Shitake

Lentinula edodes (Berk.) Pegler, also known as shiitake mushroom, is the most popular edible macrofungus, belonging to the Basidiomycota. Shiitake fruiting bodies and mycelium are a source of several nutrients and bioactive compounds with numerous positive health effects, as numerous studies have shown. Shiitake contains about 68-78% of carbohydrates (mono-, di-, tri-, and polysaccharides), exogenous amino acids (including arginine, histidine, leucine, isoleucine, lysine, methionine, phenylalanine, threonine, valine, and tryptophan), lipids (5-8% of dry matter), vitamins (including B1, B2, B12, C, D, E), minerals (including Ca, K, Mg, Mn, P, Zn, and Na), fiber, and numerous substances with antibacterial, antiviral, and antifungal properties. The most useful and extensively researched polysaccharides are extracted from shiitake mushrooms and have been shown to have anticancer, antioxidant, antiaging, antimicrobial, and immunomodulatory effects. Research on the mechanism underlying fungal polysaccharide-induced immunomodulatory effects has revealed a multifaceted interplay including immunological, metabolic, and epigenetic modifications. The majority of the biological effects are attributed to β-glucans, which are the primary polysaccharides present in the fungal cell wall ^[1].

Health Effects of Shitake

Anticancer

β-glucan from Lentinus edodes (LNT) (a β-1,3-glucan) is a type of lentinan containing two β-1,6-glucose branches, and is the first medicinal fungus to enter the field of modern biotechnology. When compared to chemotherapy alone, clinical trials have shown that chemical immunotherapy with lentinan may increase the survival time of patients with advanced gastric cancer. Treatment for stomach and lung cancers with lentinan alone or in combination with other chemotherapeutic medicines has been available since the 1970s, according to a wealth of studies. As an immunomodulator, the underlying anti-tumor mechanism may be the activation of immune responses to induce cell apoptosis. Notably, it has been recently shown that α- and β-d-glucans from Shiitake mushrooms are efficient against MDA-MB-231 breast carcinoma cells, but have no cytotoxic impact on MCF-10A cells, considered as a normal mammary gland cell counterpart ^[2].

 

 

 

Breast Cancer

The World Health Organization (WHO) states that consuming alcohol, highly processed meat, and an excessive amount of saturated fats may increase the risk of both gastrointestinal tract tumors and breast cancer. Ultra-processed food is rich in sodium, fat, and sugar, which subsequently predispose to obesity, recognized as another factor of breast cancer risk ^[3].

A peptide (latcripin-7A) isolated from L. edodes has been shown to induce cell cycle arrest and decrease the mitochondrial membrane potential in MCF7 and MDA-MB-231 breast cancer cells, resulting in apoptotic cell death. Furthermore, in the same cell lines, the peptide significantly reduced migration and promoted autophagy without affecting the survival of MCF-10A normal breast cells. Interesting results have also been observed in vivo, β-glucan from L. edodes (GLE) has also shown a significant reduction in MCF7 tumor growth in nude mice. This reduction may be attributed to the encouragement of apoptosis and suppression of cell proliferation. GLE was found to inhibit several pathways, including those regulated by NF-κB, ERK, ERα, caspase, p53, as well as PI3K/Akt/mTOR ^[3].

Nagashima and colleagues conducted a randomized double-blind study with 47 women with breast cancer who were scheduled to receive postoperative adjuvant anthracycline‑based chemotherapy. The purpose of this investigation was to assess the efficacy of L. edodes mycelia extract (LEM, a dried powder extracted from shiitake mushrooms). It was found that patients were able to retain their quality of life (QoL) and immunological function when oral LEM was given in addition to anthracycline-based chemotherapy. Overall, the quality of life and immune system of postoperative breast cancer patients who received chemotherapy were reduced. Nevertheless, QoL and immunological function did not decline with the addition of LEM ^[4].

