Hematology, Immunology & Herbs

Dr. James Manos (MD)
July 5, 2019

Herbs & dietary supplements that have been studied for hematological diseases or may enhance the immune system  

Herbs & dietary supplements that have been studied for hematological diseases

(with green color are the herbs & dietary supplements that the author of this text personally considers more important for this issue)

• Hematopoiesis (the formation of blood cellular components) restoration on bone marrow injury after radiation:  

• beta-glucan

• A study that investigated the hemopoietic effects produced by six different doses of a glucan preparation in mice showed that bone marrow CFU-s content increased and CFU-e and BFU-e contents decreased with increasing glucan doses; in the spleen, all aspects of hematopoiesis (i.e., cellularity, CFU-s, GM-CFC, M-CFC, and CFU-e) increased after glucan administration – the degree of splenic enhancement was directly correlated with the dose of glucan administered.

• Ginseng

• It has a protective effect on the blood cells during radiotherapy of cancer (it may prevent the decrease of the hematocrit).

• Sea – buckthorn

• A group in India has published several reports on the potential of a hippophae extract to protect the bone marrow from damage due to radiation. This group also showed that the extract may help the faster recovery of bone marrow cells.

• Spirulina

• A study concluded that polysaccharide of Spirulina platensis (PSp) has chemo-protective (protection of the tissues from toxic effects from anticancer drugs) and radio-protective (protection of the tissues from radiation) capability on the hematopoietic system (hematopoiesis is the formation of blood cellular components) of mouse and dogs which were damaged by injection of cyclophosphamide (CTX) and 60Co-gamma irradiation. Thus, it may be a potential adjunct to cancer therapy.

• Erythropoietic properties [Erythropoiesis is the process that produces red blood cells (RBCs; erythrocytes). It is stimulated by decreased oxygen (O2) in circulation, which is detected by the kidneys, which then secrete the hormone erythropoietin (EPO) that stimulates the proliferation and differentiation of red cell precursors, which activates increased erythropoiesis in the hemopoietic tissues, ultimately producing red blood cells (RBCs)]:  

• Stinging nettle (Urtica dioica)

• Asteracantha longifolia

• beta-glucan

• A  study that investigated the hemopoietic effects produced by six different doses of a glucan preparation in mice showed that bone marrow CFU-s content increased and CFU-e and BFU-e contents decreased with increasing glucan doses; in the spleen, all aspects of hemopoiesis (i.e., cellularity, CFU-s, GM-CFC, M-CFC, and CFU-e) increased after glucan administration – the degree of splenic enhancement was directly correlated with the dose of glucan administered.

• Brewer’s yeast - EpiCor®

• EpiCor® (EP) is a dried fermentate produced from (the yeast) Saccharomyces cerevisiae. EP has many bioavailable antioxidants and strongly activates natural killer (NK) cells in vitro. EP consumption has been shown to increase erythrocyte hematocrit levels and boost mucosal immune protection.

• Hematopoiesis (the formation of blood cellular components) restoration on bone marrow injury after chemotherapy:  

• beta-glucan

• Rehmannia & Rhodiola

• A  study explored the effect of the combined use of rehmannia and Rhodiola on peripheral leukopenia and bone marrow hematopoietic function suppression induced by cyclophosphamide in mice and concluded that rehmannia and Rhodiola mixture could regulate the hematopoietic system by promoting the production of bone marrow cells and colonies, as well as enhancing the synthesis of related cytokines, such as GM-CSF, so as to increase the amount of peripheral white blood cells and restore the hematopoietic function of the organism.

• Sea – buckthorn (Hippophae rhamnoides)

• In China, a study demonstrated faster recovery of the hemopoietic system (responsible for the formation of blood cell components) after high-dose chemotherapy (with 5-FU) in mice fed sea buckthorn oil.

• A study concluded that sea-buckthorn (SB) juice decreased the genotoxic effect of cisplatin (CP) at a dose of 1.2 mg/kg on somatic (bone marrow) and germ (sperm) cells of mice significantly, however at a higher dose of the drug the effects were not statistically significant.

• Another study concluded that oil from Hippophae rhamnoides (OHR) can improve the hematopoiesis (the formation of blood cellular components) of the erythroid lineage (red blood cell line). Like G-CSF, OHR can stimulate the recovery of hematopoiesis after chemotherapy with 5-FU (5 fluorouracil, a cancer chemotherapy drug).

• Selenium

• Selenium can be used to reduce the bone marrow suppression induced by cisplatin chemotherapy.

• Spirulina

• A study concluded that the polysaccharide of Spirulina platensis (PSp) has chemo-protective (protection of the tissues from toxic effects from anticancer drugs) and radio-protective (protection of the tissues from radiation) capability on the hematopoietic system (hematopoiesis is the formation of blood cellular components) of mouse and dogs which were damaged by injection of cyclophosphamide (CTX) and 60Co-gamma irradiation. So, it may be a potential adjunct to cancer therapy.

• Tissue damage caused by chemotherapy:

• Acetyl carnitine (acetyl – L – carnitine, ALC, or ALCAR)

• Alpha – lipoic acid

• It has been studied for its ability to protect normal cells from the side effects of chemotherapy.

• Melatonin

• It may prevent Low blood platelets (thrombocytopenia) associated with cancer chemotherapy. It may also decrease some side effects of cancer treatment.

• Iron deficiency/ iron deficiency anemia (IDA):

• Probiotics & prebiotics

• A study showed that consumption of Bifidobacterium lactis HN019 (a probiotic) and prebiotic-fortified milk resulted in a smaller number of iron-deficient preschoolers and increased weight gain

• In animal experiments, non-digestible oligosaccharides (prebiotics) increased the availability of calcium, magnesium, zinc, and iron)

• Taraxacum officinale (the common dandelion) leaves

• They have more iron than spinach.

• Spirulina

• It is a rich source of iron

• Sickle cell disease:

• Anthocyanin extracts

• Zinc

• It may help prevent complications related to sickle cell anemia in people with low zinc levels. People with sickle cell disease are often deficient in zinc – studies suggest that taking zinc supplements may help reduce symptoms of the disease.

• Thalassemia (a hereditary form of anemia that often requires blood transfusions):

• Wheatgrass

• A study in which 16 patients with thalassemia consumed about 100 mL of wheatgrass juice daily showed that blood transfusion requirement fell by >25% in 8 (50%) patients, with a decrease of >40% documented in 3 of these.

• Another study on forty children with Thalassemia Major who were treated with wheatgrass tablets (WGT) concluded that wheatgrass has the potential to increase hemoglobin (Hb) levels, increase the interval between blood transfusions, and decrease the amount of total blood transfused in Thalassemia Major patients.

• Hereditary hemochromatosis (a genetic disease characterized by excessive absorption of dietary iron, resulting in a pathological increase in total body iron stores):

• Tannins

• Foods rich in tannins can be used in the treatment of hereditary hemochromatosis.

• Children with hereditary hemochromatosis should include moderate amounts of black, green, or oolong tea in their diet – the tannin from the tea helps minimize iron absorption.

• A human study showed that regular tea drinking with meals reduces the frequency of phlebotomies required in the management of patients with hemochromatosis.

