# Remedy/Edema

Def. an "excessive accumulation of serum, a watery fluid from animal tissue, especially one that moistens the surface of serous membranes or that is exuded by such membranes when they become inflamed, such as in edema or a blister, a fluid or discharge that is pale yellow and transparent, usually representing something of a benign nature, in tissue spaces or a body cavity or a similar swelling caused by excessive accumulation of water" is called an edema.

## Human genes

* Gene ID: 240 ALOX5 arachidonate 5-lipoxygenase, 10q11.21: "This gene encodes a member of the lipoxygenase gene family and plays a dual role in the synthesis of leukotrienes from arachidonic acid. The encoded protein, which is expressed specifically in bone marrow-derived cells, catalyzes the conversion of arachidonic acid to 5(S)-hydroperoxy-6-trans-8,11,14-cis-eicosatetraenoic acid, and further to the allylic epoxide 5(S)-trans-7,9-trans-11,14-cis-eicosatetrenoic acid (leukotriene A4). Leukotrienes are important mediators of a number of inflammatory and allergic conditions. Mutations in the promoter region of this gene lead to a diminished response to antileukotriene drugs used in the treatment of asthma and may also be associated with atherosclerosis and several cancers. Alternatively spliced transcript variants encoding different isoforms have been found for this gene."
* Gene ID: 7422 VEGFA vascular endothelial growth factor A, 6p21.1: "This gene is a member of the PDGF/VEGF growth factor family. It encodes a heparin-binding protein, which exists as a disulfide-linked homodimer. This growth factor induces proliferation and migration of vascular endothelial cells, and is essential for both physiological and pathological angiogenesis. Disruption of this gene in mice resulted in abnormal embryonic blood vessel formation. This gene is upregulated in many known tumors and its expression is correlated with tumor stage and progression. Elevated levels of this protein are found in patients with POEMS syndrome, also known as Crow-Fukase syndrome. Allelic variants of this gene have been associated with microvascular complications of diabetes 1 (MVCD1) and atherosclerosis. Alternatively spliced transcript variants encoding different isoforms have been described. There is also evidence for alternative translation initiation from upstream non-AUG (CUG) codons resulting in additional isoforms. A recent study showed that a C-terminally extended isoform is produced by use of an alternative in-frame translation termination codon via a stop codon readthrough mechanism, and that this isoform is antiangiogenic. Expression of some isoforms derived from the AUG start codon is regulated by a small upstream open reading frame, which is located within an internal ribosome entry site. The levels of VEGF are increased during infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), thus promoting inflammation by facilitating recruitment of inflammatory cells, and by increasing the level of angiopoietin II (Ang II), one of two products of the SARS-CoV-2 binding target, angiotensin-converting enzyme 2 (ACE2). In turn, Ang II facilitates the elevation of VEGF, thus forming a vicious cycle in the release of inflammatory cytokines."
* Gene ID: 56262 LRRC8A leucine rich repeat containing 8 VRAC subunit A, 9q34.11, aka swelling protein 1, 9q34.11. "This gene encodes a protein belonging to the leucine-rich repeat family of proteins, which are involved in diverse biological processes, including cell adhesion, cellular trafficking, and hormone-receptor interactions. This family member is a putative four-pass transmembrane protein that plays a role in B cell development. Defects in this gene cause autosomal dominant non-Bruton type agammaglobulinemia, an immunodeficiency disease resulting from defects in B cell maturation. Multiple alternatively spliced transcript variants, which encode the same protein, have been identified for this gene."

## Angioedema

Angioedema is an area of swelling (edema) of the dermis (lower layer of skin) and subcutaneous tissue (tissue just under the skin) or mucous membranes. The swelling may occur in the face, tongue, larynx, abdomen, or arms and legs. Often it is associated with hives, which are swelling within the upper skin. Onset is typically over minutes to hours.

## Allergy

The underlying mechanism typically involves histamine. The version related to histamine is due to an allergic reaction to agents such as insect bites, foods, or medications.

## 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 idiopathy (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.

## Treatments

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 cyclosporin may be used.
Histamine-related angioedema can be treated with antihistamines, corticosteroids, and epinephrine.
Consumption of foods that are themselves vasodilators, such as alcoholic beverages or cinnamon, can increase the probability of an angioedema episode in susceptible patients. If the episode occurs at all after the consumption of these foods, its onset may be delayed overnight or by some hours, making the correlation with their consumption somewhat difficult. In contrast, consumption of bromelain in combination with turmeric may be beneficial in reducing symptoms.
In allergic angioedema, avoidance of the allergen and use of antihistamines may prevent future attacks. Cetirizine is a commonly prescribed antihistamine for angioedema. Some patients have reported success with the combination of a nightly low dose of cetirizine to moderate the frequency and severity of attacks, followed by a much higher dose when an attack does appear. Severe angioedema cases may require desensitization to the putative allergen, as mortality can occur. Chronic cases require glucocorticoid or steroid therapy, which generally leads to a good response. In cases where allergic attack is progressing towards airway obstruction, epinephrine may be life-saving.