Lung Cancer

Lung cancer is the type of cancer with high morbidity and mortality, the Lancet study shows that about 8 million people worldwide are diagnosed with lung cancer each year, and the 5-year survival rate of lung cancer is generally lower by 4%-17%. Particulate matter 2.5 (PM2.5) is an air pollutant. It is closely related to lung cancer, which may cause lung cancer by inducing cellular inflammatory factors and oxidative stress. LNT can block the PVT1/miR-199a-5p/caveolin1 pathway in lung cancer as well as the expression of IL-6 and TNF-α that is caused by PM2.5. According to a study, LNT has the ability to boost T cell immunity, encourage the expression of anti-vascular factor interferon γ (IFN-γ), and have an antitumor effect ^[5].

Furthermore, the clinical effect of LNT in treating lung cancer has been widely reported. It is known that cellular immunity mainly relies on T lymphocytes, and the ratio of suppressor T cells and helper T cells determines the level of immune function, and if the CD4/CD8 ratio is elevated, tumor growth will be inhibited ^[5].

Gastric Cancer

Among the most prevalent neoplasms, gastric cancer ranks third globally in terms of cancer-related death. When a tumor is too big to be surgically removed, the primary treatment for advanced stomach cancer is systemic chemotherapy. Despite recent advances in chemotherapeutic agents, the prognosis of advanced gastric cancer remains poor with a median overall survival (OS) of one year ^[6].

In cancer patients, it is well known that dendritic cells (DCs) are functionally defective and T-cell function as well as natural killer (NK) activity are also down-regulated. According to Mushiake et al, lentinan activates DC activity by boosting the quantity of CD86⁺ cells that infiltrate tumors in mice that are cancer-bearing. It has been observed that lentinan treatment increases the production of NK cells and killer T cells, which in turn balances the killer/suppressor T cell ratio. FcR expression was elevated by levetinan, which may have contributed to the upregulation of antibody-dependent cellular cytotoxicity (ADCC) in tumor cell death. The addition of lentinan activated either the classical or the alternative complement pathway and eventually enhanced complement dependent cytotoxicity (CDC) and complement-dependent cell-mediated cytotoxicity via complement receptor type 3 (CR3). Taken together, these observations suggest that immunotherapy using lentinan may have synergistic effects with anti-cancer mAbs ^[7].

In patients with unresectable and recurrent stomach cancer receiving an oral fluoropyrimidine (tegafur), lentinan’s therapeutic efficacy has been documented in terms of survival. A meta-analysis conducted by Oba et al showed that the addition of lentinan to chemotherapy prolonged the survival of patients with advanced gastric cancer as compared to chemotherapy alone ^[7]. An additional prospective study discovered that the combination of LNT and chemotherapy enhanced both the survival duration and quality of life of patients with advanced unresectable gastric cancer (199 days for the control group and 277 days for the shiitake combination chemotherapy group) ^[5].

Colorectal Cancer

Colon cancer is a malignant tumor of the digestive system with high clinical incidence, surgery is currently the main treatment for colon cancer, chemotherapy and targeted therapy and other adjuvant methods. Zhang et al. demonstrated how endoplasmic reticulum stress can cause colon cancer through autophagy and apoptosis, which both have anti-tumor effects. The two major pathways of apoptosis are extrinsic signaling pathways, involving tumor necrosis factor receptor gene superfamily members, including FasRL/FasR, TNF-α/TNFR1, and mitochondria-induced intrinsic signaling pathways. LNT can simultaneously initiate cell extrinsic apoptosis and intrinsic apoptosis in colon cancer by increasing TNF-α and mitochondrial membrane potential loss ^[5].

Affect immune function and inflammation

High levels of branched β (1–3)(1–6)-D-glucan (Lentinan; LNT) are produced by shiitake. The immune response can be activated differently depending on the interaction between β-glucans and various cellular receptors that cause intracellular signaling. As essential components of both the innate and adaptive immune responses, macrophages play a crucial role in coordinating pro- and anti-inflammatory responses. M1, or classically activated macrophages, produce high levels of pro-inflammatory cytokines and M2, or alternatively activated macrophages, show an anti-inflammatory profile involved in wound healing and tissue repair. Molecules differentially expressed in each macrophage subpopulation can be employed as markers of a specific differentiation pathway ^[8].