• In patients with hereditary hemochromatosis, while tannin in tea may inhibit iron absorption (blocking agent), it is not a substitute for phlebotomy.

• Radiotherapy tissue injury (including bone marrow) protective effects:

• Ginseng

• It has a protective effect on the blood cells during radiotherapy of cancer (it may prevent the decrease of the hematocrit)

• Peppermint

• It may have radioprotective effects on cancer patients undergoing cancer treatment.

• Reishi mushroom [Lingzhi mushroom]

• Sea – buckthorn (Hippophae rhamnoides)

• A study concluded that probably RH-3, an extract of Sea – buckthorn’s whole berries, acts as an antioxidant preventing cellular and mitochondrial free radical generation that could contribute to its ability to inhibit radiation-induced apoptosis (programmed cell death) and cytotoxicity (cell toxicity)]

• Spirulina

• A study concluded that the polysaccharide of Spirulina platensis (PSp) has chemo-protective (protection of the tissues from toxic effects from anticancer drugs) and radio-protective (protection of the tissues from radiation) capability on the hematopoietic system (hematopoiesis is the formation of blood cellular components) of mouse and dogs which were damaged by injection of cyclophosphamide (CTX) and 60Co-gamma irradiation. It may be a potential adjunct to cancer therapy.

• Astragalus membranaceus

• In a study, Astragalus membranaceus extracts were injected into normal mice or mice immuno-depressed by cyclophosphamide or radiation treatment or by aging; the study showed enhancement of the antibody response to a T-dependent antigen that was associated with an increase of Th cell activity in normal and immuno-depressed mice.

• beta-glucans

• A study showed that seaweed-derived (1-->3)-beta-D-Glucan Phycarine strongly shortened the recovery of leucopenia (a decrease in the number of leukocytes, white blood cells found in the blood, which places individuals at increased risk of infection) caused either by chemotherapy or irradiation.

• Chamomile

• Some early studies point to chamomile’s possible benefits for specific skin conditions and for mouth ulcers caused by chemotherapy or radiation.

• Curcumin

• A study was performed to investigate whether curcumin, known to have anti-inflammatory and antioxidant properties, could ameliorate radiation-induced pulmonary (lung) inflammation and fibrosis in irradiated lungs. Rats were given daily doses of intragastric (inside the stomach) curcumin (200 mg/kg) before single irradiation and for 8 weeks after radiation. Histopathologic findings demonstrated that macrophage accumulation, interstitial edema, alveolar septal thickness, perivascular fibrosis, and collapse in radiation-treated lungs were inhibited by curcumin administration. The results of the study indicate that long-term curcumin administration may reduce lung inflammation and fibrosis caused by radiation treatment.

• Leucopenia (decrease of WBCs (white blood cells; leukocytes) found in the blood that increases the risk of infection) improvement: 

• beta glucans/ (1-->3)-beta-D-Glucans

• The observations of a study suggest that the (1-->3)-beta-D-Glucan Phycarine is similarly effective both after i.p. and oral (by mouth) application, has powerful stimulating effects on three types of experimentally induced leucopenia, and stimulates both humoral and cellular branches of immune reactions.

• Arabinogalactan isolated from the herb Anoectochilus formosanus

• Anoectochilus formosanus is an herb well-known in Asian countries. The polysaccharide isolated from A. formosanus consists of type II arabinogalactan (AGAF), with branched 3,6-Gal as the significant moiety.

• In a study, AGAF was examined for the granulocyte colony-stimulating factor (G-CSF) production and related protein expression in RAW 264.7 murine (rats/mice) macrophages. The signaling pathway of G-CSF production involves AGAF and mitogen-activated protein kinases (MAPKs) inhibitors and pattern-recognition receptor antibodies. AGAF was evaluated to ease the leukopenia [decrease of WBCs (white blood cells; leukocytes) found in the blood that increases the risk of infection] in CT26-colon-cancer-bearing mice treated with 5-fluorouracil (5-FU) (a cancer medication chemotherapy). The results of this study showed that AGAF was a stimulant for Toll-like receptor 2 and Dectin-1 and that it induced G-CSF production through p38 and ERK MAPK, and NF- κ B pathways. In vivo examination showed that the oral (by mouth) administration of AGAF mitigated the side effects of leukopenia caused by 5-FU in colon-cancer-bearing mice. In conclusion, the botanic type II arabinogalactan isolated from Anoectochilus formosanus (AGAF) in this study was a potent G-CSF inducer in vivo and in vitro.

• Astragalus

• A Cochrane review about Huangqi (Astragalus membranaceus) for chemotherapy side effects in colorectal cancer patients mentions that in studies, there was a significant reduction in the proportion of patients who experienced nausea & vomiting when decoctions of Huangqi compounds were given in addition to chemotherapy; there was also a decrease in the rate of leucopenia.

• Leukemia:

• Astragalus

• In a study, membranaceous lectin (AML) induced apoptosis in a caspase-dependent manner in the chronic myeloid leukemia cell line, K562; also, it was observed that cytotoxicity and apoptosis of K562 cells induced by AML were abolished entirely in the presence of lactose or galactose.

• Another study concluded that astragalus polysaccharide (APS) can enhance the immune function of pDCs, and promote differentiation and maturation of plasmacytoid dendritic cells (pDCs) from chronic myelogenous leukemia (CML) patients.

• In another study, a lectin (AMML) from the roots of Astragalus mongholicus was extracted and purified; the human cervical carcinoma cell line (HeLa), human osteoblast-like cell line (MG63), and human leukemia cell line (K562) were used to check the effects of AMML on cell proliferation, apoptosis, and cell cycle; the results showed maximum growth inhibition (92%) with HeLa cells, followed by K562 cells (84%) and MG63 (48%) cells; the study also reported a significant cell cycle arrest at S phase of HeLa cells by AMML.

• Curcumin (turmeric)

• A study showed it exhibits in vitro cytotoxicity (cell toxicity) against human chronic myeloid leukemia.

• Another study showed that curcumin inhibited the proliferation of K562 cells, and the inhibitory effect was correlated with down-regulation of the abundance of p210bcr/abl, which may ultimately lead to retard the Ras signal transduction pathway. The study concluded that curcumin might be worthy of being evaluated as a potential chemotherapeutic agent for CML.

• Another study concluded that curcumin can inhibit the cellular proliferation and the expression of STAT5 mRNA, and down-regulate the activation of STAT5 in primary CML cells, thus, curcumin may be used in the treatment of leukemia.

• In another study, curcumin decreased WT1 mRNA in patient leukemic cells. Thus, curcumin treatment may provide a lead for clinical therapy in leukemic patients in the future.

• A study showed that wt1 mRNA and its protein were both highly expressed in the K562 cell; curcumin and imatinib (Glivec (R)) both inhibit cell proliferation resulting in the G(2)/M and G(0)/G(1) phase arrest respectively.

• Rosemary

• A study demonstrated that crude ethanolic rosemary extract (RO) has differential anti-proliferative effects on human leukemia and breast carcinoma cells.

