# Remedy/Anti-inflammatories

Def. an "agent that prevents or counteracts inflammation" is called an anti-inflammatory.

## Adonis vernalis

Family: Ranunculaceae
The plant is poisonous, containing cardiostimulant compounds, such as adonidin and aconitic acid. In addition, it is often used as an ornamental plant. Infusions of the plant are used in the medicine Bekhterev's mixture.
Due to the cardiac-enhancing effects of Adonis species (including Adonis vernalis), this plant has a history of use in European and Chinese folk medicine. This plant has been utilized for many different issues and health problems. The local people of the Soviet Union at one point used it to treat edema or swelling in the body, and an ethanolic extract of the aerial parts of the plant were prepared as an alternative cardiac agent. In 1879, a Russian medical doctor, N. O. Buhnow, first introduced into medicine alcoholic extracts of the plant as a cardiac stimulant. In 1898, a mixture of the plant extracts with sodium bromide or codeine was suggested (by Vladimir Bekherev) to treat heart diseases, panic disorder, dystonia and mild forms of epilepsy. Aqueous infusions of the aerial parts of the plant have been traditionally used in Siberia against edema, cardiac edema and several other issues that are heart related, kidney diseases, and even malaria. The biological activity of this extract was defined as 50–66 frog units (amount or liquid of substance that causes the arrest of the heart of a frog) and 6.3–8.0 cat units (amount or liquid of substance that causes the arrest of the heart of a cat) and large enough doses can be toxic.
There are many phytochemicals that come from the plant Adonis vernalis and these include cardiac glycosides, other glycosides, and flavones. The compounds that are cardiac glycosides include Cymarin, Adonitoxin, 16-Hydroxy-strophanthidin, Acetyladonitoxin, Vernadigin, 3-Acetylstrophagogenin, Substance N, Strophanthidine fucoside, 3-Epi-periplogenin, 17β-(2’,5’-dihydro-5’-oxo-3’-furyl)-5β-14β-androstane-3α,5β,14β-triol, Adonitoxigenin 2-O-acetylrhamnosidoxyloside, Adonitoxigenin 3-O-acetylrhamnosidoxyloside, Adonitoxigenin rhamnosidoxyloside, Adonitoxigenin 3-O-[β-D-glucopyranosyl-(1→4)-α-L-rhamnopyranoside, Adonitoxigenin 3-O-[β-D-glucopyranosyl-(1→4)-α-L-(3’-O-acetyl)-rhamnopyranoside, Adonitoxigenin-3-[O-α-L-(2’-O-acetyl) rhamnosido-β-D-glucoside, Digitoxigenin. Other glycosides include Adonilide, Fukujusonorone, Fukujusone, 12-O-Nicotinoylisolineolon (Lineolon), 12-O-Benzoylisolineolon, Nicotinoylisoramanone, and Isoramanone (digipurprogenin-II). Flavones include Adonivernith (luteolin-8-hexityl monoxyloside), Homoadonivernith, Orientin, Homoorientin, Isoorientin, Luteolin, and Vitexin.
The plant contains cardiac glycosides, and these improve the heart's efficiency by increasing its output at the same time as slowing down its rate. These glycosides also have a sedative effect and is often prescribed to patients whose hearts are beating irregularly or at an increased rate. Tinctures of Adonis vernalis are also used by homeopathic physicians in patients that are suffering from congestive cardiac failure and its action is very similar to digitalis (another drug that stimulates the heart muscle). Aqueous extracts of Adonis vernalis were found to have cardiac stimulant effects on isolated heart preparations and it also showed that production of excessive and high potassium concentrations protects against heart failure. Not only are cardiac glycosides derived from this plant but there are also some well-known flavones that were identified with pharmacological activities, including antioxidant, antimicrobial, anti-inflammatory, neuro and cardioprotective, and anti-allergic properties.

## Aloe vera

Family: Asphodelaceae.
Aloe vera leaves contain phytochemicals under study for possible bioactivity, such as acetylated mannans, polymannans, anthraquinone C-glycosides, anthrones, and other anthraquinones, such as emodin and various lectins.
For people with allergies to Aloe vera, skin reactions may include contact dermatitis with hives, mild redness and itching, difficulty with breathing, or swelling of the face, lips, tongue, or throat.
"Aloe vera could serve as a natural antihistamine herb. The antihistamine properties of aloe could be attributed, at least in part, to the presence of glycoprotein alprogen which has been demonstrated to antigen-antibody-mediated release of histamine and leukotriene from mast cells (45)."
"Aloe vera contains alprogen as one of the active compound that works by inhibition the absorption of glucose in the digestive tract so that it can reduce blood glucose levels."
Active components present in Aloe vera with properties :
| Name of the Active component | Active components present in Aloe Vera with properties |
| Vitamins | Vitamin A (beta-carotene), C and E, - antioxidants. It also contains vitamin B1, B2, B6 & B12, folic acid, and choline. Antioxidants protect the body by neutralizing free radicals. |
| Enzymes | Aliiase, alkaline phosphatase, amylase, oxidase, bradykinase, carboxypeptidase, catalase, cellulase, lipase, cylooxygenase, and peroxidase. Bradykinase helps to reduce excessive inflammation when applied to the skin topically, while the other enzymes help in the breakdown of sugars, proteins and fats. |
| Minerals | Calcium, chromium, copper, selenium, magnesium, manganese, potassium, sodium and zinc. *Some of the minerals are essential for the proper functioning of various enzyme systems in different metabolic pathways and few acts as antioxidants. |
| Sugars | Monosaccharides (glucose and fructose) and polysaccharides (glucomannans/polymannose). * The most prominent monosaccharide is mannose-6-phosphate, and the most common polysaccharides are called glucomannans [beta-(1,4)-acetylated mannan]. Acemannan, a prominent glucomannan has also been found. Recently, a glycoprotein with anti allergic properties, called alprogen and novel anti-inflammatory compound, C-glucosyl chromone, has been isolated from Aloe vera gel$^{15,16}$. |
| Organic acids | Sorbate, salicylic acid, uric acid salicylic acid possesses anti-inflammatory and antibacterial properties. |
| Anthraquinones | Aloin, barbaloin, isobarbaloin, anthranol, aloetic acid, aloe-emodin, ester of cinnamic acid, resistannol, chrysophannic acid and emodin, Acts as laxatives. Aloin and emodin act as analgesics, antibacterials and antivirals. |
| Fatty acids and Steroids | Cholesterol, campesterol, β-sisosterol and lupeol. Fattyacids like Arachidonic acid, γ-linolenic acid. All these have anti-inflammatory action and lupeol also possesses antiseptic and analgesic properties. |
| Non-essential aminoacids | Histidine, arginine, aspartic acid, glutamic acid, proline, glycine, tyrosine, alanine and hydroxyl proline. |
| Essential aminoacids | Methionine, phenylalanine, isoleucine, leucine, valine, threonine and lysine. |
| Hormones | Auxins and gibberellins that help in wound healing and have anti-inflammatory action. |
| Others | * Lignin, an inert substance, when included in topical preparations, enhances penetrative effect of the other ingredients into the skin. Saponins that are the soapy substances form about 3% of the gel and have cleansing and antiseptic properties. |
"Alprogen, an anti-allergic compound of Aloe vera inhibits calcium influx into mast cells, thereby inhibiting the antigen-antibody-mediated release of various mediators like histamine, serotonin, SRSA, leukotrienes etc from mast cells$^{22}$."