## Antihistamines

Non-sedating antihistamines that block histamine H1 receptors are the first line of therapy. First-generation antihistamines, such as diphenhydramine or hydroxyzine, block both brain and peripheral H1 receptors, and cause sedation. Second-generation antihistamines, such as loratadine, cetirizine or desloratadine, selectively antagonize peripheral H1 receptors, and are less sedating, less anticholinergic, and generally preferred over the first-generation antihistamines. Fexofenadine, a new-generation antihistamine that blocks histamine H1 receptors, may be less sedating than some second-generation antihistamines.
People who do not respond to the maximum dose of H1 antihistamines may benefit from increasing the dose, then to switching to another non-sedating antihistamine, then to adding a leukotriene antagonist, then to using an older antihistamine, then to using systemic steroids and finally to using cyclosporin or omalizumab.
H2-receptor antagonists are sometimes used in addition to H1-antagonists to treat urticaria, but there is limited evidence for their efficacy.

## Phytochemical treatments
### Arachidonate 5-lipoxygenase inhibitors

Arachidonate 5-lipoxygenase inhibitors are compounds that slow or stop the action of the arachidonate 5-lipoxygenase (5-lipoxygenase or 5-LOX) enzyme, which is responsible for the production of inflammatory leukotrienes. The overproduction of leukotrienes is a major cause of inflammation in asthma, allergic rhinitis, and osteoarthritis.
Examples of 5-LOX inhibitors include the pharmaceutical drugs meclofenamate sodium, zileuton and the natural products myxochelins/pseudochelin as well as nordihydroguaiaretic acid (NDGA).
"Zileuton is a specific inhibitor of 5-lipoxygenase and thus inhibits leukotriene (LTB4, LTC4, LTD4, and LTE4) formation. Both the (R)-(+)- and (S)-(-)-enantiomers are pharmacologically active as 5-lipoxygenase inhibitors in in vitro systems. Leukotrienes are substances that induce numerous biological effects including augmentation of neutrophil and eosinophil migration, neutrophil and monocyte aggregation, leukocyte adhesion, increased capillary permeability, and smooth muscle contraction. These effects contribute to inflammation, edema, mucus secretion, and bronchoconstriction in the airways of asthmatic patients. Sulfido-peptide leukotrienes (LTC4, LTD4, LTE4, also known as the slow-releasing substances of anaphylaxis) and LTB4, a chemoattractant for neutrophils and eosinophils, can be measured in a number of biological fluids including bronchoalveolar lavage fluid (BALF) from asthmatic patients."
Some chemicals found in trace amounts in food, as well as some dietary supplements, have been shown to inhibit 5-LOX; these include baicalein, caffeic acid, curcumin, hyperforin and St John's wort.
"These researches are according to an investigation of the effect of H. perforatum on the NF-κB inflammation factor, conducted by Bork et al. (1999), in which hyperforin provided a potent inhibition of TNFα-induced activation of NF-κB [58]. Another important activity for hyperforin is a dual inhibitor of cyclooxygenase-1 and 5-lipoxygenase [59]. Moreover, this species attenuated the expression of iNOS in periodontal tissue, which may contribute to the attenuation of the formation of nitrotyrosine, an indication of nitrosative stress [26]. In this context, a combination of several active constituents of Hypericum species is the carrier of their anti-inflammatory activity."
"Anti-inflammatory mechanisms of hyperforin have been described as inhibition of cyclooxygenase-1 (but not COX-2) and 5-lipoxygenase at low concentrations of 0.3 μmol/L and 1.2 μmol/L, respectively [52], and of PGE2 production in vitro [53] and in vivo with superior efficiency (ED50 = 1 mg/kg) compared to indomethacin (5 mg/kg) [54]. Hyperforin turned out to be a novel type of 5-lipoxygenase inhibitor with high effectivity in vivo [55] and suppressed oxidative bursts in polymorphonuclear cells at 1.8 μmol/L in vitro [56]. Inhibition of IFN-γ production, strong downregulation of CXCR3 expression on activated T cells, and downregulation of matrix metalloproteinase 9 expression caused Cabrelle et al. [57] to test the effectivity of hyperforin in a rat model of experimental allergic encephalomyelitis (EAE). Hyperforin attenuated the symptoms significantly, and the authors discussed hyperforin as a putative therapeutic molecule for the treatment of autoimmune inflammatory diseases sustained by Th1 cells."
"Hyperforin is found in alcoholic beverages. Hyperforin is a constituent of Hypericum perforatum (St John's Wort) Hyperforin is a phytochemical produced by some of the members of the plant genus Hypericum, notably Hypericum perforatum (St John's wort). The structure of hyperforin was elucidated by a research group from the Shemyakin Institute of Bio-organic Chemistry (USSR Academy of Sciences in Moscow) and published in 1975. Hyperforin is a prenylated phloroglucinol derivative. Total synthesis of hyperforin has not yet been accomplished, despite attempts by several research groups. Hyperforin has been shown to exhibit anti-inflammatory, anti-tumor, antibiotic and anti-depressant functions
* Arachidonate 5-lipoxygenase ...Specific function: Catalyzes the first step in leukotriene biosynthesis, and thereby plays a role in inflammatory processes ...
* Prostaglandin G/H synthase 1 ... General function: Involved in peroxidase activity".