• Feverfew

• A study demonstrated that parthenolide (PTL), a naturally occurring small molecule, induces robust apoptosis (programmed cell death) in primary human AML (Acute Myelogenous Leukemia) cells and blast crisis CML (Chronic Myelogenous Leukemia) (bcCML) cells while sparing normal hematopoietic cells. Compared to the standard chemotherapy drug cytosine arabinoside (Ara-C), PTL is much more specific to leukemia cells. The study concluded that the activity of parthenolide (PTL) triggers LSC (Leukemia Stem Cells)-specific apoptosis (programmed cell death) and, as such, represents a potentially significant new class of drugs for LSC-targeted therapy.

• An in vitro study showed that parthenolide, the principal bioactive component of the herb feverfew (Tanacetum parthenium), induces a stress response leading to cell death and provides further evidence suggesting that parthenolide could be useful as a novel therapeutic agent against high-risk acute lymphoblastic leukemia (ALL) with chromosomal translocation t(4;11).

• Calendula officinalis

• Ten oleanane-type triterpene glycosides, 1-10, including four new compounds, calendulaglycoside A 6'-O-methyl ester (2), calendulaglycoside A 6'-O-n-butyl ester (3), calendulaglycoside B 6'-O-n-butyl ester (5), and calendulaglycoside C 6'-O-n-butyl ester (8), along with five known flavonol glycosides, 11-15, were isolated from the flowers of marigold (Calendula officinalis); upon evaluation of the cytotoxic (toxic for the cells) activity against human cancer cell lines in vitro in the NCI Developmental Therapeutics Program, two triterpene glycosides, 9 and 10, exhibited their most potent cytotoxic effects against colon cancer, leukemia, and melanoma cells.

• Flavonoids such as quercetin and fisetin

• A study tested the apoptotic activity of 22 flavonoids and related compounds in leukemic U937 cells. Regarding the mechanisms, galangin, luteolin, chrysin, and quercetin induced apoptosis in a way that required the activation of caspases 3 and 8, but not caspase 9. In contrast, an active role of calpains, in addition to caspases, was demonstrated in apoptosis induced by fisetin, apigenin, and 3,7-dihydroxyflavone. The data on this study shows evidence of the proapoptotic properties of some flavonoids that could support their rational use as chemopreventive and therapeutic agents against carcinogenic diseases. Note: fisetin, among other flavonoids, is a potent topoisomerase inhibitor; thus, it may have carcinogenic potentials; fisetin, among other flavonoids, is suspected to increase the risk of infant acute myeloid leukemia],

• Guggul

• A study investigated the effects of guggulsterone on cyclooxygenase-2 (COX-2) and P-glycoprotein-mediated drug resistance in imatinib-resistant K562 cells (K562/IMA). The results showed that co-administration of guggulsterone significantly increased the chemo-sensitivity of K562/IMA cells to imatinib, compared with imatinib treatment alone. When imatinib (1 μM) was combined with guggulsterone (60, 120 μM), the mean apoptotic (apoptosis is programmed cell death) population of K562/IMA cells was 15.47% and 24.91%. It was increased by 3.82 and 6.79 times, compared with imatinib (1 μM) treatment alone. Furthermore, guggulsterone significantly inhibited the levels of cyclooxygenase-2, P-glycoprotein, and prostaglandin E2. The present study indicates guggulsterone induces apoptosis (programmed cell death) by inhibiting cyclooxygenase-2 (COX-2) and down-regulating P-glycoprotein expression in imatinib-resistant K562 cells (K562/IMA)./ Note: Imatinib (INN, international non-proprietary name), marketed by Novartis as Gleevec or Glivec, and sometimes referred to by its investigational name STI-571, is a tyrosine–kinase inhibitor used in the treatment of multiple cancers, most notably Philadelphia chromosome-positive (Ph⁺) chronic myelogenous leukemia (CML).

• Aged black garlic

• In a study, the apoptogenic activity and mechanisms of cell death induced by hexane extract of aged black garlic (HEABG) were investigated in human leukemic U937 cells. Cytotoxicity (cell toxicity) was evaluated by MTT (3-(4, 5-dimethyl-thiazol-2-yl)-2, 5-diphenyl tetrazolium bromide) assay. Apoptosis (programmed cell death) was detected using 4,6-diamidino-2-phenyllindile (DAPI) staining, agarose gel electrophoresis, and flow cytometry. Exposure to HEABG was found to result in a concentration- and time-dependent growth inhibition by induction of apoptosis, which was associated with an up-regulation of death receptor 4 and Fas legend, and an increase in the ratio of Bax/Bcl-2 protein expression. Apoptosis-inducing concentrations of HEABG induced the activation of caspase-9, an initiator caspase of the mitochondrial-mediated intrinsic pathway, and caspase-3, accompanied by proteolytic degradation of poly(ADP-ribose)-polymerase. HEABG also induced apoptosis via a death receptor-mediated extrinsic pathway by caspase-8 activation, resulting in the truncation of Bid and suggesting the existence of cross-talk between the extrinsic and intrinsic pathways. However, pre-treatment of U937 cells with the caspase-3 inhibitor, z-DEVD-fmk, significantly blocked the HEABG-induced apoptosis of these cells and increased the survival rate of HEABG-treated cells, confirming that HEABG-induced apoptosis is mediated through activation of the caspase cascade. In conclusion, based on the overall results, the authors suggest that hexane extract of aged black garlic (HEABG) reduces leukemic cell growth by inducing caspase-dependent apoptosis (programmed cell death) through both intrinsic and extrinsic pathways, implying its potential therapeutic value in the treatment of leukemia]

• Handroanthus impetiginosa (pink lapacho)

• Up-regulation of telomerase activity is associated with immortalization and unlimited cell division in most cancer cells. Therefore, telomerase represents a particularly attractive target for anticancer therapy. Recent reports have suggested that beta-lapachone (LAPA), the product of the South American Tabebuia avellanedae (Handroanthus impetiginosus) tree, inhibits the growth of tumor cells. However, the underlying relationship between telomerase activity and apoptosis (programmed cell death) in response to LAPA exposure in leukemia cells remains poorly understood. In this study, the authors confirmed that LAPA treatment induces direct cytotoxicity (cell toxicity) in human leukemia cells (U937, K562, HL60, and THP-1) through activation of caspase-3 and subsequent cleavage of poly(ADP-ribose) polymerase. The observed induction of cell death was associated with decreased telomerase activity, ascribed to the down-regulation of telomerase reverse transcriptase. Additionally, overexpression of anti-apoptotic Bcl-2 could not overcome the induction of apoptosis or the reduced telomerase activity in response to the treatment of U937 cells with LAPA. The authors concluded that beta-lapachone (LAPA), the product of the South American Tabebuia avellanedae (Handroanthus impetiginosus) tree, has a direct cytotoxic effect (toxic for the cells – here for the leukemia cells) and the loss of telomerase activity in leukemia cells.

