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DERIVATIVES

DERIVATIVES

APIGENIN

Identification

Ingredient

Apigenin

Structure:


Synonyms

5,7-dihydroxy-2-(4-hydroxyphenyl)-4H-1-benzopyran-4-one

Molecular Formula

C15H10O5

Molecular Weight

270.24

CAS no.

520-36-5

EINECS

208-292-3

Description

Pure Apigenin is a yellow crystalline solid. It is sparingly soluble in aqueous buffers,but soluble in organic solvent such as ethanol DMSO and dimethyl formamide.It is suggested to be stored at -20℃,then it should be stable for at least two years.

Scientific support

Apigenin is described as a nonmutagenic bioflavonoid which is presented in leafy plants and vegetables (e.g., parsley, artichoke, basil, celery) and has significant chemopreventive activity against UV-radiation. Current research trials indicate that it may reduce DNA oxidative damage; inhibit the growth of human leukemia cells and induced these cells to differentiate; inhibit cancer cell signal transduction and induce apoptosis; act as an anti-inflammatory; and as an anti-spasmodic or spasmolytic.

As with many flavonoids, apigenin has potential to reduce the risk of cancer since it has anti-tumor activity. Apigenin also could potentially be useful in allergic conditions since it can have anti-inflammatory properties.

Application

According to the US Patent and Trademark Office ( USPTO ), 107 patents involving apigenin in some manner have been obtained in the United States. These patents involve a variety of uses including the preparation of antiviral agents for the treatment of HIV and other infections, particle binders, and pharmaceuticals for treatment of diseases including inflammatory bowel disease and skin conditions ( USPTO, 2000 ).

Apigenin is recognized in traditional or alternative medicine for its pharmacological activity. For this reason, passion flower, which is rich in apigenin, has been used for treating intransigent insomnia, as an anti-spasmodic in Parkinson’s disease and asthma, to reduce nerve pain in neuralgia, and to treat shingles ( Hoffman, 2000a ).

Apigenin is a major constituent of chamomile, which is recognized for its antiphlogistic, antispasmodic, and antibacterial effects. Chamomile tea ( 3-4 cups a day ) has been used for centuries as a folk remedy for relieving indigestion or calming gastritis. Common alternativea are 2-3 grams of the herb in capsule form or 4-6 ml of tincture three times per day. Chamomile preparations are also widely used in skin care products to reduce cutaneous inflammation and other dermatological diseases ( Gruenwald et al., 1998; Healthnotes, 1999; Hoffman, 2000b; Nemecz, 2000 ).

Distribution

Apigenin is found in high amounts in parsley, thyme, and peppermint. Apigenin is also found in a number of herbs, including chamomile herb, lemon balm herb, perilla, vervain herb, and yarrow.

Availability

Commercial Apigenin is obtained by chemical synthesis from Naringin (extracted from immature fruit of Citrus Grandis Osbeck).


Dried immature fruit of Citrus Grandis Osbeck

Warning:

Above information is only knowledge,not an instruction of usage for this product. The owner of this webiste should not be responsible for any damage because of misuse of the product.


DIOSMIN

Identification


Ingredient

Diosmin


Structure:

Synonyms

3',5,7-trihydroxy-4'-methoxyflavone-7-rutinoside

Molecular Formula

C28H32O15

Molecular Weight

608.54

CAS no.

520-27-4

EINECS

208-289-7

Description

Diosmin is greyish-yellow or light yellow hygroscopic powder,practically insoluble in water, soluble in dimethyl sulphoxide, practically insoluble in alcohol. It dissolves in dilute solutions of alkali hydroxides. Melting point is 275-277 °C when purity is 95% tested by HPLC.

Scientific support

Diosmin was first isolated in 1925 from Scrophularia nodosa, and first introduced as a therapeutic agent in 1969. Diosmin is considered to be a vascular-protecting agent used to treat chronic venous insufficiency, hemorrhoids, lymphedema, and varicose veins. As a flavonoid, diosmin also exhibits anti-inflammatory, free-radical scavenging, and antimutagenic properties.

Diosmin differs molecularly from hesperidin by the presence of a double bond between two carbon atoms in diosmin's central carbon ring. Diosmin can be manufactured by extracting hesperidin from citrus rinds, followed by conversion of hesperidin to diosmin. Diosmin has been used for more than 30 years as a phlebotonic and vascular-protecting agent, and has recently begun to be investigated for other therapeutic purposes, including cancer, premenstrual syndrome, colitis, and diabetes.