## Berberis aristata

Family Berberidaceae.
Berberine is a quaternary ammonium salt from the protoberberine group of benzylisoquinoline alkaloids found in Berberis aristata (tree turmeric).
The root bark contains the bitter alkaloid berberine, which has been studied for its potential pharmacological properties.

## Boswellia serrata

Boswellia serrata is a plant that produces Indian frankincense, also known as Indian oli-banum, Salai guggul, and Sallaki in Sanskrit. The plant is native to much of India and the Punjab region that extends into Pakistan.
Boswellia serrata contains various derivatives of boswellic acid including β-boswellic acid, acetyl-β-boswellic acid, 11-keto-β-boswellic acid and acetyl-11-keto-β-boswellic acid [AKBA].
Extracts of Boswellia serrata have been clinically studied for osteoarthritis and joint function, with the research showing trends of benefit (slight improvement) in pain and function. It has been used in Indian traditional medicine for diabetes.
"To evaluate the anti-inflammatory and antioxidant effects of extract from the Boswellia serrata plant in an experimental rat model of acute ulcerative colitis induced by the administration of acetic acid (AA)[, an] extract of B. serrata (34.2 mg/kg/day) was administered by oral gavage for 2 days before and after the induction of colitis with 4 mL of 4% AA. The anal sphincter pressure in the colitis group showed a significant decrease compared to that of the control groups (p < 0.001). The analysis of the values of lipid peroxidation (LPO) obtained by substances that react with thiobarbituric acid (TBARS) showed a significantly increased LPO in the colitis group compared to the control groups (p < 0.001). The nitric oxide levels and the expression of inducible nitric oxide synthase (iNOS) showed a significant increase in the colitis group compared to control groups (p < 0.01). Both pretreatment and treatment with B. serrata exhibited significantly reduced lipid peroxidation, nitric oxide and iNOS and showed improvements in tissue injury and anal sphincter pressure in animals with ulcerative colitis. The B. serrata extract has protective anti-inflammatory and antioxidant effects that inhibit inflammatory mediators in acute experimental colitis."

## Camellia reticulata

Family Theaceae.
Camellia reticulata has a long history of cultivation, both for tea oil and for its ornamental value.

## Camellia sasanqua

Family Theaceae.
The leaves are used to make tea while the seeds or nuts are used to make tea seed oil, which is used for lighting, lubrication, cooking and cosmetic purposes.

## Camellia sinensis

Family Theaceae.
Polyphenols found in green tea include epigallocatechin gallate (EGCG), epicatechin gallate, epicatechins and flavanols, which are under laboratory research for their potential effects in vivo. Other components include three kinds of flavonoids, known as kaempferol, quercetin, and myricetin. Although the mean content of flavonoids and catechins in a cup of green tea is higher than that in the same volume of other food and drink items that are traditionally considered to promote health, flavonoids and catechins have no proven biological effect in humans.
Green tea leaves are initially processed by soaking in an alcohol solution, which may be further concentrated to various levels; byproducts of the process are also packaged and used. Extracts are sold over the counter in liquid, powder, capsule, and tablet forms, and may contain up to 17.4% of their total weight in caffeine, though decaffeinated versions are also available.
Numerous claims have been made for the health benefits of green tea, but human clinical research has not found good evidence of benefit. In 2011, a panel of scientists published a report on the claims for health effects at the request of the European Commission: in general they found that the claims made for green tea were not supported by sufficient scientific evidence. Although green tea may enhance mental alertness due to its caffeine content, there is only weak, inconclusive evidence that regular consumption of green tea affects the risk of cancer or cardiovascular diseases, and there is no evidence that it benefits weight loss.
A 2020 review by the Cochrane Collaboration listed some potential adverse effects including gastrointestinal disorders, higher levels of liver enzymes, and, more rarely, insomnia, raised blood pressure, and skin reactions.
Research has shown there is no good evidence that green tea helps to prevent or treat cancer in people.
The link between green tea consumption and the risk of certain cancers such as stomach cancer and non-melanoma skin cancers is unclear due to inconsistent or inadequate evidence.
Green tea interferes with the chemotherapy drug bortezomib (Velcade) and other boronic acid-based proteasome inhibitors, and should be avoided by people taking these medications.
Observational studies found a minor correlation between daily consumption of green tea and a 5% lower risk of death from cardiovascular disease. In a 2015 meta-analysis of such observational studies, an increase in one cup of green tea per day was correlated with slightly lower risk of death from cardiovascular causes. Green tea consumption may be correlated with a reduced risk of stroke. Meta-analyses of randomized controlled trials found that green tea consumption for 3–6 months may produce small reductions (about 2–3 mm Hg each) in systolic and diastolic blood pressures. A separate systematic review and meta-analysis of randomized controlled trials found that consumption of 5-6 cups of green tea per day was associated with a small reduction in systolic blood pressure (2 mmHg), but did not lead to a significant difference in diastolic blood pressure.
Green tea consumption lowers fasting glucose (fasting blood sugar) but in clinical studies the beverage's effect on hemoglobin A1c and fasting insulin levels was inconsistent.
Drinking green tea or taking green tea supplements decreases the blood concentration of total cholesterol (about 3–7 mg/dL), low density lipoprotein (LDL cholesterol) (about 2 mg/dL), and does not affect the concentration of high density lipoprotein (HDL cholesterol) or triglycerides. A 2013 Cochrane meta-analysis of longer-term randomized controlled trials (>3 months duration) concluded that green tea consumption lowers total and LDL cholesterol concentrations in the blood.
A 2015 systematic review and meta-analysis of 11 randomized controlled trials found that green tea consumption was not significantly associated with lower plasma levels of C-reactive protein levels (a marker of inflammation).
There is no good evidence that green tea aids in weight loss or weight maintenance.
Excessive consumption of green tea extract has been associated with hepatotoxicity and liver failure. In 2018, a scientific panel for the European Food Safety Authority reviewed the safety of green tea consumption over a low-moderate range of daily EGCG intake from 90 to 300 mg per day, and with exposure from high green tea consumption estimated to supply up to 866 mg EGCG per day. Dietary supplements containing EGCG may supply up to 1000 mg EGCG and other catechins per day. The panel concluded that EGCG and other catechins from green tea in low-moderate daily amounts are generally regarded as safe, but in some cases of excessive consumption of green tea or use of high-EGCG supplements, liver toxicity may occur.
"Green tea decoction had the highest content of phenolic groups, but the infusion of [Limonium algarvense] had higher amounts of salicylic, gallic and coumaric acids. L. algarvense was not toxic, whereas green tea was toxic for S17 cells. Under our experimental conditions, infusions and decoctions of L. algarvense flowers had similar or higher antioxidant and anti-inflammatory properties than green tea".

## Cinnamomum burmannii

Family Lauraceae.
Cinnamomum burmannii is Korintje, Padang cassia, or Indonesian cinnamon.

