Immune Benefits of Saffron

 

    Saffron, the dried, dark red stigmas of Crocus sativus L., is a well-known traditional herb that was mentioned in many oriental medical books. More than 150 volatile compounds are present in saffron stigmas; the major bioactive compounds in saffron are crocin, picrocrocin, and safranal which are responsible for colors, taste, and odor of saffron, respectively (1).

 

    Studies have documented a long list of saffron and its main constituents’ beneficial biological functions, such as anti-cancer, anti-inflammatory, antioxidant, radical scavenger, antidepressant, anti-allergic, anti-arthritic, anti-genotoxic, antiaging, antihypertensive, antihyperlipidemic, and anti-inflammatory, anti-atherogenic, antibacterial, anti-diabetic, anti-obesity, neuroprotective, hepatoprotective, nephroprotective, cardioprotective and beneficial effects on the reproductive system and so on (1-3).

 

    Saffron is rich in carotenoids such as crocin, and carotenoids affect immunity. Saffron and its main components showed anti-inflammatory, immunomodulatory, and antioxidant effects in animal models of various disorders associated with inflammation, oxidative stress, and immune system imbalance. This blog just touches on a few of such immune-related health conditions as examples.

 

Immunity

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   The effects of 100 mg saffron tablets taken daily for 6 weeks, were evaluated in healthy human volunteers in a randomized double-blind placebo-controlled study. Different hematological and immunological parameters were assessed 3 weeks after treatment in 45 healthy men and compared with the placebo group (n=44). Saffron significantly increased IgG levels while decreasing IgM levels in comparison with the baseline and the placebo. Saffron also decreased the percentage of basophils and the platelets count, while increased the percentage of monocytes. These parameters returned to the baseline levels after 6 weeks. These study results suggested that a sub-chronic daily dose of 100 mg saffron had short-term immunomodulatory effects with no side effects (4).

 

    The increase of serum IgG level induced by saffron may be utilized clinically to enhance the antibody response to routine vaccination. Besides, saffron may be used to increase the secondary immune responses (IgG) against pathogens and cancer cells. Secondary immune responses decrease in the elderly in parallel with the loss of memory T‐cells. Infections, cancers, and autoimmune diseases increase in the elderly following the reduction of the secondary immune responses. Thus saffron could have a potential role in the improvement of the specific antibody responses in immunodeficiencies such as in the elderly by enhancement of the secondary immune responses (4).

 

    To explore novel and effective adjuvants for influenza vaccines, a group of scientists screened 145 compounds from food additives approved in Japan. Of these 145 candidates, they identified 41 compounds that enhanced the efficacy of the split influenza hemagglutinin vaccine against lethal virus challenge in a mouse model. One of these effective food additives was crocin (5). Crocin is the primary color component of saffron.  

 

Cancer

 

    Vaccination is the most cost-effective and valuable tool in the prevention of infectious diseases. Today, vaccination is also becoming a safe and low toxicity approach for the treatment of cancer as well as chronic viral diseases. In a mice tumor model, adding saffron saponins to the tumor vaccine significantly stimulated antibody production compared to that of tumor vaccine alone. The saffron saponins treatment increased the delay in initial tumor appearance to over 2 weeks compared to the tumor only control group which showed tumor growth within 10 days after the tumor challenge. Also, 40% of the mice in the saffron saponins treated group remained tumor-free long term (60 days after the tumor challenge) while all untreated mice rapidly developed tumors with all having tumors within 15 days of tumor challenge. Even though the mice treated with tumor vaccine without saffron saponins delayed the tumor onset, they all still had tumors within 25 days of tumor challenge. These data demonstrated that saffron saponins adjuvanted protein vaccines give rise to functional immune responses ultimately leading to control of tumor growth (6).

 

    Saffron and its components exerted a considerable anti-tumor effect through the prevention of cell growth and stimulation of programmed cell death in another mice tumor DNA vaccine study. By the end of 55-days tumor challenge study, all mice treated with crocin were tumor-free, in contrast to DNA vaccine alone (~66.7 %) and DNA + crocin (~33.3 %) indicating the high potency of crocin as a chemotherapeutic agent (7). The insolubility of most carotenoids in water limits their therapeutic use, but the solubility of crocin and picrocrocin due to their glycosylated state, along with their cytotoxic effects on malignant cells, make them the most appropriate saffron compounds for cancer treatment (8).

 

Central nervous system

 

    Microglial cells play critical roles in the immune and inflammatory responses of the central nervous system. Under pathological conditions, the activation of microglia helps in restoring the center nervous system homeostasis. However, chronic microglial activation endangers neuronal survival through the release of various proinflammatory and neurotoxic factors. Thus, negative regulators of microglial activation have been considered as potential therapeutic candidates to target neurodegeneration, such as that observed in Alzheimer's and Parkinson's diseases (3).

 

    In cultured rat brain microglial cells, crocin or crocetin (a metabolite of crocin) treatment repressed microglial activation, reduced the production of various neurotoxic molecules from activated microglia, and blocked hippocampal cell death. These results suggest that crocin and crocetin provided neuroprotection (9). Another study showed that crocin (30 mg/kg) treated orally for 28 days was able to improve the learning and memory of tramadol-treated rats and also decreased the neurotoxicity effects of tramadol on neurons in the hippocampus (10).

 

Autoimmune disease type 1 diabetes

 

    Diabetes mellitus is a disease characterized by increased blood glucose concentrations. It results from either loss of insulin-producing β-cells of the pancreas (type 1 diabetes) or loss of insulin sensitivity on its target receptors in tissues (type 2 diabetes). Untreated diabetes drives several serious problems as nephropathy, retinopathy, neuropathy, coronary heart disease, and atherosclerosis.