• Lymphoma:

• Devil’s claw

• Two follicular lymphoma patients with objective tumor regression after taking Devil's Claw without cytotoxic therapy are reported here. Patient one presented with coexistent immunoglobulin G plasma cell dyscrasia and stage IIIa lymphoma (nodes 5 cm in diameter). A computed tomography scan 10 months later showed partial regression. On inquiry, it was learned that the patient was taking Devil's Claw and Essiac. This patient later developed overt myeloma, at which time he stopped the herbal supplements and underwent high-dose chemotherapy and stem cell transplantation since no lymphoma progression has occurred. Patient two presented with stage IIIA lymphoma (nodes 2.5 cm in diameter). He learned of patient 1 through a lymphoma patient support group and started Devil's Claw. A computed tomography scan 11 months later showed decreased adenopathy and splenomegaly, which has been sustained for 4 years. The key issue is whether disease regression was ‘spontaneous’ or causally related to therapy with Devil’s Claw. The timing of the response suggests a positive effect. Further investigation is needed.

• Curcumin/ turmeric

• Curcumin has been shown to interfere with multiple cell signaling pathways, including cell cycle (cyclin D1 and cyclin E), apoptosis (programmed cell death; activation of caspases and down-regulation of antiapoptotic gene products), proliferation (HER-2, EGFR, and AP-1), survival (PI3K/AKT pathway), invasion (MMP-9 and adhesion molecules), angiogenesis (the physiological process involving the growth of new blood vessels from pre-existing vessels) (VEGF), metastasis (CXCR-4) and inflammation (NF-kappaB, TNF, IL-6, IL-1, COX-2, and 5-LOX). Curcumin has been studied against leukemia, lymphoma, gastrointestinal, genitourinary, breast, ovarian, head and neck squamous cell carcinoma, lung, melanoma, neurological tumors, and sarcoma, reflecting its ability to affect multiple targets.

• Thrombocytopenia (a relative decrease of the platelets in the blood):

• Melatonin

• A preliminary study suggests that melatonin may be effective in the treatment of thrombocytopenia due to different reasons for which no effective standard therapy is available.

• Thromboembolic diseases prevention:

• Dark chocolate

• In a study, dark chocolate inhibited collagen-induced platelet aggregation in platelet-rich plasma.

• Platelet aggregation inhibitory effects:

• Garlic

• Soy lecithin

• Omega-3 fatty acids/ fish oil

• Extracts from the bark of Yucca schidigera

• Seeds of grape and berries of chokeberry

• Bromelain

• Reports on animal experiments claim an antimetastatic efficacy and inhibition of metastasis-associated platelet aggregation and inhibition of growth and invasiveness of tumor cells.

• Concord grape juice

• Dark chocolate

• A human study showed that dark chocolate inhibited collagen-induced platelet aggregation in platelet-rich plasma; the study concluded that dark chocolate may have a role in the prevention of cardiovascular and thromboembolic diseases in the future.

• Beetroot juice

• Pycnogenol, Proanthocyanidins/ oligomeric proanthocyanidin complexes (OPCs)

• Red wine

• Alcohol or some substances found in alcoholic beverages may prevent platelets in the blood from sticking together, reducing clot formation, and reducing the risk of heart attack or stroke.

• A study showed that resveratrol, a polyphenol present in red wine, can inhibit platelet aggregation both in vitro and in vivo, which could be one of the mechanisms by which this red wine polyphenol exerts its cardioprotective effects.

• Reishi mushroom [Lingzhi mushroom]

• Resveratrol

• A study concluded that resveratrol effectively inhibited collagen- and epinephrine-induced aggregation of platelets from aspirin-resistant (ASA-R) patients, which may contribute to its cardioprotective effects in high-risk cardiac patients.

• Another study demonstrated for the first time that resveratrol simultaneously inhibits platelet aggregation and stimulates platelet apoptosis (programmed cell death). Stimulation of platelet apoptosis by resveratrol may represent the increased therapeutic potential for patients suffering from thrombotic conditions or thrombocytosis (high platelet counts in the blood) to promote platelet destruction and thus prevent pathological clotting.

• Salvia miltiorrhiza (Danshen)

• Sea – buckthorn (Hippophae rhamnoides)

• A study showed that sea buckthorn berry oil supplementation caused a clear decrease in the rate of adenosine-5’-diphosphate-induced platelet aggregation and maximum aggregation.

• Another study showed that total flavones of Hippophae Rhamnoides (TFH) prevented in vivo thrombogenesis (clot development), probably due to inhibition of platelet aggregation, and suggested a possible clinical approach for the prevention of thrombosis]

• Antiplatelet effects:

• N-acetylcysteine (NAC)

• A study concluded that NAC might be an effective antiplatelet agent in conditions where increased oxidative stress contributes to the heightened risk of thrombosis, but only if the intra-platelet machinery converts it to glutathione (GSH) is functional.

• Omega – 3 fatty acids/fish oil

• Omega-3 fatty acids decrease platelet aggregation, resulting in a modest prolongation of bleeding times (reviewed by Knapp).

• Some evidence indicates that fish oil supplementation may enhance fibrinolysis.

• A recent study reported that coronary patients taking 5.1 grams/day of omega-3 fatty acids for 6 months experienced a reduction in von Willebrand factor (128% versus 147% for controls) and thrombomodulin (25 versus 33 ng/mL).

• Rapeseed oil

• Food-grade canola oil (contains both omega-3 and omega-6 fatty acids in a ratio of 1:2)

• Resveratrol

• Bark of Yucca schidigera

• Seeds of grape and berries of chokeberry

• An in vitro study concluded that the tested extracts, due to their anti-platelet effects, may play an important role as components of the human diet in preventing cardiovascular or inflammatory diseases involving blood platelets.

• Boswellia/ boswellic acid

• A study on rats demonstrated antioxidant and antithrombotic anticoagulant activities of water and hydroalcoholic extracts of Boswellia serrata's gum resin; the authors suggest that Boswellia serrata (BS) –gum resin is a useful source for lead/therapeutic compounds possessing antioxidant, antiplatelet, and anticoagulant activities.

• Bromelain

• A study showed that bromelain therapy led to the formation of platelets with increased resistance to aggregation

• Glucosamine & Celadrin

• An in vitro study that investigated the effects of glucosamine (a dietary supplement used for knee osteoarthritis) and celadrin (cetylated fatty acids used as topical cream also for osteoarthritis) on platelet function concluded that glucosamine and celadrin may inhibit platelet aggregation in some individuals via aspirin-like effects as well as inhibition of ADP receptor P2Y1, but not P2Y12.

• Guarana

• Aqueous extracts of guarana were studied in terms of effects on the aggregation of human and rabbit platelets. Guarana extracts have anti-aggregatory and de-aggregatory actions on platelet aggregation induced by ADP or arachidonate but not collagen. The active material was shown to be water-soluble and heat-resistant and appeared to be different from salicylates, nicotinic acid, or known xanthines. Guarana extracts inhibited platelet aggregation in rabbits following either intravenous or oral (by mouth) administration.