Biochemistry and Pharmacokinetics

Flavonoids are a large group of plant pigments sharing the same basic chemical structure; i.e., a three-ringed molecule with hydroxyl (OH) groups attached. Diosmin occurs naturally as a glycoside, meaning it has a sugar molecule attached to its three-ringed flavonoid structure.

Pharmacokinetic investigations have shown diosmin is rapidly transformed by intestinal flora to its aglycone form, diosmetin. Diosmetin is absorbed and rapidly distributed throughout the body with a plasma half-life of 26-43 hours. Diosmetin is degraded to phenolic acids or their glycine-conjugated derivatives and eliminated through the urine. Diosmin or diosmetin not absorbed is eliminated in the feces.

Mechanisms of Action

Diosmin's mechanisms of action include improvement of venous tone, increased lymphatic drainage, protection of capillary bed microcirculation, inhibition of inflammatory reactions, and reduced capillary permeability. Certain flavonoids, including diosmin, are potent inhibitors of prostaglandin E2 (PGE2) and thromboxane A2 (TxA2) as well as being inhibitors of leukocyte activation, migration, and adhesion. Diosmin causes a significant decrease in plasma levels of endothelial adhesion molecules and reduces neutrophil activation, thus providing protection against microcirculatory damage.

Clinical Indications
Varicose Veins/Chronic Venous Insufficiency
Chronic venous insufficiency is characterized by pain, leg heaviness, a sensation of swelling, and cramps, and is correlated with varicose veins. A multicenter international trial, carried out in 23 countries over two years, in which 5,052 symptomatic patients were enrolled, evaluated the efficacy of flavonoids in the treatment of chronic venous insufficiency. Patients were treated with 450 mg diosmin and 50 mg hesperidin daily for six months. Continuous clinical improvement was found throughout the study, as well as improvements in quality of life scores for participants.
Diosmin-containing flavonoid mixtures have also been effective in treating severe stages of chronic venous insufficiency, including venous ulceration and delayed healing. In a randomized multicenter trial, 900 mg diosmin and 100 mg hesperidin plus standard venous ulcer management was compared with standard venous ulcer management alone. Standard ulcer management included cleaning, compression therapy, and skin care of the adjacent skin. Forty-seven percent of patients in the treatment group compared to 28 percent in the standard management group experienced complete healing of ulcers less than 10 cm in diameter.
Hemorrhoids
Several large clinical trials have demonstrated diosmin to be effective in the treatment of acute and chronic symptoms of hemorrhoids. A double-blind, placebo-controlled study of 120 patients showed improvement of pain, pruritis, discharge, edema, erythema, and bleeding on examination. The treatment group was given a flavonoid mixture (90% diosmin and 10% hesperidin) at a dose of two 500-mg tablets daily for two months.
The use of diosmin in the treatment of hemorrhoids associated with pregnancy did not adversely affect pregnancy, fetal development, birth weight, infant growth, or infant feeding. Pregnant women suffering from acute hemorrhoids were treated eight weeks before delivery and four weeks after delivery. More than half of the women participating in the study reported relief from symptoms by the fourth day. Diosmin is non-mutagenic and does not have any significant effect on reproductive function.
Lymphedema
Diosmin acts on the lymphatic system by increasing lymph flow and lymph oncotic pressure. A flavonoid mixture containing diosmin was used to treat upper limb lymphedema secondary to conventional therapy for breast cancer. Results showed improvement of symptoms and limb volume; the mean decrease in volume of the swollen limb reached 6.8 percent. In addition, lymphatic functional parameters assessed with scintigraphy were significantly improved. Animal studies of high-protein lymphedema, such as in burns and lung contusions, showed significant improvement with diosmin.
Diabetes
Diosmin has been shown to improve factors associated with diabetic complications. Blood parameters of glycation and oxidative stress were measured in type 1 diabetic patients before and after intervention with a diosmin-containing flavonoid mixture. A decrease in hemoglobin Ale was accompanied by an increase in glutathione peroxidase, demonstrating long-term decreased blood glucose levels and increased antioxidant activity.
Diosmin can normalize capillary filtration rate and prevent ischemia in diabetics. Rheological studies of type 1 diabetics show diosmin can facilitate hemorheological improvements due to decreased RBC aggregation, which decreases blood flow resistance, resulting in reduction of both stasis and ischemia.
Cancer
Diosmin has been investigated in a number of animal models and human cancer cell lines, and has been found to be chemopreventive and antiproliferative. More clinically oriented research in this area is warranted to determine effective dosages and protocols.
Other Clinical Indications
Studies have also investigated the use of diosmin for stasis dermatitis, wound healing, premenstrual syndrome, mastodynia, dermatofibrosclerosis, viral infections, and colitis. More clinically oriented research is indicated.

