVax as adjuvant performed exceptionally in preventing/treating murine EOC, inducing high levels of IgG, significantly suppressing EOC growth, and improving overall mouse survival. These findings highlight the potential of squalene-based adjuvants in enhancing vaccine efficacy, providing new possibilities for their application in human EOC treatment.
Great COVID-19 Vaccine Immunogenicity: NARUVAX-C19 is a squalene-adjuvanted COVID-19 vaccine demonstrating good immunogenicity, efficacy and safety profiles in rhesus macaque and hamster studies. Two NARUVAX-C19 doses showed no adverse effects in macaques with neutralization against multiple variants. In hamsters, the vaccine prevented Delta variant challenge, alleviating viral loads and lung pathology. NARUVAX-C19 performed well in eliciting broad neutralizing antibodies and T cell responses, supporting the utility and sustained clinical development of its squalene-emulsified recombinant vaccine in preventing SARS-CoV-2 infection.
Promoting Antibody Titer and Cellular Immunity: With squalene as a novel adjuvant, inactivated vaccines for Newcastle disease, avian influenza H5N1 and H9 were prepared and evaluated for antibody titer levels and cellular immunity in SPF chickens. Results showed positive HI antibodies from the 2nd week post-immunization, peaking in week 3 without significant decline in week 4 (P>0.05). Concurrently, squalene as adjuvant markedly elevated T lymphocyte proliferation in peripheral blood. This study concludes that these inactivated vaccines with squalene have significant effects in promoting antibody titers and cellular immunity in SPF chickens.
Applications in Petroleum Industry
Studying phase behavior at high temperatures faces challenges with evaporation and fluid volume losses, while this device reaches 300°C without losing any fluid volume. Phase behaviors of viscoelastic surfactant (VES)/crude oil systems and VES/squalene systems were studied to investigate salinity, concentration and temperature effects on volume fractions of phases and solubilization ratios. In VES/crude oil systems, increasing salinity and surfactant concentration decreased emulsion volume, while temperature had a mixed effect with minimum volume at 90°C. In VES/squalene systems, equal solubilization was achieved for each set, with the lowest emulsion value recorded at 50% seawater salinity, 90°C temperature and 1.25% VES concentration. By providing important insights into phase behaviors in different systems at high temperatures, this study helps understand complex interactions and improve oilfield operation efficiency.
Reference：
[1]. A. Mendes et al. From Sharks to Yeasts: Squalene in the Development of Vaccine Adjuvants. DOI: 10.3390/ph15030265
[2]. M. Filipovic et al. Alp Rose stem cells, olive oil squalene and a natural alkyl polyglucoside emulsifier: Are they appropriate ingredients of skin moisturizers - in vivo efficacy on normal and sodium lauryl sulfate - irritated skin?. DOI: 10.2298/VSP150116122F
[3]. V. Kostyuk et al. Photo-Oxidation Products of Skin Surface Squalene Mediate Metabolic and Inflammatory Responses to Solar UV in Human Keratinocytes. DOI: 10.1371/journal.pone.0044472
[4]. Naoki Shimizu et al. Evaluation of squalene oxidation mechanisms in human skin surface lipids and shark liver oil supplements. DOI: 10.1111/nyas.14219
[5]. D. Pandey et al. Molecular Docking Studies for Evaluation of Amaranth Grain Squalene for Treatment of Melanoma Skin Cancer in Human Beings. DOI: 10.2174/1570178620666230331083411
[6]. Seyed Hesamoddin Bidooki et al. Squalene Loaded Nanoparticles Effectively Protect Hepatic AML12 Cell Lines against Oxidative and Endoplasmic Reticulum Stress in a TXNDC5-Dependent Way. DOI: 10.3390/antiox11030581
[7]. N. I. Stellner et al. Value-Added Squalene in Single-Cell Oil Produced with Cutaneotrichosporon oleaginosus for Food Applications. DOI: 10.1021/acs.jafc.3c01703
[8]. S. Mazumder et al. Formulation of an ovarian cancer vaccine with the squalene-based AddaVax adjuvant inhibits the growth of murine epithelial ovarian carcinomas. DOI: 10.7774/cevr.2022.11.2.163
[9]. Maxim Solomadin et al. Evaluation of a SARS-CoV-2 spike protein ectodomain subunit vaccine with a squalene emulsion adjuvant in rodents and rhesus macaques. DOI: 10.1080/21645515.2023.2258571
[10]. L. Shijun et al. Improvement of reproduction performance in AA+ meat-type male chicken by feeding with squalene. DOI: 10.3923/JAVAA.2010.486.490
[11]. Weimin Zhang et al. Feeding with supplemental squalene enhances the productive performance in boars. DOI: 10.1016/j.anireprosci.2007.08.003
[12]. M. Ahmed et al. Investigating the Phase Behavior of Viscoelastic Surfactant with Squalene and Crude Oil Systems at High Temperature. DOI: 10.1007/s13369-023-07671-6
[13]. Huang ZX. Effect of squalene on mouse hypoxia tolerance. Practical Preventive Medicine (2011)
[14]. A. Gasparoli et al. About detection of animal Squalene/Squalane in vegetable products used in the cosmetic field. Rivista Italiana Delle Sostanze Grasse 89(1):4-28
[15]. Li T. Effect of squalene on LDLR expression in HepG2 cells and preliminary exploration of its mechanism. Chinese Pharmacological Bulletin (2018): 1020-1024
[16]. Hari Narayan Bhilwade et al. Squalene as novel food factor. CURRENT PHARMACEUTICAL BIOTECHNOLOGY (2010)
[17]. Rao LJ. Study on subacute toxicity test of squalene. Strait Journal of Preventive Medicine (2008)
[18]. Li LJ. Study on immune effect of squalene as a novel adjuvant. Chinese Journal of Marine Drugs (2013)[19]. Xiaobo Yan et al. Squalene activates Wnt/β-Catenin signaling pathway to mediate NF-κB pathway to regulate inflammatory response and disease resistance in hybrid grouper (♀ Epinephelus fuscoguttatus × ♂ E. lanceolatu). Aquaculture Reports (2023): 101784
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