• Horse chestnut

• Extract from seeds and bark of horse chestnut (Aesculus hippocastanum L) is used as herbal medicine against chronic venous insufficiency. A study investigated horse chestnut's effects and mechanisms of action on the contraction of bovine mesenteric veins and arteries and human platelet aggregation. Contraction studies showed that horse chestnut extract dose-dependently contracted both veins and arteries, with the veins being the most sensitive. The 5-HT(2A) (serotonin) receptor antagonist ketanserin significantly inhibited the contraction of both veins and arteries. ADP-induced human platelet aggregation was significantly reduced by horse chestnuts. A further reduction was seen with the extract in the presence of ketanserin. In conclusion, at least partly, horse chestnut contraction of both veins and arteries is mediated through 5-HT(2A) (serotonin) receptors. Human platelet aggregation is reduced by horse chestnut.

• Antithrombotic effects: 

• Bromelain

• A study showed that bromelain, orally, inhibited thrombus formation in a time-dependent manner.

• Another study showed that bromelain therapy led to the formation of platelets with increased resistance to aggregation.

• Extra – Virgin olive oil

• A study concluded that the major effect of hydroxytyrosol (HT)-rich phenolic extract from olive mill wastewaters accounts for an anti-aggregating platelet action, leading to possible prevention of thrombotic and microthrombotic processes.

• Another study showed that animals fed the olive oil-enriched diet showed a significant delay in the thrombotic occlusion of the ΄΄aortic loop΄΄, a lower incidence of venous thrombosis (57% vs. 86%) and a prolonged bleeding time (BT), in comparison with the control group - they also had lower plasma fibrinogen concentrations.

• Feverfew

• Proanthocyanidins/ oligomeric proanthocyanidin complexes (OPCs)

• Red clover isoflavones

• Red wine

• Alcohol or some substances found in alcoholic beverages may prevent platelets in the blood from sticking together, reducing clot formation and reducing the risk of heart attack or stroke.

• Resveratrol

• A study demonstrated for the first time that resveratrol simultaneously inhibits platelet aggregation and stimulates platelet apoptosis (programmed cell death). Stimulation of platelet apoptosis by resveratrol may represent the increased therapeutic potential for patients suffering from thrombotic conditions or thrombocytosis (high platelet counts in the blood) to promote platelet destruction and thus prevent pathological clotting.

• Royal jelly

• A study suggested that lyophilized royal jelly can prevent and treat hyperlipidemia and improve the high coagulant status of blood.

• Salvia miltiorrhiza (Danshen)

• It can affect hemostasis in several ways, including inhibition of platelet aggregation, interference with extrinsic blood coagulation, antithrombin III-like activity, and promotion of fibrinolytic activity).

• Animal and human studies support the use of Salvia miltiorrhiza for circulatory disorders because it is known to decrease the blood’s ability to clot by limiting platelet accumulation and decreasing the production of fibrin - both these effects help to improve blood circulation.

• Sea – buckthorn (Hippophae rhamnoides)

• In a laboratory animal study, the flavonoids of sea buckthorn were shown to reduce the production of pathogenic thromboses (blood clots).

• Another study showed that total flavones of Hippophae Rhamnoides (TFH) prevented in vivo thrombogenesis (clot development), probably due to inhibition of platelet aggregation, and suggested a possible clinical approach for preventing thrombosis.

• Aronia melanocarpa (black chokeberry) and seeds of Vitis vinifera (common grapevine) 

• In a study, thrombin was incubated with polyphenol-rich extracts from berries of Aronia melanocarpa or seeds of Vitis vinifera and with polyphenols; the in vitro experiments showed that both extracts in all used concentrations inhibited the proteolytic activity of thrombin observed as inhibition of thrombin-induced fibrinogen polymerization, stabilized fibrin formation, and platelet aggregation; moreover, thrombin amidolytic activity was inhibited by polyphenols belonging to the flavonoid class. In conclusion, the results presented in this study indicate that polyphenol-rich extracts from berries of Aronia melanocarpa or seeds of Vitis vinifera may become promising dietary supplements in the prevention of thrombotic states.

• Boswellia/ boswellic acid

• A study on rats demonstrated the antioxidant and antithrombotic anticoagulant activities of water and hydroalcoholic extracts of Boswellia serrata's gum resin. The authors suggest that Boswellia serrata (BS) –gum resin is a good source of lead/therapeutic compounds possessing antioxidant, antiplatelet, and anticoagulant activities.

• Astaxanthin

• A study in which the effect of a proprietary astaxanthin prodrug (CDX-085) on thrombus formation was investigated using a mouse model of arterial thrombosis concluded that observations of increased nitric oxide (NO) and decreased peroxynitrite (ONOO-) levels in endothelial cells and platelets support a potential mechanism of action for astaxanthin (CDX-085 active drug) – these studies support the potential of CDX-085 and its metabolite astaxanthin in the treatment or prevention of thrombotic cardiovascular complications.

• Malaria (caused by parasitic protozoans (a type of unicellular microorganism) of the genus Plasmodium) prevention:

• Garlic

• A study demonstrated that a 4-day regimen of allicin, a cysteine protease inhibitor found in garlic extracts, administered either orally or intravenously, significantly decreased parasitemia (the presence of parasites in the blood) and increased the survival of infected mice by 10 days],

• Goldenseal

• (Note: a study showed that goldenseal root powder increased the risk for liver tumors in rats and mice. Another study showed that the administration of goldenseal root powder resulted in increased incidences of non-neoplastic lesions in the liver of male and female rats and male mice. There is little information about the safety of high dosages or the long-term use of goldenseal)

• Leishmaniasis:

• Echinacea

• An in vitro study concluded that various Echinacea extracts can inhibit the proliferation of the parasites Leishmania donovani, Leishmania major, and Trypanosoma brucei. At least one can reverse the pro-inflammatory activity of Leishmania donovani.

• Handroanthus impetiginosa (pink lapacho), Ageratum conyzoides, and Ruta graveolens 

• A study evaluated the effects of crude extracts from Handroanthus impetiginosa, Ageratum conyzoides, and Ruta graveolens on Leishmania amazonensis and Trypanosoma cruzi infection in vitro. The results showed that the extracts caused significant toxicity in promastigotes and trypomastigotes. A significant decrease in cell invasion rate by pretreated trypomastigotes and promastigotes was also observed. The extracts caused a significant reduction of the multiplication of intracellular amastigotes of both parasites. Therefore, these herbal extracts may be potential candidates for developing drugs for treating leishmaniasis and Chagas disease.

          Herbs & dietary supplements with enhancing effects on the immune system 

(with green color are the herbs & dietary supplements that the author of this text personally considers more important for this issue)

• Immune system improvement in people with HIV/AIDS:

• coenzyme Q-10

• Immune system stimulation/ enhancement – immunoenhancing effects:

• Astragalus membranaceus/  Cycloastragenol (CAG; a saponin derived from astragalus, e.g., TAT2

• A study showed that it increased the proliferative capacity of both CD4 and CD8 T cells.

• beta-glucans

• Chlorella

• A study in mice showed that hot water extracts of Chlorella vulgaris (CVE) may be useful in improving immune function; the results showed that CVE treatment significantly increased the production of both interleukin (IL)-2 and IL-4 compared with the media control.

• The results of a human study suggest that 4-week ingestion of a chlorella-derived multicomponent supplement increases salivary SIgA secretion and possibly improves mucosal immune function in humans.