Drug-Nutrient Interactions
Diosmin can cause a decrease in RBC aggregation and blood viscosity.There are no documented cases of adverse interactions between diosmin and prescription medications, but caution should be taken when combining diosmin with aspirin or other blood-thinning medications.
Data suggest that diosmin has an inhibitory effect on cytochrome P450-mediated metabolism in healthy volunteers, which may alter the pharmacokinetics of drugs taken concomitantly. Patients given metronidazole after nine days of pretreatment with 450 mg diosmin demonstrated changes in serum concentrations of metronidazole, as well as changes in urinary concentrations of metronidazole and its metabolites compared to controls.

Side Effects and Toxicity
In animal studies, a flavonoid mixture containing 90-percent diosmin and 10-percent hesperidin had an L[D.sub.50] of more than 3g/kg. In addition, animal studies have shown the absence of acute, subacute, or chronic toxicity after repeated oral dosing for 13 and 26 weeks using a dose representing 35 times the recommended daily dose.
Diosmin is considered to have no mutagenic activity, embryo toxicity, nor any significant effect on reproductive function. Transplacental migration and passage into breast milk are mini-real.

Dosage
The standard dose of diosmin is 500 mg twice daily. For acute dosing, a loading dose of 1,000 mg three times daily for four days is recommended, followed by 1,000 mg twice daily for three days, and a maintenance dose of 500 mg twice daily for two months.

Application

Diosmin is largely used in EU as a medicine in combination with Hesperidine. The formulation of Dismin 90%+Hesperidin 10% branded Alvenor by famous Servier has an annual sales of millions of dollars in EU. But FDA does not approve it as a medicine but a dietary supplement. Recently a new formulation of Diosmin 95%+Hesperidin 5% has been also approved by EU countries and FDA.

Nowadays more companies in other countries also launched similar products as the same proportion of Diosmin and Hesperidine, whatever it is used as a medicine or dietary supplement, Diosmin has been well acknowledged to be a vascular-protecting agent used to treat chronic venous insufficiency, hemorrhoids, lymphedema, and varicose veins.

Availability

Commercial Diosmin is obtained by chemical synthesis from hesperidin (extracted from immature citrus fruit).


Dried immature citrus fruit

Warning:

Above information is only knowledge,not an instruction of usage for this product. The owner of this webiste should not be responsible for any damage because of misuse of the product.

HESPERETIN

Identification

Ingredient

Hesperetin

     
Structure:

Synonyms

Hesperitin, 5,7,3'-trihydroxy-4'-methoxyflavanone, (S)-2,3-dihydro-5,7-dihydroxy-2-(3-hydroxy-4-methoxyphenyl)-4H-1-benzopyran-4-one

Molecular Formula

C16H14O6

Molecular Weight

302.28

CAS no.

520-33-2

EINECS

208-290-2

Description

Hesperetin is one of the Citrus bioflavonoid. It is solid substance, light-brown crystalline powder, poorly soluble in water. Hesperetin belongs to the flavanone class of flavonoids. Hesperetin, in the form of its glycoside hesperidin, is the predominant flavonoid in lemons and oranges.

Pharmacology

Hesperetin is a cholesterol lowering flavanoid found in a number of citrus juices. It appears to reduce cholesteryl ester mass and inhibit apoB secretion by up to 80%. Hesperetin may have antioxidant, anti-inflammatory, anti-allergic, hypolipidemic,vasoprotective and anticarcinogenic actions.

