Human immune system
Immunology is the most difficult topic in physiology. Even though I have just passed the excellent exam "Immunology" at prof. I do not feel the worse of Krč, an immunologist. From the entire course, I still remember the feeling of astonishment that I took up after studying T cell maturation and antibody development chapters. In a magazine I have forgotten, I have long ago read that about a third of the total human genes are involved in the construction of the nervous system, a third of the immune system, and a third of all other tasks. I do not know how much this claim is still valid today, but we can really say that the immune system is about as complex as the brain, with the difference that the immune system does not give anatomical clues to its understanding.
How does it go in the immune system?
Experts of immunology will forgive me when I say that the immune system is most reminded of the totalitarian police apparatus:
All cells and molecules of the human body are registered and introduced as "own" before birth. For this purpose, the thymus, in which the lymphocyte cells of the cell, is trained so as to be able to react against all possible and impossible molecules except their own.
If a foreign molecule enters the body later in life, a certain number of immune cells will always be found capable of recognizing it. The foreign molecule will be transported to the lymph node that acts as a police station. The case is first assessed. If the immune system chooses to respond to that foreign molecule, a rapid mutation and selection process takes place under the leadership of the dendritic cell, resulting in amazing optimization of the receptor recognizing the foreign molecule and cloning the original cell that carried it within 3-4 days. Optimized receptor clones can then proceed to body wand searching for and destroying cells containing a given foreign molecule (this is called type 1 response, cell or cytotoxic response). The other option is that the clones begin to freely release the optimized receptor into the extracellular space, and the diffusion itself will find the target molecules, such as the surface of the microbes (this is called the type 2 response, also the antibody response, humor = juice).
Intra-cellular parasites (e.g., viruses) and tumors are blocked by the fact that each cell (except red blood cells) carries MHC molecules functioning as a ID card on the surface. MHC molecules present as if they are a photograph of the inner environment of the wearer's cell - each individual MHC molecule is stuck on a randomly selected fragment of intracellular proteins. Cells whose fragments correspond to foreign molecules are destroyed. Those cells that would try to avoid detection by reduced MHC expression are killed by a special group of surveillance cells - NK lymphocytes.
Basic concepts of immunology
Let me briefly mention the basic immunological terms I often mention in my texts - please keep in mind that the immune system is still a lot more complex:
- Passive Immunity - Mechanical protection of skin, mucous membranes, mucus, work of ciliary epithelium that carries dirt from our bronchial tubes, chemical protection of acidity of the skin, stomach, vagina, bacteriophysial lysozyme in saliva and tears, peroxidase system (lactoperoxidase, DUOX) or blood-brain barrier, etc.
- Active immunity - Response of the immune system caused by the presence of a pathogen in the body.
- Congenital immunity - The innate ability of the immune system to discern the usual pathogens. As with robbers, it is typical that it is shaved wrongly and is standing around the corner, and the pathogens have some common molecular features that make it easy to distinguish. E.g. leukocytes have several types of so-called TLR receptors (TLR1-13) recognizing bacterial or fungal polysaccharides on their surface, inside the cells there is a DICER1 enzyme capable of recognizing and chopping double-stranded RNA viruses,
- Immunity acquired - Our immune system has the ability to develop and produce a large number of specific antibodies, tailored to specific antigens, in the course of a short period of time.
- Antigen - Any foreign molecule that causes an immune response. Typically, antigens are spoken in the style of "anti-something specifically recognizes something antigen".
- Antigen Receptor - Some negative fingerprint. They are molecules that fit precisely with their alien antigens. These include BCR (antigenic B cell receptor), TCR (T cell antigen receptor) and immunoglobulins, or antibodies , which are essentially free-flowing antigenic receptors secreted in a large number of B lymphocytes. In the process of immune system maturation before birth, our organism creates a number of antigenic receptors that have the ability to recognize all possible and impossible foreign molecules. Receptors that react to their own molecules are destroyed during the ripening process.
- Antibodies (immunoglobulins) - The antibody, or immunoglobulin, is a floating protein very similar to the B and T lymphocyte antigen receptors. The source of antibodies is B lymphocytes. The immunoglobulin shape resembles a peacock pin with a specially shaped head that fits as a negative imprint on foreign molecules. Immunoglobulin consists of two parts: larger (so-called heavy chain) and smaller (so-called light chain). Both parts undergo intensive gene manipulations for the first time in the maturation of the immune system before birth, and the second time in an infection where they are still deliberately mutated and selected to bind to the antigen as closely as possible. Immunoglobulins are further subdivided into subtypes (IgA, IgD, IgE, IgG, IgM), differing in minor detail.