## Cinnamomum cassia

Cassia or Chinese cinnamon is the most common commercial type in the USA.
Cinnamon, spice, ground :
| Energy | 1,035 kJ (247 kcal) |
| | Nutritional value per 100 g (3.5 oz) |
| Carbohydrates | 80.6 |
| Sugars | 2.2 |
| Dietary fiber | 53.1 |
| Fat | 1.2 |
| Protein | 4 |
| Vitamins | Quantity | % Daily value (DV)* |
| Vitamin A equivalent | 15 µg | 2 |
| Thiamine (B$_1$) | 0.02 mg | 2 |
| Riboflavin (B$_2$) | 0.04 mg | 3 |
| Niacin (B$_3$) | 1.33 mg | 9 |
| Pyridoxine B$_6$ | 0.16 mg | 12 |
| Folate B$_9$ | 6 µg | 2 |
| Vitamin C | 3.8 mg | 5 |
| Vitamin E | 2.3 mg | 15 |
| Vitamin K | 31.2 µg | 30 |
| Minerals | Quantity | % DV* |
| Calcium | 1002 mg | 100 |
| Iron | 8.3 mg | 64 |
| Magnesium | 60 mg | 17 |
| Phosphorus | 64 mg | 9 |
| Potassium | 431 mg | 9 |
| Sodium | 10 mg | 1 |
| Zinc | 1.8 mg | 19 |
| Other constituents | Quantity |
| Water | 10.6 gm |
* note: Source: USDA Database
Ground cinnamon is composed of around 11% water, 81% carbohydrates (including 53% dietary fiber), 4% protein, and 1% fat. In a 100 gram reference amount, ground cinnamon is a rich source of calcium (100% of the Daily Value (DV)), iron (64% DV), and vitamin K (30% DV).

## Cinnamomum citriodorum

Cinnamomum citriodorum is Malabar cinnamon.

## Cinnamomum loureiroi

Cinnamomum loureiroi is Saigon cinnamon, Vietnamese cassia, or Vietnamese cinnamon.

## Cinnamomum verum

Cinnamomum verum is Sri Lanka cinnamon, Ceylon cinnamon or Cinnamomum zeylanicum.
Cinnamon is a spice obtained from the inner bark of several tree species from the genus Cinnamomum, used mainly as an aromatic condiment and flavouring additive in a wide variety of cuisines, sweet and savoury dishes, breakfast cereals, snackfoods, tea and traditional foods, derived from its essential oil and principal component, cinnamaldehyde, as well as numerous other constituents including eugenol.
"Among the identified compounds, trans-cinnamaldehyde and p-cymene significantly reduced the [lipopolysaccharides] LPS-dependent IL-8 secretion in THP-1 monocytes. Synergistic anti-inflammatory effects were observed for combinations of trans-cinnamaldehyde with p-cymene, cinnamyl alcohol or cinnamic acid. Moreover, cinnamon extract as well as trans-cinnamaldehyde and p-cymene mitigated the phosphorylation of [Protein kinase B] Akt and [NF-κB inhibitor alpha] IκBα. [...] Trans-cinnamaldehyde and p-cymene contribute to the strong anti-inflammatory effects of cinnamon extract. [S]ynergistic effects among compounds that do not exhibit anti-inflammatory effects themselves might be present to positively influence the beneficial effects of cinnamon bark extract."

## Hibiscus sabdariffa

The Hibiscus leaves are a good source of polyphenolic compounds. The major identified compounds include neochlorogenic acid, chlorogenic acid, cryptochlorogenic acid, caffeoylshikimic acid and flavonoid compounds such as quercetin, kaempferol and their derivatives. The flowers are rich in anthocyanins, as well as protocatechuic acid. The dried calyces contain the flavonoids gossypetin, hibiscetine and sabdaretine. The major pigment is not daphniphylline. Small amounts of myrtillin (delphinidin 3-monoglucoside), chrysanthenin (cyanidin 3-monoglucoside), and delphinidin are present. Roselle seeds are a good source of lipid-soluble antioxidants, particularly gamma-tocopherol.

## Hives

Def. "[i]tchy, swollen, red areas of the skin which can appear quickly in response to an allergen or due to other conditions" is called hives.
Hives, also known as urticaria, is a kind of skin rash with red, raised, itchy bumps. They may also burn or sting. Often the patches of rash move around. Typically they last a few days and do not leave any long-lasting skin changes. Fewer than 5% of cases last for more than six weeks. The condition frequently recurs.
Hives frequently occur following an infection or as a result of an allergic reaction such as to medication, insect bites, or food. Psychological stress, cold temperature, or vibration may also be a trigger. In half of cases the cause remains unknown. Risk factors include having conditions such as hay fever or asthma. Diagnosis is typically based on the appearance. Patch testing may be useful to determine the allergy.
Prevention is by avoiding whatever it is that causes the condition. Treatment is typically with antihistamines such as diphenhydramine and ranitidine. In severe cases, corticosteroids or leukotriene inhibitors may also be used. Keeping the environmental temperature cool is also useful. For cases that last more than six weeks immunosuppressants such as ciclosporin may be used.

## Inflammations

Def. a "condition of any part of the body, consisting of congestion of the blood vessels, with obstruction of the blood current, and growth of morbid tissue, manifested outwardly by redness and swelling, attended with heat and pain" is called an inflammation.

## Justicia gendarussa

Family: Acanthaceae
The plant is widely used in various forms for many of its medicinal and insecticidal properties,
Justicia gendarussa is harvested for its leaves for the treatment of various ailments.
It maybe useful for the treatment of asthma, rheumatism and colics of children. It may have the potential to be the basis for a birth control pill for men. Clinical tests are being conducted in Indonesia.
The plant has shown promise as a source of a compound that inhibits an enzyme crucial to the development of HIV.
Justicia gendarussa was proved to contain several phytochemicals, which are natural secondary plant compounds. Overall in the plant, roots, stem and leaves, following phytochemicals were found: alkaloids, flavonoids, tannins and phenols. The ingredients of the plant may vary depending on the age, physiological stage of the organ parts or the geographic region of cultivation.
The plant was proved to have both anti-microbial and anti-fungal action on selected pathogen strains, and therefore this plant can be used to develop herbal drugs.
Justicia gendarussa leaf extract was proven to potentially become a male, non-hormonally contraceptive method due to its competitive and reversible inhibition of the spermatozoan hyaluronidase enzyme. The plant is already used as traditional contraceptive method in Indonesia.
The plant compound Patentiflorin A contained in Justicia gendarussa has shown to have a positive activity against several HIV strains, higher than the clinically used first anti-HIV drug, zidovudine AZT.
Further, extracts of the leaves have an anti-inflammatory effect. This has been demonstrated especially in mice, specific for the carrageenan-induced paw edema.
The juice of the leaves can be drizzled into the ear for earache. To treat external edema, an oil made from the leaves can be used.

