#hypervitaminosis A treatment

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Everything to know about Vitamin -D

First of all, we should know the basics of vitamins. There are two groups of vitamins depending on the solubility. 

One is Fat soluble and other is water soluble. In fat soluble group falls Vitamin A, D, E & K. In water soluble group falls Vitamin B complex & Vitamin C. vitamin D test cost

Vitamin D is synthesized in our body which involves three major steps at three different organs. In the first step, the primary form of Vitamin D is synthesized under the skin, when UV rays fall on the skin. 

One can get UV rays through sunlight with the early morning sunlight exposure. The second step occurs at Liver. 25-hydroxy cholecalciferol is synthesized in the liver by the process of hydroxylation which is still not an active form. vitamin D test cost

 The active form of vitamin D i.e. 1,25-cholecalciferol is synthesized in the kidney. This is the active form of vitamin D,it is also called as Vitamin D3/ Calcitriol. 

So, to be precise, Vitamin D synthesis starts at the skin and ends at the kidney via liver. So, any condition which affects these three organ systems, will also affects vitamin D synthesis. vitamin D test cost

Previously it was assumed that function of Vitamin D is absorption of calcium. But over the period it has been proved that it is not the only function, Vit.D plays important role in functioning of Musculoskeletal system, Skin, Neurological system, Cardiovascular system.

Normal level of Vitamin D3 is above 30ng/ml. If it is above 100 ng/ml, it is called as hypervitaminosis. vitamin D test cost

So, Vitamin D3 level has to be maintained between 30-100ng/ml. In children Vitamin D3 deficiency presents with Rickets which presents with bone pain, angular deformities of the extremities (Genu valgum, cubitus varus, coxa vara).

 If detected timely, it can be corrected with Vitamin D3 supplements. In adults, Vitamin D3 deficiency may present with many musculoskeletal symptoms like myalgia, recurrent body ache, early fatigue, fractures with trivial injury.

Long standing vitaminD3 deficiency leads to osteoporosis which means decreased bone density. vitamin D test cost

It’s ironic that though we live in India which is a tropical country with ample amount of sunlight exposure throughout the year, still a large no. of the Indian population is suffering from Vitamin D3 deficiency.  vitamin D test cost

The important cause for this is Sedentary lifestyle & dietary habits. To correct vitamin D3 deficiency, lifestyle modification, healthy dietary habits, and avoiding junk food also play a vital role.

Signs of Vitamin D Deficiency

Bone Pain: Chronic musculoskeletal pain, especially in the back, hips, and legs, can be a sign of Vitamin D deficiency.

Frequent Infections: Since Vitamin D is involved in immune function, low levels may increase susceptibility to infections. vitamin D test cost

Fatigue: Persistent fatigue and low energy levels could be indicative of Vitamin D deficiency.

Mood Changes: Depression, anxiety, and irritability may be linked to insufficient Vitamin D. vitamin D test cost

Impaired Wound Healing: Slow healing of wounds and frequent infections may occur due to compromised immune function.

For correction of Vitamin D3 levels, there are different formulations available like Injectables, capsules, sachets, solutions. vitamin D test cost

Depending on the level of vitamin D3, dosage and duration of treatment has to be decided. One need to consult Orthopaedic doctor in Baner to correct vitamin d3 levels and associated conditions with it.

Vitamin D is not just a vitamin; it’s a vital hormone that influences numerous aspects of health and well-being. From supporting bone health to bolstering the immune system and regulating mood, its impact on the body is profound.

While sunlight remains the primary source, supplementation and dietary adjustments can help maintain optimal levels, especially in populations at risk of deficiency. vitamin D test cost

By understanding the importance of Vitamin D and taking steps to ensure adequate intake, you can unlock its full potential and promote overall health and vitality.

[pillsblue]

How to Manage Acne with Acutret 10 MG ?

Acutret 10 MG Capsule is a medicine that contains isotretinoin. It is a naturally occurring derivative of vitamin A. This medicine is used for the treatment of a severe form of acne called nodular acne characterized by large, inflamed, painful acne lesions deep under the skin. It acts on skin glands to reduce the production of a substance called sebum that can cause acne or pimples. It also has an anti-inflammatory action which decreases the redness and swelling associated with acne.

Acutret 10 MG Capsule has some common side effects like cracked lips, dry eye, dry nose, dry skin and dry mouth. Consult your doctor if any of these side effects persist or bother you. Do not take this medicine if you are allergic to it. Acutret 10 MG Capsule should be taken with food.

Take this as prescribed by your doctor. Complete the whole treatment, even if you feel better after taking a few doses. Use skin protective methods like wearing sunscreen and having a balanced diet along with Acutret 10 MG Capsule for the Acne treatment. Acutret 10 MG Capsule is not recommended to be used in pregnancy and breastfeeding.

Inform your doctor if you have liver problems before taking this medicine. It is not recommended for use in children under 12 years of age. Acutret 10 MG Capsule may cause skin sensitivity to sunlight so it is advised that you avoid going out in harsh sunlight or take precautions like sunscreen.

You should avoid alcohol consumption while taking this medicine as it may cause severe side effects. Inform your doctor immediately if you experience and serious side effects like changes in mood or depression, dizziness, ringing in ears, headache, problems with vision, pain behind the eyes, increased thirst and urination while using this medicine.

When not to use?

Allergy

Avoid using Acutret 10 MG Capsule if you are allergic to isotretinoin or any other component present in this medicine. Seek medical help immediately if you notice any symptoms such as skin rashes, itching/swelling, Dizziness, breathing difficulty, etc.

Hypervitaminosis A

Hypervitaminosis A is a condition that occurs when you have too much vitamin A in your body. Symptoms of hypervitaminosis A include vision problems, changes in the skin, and bone pain. In such cases Acutret 10 MG Capsule is not recommended for use as it is also a derivative of vitamin A and it may worsen your condition.

Severe liver disease

Acutret 10 MG Capsule is not recommended for use if you have severe liver conditions as it may worsen your condition.

Dosage

Missed Dose

Do not skip a dose of Acutret 10 MG Capsule. If you forget to take a dose of this medicine, take it as soon as you remember. If it is time for your next dose, skip the missed one. Do not double the dose to compensate for the missed one.

Overdose

If you have taken more than the prescribed dose of Acutret 10 MG Capsule you may experience symptoms like vomiting, flushing, severely chapped lips, stomach pain, headache and dizziness. Consult with your doctor immediately in case of an overdose.

General Instructions

Take Acutret 10 MG Capsule as instructed by your doctor. Follow all the directions mentioned on the label. Do not take more or fewer doses than prescribed.

This medicine should be taken with food. The symptoms might get worse in the initial phase of treatment. It is advisable to avoid sunlight during the course of treatment. Take plenty of water and have a clean nutritious diet. Keep away from the reach of children and pets. Ensure that unused medicine is disposed of properly.

[mansobuzz]

Hypervitaminosis A: The Most Of Its Causes And Symptoms

Hypervitaminosis A: The Most Of Its Causes And Symptoms

Commonly, vitamins and minerals are essential and necessary for health, but over-consuming them may cause side effects, especially when we over-consume vitamin A, (Hypervitaminosis A). What is hypervitaminosis A? Hypervitaminosis A occurs when large amounts of vitamin A enter the body exceeding its need. This condition is temporary because of consuming large amounts of vitamin A in a short…

[jukanio]

Genomics and Genetics in the Biology of Adaptation to Exercise

Firmly identified with the neurological manifestations of hypervitaminosis are indications including migraine, pseudotumor cerebri, and embryotoxic impacts detailed in patients given nutrient An analogs or retinoids. 