• The results of a human study suggest a beneficial immunostimulatory effect of short-term Chlorella supplementation, which enhances the NK cell activity and produces interferon-γ and interleukin-12 as well as interleukin-1β, the Th-1 cell-induced cytokines in healthy people.

• Concord grape juice

• A study that assessed concord grape juice showed that those consuming the grape juice had significantly greater numbers of circulating γδ T cells and higher serum vitamin C levels compared to the placebo; the study concluded that regular consumption of purple grape juice in the absence of other red, blue, or purple fruits benefited immunity in healthy, middle-aged human subjects.

• Garlic

• American ginseng

• Some scientists believe American ginseng enhances the immune system. Several clinical studies have shown that American ginseng does boost the performance of cells playing a role in immunity.

• Echinacea

• A study showed that in vivo, Polinacea, a new standardized hydroethanolic extract obtained from Echinacea angustifolia roots, had an immune-stimulating activity by reducing the Candida albicans (a fungus, yeast) induced mortality both in normal and in cyclosporin A (an immunosuppressive medicine used to prevent rejection in organ transplantation) – treated mice.

• Echinacea & goldenseal as a combination

• A study in rats suggested that medicinal plants like Echinacea or Goldenseal may enhance immune function by increasing antigen-specific immunoglobulin production.

• An in vitro study concluded that goldenseal and Astragalus exhibit abilities to modulate macrophage responses during stimulation.

• Note: a study showed that goldenseal root powder increased the risk of liver tumors in rats and mice. Another study showed that the administration of goldenseal root powder resulted in increased incidences of non-neoplastic lesions in the liver of male and female rats and male mice. There is little information about the safety of high dosages or the long-term use of goldenseal),

• Holy basil (Tulsi)

• Plantago lanceolate

• Prebiotics

• Propolis

• Saffron (dried stigmas of the plant Crocus sativus)

• Sea buckthorn

• The seed oil has been found to enhance non-specific immunity.

• Selenium

• Selenium and other minerals can help build up white blood cells (WBCs).

• Studies suggest that selenium might help prevent some infections, such as a bacterial skin infection that often occurs with lymphedema and mycoplasma pneumonia.

• Also, one study suggested that when elderly people took zinc and selenium supplements, their immune systems responded better to the flu vaccine than those who took a placebo.

• Eleuthero (called wrongly by some as Siberian ΄΄ginseng΄΄)

• The active ingredients in Eleuthero, called eleutherosides, are thought to stimulate the immune system.

• A study found that healthy people who took Eleuthero for 4 weeks had more T-cells, which may indicate a strengthening of their immune systems.

• Spirulina

• Taraxacum officinale (the common dandelion)

• Andrographis paniculata

• A study in rats concluded that the methanolic leaf extract of Andrographis paniculata showed significant immunostimulant (that stimulated the immune system), cerebroprotective (neuroprotective/ protective for the brain), and nootropic activities in normal and type 2 diabetic rats. Specifically, a significant increase in blood lymphocyte count, splenic lymphocyte count, and peritoneal macrophage count was observed in both normal and type 2 diabetic rats; immunostimulant activity was observed more in type 2 diabetic rats.

• Cat’s claw

• Goji berry (wolfberry)

• A study concluded that daily consumption of GoChi (a standardized juice containing Lycium barbarum (goji berry)) significantly increased several immunological responses and subjective feelings of general well-being without any adverse reactions. Specifically, the GoChi group showed a statistically significant increase in the number of lymphocytes and levels of interleukin-2 (IL – 2) and immunoglobulin G, compared to pre-intervention and the placebo group.

• Black garlic

• The immunostimulatory activities such as cell proliferation, tumor necrosis factor (TNF-alpha), and nitric oxides (NO) production of raw garlic extract (RGE) and black garlic extracts (BGE) on individual primary lymphocytes or macrophages isolated from the blood of 21 volunteers were evaluated. The antioxidant and anticancer effects of raw garlic and black garlic ethanol extract were measured to determine the optimum conditions for extraction. The 70% ethanol black garlic extracts at 70°C for 12 hours (70% BGE) showed the strongest antioxidant and anticancer activities. Immunostimulatory activities of garlic extracts extracted under the optimal condition on primary immune cells obtained from 21 volunteers were analyzed. The results showed that the cell proliferation, TNF-α, and NO production of primary immune cells treated with 70% raw garlic extract (70% RGE) were significantly different; however, little difference was observed for the 70% BGE treatment. BGE showed stronger immunostimulatory activities than RGE. These results indicate that the immunostimulatory activities of RGE and BGE can be strongly correlated with antioxidant and anticancer activities. Determination of immunostimulatory activities of different types of garlic using immune cells isolated from volunteers was dependent on the individual constituents due to changes in the composition of garlic during processing.

• Glutathione

• The potential of dietary glutathione to alter the immune response in aging mice was studied (the study was conducted in 1987). Four (young), 17 (mature), and 24 (old) month-old C57BL/6Nia male mice were fed semi-purified, nutritionally adequate diets containing 0 (control) to 1.0% of reduced glutathione (GSH) for 4 weeks. Concanavalin A (Con A) stimulated proliferation of splenocytes (spleen white blood cells) and was assessed by [3H]thymidine incorporation. The study showed that dietary GSH supplementation improves the splenic status of this tripeptide and enhances T-cell-mediated immune responses in aging mice.

• Lysine & arginine

• Combined L-lysine-L-arginine therapy is capable of inducting recovery in age-related decline of thymic activity in mice and in elderly humans. The clinical usefulness of the association has also been shown in children with recurrent respiratory infections, while an increase in the number of CD3+ lymphocytes has been shown in patients with chronic lymphatic leukemia (CLL; a blood malignancy). Recently, in vitro effects of the association on neutrophil function have been reported. In particular, the association was able to increase random migration, chemotaxis, phagocytosis-associated- and f-MLP-induced chemiluminescence. In a study, the authors evaluated the effects of the L-lysine-L-arginine combination (lisargin) on several humoral and cell-mediated immunologic parameters in patients with recurrent infections. An increase in neutrophil random migration and chemotaxis (evaluated by a new technique based on a computer-assisted image processing system) was found. Furthermore, an increase in the absolute number of lymphocytes involved in the cytotoxic activity and IgG levels was observed]

• Immune system enhancement on the elderly:

• Goji berry (wolfberry)

• A study on mice concluded that dietary intake of a milk-based formulation of wolfberry, named Lacto-Wolfberry, may favorably modulate the poor responsiveness to antigenic challenges observed with aging. The study showed that Lacto-Wolfberry supplementation significantly increased in vivo systemic immune markers that are known to decline with aging. Indeed, antigen-(KLH) specific humoral response and cell-mediated immune responses in young adult and aged mice were enhanced compared to their respective controls.

• Immune system support:

• Astragalus

• beta-carotene

• Probiotics

• Studies have suggested that consuming yogurt or milk containing specific Lactobacillus strains or taking supplements with Lactobacillus or Bifidobacterium (probiotics) may improve the body’s natural immune response.

• Rhodiola rosea

• Selenium

• Spirulina

• A number of animal and lab studies suggest that spirulina increases the production of antibodies, infection-fighting proteins, and other cells that improve immunity and help ward off infection and chronic illnesses such as cancer. However, it has not been tested in humans.