## Mast cells

"Mast cells can recognize pathogens through different mechanisms including direct binding of pathogens or their components to PAMP receptors on the mast cell surface, binding of antibody or complement-coated bacteria to complement or immunoglobulin receptors, or recognition of endogenous peptides produced by infected or injured cells (Hofmann and Abraham 2009). The pattern of expression of these receptors varies considerably among different mast cell subtypes. TLRs (1–7 and 9), NLRs, RLRs, and receptors for complement are accountable for most mast cell innate responses."
"The contents of mast cells, along with those of basophils, are responsible for the symptoms of allergy."
"Allergies such as pollen allergy are related to the antibody known as IgE. Like other antibodies, each IgE antibody is specific; one acts against oak pollen, another against ragweed."
"Two types of degranulation have been described for MC: piecemeal degranulation (PMD) and anaphylactic degranulation (AND) (Figures 1 and 2). Both PMD and AND occur in vivo, ex vivo, and in vitro in MC in human (78–82), mouse (83), and rat (84). PMD is selective release of portions of the granule contents, without granule-to-granule and/or granule-to-plasma membrane fusions. ... In contrast to PMD, AND is the explosive release of granule contents or entire granules to the outside of cells after granule-to-granule and/or granule-to-plasma membrane fusions (Figures 1 and 2). Ultrastructural studies show that AND starts with granule swelling and matrix alteration after appropriate stimulation (e.g., FcεRI-crosslinking)."
When activated, a mast cell can either selectively release (piecemeal degranulation) or rapidly release (anaphylactic degranulation) "mediators", or compounds that induce inflammation, from storage granules into the local microenvironment. Mast cells can be stimulated to degranulate by allergens through cross-linking with immunoglobulin E receptors (e.g., FcεRI), physical injury through pattern recognition receptors for damage-associated molecular patterns (DAMPs), microbial pathogens through pattern recognition receptors for pathogen-associated molecular patterns (PAMPs), and various compounds through their associated G-protein coupled receptors (e.g., morphine through opioid receptors) or ligand-gated ion channels. Complement proteins can activate membrane receptors on mast cells to exert various functions as well.
Membrane activation events can either prime mast cells for subsequent degranulation or act in synergy with FcεRI signal transduction. Although this reaction is most well understood in terms of allergy, it appears to have evolved as a defense system against parasites and bacteria.
A unique, stimulus-specific set of mast cell mediators is released through degranulation following the activation of cell surface receptors on mast cells.
"P2X receptors are ligand-gated non-selective cation channels that are activated by extracellular ATP. ... Increased local ATP concentrations are likely to be present around mast cells in inflamed tissues due to its release through cell injury or death and platelet activation [40]. Furthermore, mast cells themselves store ATP within secretory granules, which is released upon activation [41]. There is therefore the potential for significant Ca2+ influx into mast cells through P2X receptors. Members of the P2X family differ in both the ATP concentration they require for activation and the degree to which they desensitise following agonist activation [37, 38]. This opens up the possibility that by expressing a number of different P2X receptors mast cells may be able to tailor their response to ATP in a concentration dependent manner [37]."
Examples of mediators that are released into the extracellular environment during mast cell degranulation include:
* serine proteases, such as tryptase and chymase
* histamine (2–5 picograms per mast cell)
* serotonin
* proteoglycans, mainly heparin (active as anticoagulant) and some chondroitin sulfate proteoglycans
* adenosine triphosphate (ATP)
* lysosomal enzymes
** β-hexosaminidase
** β-glucuronidase
** arylsulfatases
* newly formed lipid mediators (eicosanoids):
** thromboxane
** prostaglandin D2
** leukotriene C4
** platelet-activating factor
* cytokines
** TNF-α
** basic fibroblast growth factor
** interleukin-4
** stem cell factor
** chemokines, such as eosinophil chemotactic factor
* reactive oxygen species.
The bump and redness immediately following a mosquito bite are a good example of this reaction, which occurs seconds after challenge of the mast cell by an allergen.

## Olive oils

"Several in vitro and in vivo studies have examined the anti-inflammatory properties of olive oil and its [antioxidant phenolic compounds] p0c (Perona et al., 2006). LDL enriched in oleic acid promote less monocyte chemotaxis, compared with linoleic acid-enriched LDL, when exposed to oxidation (Tsimikas et al., 1999). Esposito et al. (2004) found a reduction in the inflammatory markers after a 2-year follow-up of patients with metabolic syndrome consuming a Mediterranean-type diet. In a recent report, from a randomized and controlled study with 772 participants at high risk for CHD, a reduction in inflammatory markers was observed after 3 months of a Mediterranean diet consumption, versus a low fat diet (Estruch et al., 2006)."
"In conclusion, consumption of [virgin olive oil] VOO during 3 weeks led to a decrease of IL6 and [C-reactive protein] CRP higher than that observed after [refined olive oil] ROO consumption, in patients with stable [coronary heart disease] CHD. Further studies are needed to establish the protective role of VOO on the inflammatory status in humans."

## Proanthocyanidins

Proanthocyanidins, including the lesser bioactive and bioavailable polymers (four or more catechins) represent a group of condensed flavan-3-ols, such as procyanidins, prodelphinidins and propelargonidins, that can be found in many plants, most notably apples, maritime pine bark and that of most other pine species, cinnamon, aronia fruit, cocoa beans, grape seed, grape skin (procyanidins and prodelphinidins). Cocoa beans contain the highest concentrations.
Proanthocyanidins also may be isolated from Quercus petraea and Quercus robur heartwood (wine barrel oaks). Açaí oil, obtained from the fruit of the açaí palm (Euterpe oleracea), is rich in numerous procyanidin oligomers.
Apples contain on average per serving about eight times the amount of proanthocyanidin found in wine, with some of the highest amounts found in the Red Delicious and Granny Smith varieties.
An extract of maritime pine bark called Pycnogenol bears 65-75 percent proanthocyanidins (procyanidins).
Proanthocyanidin glycosides can be isolated from cocoa liquor.
The seed testas of field beans (Vicia faba) contain proanthocyanidins that affect the digestibility in piglets and could have an inhibitory activity on enzymes. Cistus salviifolius also contains oligomeric proanthocyanidins.

## Protuberances

Def. a "bulge, knob, swelling, [spine] or anything that protrudes" is called a protuberance.
Def. a "bulge or protuberance" is called a swell or swelling.

## Prunus cerasus

Family: Rosaceae.
Prunus cerasus (sour cherry, tart cherry, or dwarf cherry) a species of Prunus in the subgenus Prunus subg. Cerasus (cherries), native to much of Europe and southwest Asia is closely related to the sweet cherry (Prunus avium), but has a fruit that is more acidic. Its sour pulp is edible.
There are two main varieties (groups of cultivars) of the sour cherry: the dark-red Morello cherry and the lighter-red Amarelle cherry.
"Fruits of sour cherry (P cerasus L) cv Amarena Mattarello (AM), Visciola Ninno (VN), and Visciola Sannicandro (VS) (genotypes from the local germplasm) were picked up in June 2003 on a local experimental field (Bari, Italy)."
Anthocyanins: "Cyanidin 3-glucosylrutinoside, cyanidin 3-sophoroside, cyanidin 3-rutinoside, and cyanidin 3-glucoside were identified as major components in the analyzed samples in agreement with the findings previously reported in the literature [4]."
The "in vivo antioxidant efficacy (superoxide dismutase, SOD; catalase, CAT; glutathione peroxidase; Gpx, lipid peroxidation (LPO) and anti-inflammatory properties (cyclooxygenase-2; COX-2) of sour cherry juices [was] obtained from an autochthonous cultivar (Prunus cerasus cv. Maraska) that is grown in coastal parts of Croatia. Antioxidant potential was tested in mouse tissue (blood, liver, and brain), LPO (liver, brain) and anti-inflammatory properties in glycogen elicited macrophages. Additionally, the concentration of cyanidin-3-glucoside, cyanidin-3-rutinoside, pelargonidin-3-glucoside, pelargonidin-3-rutinoside and total anthocyanins present in Prunus cerasus cv. Maraska cherry juice was determined."
"In various pathologies (atherosclerosis, apoptosis, ageing, diabetes), cell oxygen radical-related damage can be protected by the antioxidant potential of anthocyanins [5, 6]. Early studies revealed that anthocyanins are related to the quality index of sour cherries and found that sour cherry extracts reduce inflammation, paw edema, alleviate the pain of gout and arthritis [7, 8]."
"Prunus cerasus (P. cerasus) is an alternative-medicine used traditionally for amelioration of chronic-ailments marked by elevation in oxidative-stress like neuropathy. The oxidative-stress control was reported to ameliorate the inflammatory-process."
"[C]yanidin-3-glucoside (Cy3G) was the most-active constituent in [Prunus cerasus fruit], while linoleic-acid (LA) was the most-active constituent in [Prunus cerasus seeds]."
"[Prunus cerasus fruit], [Prunus cerasus seeds], Cy3G, and LA have shown significant anti-inflammatory and antinociceptive potentials against carrageenan induced-edema and nociceptive-pain, respectively".
"P. cerasus has shown potent gastro-protective, antinociceptive, and anti-inflammatory effects, utilizing a potential decline of the pro-inflammatory TNF-alpha and IL-6, and the elevation of the anti-inflammatory factor IL-10 levels, spleen-regenerative and anti-oxidative stress ameliorative mechanism."