Since nutrient An and analogs enter the CNS better than most nutrients, and on the grounds that retinoids effectsly affect catalyst movement and quality articulation, Vitamin A neurotoxicity is almost certain than any remaining nutrients. Megadose nutrient treatment might cause injury that is mistaken for illness indications. 

An examination showed that following Isozyme mtx  49 months of follow up, ingestion of retinol caused a 7% expansion in basic phosphatase, 11% increment in triacylglycerol, 3% increment in cholesterol and 1% lessening in HDL. The members were haphazardly alloted to get retinol (7,576 retinol counterparts RE, or 25,000 IU) or a fake treatment day by day. Since a 1% expansion in cholesterol focuses has been accounted for to be related with a 2% increment in coronary vein illness hazard, long haul ingestion of 7,576 RE nutrient An ought to be considered with alert. 

Devouring an excessive amount of nutrient A could build your danger of osteoporosis. Two investigations showed that a day by day nutrient An admission > 1.5 mg brought about a 6% abatement in generally speaking bone thickness and multiplied the danger of hip crack. Abundance levels of this nutrient debilitate bones by expanding its pace of resorption. 

[r1-fitness]

Scientific Facts About The Benefits And Dangers Of Vitamin A

What Is Vitamin A

Vitamin A is called retinoids – a group of substances consisting of retinol, retinal and retinoic acid. In addition, a person receives a significant part of vitamin A from carotenoids – these are the precursors of vitamin A, which are converted into it already in the body. The most abundant of the carotenoids is β-carotene, 6 mg of which is converted into 1 mg of vitamin A. On average, people get about 20-30% of vitamin A from carotenoids and 70-80% from retinoids.

Retinoids are found in animal foods – beef offal, redfish, fish oil, milk, eggs, butter. Orange, red and green fruits are rich in carotenoids.

Vitamin A is fat-soluble. It is absorbed in the duodenum, from there it enters the liver, and then into the blood. Excess vitamin A is almost not excreted from the body and accumulates in the liver, both in humans and in animals. Therefore, the most retinoid-rich product is beef or chicken liver.

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In vitamin supplements or cosmetics, vitamin A is most commonly found in the form of β-carotene, palmitate, or retinol acetate. Many drugs contain a combination of retinoids and carotenoids.

Vitamin A Intake  :

up to 6 months – 0.4 mg (400 mcg);

from 7 months to a year – 0.5 mg;

1-3 years – 0.3 mg;

4-8 years old – 0.4 mg;

9-13 years old – 0.6 mg;

after 14 years – 0.9 mg for men and 0.7 mg for women;

pregnant women – 0.77 mg;

lactating women – 1.3 mg.

Sometimes the dosage of vitamin A is indicated not in terms of the metric system, but in international units – IU or IU. One IU of vitamin A contains 0.3 mcg.

Proven Vitamin A Benefits

Protects the eyes

Vitamin A is involved in the synthesis of rhodopsin, or visual purpura, an eye pigment that is responsible for adapting vision to darkness and distinguishing colors. This relationship was already known to ancient Egyptian doctors who treated night blindness by squeezing fluid from the lamb’s liver directly into the eyes of patients.

Vitamin A supplementation has also been shown to reduce the risk of macular degeneration and age-related vision loss. However, in this case, it is effective only when combined with treatment with other drugs.

Good for the skin

Retinoids are found in many beauty products, such as anti-aging creams, sunscreens, moisturizing serums, and acne and acne remedies – and for good reason. Vitamin A:

stimulates the production of collagen – a protein that is responsible for the elasticity of the skin, thereby protecting it from sagging and premature wrinkles ;

participates in the production and renewal of epidermal cells;

moisturizes the skin and normalizes sebum production;

effective for the treatment of inflammation, wounds and acne. The American Academy of Dermatology recommends the use of vitamin A supplements for the treatment of acne.

Finally, vitamin A regulates skin pigmentation, thereby protecting it from dark spots.

Strengthens the immune system

Vitamin A is important for the immune system because it:

participates in the synthesis of leukocytes – white blood cells, which are responsible for fighting disease (a sufficient amount of vitamin A in the diet makes leukocytes more tenacious and effective in destroying parasites and tumors)

participates in the production of antibodies – blood plasma proteins that also fight infections;

protects the body from diseases by stimulating the production of new cells of epithelial and mucous tissues, namely, they serve as the body’s natural shield against diseases from the external environment.

Vitamin A is often prescribed as an adjunct in the treatment of many infectious diseases such as tuberculosis, pneumonia and malaria.

Improves reproductive function and protects the fetus

Vitamin A is necessary for both the male and female body for the normal functioning of the reproductive function. In men, its deficiency inhibits sperm production.

For women, vitamin A is essential primarily during pregnancy. Numerous studies show that taking additional vitamin A in pregnant women reduces the risk of many pathologies and developmental delays in the fetus.

The existence of this relationship has been proven, but so far it is poorly understood. Nevertheless, doctors recommend that women make sure that there is no vitamin A deficiency before conception and increase the dosage during pregnancy and lactation.

Vitamin A Deficiency

Vitamin A deficiency is common today in developing countries and almost never in developed countries. According to UN statistics, acute deficits are common in central Africa, Mexico, India and Central Asia.

Most often, vitamin A deficiency occurs in newborns, premature babies, as well as in pregnant and lactating women. Often, chronic deficiency develops in members of poor communities in infancy and leads to vision diseases, delays in physical development, and also lowers immunity.

In some developing countries with famine, vitamin A deficiency during pregnancy and infancy is the most common cause of preventable blindness in children. However, residents of countries that are not familiar with the regular shortage of food are not in danger.

Also, a lack of vitamin A is often found in people with cystic fibrosis, a serious chronic disease that disrupts the functioning of the pancreas.

Another cause of vitamin A deficiency can be a genetic mutation.

“The absorption of vitamin A and the need for it largely depend on the correct functioning of the enzyme that is involved in the conversion of carotenoids into retinol, the active form of vitamin A,” explains nutritionist Maria Volchenkova. – If this conversion process goes right, a person can easily get all vitamin A from food. It is enough to consume foods rich in carotenoids and retinol in moderation.

But the transformation process can be disrupted. This is due to a breakdown in the BCMO1 gene. It reduces the rate at which vitamin A is synthesized from carotenoids and increases vitamin requirements. If this enzyme does not work in a vegan, he will surely experience visual impairment (after all, there is no retinol in plants). Therefore, ideally, to prevent vitamin A deficiency, both genetics and blood levels of beta-carotene and retinol should be tested. ”

The Most Common Symptoms Of Vitamin A Deficiency Include :

dry skin, which can flow into eczema ;

acne;

dry eyes;

night blindness (blurred vision in the dark);

reproductive disorders;

developmental delays in children;

increased risk of respiratory tract infections.

Excess Vitamin A

Excess vitamin A is almost not excreted from the body. It accumulates in the liver and in large quantities can be very toxic.