Mechanism of Action

Hesperetin reduces or inhibits the activity of acyl-coenzyme A:cholesterol acyltransferase genes (ACAT1 and ACAT2) and it reduces microsomal triglyceride transfer protein (MTP) activity. Hesperetin also seems to upregulate the LDL receptor. This leads to the reduced assembly and secretion of apoB-containing lipoproteins and enhanced reuptake of those lipoproteins, thereby lowering cholesterol levels.

Application

Hesperetin has properties of antioxidant,anti-inflammatory, anti-allergic, hypolipidemic,and anticarcinogenic actions. Hesperidin can also act as a vasodilator, which may be useful in Hypertension. 

Hesperetin is also used in functional food or dietary supplement as its properties. More studyings are in process to enlarge its use in more industries.

Availability

Commercial Hesperetin can be obtained by hydrolyzation from Hesperidin (extracted from immature citrus fruit).


Dried immature citrus fruit

Warning: 

Above information is only knowledge,not an instruction of usage for this product. The owner of this webiste should not be responsible for any damage because of misuse of the product.

HEPSERIDIN METHYL (CHALCONE)

Description

Hesperidin methyl is methylated derivative of the flavonoid hesperidin. Due to different control in chemical reaction, two styles of hesperidin methyl are obtained: Chalone style and Dihydro-Flavone style

Hesperidin methyl - Chalone style

Hesperidin methyl -Dihydro-Flavone style

Structure:

R: CH3- or H-
G: Glucose or Glucose methyl
R1:Rhamnose or Rhamnose methyl

Structure:

R:CH3- or H-
G:Glucose or Glucose methyl
R1:Rhamnose or Rhamnose methyl

Scientific support

Hesperidin methyl (chalcone) supports and protects the integrity of the vascular system with particular activity in the capillaries and veins. Hesperidin methyl (chalcone) has been shown to help strengthen capillaries by increasing capillary resistance and decreasing capillary permeability. Increased venous motility, tone, and the ability of vessels to dilate are also enhanced by hesperidin methyl (chalcone).

HESPERIDIN METHYL
Identification

Structure

Dihydro-Flavone style

Molecular Formula

C29H36O15

Molecular Weight

624.59

CAS no.

11013-97-1

Character

Light yellow crystalline powder,slightly bitter taste,soluble in water

Application
Hesperidin methyl is approved as medicine used in China.

HESPERIDIN METHYL CHALCONE
Identification

Structure

Dihydro-Flavone style: chalcone style ≈ 1:1

Molecular Formula

C29H36O15

Molecular Weight

624.59

CAS no.

24292-52-2

Character

Light yellow crystalline powder,slightly smell, slightly bitter taste,soluble in water and ethanol

Application

Hesperidin methyl chalcone is widely used outside of China,such as Japan, USA,EU,not only in pharmaceutical but also in dietary supplement and cosmetic products.

Availability

Commercial hesperidin methyl (chalcone) is obtained by chemical synthesis from Hesperidin (extracted from immature citrus fruit )

HESPERIDIN METHYL (CHALCONE)
Dried immature citrus fruit

Warning:

Above information is only knowledge,not an instruction of usage for this product. The owner of this webiste should not be responsible for any damage because of misuse of the product.

NARINGENIN

Identification

Ingredient

Naringenin


Structure:

Synonyms

4',5,7-trihydroxyflavanone; 5,7-dihydroxy-2-(4-hydroxyphenyl)-2,3-dihydro-4h-chromen-4-one; (s)-2,3-dihydro-5,7-dihydroxy-2-(4-hydroxyphenyl)-4-benzopyrone

Molecular Formula

C15H12O5

Molecular Weight

272.26

CAS no

480-41-1

EINECS

207-550-2

Description

Naringenin is a compound that naturally occurs in grapefruit and other citrus fruits. 95% of Naringenin is a light yellow to brown powder, soluble in ethanol,ether and almost insoluble in water. Meling point is 251-253℃.

Scientific support

Naringenin is a flavonoid that is considered to have a bioactive effect on human health as antioxidant, free radical scavenger, anti-inflammatory, carbohydrate metabolism promoter, and immune system modulater.

This substance has also been shown to reduce oxidative damage to DNA in vitro. Scientists exposed cells to 80 micromoles of naringenin per liter, for 24 hours, and found that the amount of hydroxyl damage to the DNA was reduced by 24% in that very short period of time. Unfortunately, this bioflavonoid is difficult to absorb on oral ingestion. In the best case scenario, only 15% of ingested naringenin will get absorbed in the human gastrointestinal tract. A full glass of orange juice will supply about enough naringenin to achieve a concentration of about 0.5 micromoles per liter. There are speculations that, given more time at a lower concentration, it could have similar effects.