## Quercetins

Quercetin is a plant flavonol from the flavonoid group of polyphenols found in many fruits, vegetables, leaves, seeds, and grains; red onions and kale are common foods containing appreciable amounts of quercetin.
Quercetin is a flavonoid widely distributed in nature. The name has been used since 1857, and is derived from quercetum (oak forest), after the oak genus Quercus. It is a naturally occurring polar auxin transport inhibitor.
Quercetin is one of the most abundant dietary flavonoids, with an average daily consumption of 25–50 milligrams.
| Foods | Quercetin (mg/100g) |
| capers, raw | 234 |
| capers, canned | 173 |
| lovage leaves, raw | 170 |
| buckwheat seeds | 90 |
| rumex (dock) like sorrel | 86 |
| radish leaves | 70 |
| carob fiber | 58 |
| dill | 55 |
| cilantro | 53 |
| Hungarian wax pepper | 51 |
| fennel leaves | 49 |
| red onion | 32 |
| radicchio | 32 |
| watercress | 30 |
| kale | 23 |
| chokeberry | 19 |
| Vaccinium uliginosum (bog blueberry) | 18 |
| cranberry | 15 |
| lingonberry | 13 |
| black plums | 12 |
In red onions, higher concentrations of quercetin occur in the outermost rings and in the part closest to the root, the latter being the part of the plant with the highest concentration. One study found that organically grown tomatoes had 79% more quercetin than non-organically grown fruit. Quercetin is present in various kinds of honey from different plant sources.
| Glycosides | Aglycone | Glycone | Plants | Genus species |
| Flavonoid glycosides | Flavonoid | Glycone | Common name | Genus species |
| Rutin | Quercetin | Rutinose | Common rue | Ruta graveolens |
| Quercitrin | Quercetin | Rhamnose | American white oak | Quercus alba |
"Quercetin is a flavonoid that helps to control allergy symptoms of rhinitis and sinusitis. It stabilizes the membranes of mast cells, reducing the release of histamine. It is also helpful in lowering the risk of cataract by inhibiting glycoprotein formation in the lens (Cornish, et al 2002). Typical doses of quercetin are 800 mg to 1200 mg daily."