There are cases when participants in expeditions to the Far North received acute poisoning after eating the liver of a polar bear. A couple of hours after such a dinner, the polar explorers developed weakness and drowsiness – however, they could not sleep due to severe vomiting. The next day, their skin was peeling and peeling off – in some, the affected area was limited to the face, while in others, the whole body was damaged. Some polar explorers died. Later, scientists were able to establish the cause of these poisonings. The body of a healthy adult can assimilate 10 thousand units of vitamin A. Problems, if they arise, are when using 25-33 thousand units. Moreover, a piece of polar bear liver weighing 450 g can contain 9 million units of vitamin A.

Getting a “bearish” dose of vitamin A from your usual food is unlikely to succeed, but earning an acute overdose is not so difficult.

Scientists Have Established A Safe Maximum Daily Intake Of Vitamin A:

from birth to 3 years – 0.6 mg;

4-8 years old – 0.9 mg;

9-13 years old – 1.7 mg;

14-18 years old – 2.8 mg;

19 and older – 3 mg.

If for other vitamins the norm and maximum permissible value can differ tens or even hundreds of times, the difference here is very small, therefore, taking medicated vitamin A is only worth taking as directed by a doctor.

For an adult, there is only one realistic way to exceed these limits, getting vitamin A only from food – for this you will have to eat 170 g of beef liver every day. Therefore, the UK National Health Service recommends eating less than 200 g of liver per week.

Symptoms of a vitamin A overdose :

headache;

rash;

irritability;

increased intracranial pressure;

dry eyes;

chapped lips;

flaky skin.

This only applies to vitamin A in the form of retinoids – an overdose of β-carotene is impossible.

“Unlike vitamin A, high doses of β-carotene do not have toxic properties and do not cause hypervitaminosis, since its excess accumulates in adipose tissue,” explains endocrinologist Anastasia Danilova. “Excessive use of plant foods or dietary supplements containing carotene leads to carotenoderma, a harmless condition characterized by a yellow-orange skin tone due to the accumulation of carotenoids in the epidermis.”

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Vitamin D, Ergocalciferol

Brand Name: Drisdol

Generic Available

Common Dosage Forms:

Capsules: Each softgel contains Ergocalciferol, USP 1.25 mg (equivalent to 50,000 IU of vitamin D), in vegetable oil.

Drops: 200 IU of ergocalciferol/drop (8,000 IU/mL)

*Also available in lower strength OTC forms

FDA Indications/Dosages:

For the treatment of refractory rickets, also known as vitamin D resistant rickets: 12,000-500,000 IU/day

For the treatment of hypoparathyroidism: 50,000-200,000 IU/day concomitantly with calcium lactate 4 grams, six times a day.

Non-FDA Indications/Dosages:

For the treatment of vitamin D deficiency in adults (25-hydroxyvitamin D3 <20 ng/mL): 50,000 IU weekly for 8 weeks given with supplemental calcium followed by 1,000 IU daily with supplemental calcium.

Pharmacology/Pharmacokinetics: Ultraviolet light converts 7-dehydrocholesterol in the skin to cholecalciferol (vitamin D3). Both cholecalciferol and ergocalciferol (vitamin D2) are converted in the liver to 25-hydroxyvitamin D forms and then in the kidney to 1,25-dihydroxyvitamin D forms. Vitamin D (D2 or D3) is essential for the proper regulation of calcium in plasma and the activity of parathyroid hormone. Vitamin D is involved in the absorption of calcium and phosphorous from the small intestine thereby providing the necessary levels of calcium and phosphate in the plasma to promote bone mineralization. Ergocalciferol is effective in treating the hypocalcemia and hyperphosphatemia seen in hypoparathyroidism.

Drug Interactions: Mineral oil interferes with the absorption of fat-soluble vitamins, including vitamin D. Addition of thiazide diuretics to hypoparathyroid patients concurrently taking ergocalciferol may cause hypercalcemia.

Contraindications/Precautions: Contraindicated in patients with hypercalcemia, malabsorption syndrome, and hypervitaminosis D. Idiopathic hypercalcemia may be caused by hypersensitivity to vitamin D. In these cases, vitamin D must be strictly restricted. The range between therapeutic and toxic doses is narrow. Dosage levels must be individualized to prevent toxic effects. Frequent blood calcium levels should be taken. Adequate dietary calcium is necessary for clinical response to vitamin D therapy.

Adverse Effects: The range between therapeutic and toxic doses is narrow. Toxicity may result in impairment of renal function, mental retardation, bone demineralization, calcification of the soft tissues, nausea, anorexia, constipation, anemia, and weight loss.

Patient Consultation: May be taken without regard to meals. Closely follow prescribed calcium supplementation. Do not exceed prescribed dosage. Contact a physician if the above side effects are severe or persistent. Store in a cool, dry place away from light and children. If a dose is missed, skip it and return to dosing schedule.

[virali10]

5 Ways To Increase Hemoglobin

Hemoglobin, a protein in the red blood cells is used to carry the oxygen to the rest of the body. It is also used to transport carbon dioxide out of the cells and back to the lungs for it to be exhaled. The normal hemoglobin rate for men is below 13.5 per deciliter and for women it is 12 grams per deciliter. Low hemoglobin levels can occur due to iron deficiency anemia, pregnancy, liver problems and urinary tract infection.

Iron And Folate Rich Foods

Iron plays a very vital role in the production of hemoglobin. A protein named transferrin is binded to iron which then transports throughout the body. This is helpful in making red blood cells which actually contains hemoglobin. If the hemoglobin level is detected low, then the first thing that one needs to start eating is iron. Foods high in iron include- 

liver and organ meats

shellfish

broccoli

kale

spinach

green beans

cabbage

beans and lentils

tofu

baked potatoes

fortified cereals and enriched bread. 

In this, folate is a Vitamin B supplement that the body uses to produces heme. Heme is a part of the red blood cells that contains hemoglobin. If the folate level is not enough the red blood cells fail to mature. It can further lead to folate deficiency anemia and low hemoglobin levels. 

Supplements that are rich in folate are-

beef

spinach

black eyed peas

avocado

lettuce

rice

kidney beans

peanuts

Iron Supplements

If the hemoglobin levels have to be increased, one must start taking the oral iron supplements. But too much of iron cause a condition called hemochromatosis. It can lead to liver diseases like cirrhosis, and side effects like constipation, nausea and vomiting. A proper prescribed medicine with the doctor consultation should be taken where the dose of one time should not be more than 25mg.  Once the medicines start, a difference in the iron level should be noticed within a week and upto a month. These iron supplements should be kept away from children. The most recommended iron supplements are-

Epoetin Alfa (Procrit, Epogen)

Darbepoietin  Alfa(Aranesp)

Multivitamin with Iron

Integra F

These medicines can be ordered online form the best online medical store in India.

Maximize The Absorption Of Iron

When one increases the intake of iron through food or supplements, it is necessary to make sure that the body can easily process the extra iron that one is consuming. Thus, the best online medical app of India provides you some useful information which can be looked upon. There are certain things that can either increase or decrease the amount of iron that the body absorbs. 