 

    Type 1 diabetes’ progression was associated with a significant increase in blood glucose with reduced insulin and increased glucagon secretion. Pancreatic oxidative products significantly escalated, while antioxidant capacity significantly declined. This was associated with a significant increase in pancreatic caspase-3 contents (programmed cell death indicator) and pancreatic infiltration with inflammatory cells in β-islets.

 

    Crocin was compared with sitagliptin (a drug for lowering glucose) in an induced diabetes mice study (11). Both sitagliptin and crocin significantly reduced blood glucose levels, enhanced pancreatic insulin expression and secretion, and suppressed glucagon secretion with an enhancement of antioxidant defenses and reduction of the oxidative burden, with evident anti-inflammatory impacts. Both sitagliptin and crocin also improved the morphological changes in the pancreatic β cell islets. Interestingly, crocin had a superior effect compared to sitagliptin on blood sugar level, β-islets diameter, and insulin immune-reactivity. Serum insulin level significantly increased and serum glucagon level significantly declined with histopathological improvement and preservation of β-islets morphology and secretory functions (11).

 

    In another study, induced diabetic mice were treated orally with saffron extract (500 mg/kg) for 3 weeks. Treatment with the saffron extract significantly reduced the incidence of hypoglycemia and restored insulin secretion and histopathological changes in pancreas sections. Saffron also reduced lymphocyte proliferation index in the cells isolated from the pancreas of diabetic mice. Also, the saffron extract markedly decreased the production of pro-inflammatory molecules as a result of diabetes. The histopathological evaluation showed that the average size of the pancreatic islets was significantly regressed in mice with type 1 diabetes compared to normal mice. Fortunately, daily treatment with the saffron extract (500 mg/kg) for 3 weeks could markedly restore the average size of the pancreatic islets in diabetic rats (12). Thus, saffron can be considered as a useful strategy in the treatment of type 1 diabetes.

 

    Saffron may be the most expensive spice known and is used mainly to give color and flavor to foods and also is a valuable herb used in oriental medicine for treating numerous diseases. Saffron has an immune-modulatory effect in many health conditions. One blog is not possible to cover the details or the extensive benefits of saffron. If you would like to learn and discuss more saffron’s potential benefits related to various health conditions, please feel free to contact us.

 

References:

1. Zeinali, M., Zirak, M. R., Rezaee, S.A., Karimi, G., Hosseinzadeh, H. Immunoregulatory and Anti-Inflammatory Properties of Crocus sativus (Saffron) and Its Main Active Constituents: A Review. Iran J Basic Med Sci.2019.22(4):334-344.

2. Boskabady, M. H., & Farkhondeh, T. Antiinflammatory, Antioxidant, and Immunomodulatory Effects of Crocus sativus L. and its Main Constituents. Phytotherapy Research. 2016. 30(7), 1072–1094. 

3. Moshiri, M., Vahabzadeh, M., & Hosseinzadeh, H. Clinical Applications of Saffron (Crocus sativus) and its Constituents: A Review. Drug Research. 2014. 65(06), 287–295.

4. Kianbakht, S., & Ghazavi, A. Immunomodulatory Effects of Saffron: A Randomized Double-Blind Placebo-Controlled Clinical Trial. Phytotherapy Research. 2011. 25(12), 1801–1805.

5. Feng H, Yamashita M, Wu L, Jose da Silva Lopes T, Watanabe T, Kawaoka Y. Food Additives as Novel Influenza Vaccine Adjuvants. Vaccines (Basel). 2019. 7(4). pii: E127.

6. Castro-Díaz, N., Salaun, B., Perret, R., Sierro, S., Romero, J. F., Fernández, J.-A., Romero, P. Saponins from the Spanish saffron Crocus sativus are efficient adjuvants for protein-based vaccines. Vaccine. 2012. 30(2), 388–397. 

7. Khavari, A., Bolhassani, A., Alizadeh, F., Bathaie, S. Z., Balaram, P., Agi, E., & Vahabpour, R. Chemo-immunotherapy using saffron and its ingredients followed by E7-NT (gp96) DNA vaccine generates different anti-tumor effects against tumors expressing the E7 protein of human papillomavirus. Archives of Virology. 2014.160(2), 499–508.  

8. F.I. Abdullaev, J.J. Espinosa-Aguirre, Biomedical properties of saffron and its potential use in cancer therapy and chemoprevention trials, Cancer Detect. Prev. 2004. 28: 426–432.

9. Nam, K. N., Park, Y.-M., Jung, H.-J., Lee, J. Y., Min, B. D., Park, S.-U., … Lee, E. H. Anti-inflammatory effects of crocin and crocetin in rat brain microglial cells. European Journal of Pharmacology. 2010. 648(1-3), 110–116. 

10. Baghishani F, Mohammadipour A, Hosseinzadeh H, Hosseini M, Ebrahimzadeh-Bideskan A. The effects of tramadol administration on hippocampal cell apoptosis, learning and memory in adult rats and neuroprotective effects of crocin. Metab Brain Dis. 2018; 33: 907-916.

11. Samaha, M. M., Said, E., & Salem, H. A. (2019). A comparative study of the role of crocin and sitagliptin in attenuation of STZ-induced diabetes mellitus and the associated inflammatory and apoptotic changes in pancreatic β-islets. Environmental Toxicology and Pharmacology. 2019. 103238. 

12. Shole Faridi, S., Delirezh, N., Froushani, S. M. A. Beneficial Effects of Hydroalcoholic Extract of Saffron in Alleviating Experimental Autoimmune Diabetes in C57bl/6 Mice. Iran J Allergy Asthma Immunol. 2019. 18(1):38-47.