## Resveratrols

Inflammation induces the the activation of several cell signaling pathways. The exact mechanism of RSV-mediated protection is activation of several cell signaling pathways.
Stilbenoids, such as resveratrol, are hydroxylated derivatives of stilbene. They are formed through an alternative cyclization of cinnamoyl-CoA or 4-coumaroyl-CoA.
A 2018 meta-analysis found no effect of resveratrol on systolic or diastolic blood pressure; a sub-analysis revealed a 2 mmHg decrease in systolic pressure only from resveratrol doses of 300 mg per day, and only in diabetic people. A 2014 Chinese meta-analysis found no effect on systolic or diastolic blood pressure; a sub-analysis found an 11.90 mmHg reduction in systolic blood pressure from resveratrol doses of 150 mg per day.
One review found limited evidence that resveratrol lowered fasting plasma glucose in people with diabetes. Two reviews indicated that resveratrol supplementation may reduce body weight and body mass index, but not fat mass or total blood cholesterol. A 2018 review found that resveratrol supplementation may reduce biomarkers of inflammation, TNF-α and C-reactive protein.
Resveratrol (RSV, 3,4′,5-trihydroxystilbene) "RSV exists as two geometric isomers: cis (Z) and trans (E). The trans-isomer is more abundant and biologically active than the cis-isomer. However, it was already demonstrated that RSV is extremely photosensitive, and 80–90% of the trans-RSV in solution is converted to cis-RSV upon exposure to light for 1 h [82]. Furthermore, the poor water solubility of RSV is another constraint for its biological application."
"Although the oral absorption of RSV by humans is high (approximately 75%) [83,84], its bioavailability is less than 1% due to extensive intestinal and liver metabolism, involving glucuronic acid conjugation and sulfation that generate the key metabolites trans-resveratrol-3-O-glucuronide and trans-resveratrol-3-sulfate, respectively [83,85–87]. Since this polyphenol is known to have poor bioavailability in that it is rapidly metabolized and excreted, only trace concentrations of free RSV can be found in systemic circulation [83,85]. Therefore, the high concentrations of RSV commonly used for in vitro studies may not be physiologically relevant. Furthermore, the results of these studies are not expected to correlate well with those of in vivo studies, thus leading to disappointing outcomes in human clinical trials. Consequently, the successful clinical application of RSV is a severe challenge for the scientific community. To overcome these challenges, efforts were made to develop adequate drug delivery systems to achieve better clinical efficacy. These strategies include various approaches, such as the development of myriad RSV nanoformulations that can improve these inherent biologic limitations of RSV, increase its solubility, and prevent its degradation while preserving its biological activity [88–92]."
"Some studies suggest that the effects of RSV on metabolic syndrome are associated with its ability to mimic caloric restriction, due to increased levels and activity of the protein deacetylase enzyme—silent information regulator 2/sirtuin-1 (SIRT1). SIRT1 plays a central role in the body’s response to diet and exercise [99,100]. In mice fed a high-calorie diet, several studies showed that long-term treatment with RSV improves factors associated with a longer lifespan, including increased insulin sensitivity [31,34–36], and reduced insulin-like growth factor-1 (IGF-1) levels [31]. RSV treatment also leads to increases in the metabolic rate and mitochondrial number, which might be correlated with increases in peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) activity and expression, which control mitochondrial biogenesis in the liver and muscle [31,34]. Additionally, weight loss [34,35,37], reduced fat mass [34], improvements in glucose homeostasis [34,37], and reductions in plasma triglyceride, tumor necrosis factor-alpha (TNF-α), and monocyte chemoattractant protein-1 (MCP-1) levels [37] were observed. In adipose tissues in mice, TNF-α, interferon (IFN)-β, IFN-α, and interleukin (IL)-6 levels were attenuated, as well as their upstream signaling molecules—toll-like receptors 2 and 4 (TLR2/4), myeloid differentiation primary response 88 (MyD88), and the transcription factor, nuclear factor kappa B (NF-κB) [37,38]. These findings were, in part, correlated with increases in AMP-activated protein kinase (AMPK) [31,34,36,38] and SIRT1 activity [35,38,101]. In addition, some clinical studies evaluated the effects of RSV in patients with metabolic syndrome, and achieved promising preliminary results, such as weight reduction [102], improved insulin sensitivity [103,104], and glycemic control [104,105]. However, further research should be conducted to confirm the pharmacological potential of RSV for treating the physiological changes of metabolic syndrome."
"Several in vitro studies revealed the anti-inflammatory effects of RSV in cardiac tissue, as evidenced by the inhibition of intercellular adhesion molecule 1 (ICAM-1), inducible nitric oxide synthase (iNOS), and IL-1β messenger RNA (mRNA) expression in human coronary arterial endothelial cells stimulated by TNF-α and treated with RSV [39]. Notably, it was already demonstrated that RSV inhibits TNF-α- and IL-6-induced increases in monocyte adhesion in primary human coronary arterial endothelial cells, which reduces pro-inflammatory NF-κB levels [40]. Another study showed that RSV decreases the level of eotaxin-1, a chemokine related to eosinophil recruitment, in human pulmonary artery endothelial cells stimulated with TNF-α or IL-13. This reduction was followed by the inhibition of the expression of the pro-inflammatory transcription factors, Janus kinase 1 (JAK1), phosphorylated extracellular signal-regulated kinase (ERK) 1/2, c-Jun N-terminal kinase (JNK), and signal transducer and activator of transcription (STAT) 6, and the reduction of the p65 subunit of NF-κB [109]. It is known that treatment with RSV also suppresses the bacterial lipopolysaccharide (LPS)-induced tissue factor expression in human peripheral blood mononuclear cells, which is the major initiator of the extrinsic blood coagulation pathway that is also involved with intracellular inflammation signaling [110]. Moreover, a study by Planavila and colleagues showed that RSV prevents phenylephrine, a hypertrophic agonist, or LPS-induced increases in MCP-1 levels in neonatal cardiomyocytes, suggesting that this effect is due to the activation of SIRT1 [41]. Csiszar et al. already showed the association between the anti-inflammatory effects of RSV and SIRT1 activation. Importantly, the authors showed that cultured coronary arterial endothelial cells stimulated with cigarette smoke extract, but previously treated with RSV, had decreased NF-κB transcriptional activity and iNOS, ICAM-1, IL-6, IL-1β, and TNF-α expression. Curiously, these effects were significantly attenuated by SIRT1 knockdown [42]."
"Cardiovascular diseases can result in heart failure, a progressive cardiac muscle disorder that leads to the deterioration of heart function, and results in the inability to meet the normal metabolic and energy needs of the body [111]. Some studies investigated the anti-inflammatory effects of RSV on heart failure using various animal models. A previous study showed that oral RSV treatment for 28 days significantly attenuated macrophage and mast-cell infiltration in the left ventricles of C57BL6 mice subjected to pressure overload-induced heart failure, induced by transverse aortic constriction surgery [112]. Furthermore, daily RSV intake for eight weeks resulted in cardioprotective effects against advanced-stage heart failure in rats subcutaneously injected with isoproterenol, a strong sympathetic agent used to induce myocardial infarction. Interestingly, this protective effect was accompanied by a reduction in pro-inflammatory members of the mitogen-activated protein kinase superfamily (p38-MAPK) and ERK1/2, suggesting that the regulation of these pro-inflammatory pathways may contribute to the beneficial effects of RSV in cardiac disorders [43]."
"Cong and co-workers showed that reduced myocardial infarction areas and myocardial myeloperoxidase levels, induced by RSV in a model of myocardial ischemia, were accompanied by decreased TNF-α concentrations in the serum and myocardium. Notably, these effects were abolished when the animals were treated with RSV combined with a nitric oxide (NO) synthase inhibitor and with a cyclic guanosine monophosphate (cGMP) inhibitor, indicating that these pathways are important for the anti-inflammatory activity of RSV [44]. Similarly, the authors showed that RSV also reduces the expression levels of NF-κB and TLR4, a known receptor that triggers innate immune responses; these findings further indicate the anti-inflammatory effects of RSV in protecting against myocardial ischemia [45]. These results are in line with previous work showing that RSV protects cardiomyocytes against anoxia/reoxygenation injury via the TLR4/NF-κB signaling pathway [46]. Hypertension is another factor that may drive the development of heart failure. RSV administration for eight weeks significantly reduced serum TNF-α and IL-6 levels in spontaneously hypertensive rats, but this treatment did not improve blood pressure [114]. These results suggest that combining RSV with blood pressure-lowering agents, which commonly do not affect the inflammatory profile, may provide optimal outcomes for reversing cardiovascular complications in hypertensive patients."
"RSV improved cardiovascular functions in rats injected with streptozotocin, a compound toxic to pancreatic β cells. The improvement was linked to decreased serum levels of inflammatory factors, such as TNF-α, IL-1β, and IL-6, and the inhibition of vascular endothelial growth factor (VEGF), and the suppression of the p38-MAPK and NF-κB pathways [47]. Similarly, 12 weeks of RSV treatment reduced the circulating levels of TNF-α, IL-1β, and IL-6, and decreased the activation of the inflammatory factors angiotensin type 1 receptor (AT1R), ERK1/2, and p38-MAPK in rat hearts [48]. Furthermore, by treating mice with RSV for two months, Wu and co-workers found reduced serum, heart, and bone marrow-derived monocyte levels of high mobility group box 1 (HMGB-1), a pro-inflammatory cytokine that exerts its effects via binding to receptor for advanced glycation end products (RAGE) and toll-like receptors [116]. In line with these results, Delucchi and collaborators reported decreased HMGB-1 expression in left ventricular myocardial tissue in rats injected with streptozotocin and receiving a low dose of RSV [117]."