In several animal models, the in vivo injection of β-glucans has proven advantageous in combating pathogens such fungi, bacteria, viruses, and protozoa by inducing innate immunity, cytokine production, and oxidative stress. Despite this pro-inflammatory role, β-glucans may decrease tissue damage in already established inflammatory processes. LNT from shiitake increased cytotoxicity against cancer cells, changed cytokine production, and produced beneficial anti-inflammatory responses in cell culture ^[8].

Oral consumption of β-glucans was found to drastically alter the maturation profile of macrophages, indicating that protective activities may be contingent on macrophage differentiation upon identification of branched β-glucans. High molecular weight or highly branched β-glucans can generally directly activate phagocytosis and cytotoxicity by generating oxygen and nitrogen reactive species as well as proinflammatory cytokines as IL-8, IL-1β, IL-6, and TNF-α. β-glucan from L. edodes is highly branched and production is high when compared to other mushrooms ^[8].

 

References

1. Roszczyk A, Turło J, Zagożdżon R, Kaleta B. Immunomodulatory Properties of Polysaccharides from Lentinula edodes. International Journal of Molecular Sciences. 2022 [cited 2024 February 3]; 23: 1-13. Available form: https://www.mdpi.com/1422-0067/23/16/8980
2. Zhang X, Li T, Liu S, Xu Y, Meng M, Li X, et al. β-glucan from Lentinus edodes inhibits breast cancer progression via the Nur77/HIF-1α axis. Bioscience Reports. 2020 [cited 2024 February 3]; 40: 1-12. Available form: https://portlandpress.com/bioscirep/article/40/12/BSR20201006/227063/glucan-from-Lentinus-edodes-inhibits-breast-cancer
3. Gariboldi M, Marras E, Ferrario N, Vivona V, Prini P, Vignati F, et al. Anti-Cancer Potential of Edible/Medicinal Mushrooms in Breast Cancer. International Journal of Molecular Sciences. 2023 [cited 2024 February 3]; 24: 1-30. Available form: https://www.mdpi.com/1422-0067/24/12/10120
4. Dan A, Swain R, Belonce S, Jacobs R. Therapeutic Effects of Medicinal Mushrooms on Gastric, Breast, and Colorectal Cancer: A Scoping Review. Cureus. 2023 [cited 2024 February 3]; 15: 1-15. Available form: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10183216/
5. Zhou G, Liu H, Yuan Y, Wang Q, Wang L, Wu J. Lentinan progress in inflammatory diseases and tumor diseases. European Journal of Medical Research. 2024 [cited 2024 February 3]; 29: 1-12. Available form: https://eurjmedres.biomedcentral.com/articles/10.1186/s40001-023-01585-7
6. Ina K, Furuta R, Kataoka T, Kayukawa S, Ina H, Yoneda M. Chemo-Immunotherapy Using Lentinan for the Treatment of Gastric Cancer with Liver Metastases. Medical Sciences (Basel). 2016 [cited 2024 February 3]; 4: 1-8. Available form: https://www.mdpi.com/2076-3271/4/2/8
7. Ina K, Kataoka T, Ando T. The use of lentinan for treating gastric cancer. Anticancer Agents Med Chem. 2013 [cited 2024 February 3]; 13: 681-8. Available form: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3664515/
8. Crespo H, Guillén H, de Pablo-Maiso L, Gómez-Arrebola C, Rodríguez G, Glaria I, et al. Lentinula edodes β-glucan enriched diet induces pro- and anti-inflammatory macrophages in rabbit. Food & Nutrition Research. 2017 [cited 2024 February 3]; 61: 1-8. Available form: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5727452/