Naringenin found in grapefruit juice has been shown to have an inhibitory effect on the human cytochrome P450 isoform CYP1A2.Naringenin has also been shown to reduce hepatitis C virus production by infected hepatocytes (liver cells) in cell culture. This seem to be secondary to Naringenin ability to inhibit the secretion of very low density lipoprotein by the cells.

Application

Naringenin is now mainly used in cosmetic products, dietary supplement, beverage and so on.

Availability

Commercial naringenin is obtained by hydrolyzation from Naringin (extracted from immature fruit of Citrus Grandis Osbeck).


Dried immature fruit of Citrus Grandis Osbeck

Warning:

Above information is only knowledge,not an instruction of usage for this product. The owner of this webiste should not be responsible for any damage because of misuse of the product.


NARINGIN DIHYDROCHALCONE

Identification

Ingredient

Naringin dihydrochalcone

Structure:

Synonyms

1-[4-[[2-O-(6-Deoxy-L-mannopyranosyl)-D-glucopyranosyl]oxy]-2,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)-1-propanone

Molecular Formula

C27H34O14

Molecular Weight

582.56

CAS no.

18916-17-1

Description
Naringin Dihydrochalcone is a off-white powder, soluble in hot water, Melting point is 156°C-158°C.

Application

As a new-style sweetening agent, naringin dihydrochalcone(naringin DC) is 500-700 times sweeter than sucrose. Due to its many advantages like high sweet taste, low caloric, innocuity and safety, it can be used in edible, medicine and commodity trade. And because it tastes cleanlily, has long aftertaste and special faint scent and owns fine virtue of shielding bitterness, Naringin DC is in particular used for milky goods, fattiness and grease, freezed foodstuff, machining vegetable, jelly, comfiture, nonalcohol beverage, chewing gum, toothpaste and troche. Besides, it can substitute sugar for decreasing body absorption to sugar. It is really a evangel for fat person and patients who can not eat sugar.

Availability

Commercial Naringin Dihydrochalcone is obtained by chemical synthesis from Naringin (extracted from immature fruit of Citrus Grandis Osbeck).


Dried immature fruit of Citrus Grandis Osbeck

Warning:

Above information is only knowledge,not an instruction of usage for this product. The owner of this webiste should not be responsible for any damage because of misuse of the product.


NEOHESPERIDIN DIHYDROCHALCONE

Identification

Ingredient

Neohesperidin dihydrochalcone



Structure:

Synonyms

Neohesperidin DHC; NHDC;Hesperetin dihydrochalcone-4’-β-neohesperidoside,Neohesperidin DC

Molecular Formula

C28H36O15

Molecular Weight

612.58

CAS no.

20702-77-6

EINECS

243-978-6

FEMA

3811

CEE no.

E959



Description

Appearance: white to pale yellow powder
Solubility: in cool water is 0.4-0.5 g/l but it has high solubility in hot water, also soluble, in ethanol, water:ethanol solutions and alkaline water solutions.
Odor: Odorless
Metling point: 156.00 - 158.00 °C
Stability: very stable in crystalline form and in water solutions.

Scientific support

NHDC was discovered during the 1960s as part of a United States Department of Agriculture research program to find methods for minimizing the taste of bitter flavorants in citrus juices. Neohesperidin is one such bitter compound. When treated with potassium hydroxide or another strong base, and then catalytically hydrogenated, it becomes NHDC, a compound roughly 1500-1800 times sweeter than sugar at threshold concentrations; around 340 times sweeter than sugar weight-for-weight. Its potency is naturally affected by such factors as the application it is used for, and the pH of the product.

Like other highly sweet glycosides, such as glycyrrhizin (from the licorice root) and those found in stevia, NHDC's sweet taste has a slower onset than sugar's and lingers in the mouth for some time. Unlike aspartame, NHDC is stable to elevated temperatures and to acidic or basic conditions, and so can be used in applications that require a long shelf life. NHDC itself can stay foodsafe for up to five years when stored in optimal conditions.