"Atherosclerosis is another coronary heart disease associated mainly with metabolic derangements, and the development of new therapies for this disorder is needed. This chronic disease is associated with arterial inflammation, lipid accumulation in the vessel wall, plaque formation, thrombosis, and late mortal complications, such as myocardial infarction and ischemic stroke [118]. Inflammatory responses play a crucial role in all phases of atherosclerotic development and progression, so the anti-inflammatory activity of RSV could be an interesting alternative for the control of the disease. In cultured THP-1-derived macrophages stimulated with LPS, pretreatment with RSV suppressed the formation of foam cells, which are considered to initiate atherosclerosis; in addition, the MCP-1 concentrations were reduced, and the expressions of SIRT1 and AMPK, a factor that is involved in glucose and lipid metabolism, and inhibits inflammation, were upregulated [49]. In a hyperlipidemia animal model in which rats were fed a cholesterol-enriched diet combined with vitamin D2, RSV treatment decreased the serum levels of IL-1β. Additionally, reduced MCP-1, ICAM-1, p65 NF-κB, and p38-MAPK mRNA and protein expression levels were found in the thoracic aortas of hypercholesterolemic rats treated with RSV, as well as decreased inflammasome nucleotide binding and domain-like receptor 3 (NLRP3) oligomerization. These effects were followed by the upregulation of SIRT1 mRNA and protein expression [50]. Interestingly, Chang and colleagues previously demonstrated that RSV reduces inflammatory markers, such as aortic macrophage infiltration and NF-κB expression, in an atherosclerosis model in which apolipoprotein E-deficient mice were fed a high-cholesterol diet [51]. Furthermore, an elegant study conducted by Cabo and co-workers showed that RSV prevented high fat and sucrose diet-induced arterial wall inflammation, and the accompanying increase in aortic pulse wave velocity in nonhuman primates [119]."
"RSV, as mentioned above, is widely known for its antioxidant and anti-inflammatory effects. Growing evidence indicates that RSV plays a protective role in respiratory diseases, which was already demonstrated in preclinical models of important respiratory conditions, such as chronic obstructive pulmonary disease (COPD), allergic inflammation (asthma models), and acute respiratory distress syndrome (ARDS)."
"RSV further alleviates the inflammation and reconstruction of small airways in the lungs by upregulating SIRT1 and PGC-1α expression [54]. In line with in vitro data, RSV treatment increases the activity of superoxide dismutase (SOD), GSH peroxidase, and catalase (CAT), as well as preventing the translocation of NF-κB to the nucleus and its binding activity [55]."
"Asthma is a heterogeneous clinical syndrome that mainly affects the lower respiratory tract; it is characterized by chronic inflammation, bronchoconstriction, increased airway hyperresponsiveness (AHR), and mucus production [128,129]. Current therapy consists of the combined use of short-acting β2 agonists and inhaled corticosteroids, as well as avoiding aggravating environmental factors [128]. In vivo studies over the past few years showed that RSV can effectively control asthma in murine models. RSV has anti-inflammatory effects by suppressing AHR [56,57,130,131], and reducing the infiltration of inflammatory cells, mainly eosinophils, into bronchoalveolar lavage fluid (BALF) [130] and lung tissue [56–58]. Total immunoglobulin E (IgE) and ovalbumin (OVA)-specific IgE levels were diminished in an OVA-induced asthma model, and reductions in IL-4, IL-5 [56,130], TNF-α [132,133], and TGF-β1 [57] cytokine levels were found. TGF-β1 and TGF-β1/phosphorylated Smad2/3 receptor expression levels in lung tissues were also significantly decreased with RSV treatment [57,131]. In addition to the anti-inflammatory effects, using RSV to treat asthma significantly downregulated oxidative stress by decreasing 8-isoprostane levels (an in vivo marker of oxidative stress) [56], reducing reactive oxygen species (ROS) production, and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase cytosolic subunit p47phox expression, and enhancing SOD levels [133] and mitochondrial function [56]. Concerning airway remodeling, RSV attenuated the fibrotic response, and reduced sub-epithelial collagen deposition [131] and mucus hypersecretion [130]; RSV reduced mucus hypersecretion via inhibiting Mucin 5AC (Muc5AC), a major component of mucus [59]. The molecular mechanisms underlying the improvement of asthma include the increased lung expression levels of phosphatase and tensin homolog (PTEN) [58] and inositol polyphosphate 4 phosphatase (INPP4A), which are related to reduced protein kinase B (PKB/Akt) phosphorylation and activity [56]. It was also reported that RSV inhibits degranulation in mast cells and the protein expression of spleen tyrosine kinase (Syk), which plays an essential role in immune cell activation and lymphocyte development."[132]
"A range of protocols to induce acute lung inflammation were used to demonstrate the beneficial activity of RSV in protecting against lung damage, and reducing inflammation through several possible molecular mechanisms. Similar data showed that RSV treatment improves structural changes in the lungs [60,136–139], decreases pulmonary edema [137–139], improves lung function [137], and diminishes neutrophil infiltration [134,137,138] and myeloperoxidase protein expression and activity in lung tissue [60,61]. Regarding cytokines, RSV significantly modulates IL-1β [60,139], IL-18 [60] IL-6, COX-2 [138], and macrophage inflammatory protein (MIP)-1α [139] in BALF and systemic TNF-α [61]. Its antioxidant effects are evidenced by reduced oxidative stress, including decreases in the pro-oxidant biomarker malondialdehyde (MDA) and hydrogen peroxide levels, increases in antioxidant biomarkers (GSH, CAT, and SOD activity) [136,140], and the inhibition of iNOS expression, ROS and NO production [60,139], and peroxynitrite formation [136]. These effects of RSV found in the ARDS model are associated with the downregulation of NLRP3 inflammasome activation through blocking NF-kB p65 nuclear translocation and its DNA-binding activity [60,138,139,141]. Moreover, the TLR4/Myd88 [138] and p38-MAPK [61,141] pathways are significantly downregulated by RSV."
"RSV was found to reduce LPS-induced NO and TNF-α production in primary microglia [158], prevent LPS-induced microglial BV-2 cell activation [62], inhibit PGE2 and free radical production by rat primary microglia [159], and differentially modulate microglia and astrocyte inflammatory responses [160]. In addition, several studies used the N9 microglial cell line to indicate that RSV attenuated the LPS-induced phosphorylation of p38-MAPK and the degradation of inhibitor of κB (IκB), thus reducing the production of NO and TNF-α [158,161]. Furthermore, it was shown that RSV can prevent apoptosis in dopamine-producing neurons by inhibiting the production of microglia-derived TNF-α and IL-1β [162], and RSV can suppress IL-6 gene expression and protein secretion in mixed glial cultures under hypoxia/hypoglycemia conditions [163]."
"Attenuating neuroinflammation is a therapeutic strategy for treating ischemic stroke, and several in vivo studies showed that RSV effectively reduces the increased expression of pro-inflammatory cytokines, inhibits NF-κB, reduces the phosphorylation of p38-MAPK and JNK activation via decreased COX-2 and iNOS expression, and inhibits astroglial and microglial activation induced by ischemia/reperfusion [164–168]. These findings suggest that the suppression of inflammation is associated with the neuroprotective effects of RSV, and RSV could be a promising candidate for stroke treatment."
"Once microglia were shown to have functional plasticity and dual pro-inflammatory M1 and anti-inflammatory M2 phenotypes, Yang and collaborators reported that RSV suppressed microglia activation by promoting polarization toward the M2 phenotype via PGC-1α overexpression [63]. The increased M2 marker expression induced by RSV was accompanied by coactivation of the STAT6 and STAT3 pathways, and linked to the inhibition of NF-κB. The notion that RSV promotes PGC-1α expression could lead to the application of this polyphenol for PD therapy, as it was already demonstrated that PGC-1α expression and activation protect dopaminergic neurons in an MPTP mouse model of PD [64]. Interestingly, Jin and collaborators previously found that RSV decreased COX-2 and TNF-α levels in the substantia nigra of rats with 6-hydroxydopamine (6-OHDA)-induced PD [65]; however, thorough studies showing the mechanisms involved in the anti-inflammatory effects of RSV in PD are missing."
"Our previous study suggests that the chronic administration of RSV blocked cognitive impairment in an animal model of AD, and this effect seemed to be related to the inhibition of synaptic dysfunction, and microglial and astroglial activation triggered by Aβ [67]. In addition, RSV treatment modulated important cell signaling pathways, such as the JNK, GSK-3β, and β-catenin pathways, which might be involved in neuroinflammation, cell metabolism, and survival. Importantly, the administration of RSV in a mouse model of cerebral amyloid deposition decreased the microglia activation associated with amyloid plaque formation [62,180]. Although a mechanistic link between inhibited microglia activation and the anti-inflammatory effects of RSV was not described in these studies, it is already known that microglial-derived cytokines enhance amyloid precursor protein (APP) processing, induce tau phosphorylation, and contribute to synapse plasticity impairment in neurons [174]. Altogether, these observations are consistent with the idea that RSV can modulate several signaling pathways involved in neuroinflammation."
"Another outstanding effect of RSV against cancer promotion and progression is related to the control of the expression of microRNAs (miRNAs), mainly those at the crossroads of inflammation, cell differentiation, and homeostasis. For instance, RSV activity appears to be partially dependent on the impaired expression of miR-663, miR-21, and miR-155, which are linked to tumor suppression, oncogenicity, and pro-inflammatory effects, respectively. Modulation of these miRNAs by RSV led to decreased secretion of pro-inflammatory cytokines IL-6, IL-8, and TNF-α, reduced expression of adhesion proteins, such as ICAM-1, and leukocyte chemoattractants, and increased production of anti-inflammatory cytokines [211]."