- MHC (main histocompatibility complex) - All body cells have the obligation to demonstrate on their surface a sufficiently high number of MHC I molecules with linked randomized chains of their internal proteins. It can be likened to a citizen's ID card with photos of the owner's internal peptides. If a cell presents foreign peptides, T C lymphocytes control apoptosis, and the affected cell still aids by piercing its wall with a special perforin poison. The same fate is encountered if it does not show sufficient MHC I, which is monitored by NK lymphocytes. The MHC II molecule, on the other hand, is not a citizen's card, but a police file with criminal photographs. MHC II molecules carry professional immune cells on their surface. If a foreign peptide is captured in MHC II, it means that the affected immune cell is just handling its case.
- White blood cells (leukocytes) - Cellular police. They are divided into line guards (granulocytes) and specialists (lymphocytes). A particular type of leukocytes are monocytes, cellular garbage, who have a lot of work to do in the immune reaction.
- Granulocytes - Watchmen serving with samurai determination. They have the shortest life of all cells. Even if the immune reaction does not participate or survive, they will commit program dismantling (apoptosis) for each case after several days. The life of the tank is about 15 minutes long, so its durability can be sacrificed for other benefits (eg the turbine engine at Abrams or wankel at British tanks, bud2002cwh ). Likewise, there are granulocytes that do not need to take care of their health when choosing destructive methods against microbes that are consumed. Granulocytes have a number of molecular warfare agents that can be seen in their cytoplasm as grains - granules. According to the equipment, it is divided into three types:
- neutrophilic granulocytes - The most abusive type.
- eosinophilic granulocytes - Medium abundant.
- basophilic granulocytes - Rare, except that they very resemble so-called mast cells (mast cells) living in stale life as stationary defense in tissues.
Granulocyte methods include microbial feeding, acid burning, superoxide, peroxide, hypochlorite (in a drug known as Savo) and other caustics, digestive enzymes destruction and, among other things, large amounts of nitric oxide, which is otherwise necessary and beneficial in cellular communication at appropriate concentrations . The immune system is using all possible methods, including today's loudly shattered DNA nanotechnology - Granulocytes seem to use DNA as a building material to construct miniature cages for microbes ( wartha2007net ).
- Lymphocytes - Police specialists. When an encyclopaedia comes to the MHC II peripheral lymph node with a stuck foreign peptide, the immune response will not be answered immediately. The case is first resolved, judged, weighing and aggravating circumstances and the overall situation in the body are considered. Research shows that lymphocytes in lymphoid tissue are still in a hurry and are still arguing with other lymphocytes. When a decision on the immune response occurs, B and T cells are grouped around the dendritic cell, and the mutation process and clonal selection (controlled evolution) that optimizes the antigenic receptor over the course of 3-4 days first resolves the foreign molecule. Lymphocytes are divided into:
- B lymphocytes - They are responsible for the production of antibodies (immunoglobulins). Both B lymphocytes and T lymphocytes have antigenic receptors - molecules capable of recognizing foreign struc- tures. While T cells retain their antigenic receptors (TCRs) on their surface, B lymphocytes are famous for their release into the environment as antibodies. B lymphocytes also have their surface antigen receptor (BCR), which are basically antibodies bound to the surface of the cell. After the immune response has subsided, part B lymphocytes are transformed into memory cells that provide long-term immunity.
- T lymphocytes - Cell lysing. Divided into:
- T C (cytotoxic) lymphocytes - Control of civilians. They have the ability to destroy suspect cells, so they are called "cytotoxic". They carry the "Civilian Controller Certificate", a CD8 molecule that binds to the "ID card" of MHC I. Using the TCR receptor, which is the equivalent of B lymphocyte antibodies, the T C lymphocytes look at the photograph of the cell's internal environment stuck in the MHC I card and decide whether the cell needs to be destroyed. The method by which MHC B and T lymphocytes are controlled by BCR and TCR receptors also relates to prof. Hotter .
- T H (helper, "helper") lymphocytes - Investigation. They carry on the surface a "CD4 investigator's license", which is linked to the "police file" of MHC II and, unfortunately, also to the HIV virus. It is divided into several other subtypes, of which the most important are T H 1, issuing T-cells and T H 2, which in turn authorize B lymphocytes.