Things that increase iron absorption

 When one starts consuming foods that are rich in iron or iron supplements, at the same time foods rich in Vitamin C should also be consumed. Vitamin C is helpful in increasing the amount of iron the body absorbs. Squeezing of fresh lemon after having iron rich foods helps in increasing the absorption. Foods high in Vitamin C are citrus fruits, strawberries and dark, leafy greens. Vitamin A and beta carotene helps the body to produce Vitamin A which in turn helps the body to absorb iron. Vitamin A can be found in animal food sources like fish and liver. Beta Carotene is found in red, yellow and orange fruits and vegetables like-

carrots

winter squash

sweet potatoes

mangoes

These should be taken only under the guidance of a doctor because too much of Vitamin A can lead to Hypervitaminosis A.

Things that decrease the absorption of iron

Calcium intake from food as well as supplements make it difficult for the body to absorb iron. But eliminating calcium totally is no solution. It is necessary to avoid calcium rich foods before or after the iron supplements. Foods high in calcium are dairy, soybeans, seeds and figs. Phytic acid reduces the absorption of iron in those people who dont eat meat. It affects only in that meal and not throughout the day. Foods like walnuts, brazil nuts and sesame seeds should be avoided as they are rich in phytic acid. 

Doctor’s call

There are some cases where the doctors have to fix the hemoglobin level as it cannot be done with food and supplements. If any of the following symptoms are observed then the treatment under doctor should start immediately.

Pale skin and gums

Fatigue and muscle weakness

Fast or irregular heartbeat

Frequent headaches

Frequent or unexplained bruising.

Outlook

Though there are several ways of increasing hemoglobin levels but these should be done only under the guidance of the doctors. It might be that some additional treatment like iron transfusion may be required in case of a pregnancy or a chronic health condition. 

[thenanosoma]

Vitamin D versus Vitamin D3, which is Better for You

What is vitamin D (D2)?

Vitamin D (D2—ergocalciferol) is a vitamin D supplement accessible in both solution and over-the-counter plans. It is accessible in oral tablets and cases, just as an oral arrangement. Vitamin D2 originates from plant sources and is the most well-known type of vitamin D found in strengthened (strengthening) nourishments. The Nano soma products are original and natural and always proven as result oriented.

What is vitamin D3?

Vitamin D3 (cholecalciferol) is an over-the-counter vitamin D supplement accessible in an assortment of qualities. It is accessible in oral tablets and cases, just as oral and sublingual arrangements. 

Vitamin D3 originates from creature sources, for example, fish oil, greasy fish, liver, or egg yolks.

What are the principle contrasts between vitamin D and D3?

The term Vitamin D Nano is somewhat of a misnomer since you won't (don't) discover anything named just as "vitamin D" in a drug store vitamin path. Or maybe, your decisions will be vitamin D2 or vitamin D3. By and large, when one notices vitamin D, the inferred determination is vitamin D2. With the end goal of this article, when vitamin D is referenced, it will allude to vitamin D2. The names can be confounding, on the grounds that multiple occasions, patients go into the drug store searching for vitamin D and are amazed that there is a D2 and a D3.

Vitamin D (D2) originates from plant sources, for example, wild mushrooms, just as strengthened nourishments, for example, milk or oat items. Its quality is regularly estimated in global units, which is contracted as "IU" on marking. The 50,000 IU cases are remedy just, while lower qualities are accessible over-the-counter. Vitamin D is more affordable to deliver and along these lines is the structure most regularly found in braced food items.

Vitamin D3 chiefly originates from creature sources, for example, fish oil, greasy fish, liver, and egg yolks. At the point when your skin is presented to daylight, it produces vitamin D3. Therefore, it is now and then alluded to as the daylight vitamin. The Nano soma products quality is additionally estimated in global units. All types of vitamin D3 are accessible over-the-counter.

Conditions treated by vitamin D and D3

Vitamin D2 as a solution is utilized to treat hypoparathyroidism (diminished thyroid hormone discharge) , vitamin D safe rickets, and hypophosphatemia (low degrees of phosphorus in the blood). It is usually utilized for vitamin D deficiency in the two its solution and over-the-counter formulations. The FDA doesn't endorse treatment claims for over-the-counter vitamin enhancements, accordingly, despite the fact that this utilization is normal, it is considered off-mark.

All types of Vitamin D3 supplements are accessible over-the-counter and(but) consequently are not FDA affirmed to make treatment claims. In any case, vitamin D3 is regularly utilized off-mark to treat hypoparathyroidism and vitamin D insufficiency, just as for osteoporosis avoidance.

Different employments of vitamin D supplementation are recorded in the table beneath. You ought to consistently look for clinical guidance before starting vitamin D supplementation.

Basic symptoms of vitamin D versus D3

Vitamins for Joints basic symptoms to treatment with either vitamin D2 or D3. Symptoms identified with vitamin D are the consequence of hypervitaminosis D, an incredibly uncommon condition that happens when your admission a lot of vitamin D. This is now and then found in patients who take mega doses of vitamin D, prompting vitamin D harmfulness. The outcome is a development of perilously elevated levels of calcium in the blood which can prompt sickness, retching, blockage and successive pee. Whenever left untreated, irreversible renal disappointment can happen alongside the calcification of organs and delicate tissues.

The accompanying table records reactions identified with hypervitaminosis D, not typical vitamin D supplementation. More data on vitamin D harmfulness might be acquired from your PCP or drug specialist, as this may not be a finished rundown.

Learn more about vitamins visit The Nano Soma.

[latestanalysis]

Global Vitamin D Therapy Market Assessment, Opportunities, Insight, Trends, Key Players – Analysis Report to 2027

Global Vitamin D Therapy Market

Vitamin D is defined as the fat-soluble vitamin which is responsible for maintaining healthy bones & teeth. Although our body cannot produce Vitamin D, it is mainly obtained by the cutaneous production during sun exposure. The deficiency of vitamin D causes to bone pain & weakened muscles. Vitamin D therapy is provided to treat various conditions including rickets, muscle weakness, osteoporosis, skin diseases, and others.

Market Drivers

The increase in target patient population is the key driving factor which expected to boost the global vitamin D therapy market growth over the forecast period. Furthermore, the growing awareness about vitamin D deficiency, the rise in patient compliance to oral medications, growing prevalence of hypovitaminosis D, sedentary lifestyles, aging population, and lack of exposure to sun are some prominent factors which expected to drive the global vitamin D therapy market growth. Moreover, strategic acquisitions and mergers among companies contribute to the growth of the vitamin D therapy market. For Instance, in 2018, GSK completed the buyout of Novartis’ 36.5% stake in Consumer Healthcare Joint Venture as well as GSK had entered into collaboration with Pfizer to form a consumer health care joint venture which would provide a range of products in vitamin & mineral supplements, therapeutic oral health, skin health, respiratory, pain relief, and digestive health, and others.

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Also, the rise in use of vitamin D in the treatment of diseases is expected to provide a significant opportunity to the market of vitamin D therapy. For Instance, research article published in “Clinical Breast Cancer”, a magazine published by Elsevier found that vitamin D supplement intake with chemotherapy can advance disease-free survival in women with HER2+ breast cancer. The study reveals that patients who consumed Vitamin D supplements during treatment have better survival as compared to the patients who did not take vitamin D supplements. This research is expected to propel the Vitamin D therapy market growth in near future.