### Boswellia serrata

Boswellic acid (acetyl-keto-beta-boswellic acid (AKBA)), one of the bioactive boswellic acids found in Boswellia serrata (Indian Frankincense) has been found to inhibit 5-lipoxygenase strongly as an allosteric inhibitor. Boswellia administration has been shown to reduce brain edema in patients irradiated for brain tumor and it's believed to be due to 5-lipoxygenase inhibition.

### Hippomane mancinella

Family: Euphorbiaceae
The tree contains 12-deoxy-5-hydroxyphorbol-6-gamma-7-alpha-oxide, hippomanins, mancinellin, and sapogenin, phloracetophenone-2,4-dimethylether is present in the leaves, while the fruits possess physostigmine.
A gum can be produced from the bark which reportedly treats edema, while the dried fruits have been used as a diuretic.

### Hypericum perforatum

Some chemicals found in trace amounts in food, as well as some dietary supplements, have been shown to inhibit 5-LOX; these include baicalein, caffeic acid, curcumin, hyperforin and St John's wort.
"These researches are according to an investigation of the effect of H. perforatum on the NF-κB inflammation factor, conducted by Bork et al. (1999), in which hyperforin provided a potent inhibition of TNFα-induced activation of NF-κB [58]. Another important activity for hyperforin is a dual inhibitor of cyclooxygenase-1 and 5-lipoxygenase [59]. Moreover, this species attenuated the expression of iNOS in periodontal tissue, which may contribute to the attenuation of the formation of nitrotyrosine, an indication of nitrosative stress [26]. In this context, a combination of several active constituents of Hypericum species is the carrier of their anti-inflammatory activity."
"Anti-inflammatory mechanisms of hyperforin have been described as inhibition of cyclooxygenase-1 (but not COX-2) and 5-lipoxygenase at low concentrations of 0.3 μmol/L and 1.2 μmol/L, respectively [52], and of PGE2 production in vitro [53] and in vivo with superior efficiency (ED50 = 1 mg/kg) compared to indomethacin (5 mg/kg) [54]. Hyperforin turned out to be a novel type of 5-lipoxygenase inhibitor with high effectivity in vivo [55] and suppressed oxidative bursts in polymorphonuclear cells at 1.8 μmol/L in vitro [56]. Inhibition of IFN-γ production, strong downregulation of CXCR3 expression on activated T cells, and downregulation of matrix metalloproteinase 9 expression caused Cabrelle et al. [57] to test the effectivity of hyperforin in a rat model of experimental allergic encephalomyelitis (EAE). Hyperforin attenuated the symptoms significantly, and the authors discussed hyperforin as a putative therapeutic molecule for the treatment of autoimmune inflammatory diseases sustained by Th1 cells."
"Hyperforin is found in alcoholic beverages. Hyperforin is a constituent of Hypericum perforatum (St John's Wort) Hyperforin is a phytochemical produced by some of the members of the plant genus Hypericum, notably Hypericum perforatum (St John's wort). The structure of hyperforin was elucidated by a research group from the Shemyakin Institute of Bio-organic Chemistry (USSR Academy of Sciences in Moscow) and published in 1975. Hyperforin is a prenylated phloroglucinol derivative. Total synthesis of hyperforin has not yet been accomplished, despite attempts by several research groups. Hyperforin has been shown to exhibit anti-inflammatory, anti-tumor, antibiotic and anti-depressant functions
1. Arachidonate 5-lipoxygenase ...Specific function: Catalyzes the first step in leukotriene biosynthesis, and thereby plays a role in inflammatory processes ... 2. Prostaglandin G/H synthase 1 ... General function: Involved in peroxidase activity."

### Justicia gendarussa

To treat external edema, an oil made from the Justicia gendarussa leaves can be used.

### Myxococcus xanthus

"Zileuton is a specific inhibitor of 5-lipoxygenase and thus inhibits leukotriene (LTB4, LTC4, LTD4, and LTE4) formation. Both the (R)-(+)- and (S)-(-)-enantiomers are pharmacologically active as 5-lipoxygenase inhibitors in in vitro systems. Leukotrienes are substances that induce numerous biological effects including augmentation of neutrophil and eosinophil migration, neutrophil and monocyte aggregation, leukocyte adhesion, increased capillary permeability, and smooth muscle contraction. These effects contribute to inflammation, edema, mucus secretion, and bronchoconstriction in the airways of asthmatic patients. Sulfido-peptide leukotrienes (LTC4, LTD4, LTE4, also known as the slow-releasing substances of anaphylaxis) and LTB4, a chemoattractant for neutrophils and eosinophils, can be measured in a number of biological fluids including bronchoalveolar lavage fluid (BALF) from asthmatic patients." and the natural products myxochelins/pseudochelin as well as nordihydroguaiaretic acid (NDGA).

### Solanum virginianum

Solanum virginianum L. herb is useful in cough, chest pain, against vomiting, hair fall, leprosy, itching scabies, skin diseases and cardiac diseases associated with edema (Kumar et al., 2010).