- T S (suppressor, "suppressive") lymphocytes - (more recently they say T reg , regulatory) - State advocates. They have access to various files and block the immune response.
- T M (memory, "memory") lymphocytes - Police archive. After a successful immune response, part of the veterans of the different T and B class lymphocytes will be converted to memory cells that retain their long-term ability to recreate the appropriate antibody. Creating appropriate memory cells is the principle of vaccination.
- other specialty classes of lymphocytes - They have different special abilities, eg they can cure bacteria according to specific bacterial metabolites otherwise in the body of absent,
- NK Cells - Discipline Supervision for Carrying Citizen Cards. Sick cells would, in theory, have avoided the destruction of T C lymphocytes by not carrying MHC I at all. For this case, there are NK lymphocytes that destroy cells with too little MHC I expression. The abbreviation NK is derived from the "natural killer," which is a phrase I do not like. NK cells also have many other functions.
- Monocytes - Cellular garbage collectors who also have police and combat functions. This division of guardians, specialists and garbage collectors is just for illustration - the division of labor between cells has no logic from the point of view of human occupations. In theory, all cells can do everything (they have a complete set of genes). When monocytes operate in tissues, they are called macrophages (literally large stomachs). When they settle down, they spread a network of numerous protrusions around them and call them dendritic (tree-like) cells. Part of the monocytes penetrate into the brain where they must behave quietly and disrespectfully as a hotel maid so as not to disturb the neurons in thought - such monocytes are called microglia . However, the microglie must have the ability to change in a critical situation in a snap, in a hotel blast, and to deal with the intruders without the help of lymphocytes, which usually do not go to the brain.
- Immune system digestion - With T and B lymphocytes, our immune system has the ability to respond to pathogens that we and our ancestors have never encountered before. This is because shortly before birth our immune system carries out the registration of all the body of its own molecules. They are trained by billions of T and B lymphocytes capable of recognizing all possible and impossible molecules except those that are our own.
High school for T lymphocytes is the thymus (thymus, from there T), in which it is initially amplified, the development of individuality by targeted gene manipulations at the antigenic TCR receptor and subsequent selection. When selecting, those T cells that do not have sufficient discernible talent are first destroyed. In the second round, those that respond to their own structures are destroyed (therefore, for example, in congenital syphilis there is no immune response). B lymphocytes in mammals undergo the same training in bone marrow or lymph nodes, but birds have a special organ for the B lymphocyte training, a bloom of the cloak ( bursa fabricii , from there B). The training will survive about 2% of the cells involved, 98% undergo apoptosis and macrophages are cleared.
Taught lymphocytes then enter the waiting phase. They deal with a foreign peptide that, as well as their antigenic receptor, activates and, in agreement with other lymphocytes, they can become the main actors of the affinity maturation process in which ultra-fast controlled evolution occurs (somatic hypermutation and clonal selection ). Ultrary because it is not expected until the division is complete - the eukaryotic cell cycle would last for at least 24 hours, and only 4 iterations would be achieved in 4 days. Instead, mutated genes are selected by instant testing of their protein product. The result is a highly optimized antigen receptor. If Golem XIV Stanisława Lema complains that Evolution moves from the initial molecular genius to the worse technical solution ( work here , unfortunately in the net only in English), it can be said that in the immune system this genius remained under pressure parasites are partially preserved.
- Communication molecules - All components of the immune system work together. For example, only B lymphocytes have the ability to produce specific immunoglobulins, but they are ultimately used by all the immune cells and the complement. Immunoglobulin can be considered an information molecule - it is a negative, or rather a negative, fingerprint of a criminal. In addition, the immune system uses a variety of other communication molecules:
- cytokines, chemokines - Common name for communication molecules of a herbicidal nature. These include interleukins, interferons, and dozens of other peptides with ugly names.
- interleukins - Protein-based communication molecules in general managing strategy and tactics of immune responses: They trigger fever, control leukocyte proliferation, control inflammation, proclaim martial law,
- interferons - Three types of antiviral alarm peptides.
- TNF (tumor necrosis factors) - Polyfunctional immune communication peptides that have received glory in human scientists as anticancer alarm molecules.
- eicosanoids (prostaglandins, leukotrienes, thromboxanes and others, so-called non-classical eicosanoids) - Communication molecules derived from twenty-carbon (twenty-20) fatty acids, arachidonic acid. It belongs to the world of essential fatty acids, well-known omega-3 and omega-6 unsaturated fatty acids, formerly called vitamin F. Our organism first has omega-3 and omega-6 unsaturated bonds still assigned ω-9 and ω- to form arachidonic acid. In addition, specialized enzymes produce communication eicosanoids. The key enzyme in their production is cycloxygenase , which is the target of the most common analgesics . Acetylsalicylic acid (aspirin) , paracetamol (paralen) and ibuprofen (brufen) share the same main effect - they block cycloxygenase.