Market Restraints

The increase in cases of a medical condition associated with the excessive consumption of Vitamin D is expected to restrict the market growth of Vitamin D therapy market. High level of Vitamin D in the body can cause Vitamin D toxicity commonly called as Hypervitaminosis D. Though it is rare, but the serious condition can result in a buildup of excess calcium in the blood which is called as hypercalcemia. Therefore, excessive consumption of Vitamin D can occur serious medical conditions, this factor is anticipated to hamper the market growth of Vitamin D therapy market.

Market Segmentation

The Global Vitamin D Therapy Market is segmented into route of administration such as Oral, and Parenteral. The oral route is anticipated to register the largest share and highest CAGR during the forecast period. Due to the ease of administration, better pharmacokinetic and pharmacodynamic activity, reduced chance of toxicity, increased patient compliance, and higher preference for the oral route.

Further, market is segmented into application such as Rickets, Muscle Weakness, Osteoporosis, Skin Diseases, and Others. The osteoporosis segment is anticipated to register the highest growth over the forecast period. This growth can be attributed to the growing incidence of falls & fractures in senior adults due to the elevated levels of parathyroid hormones and the poor absorption of calcium from their diets.

Regional Analysis

The Global Vitamin D Therapy Market is segmented into five regions such as North America, Latin America, Europe, Asia Pacific, and Middle East & Africa.

The Asia Pacific is expected to expand at the highest CAGR during the forecast period, owing to the awareness about vitamin D deficiency as well as supportive government policies & programs for the implementation of vitamin D deficiency treatment plans, sedentary lifestyles, growing incidence of vitamin D deficiency, decreasing sun exposure, atypical diets, and rising malnutrition levels.

Also, the North America is anticipated to dominates the vitamin D therapy market during this forecast timeline. Due to the presence of leading players based in the United States, focus on research activities to develop more patient compliant products with enhanced efficiency along with the government support & the increase in healthcare expenditure contributing to its outstanding market revenue share in the overall market growth.

Key Players

Various key players are listed in this report such as Abbott Laboratories, Novartis International AG, Torrent Pharmaceuticals Ltd., Merck & Co., Inc., Sanofi, Pfizer, Inc., Cadila Healthcare Ltd., Sun Pharmaceutical Industries Ltd, Biotics Research Corporation, Alkem Laboratories Ltd, etc. Abbott Laboratories has a global distribution network & a good brand reputation among end users. The company’s strong presence as well as wide distribution channels across the world have helped it to maintain its leading position in the market. The company focusing on the mergers & acquisitions, with strategic alliances such as technology, licensing, to obtain an edge over competitors.

Market Taxonomy

By Route of Administration

Oral

Parenteral

By Application

Rickets

Muscle Weakness

Osteoporosis

Skin Diseases

Others

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[beautynotesstuff]

Best hair treatment dubai For Hair Fall.

Because it is rightly said by Martin Luther, "The hair could be the richest ornament of women." Shimmering lustrous long hair is just a sign of a healthier person. It shows off to the world about our wellbeing and vitality. Unhealthy hair is one of many first few signs of Mental and/or Bodily unwell being. As our body requires proper nutrition for the growth and maintenance, so does our Hair. So, eating the correct food is the best hair treatment for hair fall. So let us have an overview regarding what are the different nutrients required and their role in keeping our Hair healthy and preventing hair fall.

Proteins:

Rightly called the building blocks of our body, Proteins constitute up 98% of our hair. This makes proteins one of the most important nutrients for healthy hair. It promotes healthy hair development cycles. There are numerous sources of proteins. Of the protein sources however, the reduced fat sources like fish, poultry and pulses such as for instance soy, ragi, etc. are preferred. This is because high fat diet is associated with hair loss. Also taking protein in excess is unhealthy for hair because it offsets the acid base balance of your body resulting ultimately to hair loss. It causes deficiency of minerals like calcium further worsening the hair loss. Individuals that are dieting or are on a vegan diet should keep a case on their protein intake and replenish themselves appropriately.

Vitamins:

Vitamins are a small grouping of most critical micronutrients. They need to be replenished in our body by dietary means only. You ought to make sure that he's not deficient on vitamins, because it is quite common in the present life design of constant stress and pressures, whereby one cannot concentrate on good and healthy eating habits. Deficiency if present can cause general lowering of health and hair fall and hair treatment dubai is the solution for it. Let's look at some of the most important vitamins that promote hair growth.

Vitamin A:

It is an important nutrient for healthy hair. Hair Loss is one of many signs to gauge Vitamin A deficiency. Good Sourced elements of Vitamin A are Yellow and orange coloured fruits and dark green leafy vegetables like broccoli and Kale. Other sources include liver, egg yolk, milk and butter. Oral Vitamin A supplements may also be a source for replenishing vitamin A but you need to be mindful while taking them as it may cause an excess of Vitamin A resulting in Vitamin A hypervitaminosis.

Vitamin B:

Vitamin B are a small grouping of vitamins that are essential for healthy hair. Vitamin B deficiency is just a reasons for Baldness. Of the different vitamins, Biotin is one of the extremely important ones. Its deficiency results in eczematous changes and hair fall. Yeast is one of many richest sources of Biotin. Vitamins B3 and B5 are important for hair growth. B6 can be essential because it helps in processing of the different nutrients necessary for good and healthy hair growth.

Antioxidants:

They are the nutrients consisting of vitamins C, E and beta carotene. They may be supplemented using a pill or diet.

Vitamin E:

Vitamin E is another important nutrient for healthy hair. It's few vegetarian sources like green leafy vegetables including spinach, mustard green, parsley etc; whole grains, nuts like sunflower seeds and almonds. Extra virgin essential olive oil, avocados etc.

Vitamin C:

The key sources of vitamin C comprises of most forms of citrus fruits and few vegeables like tomato. Tomato also has Lycopene which also enhances the skin and protects it form UV rays.

Essential Fatty Acids:

Among the most important essential fatty acids in terms of healthy hair growth is worried is Omega 3 fatty acids. They're mainly within sea foods like salmon, tuna and halibut. Vegetarian sources for omega 3 fatty acids are nuts like Flax Seeds, and walnut.

Minerals:

You can find certain minerals that are important to us in the form of Micro along with Macro Nutrients. Example being Zinc, Silica, Selenium, Sulphur, Manganese. They are essential for improving the hair strength. These minerals are present in food sources like egg, chicken, egg, meat, cheese, milk, pumpkin seeds etc.

Iron:

Iron is an essential mineral for augmenting the hair health. Its deficiency results in hair loss. Deficiency of iron leads to lower Hemoglobin levels thereby leading to sluggish blood circulation and lower oxygen supply to the scalp. Therefore results in diminished nutrients that are supplied to the hair follicles, leading to hair fall.

Iodine:

Iodine is just a micro nutrient mineral and is accountable for imparting strength to the hair. It sometimes appears that individuals experiencing Hypothyroidism, that is caused due to lower quantities of iodine in our body, possess a high incidence of hair loss. The sources for iodine are Sea food like salmon, Potatoes, molasses, Lima beans, eggs, watercress, garlic and seaweed. Also nowadays, common salt is fortified with iodine to cope with iodine deficiency in our daily diet.