## Sambucus peruviana

Family: Adoxaceae.
The leaves, flowers and fruits have medicinal properties; analgesic, anti-inflammatory, antiseptic, sudorific.

## Scutellaria baicalensis

Family: Lamiaceae.
The main compounds responsible for the biological activity of skullcap are flavonoids. Baicalein, one of the important Scutellaria flavonoids, was shown to have cardiovascular effects in in vitro. Research also shows that Scutellaria root modulates inflammatory activity in vitro to inhibit nitric oxide (NO), cytokine, chemokine and growth factor production in macrophages. Isolated chemical compounds including wogonin, wogonoside, and 3,5,7,2',6'-pentahydroxyl flavanone found in Scutellaria have been shown to inhibit histamine and leukotriene release. Other active constituents include baicalin, apigenin, oroxylin A, scutellarein, and skullcapflavone.
A variety of flavonoids in Scutellaria species have been found to bind to the benzodiazepine site and/or a non-benzodiazepine site of the GABA$_A$ receptor, including baicalin, baicalein, wogonin, apigenin, oroxylin A, scutellarein, and skullcapflavone II. Baicalin and baicalein, wogonin, and apigenin have been confirmed to act as positive allosteric modulators and produce anxiolytic effects in animals, whereas oroxylin A acts as a negative allosteric modulator (and also, notably, as a dopamine reuptake inhibitor). As such, these compounds and actions, save oroxylin A, are likely to underlie the anxiolytic effects of Scutellaria species.
Scutellaria also contains rosmarinic acid which inhibits GABA transaminase which breaks GABA down, thus making it available longer.

## Stachys sieboldii

Family: Lamiaceae.
Stachys affinis, commonly called crosne, Chinese artichoke, Japanese artichoke, knotroot, or artichoke betony, is a perennial herbaceous plant of the family Lamiaceae, originating from China, with rhizomes that are a root vegetable that can be eaten raw, pickled, dried or cooked, where Stachys sieboldii is a synonym.
Vacuoles in the tuber of S. affinis are rich in stachyose. Stachyose is a tetrasaccharide, consist out of galactose, glucose and fructose. Stachyose is up to 80-90% in dry tubers.
The entirety of S. affinis is used as an agent to treat colds and pneumonia.
Root extract of S. affinis has shown antimicrobial activity. Antioxidant activity has been observed, plus inhibitory effects on acetylcholine esterase, monoamine oxidase and xanthine oxidase activities were observed in rat brains after 20 days feeding with methanolic extracts of S. affinis. Ethanol extract from this plant also seems to have antitumour activity.
"Japanese artichoke [...] contain germacrene D, caryophyllene, cadinene. [...] methanolic tuber extract of Japanese artichoke, which contains glycosides, including acteoside and stachysosides C, significantly inhibits induced mortality from potassium cyanide poisoning in mice [19]. This extract inhibits hyaluronidase activity, has anti-inflammatory action, and is effective in kidney disease [15]."
The "methanol extract from the leaves and root tubers and ethanol extract from the root tubers of Stachys sieboldii have a pronounced antibacterial effect on the culture of Salmonella typhimurium. In addition, methanol extract from the leaves of Stachys sieboldii showed a significant antibacterial effect on the culture of Bacillus cereus. It is believed that the antibacterial effect of Japanese artichoke is associated with the total content of polyphenols and flavonoids contained in the plant and which are extracted with methanol and ethanol [20]."

## Theobroma cacao

Family: Malvaceae.
Cocoa contains various phytochemicals, such as flavanols (including epicatechin), procyanidins, and other flavanoids. A systematic review presented moderate evidence that the use of flavanol-rich chocolate and cocoa products causes a small (2 mmHg) blood pressure lowering effect in healthy adults—mostly in the short term.
The highest levels of cocoa flavanols are found in raw cocoa and to a lesser extent, dark chocolate, since flavonoids degrade during cooking used to make chocolate. Cocoa also contains the stimulant compounds theobromine and caffeine. The beans contain between 0.1% and 0.7% caffeine, whereas dry coffee beans are about 1.2% caffeine.
"Cocoa is rich in polyphenols that have beneficial effects on cardiovascular disease.22 In cocoa, the polyphenols of particular interest are flavanols, a subclass of flavonoids, which are in turn a subclass of polyphenols. Cocoa is more than 10% flavanol by weight. Flavanols can be monomeric: in cocoa beans these are mainly (−)-epicatechin and (+)-catechin, dimeric (consisting of 2 units of epicatechin with differing linkages), or polymeric (combinations of monomers and chains of up to 10 units or more have been found). These polymers are known as procyanidins.1, 7, 16, 23, 24, 25, 26, 27, 28, 29, 30"

## Urticaria

Def. "[i]tchy, swollen, red areas of the skin which [can] appear [quickly] suddenly in response to [an] allergen [or due to other conditions]" is called urticaria.

## Veratrum grandiflorum

Veratrum is a genus of flowering plants in the family Melanthiaceae. It occurs in damp habitats across much of temperate and subarctic Europe, Asia, and North America.
Veratrum species are vigorous herbaceous perennials with highly poisonous black rhizomes, and panicles of white or brown flowers on erect stems. In English they are known as both false hellebores and corn lilies. However, Veratrum is not closely related to hellebores, corn, or lilies.
"First isolated from Veratrum grandiflorum by Takaoka in the 1940s [19], [resveratrol (RSV, 3,4′,5-trihydroxystilbene)] RSV is found in food sources such as fruits, vegetables, and chocolate, and is better known as a constituent of grapes and wines, although it is present in only minimal quantities [18,20]. Due to its presence in wine, RSV attracted attention in the early 1990s to explain "the French paradox", which suggested that people from France had a lower incidence of cardiovascular disease despite their high intake of saturated fats, presumably as a result of moderate red wine consumption [21]."

## Vitamin D$_3$

Cholecalciferol, also known as vitamin D$_3$ and colecalciferol, is a type of vitamin D which is made by the skin when exposed to sunlight; it is also found in some foods and can be taken as a dietary supplement.
Cholecalciferol is made in the skin following UVB light exposure. It is converted in the liver to calcifediol (25-hydroxyvitamin D) which is then converted in the kidney to calcitriol (1,25-dihydroxyvitamin D). One of its actions is to increase the uptake of calcium by the intestines. It is found in food such as some fish, beef liver, eggs, and cheese. Certain foods such as milk, fruit juice, yogurt, and margarine also may have cholecalciferol added to them in some countries including the United States.
Cholecalciferol can be taken as an oral dietary supplement to prevent vitamin D deficiency or as a medication to treat associated diseases, including rickets. It is also used for familial hypophosphatemia, hypoparathyroidism that is causing low blood calcium, and Fanconi syndrome. Vitamin-D supplements may not be effective in people with severe kidney disease. Excessive doses in humans can result in vomiting, constipation, weakness, and confusion. Other risks include kidney stones. Doses greater than 40,000 International unit (IU) (1,000 μg) per day are generally required before high blood calcium occurs. Normal doses, 800–2000 IU per day, are safe in pregnancy.
"Non-classic actions of vitamin D are being increasingly recognized because of the ubiquitous expression of the [vitamin D receptor] VDR in various organs and systems, including hematopoietic cells, such as neutrophils, monocytes, dendritic cells, and lymphocytes (3,6). Vitamin D modulates the immune response through the inactivation of the NF-κB pathway, reducing inflammation and immune cell activation (5,19). Some studies have reported that vitamin D supplementation may increase the 25(OH)-vitamin D levels and reduce the serum levels of inflammatory cytokines, such as interleukin 6 (IL-6), tumor necrosis factor (TNF-α), and MCP-1, in both pre-dialysis and hemodialysis patients (20,21)."

## Weals

Def. "a raised longitudinal wound usually purple on the surface of flesh caused by stroke of rod or whip" is called a weal.

## Welts

Def. "[a ridge or lump on the skin, as] a raised mark on the body caused by a blow" is called a welt.

## Wheals

Def. "a small raised swelling on the skin, often itchy, caused by a blow from a whip or an insect bite etc" or an "elevation of the surface of the skin that is formed rapidly" is called a wheal.

## Hypotheses

* Polyphenols occurred in plants and other life forms since the beginning of life.