- Complement - A set of mutually interacting protein molecules (labeled C1 to C9, possibly more than nine) capable of self-identifying and destroying or at least labeling pathogens. The C1 molecule detects the pathogen either directly or with immunoglobulins, and the C2-C8 molecules then assess the situation to prevent the destruction of the good cell by mistake, and C9 then creates an attacking complex that perforates the target membrane. Additionally, the cells in addition to the complement protect the protectin antidote, which inhibits the action of the C9 molecule. Just like the slow-down conclusion of the 45th Sturmkwire , or the mechanical ladybird that our cyber theoretician and Slovak immigrant Jozef Kelemen are so happy about, the complement is an example of genius in simplicity. Magazines are slowly starting to bombard us with reports of "smart" antibiotics in America, so we do not feel inferior, it's good to know that up to 5% of our blood serum proteins are the molecules of the smartest antibiotic-complement.
- Defensins - Effective antibiotics created by our body. It can be said that from the point of view of common microbes, we are among poisonous animals.
- a-defensiny - A weapon of granulocytes and other immune cells.
- β-defensins - Antibacterial poisons that we excrete on the surface of our skin, mucous membranes and body cavities.
- Apoptosis - Controlled cellular disassembly. Older cells undergo DNA damage when they are parasitic, or if they suspect tumor growth itself. I consider the term "cellular suicide" to be misleading. (I also think of "death" as a completely unscientific expression, but that is another.)
- Autoimmunity - As with any system, even in the immune system, errors occur. There are quite a few cases where certain proteins in our cells appear in the course of their lives, and lymphocytes have to understand that these proteins are not hostile. Lymphocytes themselves can even produce a faulty judgment and accidentally trigger an autoimmune response. Immune errors are very dangerous because they can accidentally easily destroy the population of their own cells, as is the case with type 1 diabetes mellitus . The immune system should also not over react to dozens of useful bacteria, fungi and (possibly) useful viruses occurring on the skin and the digestive tract.
Immune system problems
It turns out that most of the civilization diseases, or diseases of longevity, are somehow related to poor functioning of the immune system. We already know several mechanisms of aging . We have the theory of oxidative aging and antioxidants, the theory of DNA aging, the theory of telomere shortening, the theory of mitochondrial aging ... I believe that the theory of immune system degradation should be added to this list. It is not just allergy and asthma, but also arthritis, arthrosis , diabetes , or seemingly unrelated atherosclerosis . Immunomodulatory drugs should be considered for all these diseases.
Immunomodulatory effects of natural medicines with emphasis on ginseng
Many of the natural adaptogen (and non-adaptagens) affect the immune system. Sensor stricto adaptogens can be expected to interact with the glucocorticoid axis, whose immunomodulatory significance is well known ( Sapolsky2000hdg ). A great deal of scientific effort has been devoted to modeling ginseng adaptogen and healing fungi of the Polyporales group , for which the immunomodulatory effect is considered to be the most important. Another known immunomodulatory adaptogen is purpura ( Echinacea purpurea ) , Astragalus membranaceus . The active substances are triterpenoids ( Christensen2009gcb , Paterson2006gtf ) and other secondary metabolites ( Percival2000uem , Block2003ise ), but also specific proteoglycans / polysaccharides are very important in all of the plants / fungi.
Essence of immunomodulatory effects
The immune response can roughly be divided into two types that compete with each other:
- cytotoxic (against viruses, tumors): -> maturation T H 1 -> activation of T C lymphocytes
- antibody (against most bacteria): -> maturation T H 2 -> activation of B lymphocytes
When the disease occurs, the immune system has to properly assess the type of threatened danger and consider what kind of pathogens it concentrates on. Antigens from the affected tissue are transported to the lymph node, where interleukin IL-2 is produced and the immune response is triggered. The type of response is the result of a discussion of T lymphocytes and dendritic cells (DB) on the antigen. Their cell expression is expressed using communication cytokines:
- DB type 1, T H 1 - production of IFN-γ (gamma interferon), TNF (tumor necrosis factor alpha), IL-12
- DB type 2, T H 2 - production of interleukins IL-4, IL-10
The final decision is in the hands of DB - at its discretion, governs adolescence of T H lymphocytes either to T H 1 type (cytotoxic response) or T H 2 type (antibody response).