The present scenario where the life style has become stressful with your busy schedules and work pressures, the incidence of baldness is on a high. Most these can be treated by just incorporating a healthier dietary regimen whereby we include most of the nutrients in our regular meals in a balanced manner. The significance of diet as a preventive and therapeutic tool for adorning our heads with beautiful and healthy looking hair and as the most effective hair treatment for hair fall, can't be underestimated.

[healthfoodbeauty]

What Are the Side Effects of too much Vitamin C?

What are the side effects of too much vitamin C, and how to avoid? Vitamin C is the first remedy in the defense against viruses, which protects us from various colds, viruses, and other diseases. However, excessive consumption of vitamin C can be extremely harmful to our body and very poisonous. Strong immunity and a life without colds is the first thing that comes to mind when we all think of vitamin C. However, those who have taken too much of this important vitamin only once will certainly remember the symptoms. Vitamin C is not only used to strengthen the body, but it also improves the absorption of iron and calcium, so it helps against allergies and relieves weight loss. This vitamin is extremely important for both eye health and good eyesight. It has also been found that those whose diet contains more vitamin C are three times more protected from developing arthritis than those who do not consume enough of the vitamin. Vitamin C large or small doses Vitamin C toxicity is rare because it is easily excreted by the body. The consequences of overdose (more than 2 grams per day) most often occur in the form of digestive problems. Symptoms of hypervitaminosis (vitamin overdose) include burning when urinating, diarrhea, intestinal gas, abdominal pain, rash, and nausea. Vitamin C taken in large doses with large doses of acetylsalicylic acid (aspirin) can in most cases erosive gastritis and in some people a vertical ulcer. Ascorbic acid accumulates in the body and accumulates as a kidney stone. Therefore, those who have kidney stones or are prone to kidney stones are advised to avoid excessive amounts of this vitamin. Be very careful with your intake of vitamins and minerals, especially when it comes to dietary supplements. Because only by consuming food can you find it much harder to overdose on vitamins, you can't overdose with vitamin C when consuming food. Large doses of vitamin C will not be of any use, and they can easily harm your health. In addition, high consumption of one nutrient can reduce absorption or mask the deficiency of another nutrient. So be moderate! Vitamin C in the daily diet can be found in peppers, oranges, pineapples, lemons, strawberries, broccoli, cabbage, parsley, and so on. It should be noted that the heat treatment of food completely destroys vitamin C. Practice cooking less food with vitamin C to make the most of this important vitamin, or cooking at low temperatures.

Vitamin C and its importance for our body

Vitamin C is a true natural friend and remedies for our skin. Just like vitamins A and E, vitamin C is a significant natural powerful antioxidant. It reduces the damage caused by free radicals, protects the skin from the sun's rays, helps heal wounds, and also improves our complexion on the skin. Green vegetables, citrus fruits, potatoes, tomatoes, and parsley are rich in vitamin C. Vitamin C, also known as ascorbic acid, helps heal bones, lower bad cholesterol, and normalize blood pressure in our bodies. It is very successful and preventive in protecting against cancer, heart disease, sclerosis, arthritis, and many other diseases and inflammations. We all know that vitamin C strengthens the immune system and makes us much more resistant to viruses and colds. Therefore, in the periods when colds are common, most doctors give advice with a recommendation to take vitamin C to protect ourselves.

When our body has less vitamin C?

Some of the symptoms of vitamin C deficiency (hypovitaminosis C) are well known and therefore we need to react in such situations. The most common symptoms when we do not have enough vitamin C are the following: Weak immunity and propensity for colds and viruses; Bleeding gums; Leg pain; Slow healing of wounds and bones; The occurrence of various blemishes on our skin; The occurrence of anemia; Some scientists believe that hypervitaminosis C cannot develop because part of vitamin C is excreted in the urine. But recent research in this area shows that there are cases of vitamin C overdose, although they are not as common. The most common symptoms that indicate hypervitaminosis C are headaches and stomach upsets and problems. The daily dose of vitamin C Remember that the recommended daily requirement of vitamin C varies and varies according to gender and of course, depends on age.

As we have already said, vitamin C loses its value when exposed to high temperatures, so consume it from fresh food. Babies (0-6 months) - 40mg Babies (7-12 months) - 50mg Children (1-3 years) - 15mg Children (4-8 years) - 25mg Boys(9-13 years) - 45mg Teenagers (14-18 years) - 75mg Men (19 years and older) - 90mg Girls (9-13 years) - 45mg Teenage girls (14-18 years) - 65mg Women (19 years and older) - 75mg Pregnant women (19 years and older) - 85mg Breastfeeding (19 years and older) - 120mg Should we take an additional vitamin C supplement and when? Smokers are certainly at the top of the list, as it has been proven that every cigarette smoked leads to a loss of 10-30mg of vitamin C. If you drink alcohol regularly, you will definitely need vitamin C. Frequent consumption of alcohol leads to loss of vitamin C from the body, with alcohol we also lose many other vitamins. Stress causes a decrease and loss of vitamin C in our body, try to be calmer and relaxed. Active exercise and some physical activity reduce the amount of vitamin C in our bodies If you are involved in some sports activities such as bodybuilding, fitness, boxing, light athletics, or other sports in which a lot of effort is put into your body, your body needs an extra amount of vitamin C. The diet is based on the amount of vitamin C, if you eat roasted or very cooked food you will have fewer vitamins. Vitamin C loses its value when exposed to high temperatures, so try to avoid, and cooked at low temperatures. It is important to take more vitamins during pregnancy than at other times in a woman's life. Vitamin C belongs to the group of vitamins important during pregnancy. But if you decide to take vitamin C as a dietary supplement, you should first consult a doctor for any side effects of too much vitamin C. Which foods are rich in vitamin C Vitamin C does not stay in our body for a long time, so it should be taken daily. It is present in many green vegetables, tomatoes, red fruits (blackberries, raspberries, blueberries), citrus fruits (oranges, lemons, grapefruit), parsley, potatoes, and more. When consuming vitamin C through the diet, you should be careful, because it easily loses its value in the cooking process. Vitamin C is not very resistant to either high or low temperatures. Fruits and vegetables cooked for 10-20 minutes lose half of the vitamin C they contain. Therefore, eat fresh vegetables and fruits or steam them for the best utilization. This will give you the maximum amount of this important vitamin.

Why not overdose on vitamin C?

When it comes to disease prevention, many see salvation in vitamin C, and rightly so, says German doctor Klaus Schaefer. We need vitamin C for the body's defense system, he says. However, Schaefer advises not to take the maximum amount of vitamin C that is indicated on the packaging. He warns that the risk of long-term use of the maximum permitted amounts has not been sufficiently investigated. It is better to use a moderate dose of vitamin C. Vitamin C overdose adversely affects and can damage the kidneys. It increases the acidity of the urine, which can lead to kidney stones. A balanced diet is the best way to prevent vitamin C deficiency, and rich foods include citrus fruits, broccoli, and sauerkraut. Fruits and vegetables are not only an ideal source of vitamins but also contain fiber and minerals. - They are healthy for the organism and do not have side effects, the doctor emphasizes.