• Zinc

• The body’s immune system needs zinc to do its job.

• Older people and children in developing countries with low zinc levels might have a higher risk of developing pneumonia and other infections.

• Panax ginseng

• Immunoadjuvant:

• Papaya

• Carica papaya leaf extract may serve as an immunoadjuvant for vaccine therapy.

• Immunomodulatory effects (modulatory effects on the function of the immune system):

• Aloe vera

• Astragalus membranaceus

• Modulates macrophage responses during stimulation.

• beta glucans/ (1-->3)-beta-D-Glucans

• The observations of a study suggest that the (1-->3)-beta-D-Glucan Phycarine is similarly effective both after i.p. and oral (by mouth) application and has very strong stimulating effects on three types of experimentally induced leucopenia (a decrease in the number of leukocytes, white blood cells found in the blood, which places individuals at increased risk of infection) and stimulates both humoral and cellular branch of immune reactions.

• The results of a study showed that IFN-gamma and each cytokine were induced in the spleens and thymus of mice treated with soluble beta-1,3-glucan; the adjuvant effect was observed on antibody production.

• Cereal beta-glucans have shown in vitro activity on cytokine secretion, phagocytic activity (phagocytosis is the cellular process of engulfing solid particles by the cell membrane to form an internal phagosome by phagocytes and protists), and cytotoxicity (cell toxicity) of isolated immune cells, and activation of the complement system; animal studies suggest a possible protective effect against an intestinal parasite, against bacterial infection, and a synergistic effect in antibody-dependent cellular cytotoxicity.

• Holy basil (Tulsi)

• Tulsi (Holy basil; Ocimum sanctum Linn.) is considered a sacred herb, and traditionally it is believed that consumption of Tulsi leaf on an empty stomach increases immunity. Experimental studies have shown that the alcoholic extract of Tulsi modulates immunity. A double-blind randomized controlled cross-over trial on healthy volunteers evaluated the immunomodulatory effects of ethanolic extract of Tulsi leaves. Three hundred milligram capsules of ethanolic extracts of Tulsi leaves or placebo were administered to twenty-four healthy volunteers on an empty stomach. The results of 22 subjects who completed the study were analyzed. The results showed a statistically significant increase in the levels of IFN-γ (interferon-gamma), IL-4 (interleukin – 4), and percentages of T-helper cells and NK-cells (natural killer cells) after 4 weeks in the Tulsi extract intervention group, in contrast to the placebo group. The study concluded that its observations clearly ascertain the immunomodulatory role of Holy basil (Tulsi) leaf extract on healthy volunteers.

• Kale

• A study mentions that the water-soluble fraction of kale triggered immunoglobulin (Ig) production, stimulating activity in human hybridoma HB4C5 cells and human peripheral blood lymphocytes.

• The water-soluble fraction of kale (Brassica oleracea L. var. acephala DC.) had immunoglobulin (Ig) production stimulating activity in human hybridoma HB4C5 cells and human peripheral blood lymphocytes. The findings of a study provide the beneficial aspect of kale as a health-promoting foodstuff.

• A study investigated whether curly kale extracts affect the cytokine-induced expression of endothelial cell adhesion molecules as well as the adhesion of leukocytes to endothelial cells, depending on their polyphenol content and composition. Curly kale leaves were extracted by applying two solvents with different polarities (methanolic extracts (ME) and aqueous water extracts (WE)). In conclusion, the inhibitory effect of water and methanolic soluble ingredients of curly kale leaves on cell-cell interaction and gene expression events support their health-promoting effect under inflammatory conditions]

• Coenzyme Q10 and vitamin B6 (pyridoxine)

• In a study, the blood levels of IgG increased when CoQ10 and pyridoxine were administered together and when CoQ10 was administered alone; the blood levels of T4-lymphocytes increased when CoQ10 and pyridoxine were administered together and separately; the ratio of T4/T8 lymphocytes increased when CoQ10 and pyridoxine were administered together and separately.

• Soy–derived lecithin.

• Dietary soy lecithin supplementation decreases hyperlipidemia (high blood lipids, i.e., fats) and influences lipid metabolism. Although diabetic patients use this product, there is no data about the effect of soy lecithin supplementation on the immune system. The addition of phosphatidylcholine, the main component of lecithin, to a culture of lymphocytes has been reported to alter their function. If phosphatidylcholine changes lymphocyte functions in vitro, as previously shown, it could also affect immune cells in vivo. A study examined the effect of dietary soy lecithin on macrophage phagocytic capacity and lymphocyte number in response to concanavalin A (ConA) stimulation in non-diabetic and alloxan-induced diabetic rats. The study concluded that lymphocyte and macrophage functions were altered by lecithin supplementation, indicating an immunomodulatory effect of phosphatidylcholine.

• Melatonin

• A study concluded that it has the potential therapeutic value to enhance immune function in aged individuals.

• Oldenlandia diffusa (Hedyotis diffusa)

• A study concluded that Oldenlandia diffusa extract has immuno-modulating and anti-tumor activity in vitro by stimulating the immune system to kill or engulf tumor cells, which could be used clinically for immune function modulation and treating tumors and other diseases.

• Phosphatidylserine

• A study showed that phosphatidylserine liposomes specifically inhibited responses to Ags (antigens) as determined by decreased draining lymph node tissue mass, with reduced numbers of total leukocytes and Ag-specific CD4⁺ T cells.

• There was also a decrease in the formation and size of germinal centers in the spleen and lymph nodes, accompanied by decreased levels of Ag-specific IgG in the blood.

• Prebiotics

• There is increasing evidence that the newly described prebiotics and innovative means of administration can modulate various immune system properties, including those of the gut-associated lymphoid tissues (GALT).

• Propolis

• Reishi mushroom (Lingzhi mushroom)

• Royal jelly

• Saffron (dried stigmas of the plant Crocus sativus)

• A study on healthy men showed that after 3 weeks, saffron increased the IgG level and decreased the IgM level compared with the baseline and placebo, decreased the percentage of basophils and the count of platelets compared with baseline, but increased the percentage of monocytes compared with placebo. However, these parameters returned to the baseline levels after 6 weeks.

• Schisandra chinensis (Wu wei zi)

• A study showed that Schisandra chinensis may be therapeutically beneficial by promoting humoral and cell-mediated immune responses.

• Sea – buckthorn

• A study suggested that the leaf extract of Sea buckthorn has significant immunomodulatory activity and specifically activates the cell-mediated immune response.

• Sesame oil (lignans)

• Eleuthero (called wrongly by some as Siberian ΄΄ginseng΄΄) & Andrographis paniculata combination

• An in vitro study that investigated the immunomodulatory properties of a diterpene lactone andrographolide and Kan Jang – a standardized fixed combination of Andrographis paniculata extract SHA-10 and Eleuthero (Eleutherococcus senticosus) extract SHE-3 showed that andrographolide and Kan Jang stimulated the INF-gamma, Neopterin, and beta2MG formation; in the peripheral blood lymphocytes (PBL) – stimulated blood cells both andrographolide and Kan Jang increased the formation of TNF-alpha and beta2MG in cultivated whole blood cells; thus, andrographolide and Kan Jang can have an in vitro effect on the activation and proliferation of immunocompetent cells as well on the production of key cytokines and immune activation markers.