Immunomodulatory effects of ginseng right
The fact that ginseng affects the immune system is now beyond doubt ( Christensen2009gcb , Choi2008bcp , Xiang2008cau ). Ginseng enhances immunity especially against viruses and tumors. Cancer can also be seen as immune failure . In cancer, ginseng is a welcome supportive agent, also with some direct antitumour effects .
Ginseng content substances influence the choice of immune response. Christensen2009gcb (chapter "Immunomodulatory action") refers to the thesis that ginseng supports a cytotoxic response (against tumors and viruses). In contrast, Lee2004gre demonstrates that the majority panaxoside Rg 1 of ginseng has the opposite effect. To third, ginseng has a proven anti-inflammatory and anti-allergic effect. A comprehensive scientific view of the immunomodulatory effect of ginseng is not available, but the current data confirm that its constituents have immune-tolerant effects on the immune system, which is typical of the adaptogenic effects .
Stimulating effect of ginseng on the immune system
Adaptogens in general and ginseng, in particular, have several adverse effects on the active substances . Specifically, ginseng limits inflammation , works against autoimmune diseases, and often applies where doctors usually prescribe immunosuppressive corticosteroids. Is ginseng immunosuppressive?
The answer to this question is not clear. Acute Fever (ie infection ) is one of the few traditional contraindications of ginseng. I therefore think that at least some infections that reassure the effect of ginseng on white blood cells are not welcome. However, ginseng is by no means merely an immunosuppressant (which, moreover, is not even mentioned corticoids, Sapolsky2000hdg ). In many bacterial and most viral infections, ginseng helps - immune improves.
Ginseng specific polysaccharides have been shown to suppress Staphylococcus aureus septicemia at an optimal dose of 25μg / kg ( Lim2002aep , Lim2004iap ). The effect was associated with multiple increases in NO production and cytokines (TNF-α, IL-1, IL-6 and IFN-γ) macrophages.
The effect of ginseng on the ability of macrophages to respond to long-term stress infection ( Pannacci2006pgm ) was investigated. It is generally known that long-term stress decreases immunity ( Viswanathan2005saa ), but short-term macrophage stress activates ( Berczi1998scn ). Ginseng ginsan ginseng polysaccharide (25 mg / kg / day per os) in mice increased the expression of TLR receptors in macrophages (these receptors non-specifically recognize pathogens) and thus the ability of macrophages to respond to infection ( Ahn2006igi ). Ginseng also positively affects anti-cancer immunity .
Specific immunomodulatory effects:
- On monocytes / macrophages : Panaxosides Rb 1 and Rb 2 suppressed TNF-α production in both mouse and human macrophage stimulated lipopolysaccharides with IC 50 ~ 50 and ~ 25 μM ( Cho2001vi ). According to Lee2002fma , red ginseng increased the production of TNF-α macrophages. In contrast, according to Cho2001vie , ginsenosides Rb1 , Rb2 , Rg1 are potent inhibitors of TNF-α production in macrophages stimulated by bacterial lipopolysaccharides. The aforementioned panaxosides suppress the production of other inflammatory cytokines such as IL-6 and IL-1β ( Rhule2006pna ).
- The spleen lymphocytes were found to be pxsd. Rb 1 and Re at a concentration of about 100 μM significantly increased the proliferation of mitogens stimulated by T H (CD4 +) and B lymphocytes, Rg1 had no effect on it, while Rb 2 reduced it with IC 50 about 25 μM. Rb2 also suppressed the production of IL-2 lymphocytes following concavalin stimulation with IC 50 ~ 13.3 μM. UT C (CD8 +) lymphocytes were different results - Rb 2 and Rb 1 did not replicate their proliferation after IL-2 stimulation, whereas Re and Rg 1 of their proliferation were limited by IC50 57.5 and 64.7 μM ( Cho2002gfp ) respectively. According to Lee2004gre , gssd. Rg 1 promotes the maturation of T H 2 lymphocytes and the production of IL-4. By contrast, Lee2006grh claims that gssd. Rg1 promotes the maturation of T H 1 lymphocytes.