Vitamin C overdose

Ascorbic acid, contained in maximum amounts in citrus, kiwi, and cabbage, is very useful for the body, especially during weakened immunity and various infectious or viral diseases. Vitamin C overdose is a rare occurrence, but it can cause unpleasant symptoms and lead to some negative consequences. Is it possible to overdose on vitamin C? In fact, the side effects of too much vitamin C, the phenomenon under consideration has never been found in medical practice. Ascorbic acid is not produced in our body, so it can only get it from the outside. It is absorbed by the human body only in the doses it needs. Any excess vitamin C is excreted unchanged by the kidneys along with the urine. Some people simply do not react to ascorbic acid or are allergic to the substance. In such cases, obvious symptoms such as skin rash and diathesis appear, but these signs do not mean that the body has an overdose of vitamin C, but indicates an increased sensitivity to it. Large doses of vitamin C As you know, ascorbic acid is a powerful antioxidant, preventing the formation of malignant tumors and premature aging, cell death. Therefore, the treatment of large doses of vitamins is often used in therapeutic practice. The maximum daily dose of ascorbic acid is 100 mg per day, for athletes and pregnant women. As well as for people whose work is associated with the constant performance of heavy physical labor, this amount increases. The determined value of the substance is capable of the following effects: strengthening of the vascular walls; support the production of steroid hormones in the adrenal glands; neutralization, binding, and removal from the body of toxic substances, nitrates, toxins, carcinogens; antioxidant effect; liver tissue restoration; activation of the pancreas; Thus, even a large amount of ascorbic acid does not cause any complications. So, an overdose of vitamin C leads to excretion in the urine not only of excess but also of important vitamin B12. This fact causes a number of serious diseases.

Side effects of too much vitamin C

Significant and persistent excess of the prescribed dose of ascorbic acid with the simultaneous removal of vitamin B12 from the body leads to such complications: -Kidney stones. First, the so-called sand is formed in the ureter, but by increasing solids they can block the urinary tract, causing severe pain and urinary problems. -Increased blood glucose (sugar) concentration or hyperglycemia. The fact is that vitamin C reduces the production of insulin in the pancreas. Because of this, the absorption of glucose into the tissues deteriorates and accumulates in the blood. The disease manifests itself as a constant feeling of lack of fluid, dry skin, lips and mucous membranes, redness of the face. -Excessive estrogen production. For this reason, taking oral contraceptives may not be as effective as it should be. Vitamin C - contraindications It is not recommended to take ascorbic acid with increased sensitivity to the relevant vitamin. With great care and only after consulting a doctor, you should use the medicine for the following diseases: hyperoxaluria; hemochromatosis; diabetes mellitus; nephrolithiasis; thalassemia; oxalosis.

Conclusion

Vitamin C is one of the most important vitamins for the health of our bodies. Cooking at a high temperature contributes to the loss of much of vitamin C. With the help of vitamin C, it is easier to deal with colds, viruses, and other diseases. A normal amount of vitamin C intake helps to have healthy skin, immunity, healthy bones, regulates cholesterol, blood pressure, is good for the heart, and many other benefits. Vitamin C deficiency causes poor body posture, bleeding gums, cholesterol problems, slow bone healing, anemia, and other health problems. This vitamin should be used by smokers, athletes, those who drink more alcohol, pregnant women, and others. Vitamin C overdose is a rare occurrence that leads to kidney stones, more blood sugar, and other side effects. Vitamin C is found mostly in a variety of fruits (pomegranates, raspberries, oranges) and vegetables (tomatoes, peppers, lemons) and many other fruits. Read the full article

[biomedgrid]

Biomed Grid | Vitamin A and its Derivatives- Retinoic Acid and Retinoid Pharmacology

       Introduction        

In vivo, the fat soluble Vitamin A (retinol) can be reversibly metabolised to the aldehyde (retinal) which can in turn, be further oxidised in a non-reversible manner to retinoic acid (RA). Enzymes that oxidize retinol to retinaldehyde belong to two classes: the cytosolic alcohol dehydrogenases (ADHs) belonging to the mediumchain dehydrogenases/ reductase family; and microsomal shortchain dehydrogenases/reductases (retinol dehydrogenases, RDHs [1]. The next step in RA synthesis is the oxidation of retinaldehyde to RA, which is carried out by three retinaldehyde dehydrogenases (RALDHs): RALDH1, RALDH4 and RALDH3 [1,2]. The orange pigment of carrots (beta-carotene) can be represented as two connected retinyl groups, which are used in the body to contribute to vitamin A levels [3]. The physiological and biological actions of this class of substances centre on vision, embryonic development and production, cellular growth and differentiation, skin health, and maintenance of immune function.

Initial studies had focused on vitamin A deficiency and its major consequences: night blindness and Xerophtalmia. Fridericia and Holm [4] investigated the influence of dietary A in the rhodopsin of the retina. Clearly, the rats lacking the fat-soluble vitamin A had a defect in the function of visual purple. Yudkin [5] achieved one of the earliest identifications of vitamin A as a component of the retina. Subsequently, Wald [6] determined the amount of vitamin A present in pig retinas. Wald G [7,8] was well established the visual cycle: light decomposed rhodopsin to retinal and opsin. Retinal could either recombine with opsin to reform rhodopsin or it converted to free retinol. Retinol could reform rhodopsin, but only in the presence of the RPE(Kuhne). The further structure and metabolism of retinoids implicated that retinaldehyde was the visual pigment.

       Biochemistry of Vitamin A        

There is now a well-developed medicinal chemistry of RA (Figure 1 & 3) [9]. The group of pharmacologically used retinoids include vitamin A (all-trans retinol), tretinoin (all-trans retinoic acid), isotretinoin (13-cis retinoic acid) and alitretinoin (9-cis retinoic acid). The monoaromatic retinoids include acitretin and etretinate. The third generation polyaromatic retinoids include bexarotene and tazarotene. In view of this broad spectrum of pharmacological activity, these substances provide useful to treat multifactorial dermatological disorders and other hematological disorders such as acute promyelocytic leukemias (APL) (Figure 1 & Figure 2) [8,10-12].

Figure 1

Figure 1 & 2: Discovery of the molecular basis of vitamin A derivative retinoic acid action (Figure data adapted from Zhu G,January1991,2013,at the top);and vitamin A in vision cycle (Figure data adapted from Wald G,1935;Wolf G,2001,at the bottom).

                         Function of Vitamin A and its Physiological Role Vision

Vitamin A is needed by the eye retina,11-cis-retinal (a derivative of vitamin A) is bound to the protein “opsin” to form rhodopsin (visual purple) in rods cells [8], the molecule necessary for both low light (scotopic vision). As light enters the eye, the 11-cis-retinal is isomerized to all-trans retinal in photoreceptor cells of the retina. This isomerization induces a nervous signal (a type of G regulatory protein) along the optic nerve to the visual center of the brain. After separating from opsin, the all-transretinal is recycled and converted back to the 11-cis-retinal form via a series of enzymatic reactions. The all-trans- retinal dissociates from opsin in a series of steps called photo-bleaching. The final stage is conversion of 11-cis-retinal rebind to opsin to reform rhodopsin in the retina [6-8] (Figure 2) vision cycle. Kuhne showed that rhodopsin in the retina is only regenerated when the retina is attached to retinal pimented epithelium (RPE) [8]. As the retinal component of rhodopsin is derived from vitamin A, a deficiency of vitamin A inhibit the reformation of rhodopsin and lead to night blindness. Within this cycle, all-trans retinal is reduced to all-trans retinol in photoreceptors via RDH8 and possible RDH12 in rods and transported to RPE. In the RPE, all-trans retinol is converted to 11- cis retinol, then 11-cis retinol is oxidized to 11-cis-retinal via RDH5 with possible RDH11 and RDH11 [1]. This represent each RDH for the roles in the visual cycle (Figure 2) .