• Andrographis paniculata

• A study on different in vivo and in vitro experimental models showed that HN-02, an extract containing a mixture of andrographolides, can enhance immune function, possibly through modulation of immune responses altered during antigen interaction, and to reverse the immunosuppression induced by cyclophosphamide (CYP; a nitrogen mustard alkylating agent used to treat cancer and immune diseases).

• Tannins

• Goji berry (Wolfberry)

• In a human study, the GoChi (Lycium barbarum; known as Goji berry) fruit juice group showed a statistically significant increase in the number of lymphocytes and levels of interleukin-2 (IL – 2) and immunoglobulin G compared to pre-intervention and the placebo group.

• Another study in mice showed that dietary intake of a milk-based formulation of wolfberry, named Lacto-Wolfberry, may favorably modulate the poor responsiveness to antigenic challenges observed with aging.

• Bromelain

• In a study, bromelain has been shown to modulate the cellular responses of lymphocytes after oral use; it is postulated that the immunomodulating effect of bromelain observed in this trial is part of its known anti-inflammatory activities]

• Astaxanthin

• A study that investigated the action of dietary astaxanthin in modulating the immune response, oxidative status, and inflammation in young healthy adult female human subjects showed that dietary astaxanthin stimulated mitogen-induced lymphoproliferation, increased natural killer (NK) cell cytotoxic activity and increased total T and B cell subpopulations, but did not influence populations of T-helper, T-cytotoxic or natural killer (NK) cells]

• Long-chain polyunsaturated fatty acids (LCP) 

• A study on formula-fed infants concluded that formula-fed infants, at low risk for allergy, respond differently to mitogen and food proteins ex vivo than those fed human milk (HM); feeding long-chain polyunsaturated fatty acids (LCP) altered some of these differences in the direction that is hypothesized to confer immune benefits]

• Horsetail

• In Europe, extracts of Equisetum arvense (common horsetail) have a long tradition in the treatment of inflammatory disorders. To understand the molecular basis for its use, a study investigated the immunomodulatory capacity of a standardized commercially available common horsetail extract on human primary lymphocyte function in vitro. The standardized extract of Equisetum arvense was phytochemically characterized. Effects on proliferation, viability, and activity of mitogen-activated human lymphocytes were assessed in comparison to cyclosporine A. In conclusion, the data indicate that the used extract of Equisetum arvense (common horsetail) interferes with the polyfunctionality of immunocompetent cells, thereby providing an anti-inflammatory mode of action]

• Brewer’s yeast – EpiCor^®

• EpiCor^®, derived from (the yeast) Saccharomyces cerevisiae, has been shown to have immunomodulating properties in human clinical trials and in vitro. A study using an integrated in vitro approach evaluated the metabolism of EpiCor^® by the intestinal microflora, its modulating effect on the gut microbiota, and its anti-inflammatory activity on human-derived cell lines. Using the SHIME model, combined with a mucus adhesion assay, has shown that low doses of EpiCor have a prebiotic-like modulatory effect on the luminal- and mucosa-associated microbiota. 

• Diverse and significant benefits against cold/flu symptoms and seasonal allergies have been observed with a dried fermentate (DF) derived from (the yeast) Saccharomyces cerevisiae (EpiCor®) in multiple published randomized trials. Two separate animal studies were conducted to determine if DF may influence other immune conditions. Study 1 examined the ability of DF to prevent or reduce inflammation when given orally for 14 days to rats prior to receiving 1% carrageenan (a localized inflammation model).. The study concluded that dried fermentate (DF) derived from (the yeast) Saccharomyces cerevisiae (EpiCor) favorably impacts multiple acute and potentially chronic immunologic inflammatory control mechanisms and should be further tested in clinical trials.
• A pilot study investigated the acute effects on circulating lymphocyte subsets, antioxidant status, and cytokine profile after consumption of EpiCor(®) (EP), a dried fermentate produced from (the yeast) Saccharomyces cerevisiae, using a placebo-controlled randomized crossover study design with 12 healthy adult human subjects. EP contains elevated levels of bioavailable antioxidants and strongly activates natural killer (NK) cells in vitro. EP consumption has been shown to increase erythrocyte hematocrit levels, boost mucosal immune protection, reduce cold/flu symptoms, reduce seasonal allergy symptoms and the need for rescue medication, and increase salivary secretory immunoglobulin A levels. This warranted further study on immune effects in humans. A within-subject analysis of data collected before and at 1 and 2 hours after consumption of a single dose of 500 mg of EP versus placebo was performed. . Consumption of a single 500 mg dose of EpiCor(®) (EP), a dried fermentation produced from the yeast Saccharomyces cerevisiae, provides a rapid and transient effect on the trafficking and activation status of specific lymphocyte subsets, as well as increased antioxidant protection]

• Colostrum

• A study investigated whether bovine colostrum (BC) had any immunomodulatory effect on human peripheral blood mononuclear cells (PBMC) from healthy donors. To this aim, the authors focused on producing IL-12 and IFN-gamma cytokines involved in the Th1 polarization required for a successful immune response towards intracellular pathogens, such as bacteria and viruses. The results showed that BC induced a dose-dependent production of IL-12 by CD14+ monocytes but was unable to induce IFN-gamma production. However, BC differentially affected stimuli-induced IFN-gamma production: it enhanced IFN-gamma in response to weak antigenic stimulation and inhibited IFN-gamma in response to strong antigenic stimulation. These effects were not dose dependent. The authors also measured PBMC proliferation, which was substantially unaffected by BC. In conclusion, these data suggest that the Th1-promoting activity of bovine colostrum (BC) could contribute, together with the antibodies, to the protective effect of BC on the offspring. BC could also represent an inexpensive therapeutic tool in the prevention and treatment of several human microbial infections, including influenza (flu)]

• Glutathione

• The effect of in vitro glutathione (GSH) supplementation on mitogenic response, interleukin-1, interleukin-2, and prostaglandin E2 production, and cellular GSH level in peripheral blood mononuclear cells (PBMC) from healthy young and old human subjects were studied (the study was conducted in 1994). In vitro addition of GSH increased cellular GSH levels. Glutathione supplementation at concentrations between 2 to 10 mmol/L enhanced lymphocyte proliferation but decreased mitogenic response at low concentrations (0.5 and 1 mmol/L). Glutathione-induced enhancement of lymphocyte proliferation due to phytohemagglutinin or concanavalin A was greater in the PBMC from old subjects than in those from young subjects. The study concluded that glutathione (GSH) supplementation enhances T cell-mediated mitogenic response in young and old subjects. This effect is due, at least in part, to decreased eicosanoid production.

• Immunoprotective effects

• Proanthocyanidins/ oligomeric proanthocyanidin complexes (OPCs)/ Grape seed proanthocyanidin extract (GSPE)

• The cytoprotecting (cell protection) effects of GSPE were examined on DMN-induced immunotoxicity).

• Astragalus

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