- Pxsd. F1 and Rg1 in mouse splenocyte culture selectively increase the production of cytokines type 2 (IL-4 in splenocytes, IL-12 in macrophages) and their transcription factor GATA-3, while pxsd. Rh 1 and 20 (R) -Rh 1 selectively enhance the production of cytokines type 1 (IFN-γ in splenocytes) and their transcription factor T-bet. All of the mentioned pxsd. (F1, Rg1, Rh1 and 20 (R) -Rh1) increase the binding of the transcription factor NF-κB to DNA. Interestingly, the maximal increase in cytokines occurs at concentrations of 5μM and 10μM, higher concentrations increase cytokines again less, at 50μM more than twice less than 10μM ( Yu2005pgd ).
- On dendritic cells : According to Takei2004dcm and Takei2008dcp , compound K and gssd. 20 (S) -PPT affect monocytic dendritic cells toward type 1 immune responses. These studies discuss the possibility of anticancer effect of ginseng and the opportunity for immunotherapy of tumors affected by dendritic cells.
- On NK cells : Choi2008bcp discusses the ability of ginseng extract and specifically panaxoside Rh 2 to restore NK cell activity and immune cells after their mitomycin challenge.
- Granulocytes : Gssd. Re activates neutrophilic granulocytes against tumor cells ( Plohmann1997iae ).
- Against Influenza : The effect of ginseng on influenza is revealed in the article influenza and viral diseases .
- HIV: Choi2008bcp ginseng suppresses HIV proliferation and alleviates AIDS.
- On the adhesion of lymphocytes to endothelium and diapedesis : Some panaxosides, such as notoginsenoside R1 ( Chen2008enr ) or ginsenoside Rb1 ( He2007peg ), restrict the adhesion of lymphocytes to the endothelium, explaining the observed effect against atherosclerosis and inflammation .
Immunomodulatory proteoglycans and polysaccharides
In the immunomodulatory effects of natural drugs, proteoglycans and polysaccharides play an important role. It is also true ginseng ( Sun2011sba , Yun1993iat ), American ginseng ( Assinewe2002epp , Wilson2013uai Azike2015ssi ) and other herbs. Again, when taking P. ginseng , for example, acidic polysaccharides ginsenan PA and ginsenan PB increase serum immunoglobulin IgG and activate phagocytosis ( Tomoda1993cta , Tomoda1994csg ). Information in this field is constantly developing; relevant publications on the immunomodulatory effect of ginseng polysaccharides include Lim2004iap , Choi2008rga , Yoo2012peg , Wang2013mmb and others.
Other classical adaptogens with immunomodulatory effects
- Japanese ginseng ( Panax japonicus ) in the mouse model improves the recovery of the damaged immune system. ( Zhang2011epi )
Immunomodulatory effects of glossy gloss
The proteoglycan fraction of the gloss has activated immunity in human monocytes (22364151) and improves immunity to the mouse immunosuppression model (22403542). Otherwise, the work on the influence of glossary on the immune system is large and most of them comment on their anti-tumor effects .
Other immunomodulatory adaptogens
Immunomodulatory effect is essential for a large number of adaptogens, so it is difficult to navigate according to scientific publications. I recommend using the tradition of TCM as an orientation in specific illnesses. But to make the local list of immunomodulatory adaptogens empty, then relevant references point to
- vitania ( Rasool2006irw , Minhas2012tew , Ku2014wii , Ichikawa2006wpa )
- ginger ( Lakhan2015zep )
- kurkumu ( Lakhan2015zep )
- opuncii ( Zhao2012ieo )
- Chinese caterpillar ( Lee2014aec ).
An overview of the most widely known immunomodulatory herbs Ilyas2016rhi (except the above) states:
- umbilical cord (Centella asiatica)
- licorice (Glycyrrhiza spp.)
- asparagus spp.
- aralia (Aralia mandshurica)
- Picrorrhiza kurroa
- Lawsonia alba
- cabbage (Brassica oleracea)
- mistletoe (Viscum album)
- Canavalia ensiformis
- len (Linum usitatissimum)
- wormwood (Artemisia princeps)
- Purple Thuja (Echinacea purpurea)
- wheat bran
- rice bran
- aloe vera (Aloe vera)
- sorrel (Rumex acetosella)
- Membrane dioscorea
- Tinospora cordifolia
- Litter (Litchi chinensis)
- lead (Plumbago zeylanica)
- aniseer (Pimpinella anisum)
- poisonous Catharantus roseus (vinkristin)
- poisonous Claviceps purpurea (ergot alkaloids)
- Uncaria tomentosa
- Amur Cork (Phellodendron amurense)
- Berberin from Cissampelos pareira