The European Union approved NHDC's use as a sweetener in 1994. It has not been approved as a sweetener in the United States. It is sometimes said that NHDC is considered a Generally Recognized as Safe flavour enhancer by the Flavour and Extract Manufacturers' Association, which is a trade group with no legal standing. NHDC has never appeared on the FDA's GRAS listing. It is particularly effective in masking the bitter tastes of other compounds found in citrus, including limonin and naringin. Industrially, it is produced by extracting neohesperidin from the bitter orange, and then hydrogenating this to make NHDC.

The product is well known for having a strong synergistic effect when used in conjunction with other artificial sweeteners such as aspartame, saccharin, acesulfame potassium, and cyclamate, as well as sugar alcohols such as xylitol. NHDC usage boosts the effects of these sweeteners at lower concentrations than would otherwise be required; smaller amounts of other sweeteners are needed. This provides a cost benefit.

As a flavour enhancer, NHDC is used in a wide range of products and is indicated by the E number E 959. It is noted particularly for enhancing sensory effects (known in the industry as 'mouth feel.') An example of this is 'creaminess' in dairy foods such as yogurt and ice cream but is also widely favoured for use in otherwise naturally bitter products. Pharmaceutical companies are fond of the product as a means of reducing the bitterness of pharmacological drugs in tablet form and it has been used for livestock feed as a means of reducing feeding time. Other products NHDC can be found in may include a wide variety of alcoholic beverages (and non-alcoholic), savoury foods, toothpaste, mouthwash and condiments such as ketchup and mayonnaise.

Application

1. Soft drink
Fruit drink, Carbonated drink, still drinks, Powdered drink concentrate, syrups,sports drink, dark sweet beer, ice tea, grapefruit juice, cola drink, citrus drink, juices, milk and derivatives, water based flavoured drinks, alcoholic drinks.
Dosage: 10-30 ppm( sweetener) , 1-5 ppm ( Flavor enhancer)
2. Chewing gum
Dosage: 400 ppm( sweetener), 1-5 ppm( Flavor enhancer)
3. Dairy products & desserts:
Chocolate based products,  spreads, yoghourt,  ice-creams.
Dosage: 10-35 ppm ( sweetener) , 1-5 ppm( flavor enhancer)
4. Confectionery
Chocolate based products, dry fruits,  spreads, marmalades, jams, jelly,  sweets, cider,  fruit preserves, bakery, low calorie food.
Dosage : 15-50 ppm( sweetener), 1-5 ppm(Flavor enhancer)
5. Spice flavor
Sauces, pat condiments,  seasonings, mayonnaise, soups, fish.
Dosage: 1-5 ppm( Flavor enhancer)
6. Pharmaceutical industry
Maskering bitter taste.
Dosage: 10-30 ppm( sweetener) , 1-5 ppm( flavor enhancer)
7. Cosmetics:
Tooth-paste, mouth-wash.
8. Animal feed industry:
Pet foods, veterinary products, vitamin and mineral preparations, feed stuffs for farm animals , and special feedstuff for young animals.
Dosage: 1-5 ppm(Flavor enhancer)
Legislation
Food:
Common Market: CEE No. E-959     See files:  94/35/EC   (english) (dosis) and
95/31/EC  (english), 2106/1996 (spanish),  2001/30/CE  (spanish), SCO/1050/2002 (spanish) (for the purity of Neohesperidin Dihydrochalcone) and 96/83/EC
USA. FEMA/GRAS: 3811
Pharmacy:
European Pharmacopoeia 4rd Edition - E 959
Feed:
COUNCIL DIRECTIVE  70/524/EEC (english) and see file:  97/6/CE  (french) (dosis)
Regulations 1991
Authorized Daily Dose: COM/2001-DDA 5mg/kg
World Health Organization: Codex Alimentarius

Documents available

For different application, following documents are available upon customer’s requirement.

--- Specification sheet
--- Material Safety Date Sheet
--- Typical Certificate of analysis
--- FAMI-QS
--- Health certificate
--- Kosher certificate

Availability

Commercial neohesperidin dihydrochalcone is obtained by chemical synthesis from Naringin or Neohesperidin which exist largely in Citrus fruits.


Dried immature citrus fruit.

Warning:

Above information is only knowledge,not an instruction of usage for this product. The owner of this webiste should not be responsible for any damage because of misuse of the product.