Figure 3: A well developed medical chemistry of retinoic acid (RA). The all-trans and 13-cis forms of retinoic acid,two isomers of RA,are equally effective inhibiting proliferation. Retinyl acetate,and retinal(Vitamin A) are less potent inhibitor. Am80(Tamibarotene) is more potent inhibitor. The chemical structures of more potent analogues involved from labile flexible polyene structures to aromatic stable moieties are shown[9,10].

           Embryonic Development        

More recent, vitamin A and its metabolites play a key importance in embryo morphogenesis, development and differentiation in normal tissues. Retinoic acid (RA) is lipophilic molecule that act as ligand for nuclear RA receptors (RARs), converting them from transcriptional repressor to activators [2,11,12] in RA signaling pathway. It has been demonstrated that retinoic acid was identified as a morphogen(teratogen) responsible for the determination of the orientation of the limb outgrowth in chicken [13,14] and its retinoic acid receptors (RARs) appear at early stage of human embryonic development in certain types of tissues [15]. Vitamin A play a role in the differentiation of this cerebral nerve system in Xenopus laevi. The other molecules that interact with RA are FGF-8, Cdx and Hox genes, all participating in the development of various structures within fetus. For instance, this molecule plays an important role in hindbrain development. Both too little or too much vitamin A results in the embryo:defect in the central nervous system, various abnormalities in head and neck, the heart, the limb, and the urogenital system [15]. With an accumulation of these malformations, an individual can be diagnosed with DeGeorge syndrome [2].

                     Dermatology        

Vitamin A, in the retinoic acid form, plays an important role in maintaining normal skin health through differentiating keratinocytes (immature skin cells) into immature epidermal cells. In earlier studies, Frazier and Hu (1931) [16] made the observation that both hypovitaminosis A and hypervitaminosis A provokes epithelial alterations together with decreased keratinization and hair loss. At present,13-cis retinoic acid (Isotretinoin) in clinical used to acne treatment. The mechanism was shown to reducing secretion of the sebaceous glands, triggering NGAL (neutrophil gelatinase-associated lipocalin) and other gene expression and selectively inducing apoptosis [17]. But precise action of retinoid therapeutic agents in dermatological diseases are being researched.

       Hematopoiesis        

vitamin A is important for the regulation of hematopoietic stem cell dormancy [18]. Mice maintained on a vitamin A-free diet loss HSCs (hematopoietic stem cells), showing a disrupted re-entry into dormancy after exposure to inflammatory stress stimuli. This condition highlight the impact of dietary vitamin A on the regulation of cell-cycle mediated stem cell plasticity [19]. In vitro, all-trans retinoic acid (ATRA) stimulates at least two-fold the clonal growth of normal human CFU-GM and early erythroid precursor BFU-E [20]. Cis-RA stimulates clonal growth of some myeloid leukemia cells. In suspension culture, there was an increase in cell number at day 5 in the presence of RA in half of 31 samples, which suggest that RA may play a role in the proliferation and survival of certain leukemia clones in vitro [21,22].

In contrast to the enhancement of normal hematopoietic proliferation, RA (10-6 - 10-9 mol/l) is capable of inducing differentiation of the F9 mouse teratocarcinoma, HL-60 cells [23,24] and some blasts from patients with promyelocytic leukemia [23]. Maximum HL-60 differentiation (90% of cells) occurs after a 6 day exposure to 10-6mol/l retinoic acid. Further in vitro studies found that retinoic acid induced differentiation of leukemic blast cells in only 2 of 21 patients with AML, both of these patients had promyelocytic variant [24]. These data suggest that retinoids may induce maturation of promyelocytes. Retinoic acid also inhibits the proliferation of other dermatological malignant cells (Myger,1975; Peck,1975).

       Maintenance of Immune Homeostasis        

There is a link between retinoid and immune homeostasis. RA is crucial for maintaining homeostasis at the intestinal barrier and equilibrating immunity and tolerance. de Mendonca Oliveira LM and colleagues [25] have in detail illustrated the impact of retinoic acid on immune cells and inflammatory diseases. After the absorption and metabolism of vitamin A and its precursor(β-carotene) into RA by alcohol dehydrogenase(ADH) and retinal dehydrogenase(RALDH) in CD103+ DC cells in gut, RA plays an important roles in mucosal immune response by promoting differentiation of Foxp3+ inducible regulatory T (Treg) cell and immunoglobulin(Ig) A production. In this process, RA promote dendritic cells to express CD103 and to produce RA. Vitamin A and zinc deficiency (VAD) lead to a decrease of serum IgA. Oral administration of RA in VAD mice can efficiently be reestablishing IgA production. These effects are mediated by an increase of the early B cell factor 1(EBF1) and paired box protein-5(pan-5) transcription factors, which are critical for B cell development. RA accelerates the maturation of human B cells and their differentiation into antibody-secreting plasma cells.

In addition, RA induces the homing of innate immune cells, such as innate lymphoid cells (ILCs) besides regulatory and effector T and B cells, to the gut. Among three ILCs, ILC3 depend on the transcription factor retinoic acid receptor-related orphan nuclear receptor gamma (RORrt) and secrete IL-17 and IL-22. During infections, RA can induce the production of proinflammatory cytokines by dendritic cells (DCs), promoting the generation of effector T cells and restoring the balance of Th17/Treg cells in the GALT (gut-associated lymphoid tissue), and the protection of the mucosa. Moreover, vitamin A is capable of inducing the IL-6- driven induction of proinflammatory T(H) 17 cells, promoting antiinflammatory T reg cells differentiation, regulating the balance between pro- and anti-inflammatory immunity [26,27].

                     Retinoid Acids in MDS Treatment        

The geometric isomer of the naturally occurring retinoic acid is 13-cis retinoic acid (13-CRA). Based on in vitro and in vivo antineoplastic activity, this agent has entered clinical trials for a variety of neoplasms including MDS. Retinoic acid is one of the biological inducers of differentiation that has been preliminarily tested in patients with preleukemia. Myelodysplastic syndrome (MDS) are a group of hematopoietic disorders characterized by ui- or multilineage maturation defects of the bone marrow [28]. Differentiation induction therapy is used in MDS to improve this maturation defects and induce a multilineage clinical response in a subgroup of MDS patients.13-CRA may have moderate effect on 20-30% of patients with MDS [29]. A various of combination therapy with 13-cis RA and growth factors G-CSF or erythropoietin (EPO) improve impaired cytokine secretion (IL-1beta, IL-6, IL-8) from monocytes [30]. In a prospective multicenter study, EPO-beta- ATRA [31] or EPO-13-cis RA [32] combination appears to erythroid response reaching about 36%-60% of therapeutic efficacy in anemia of low/intermediate risk MDS(LDMDS) (marrow blasts < 10% or excluding RARBt). More data analysis, erythroid response maintained an independent positive impact on survival, particularly in non-RARE patients in the first 3 years from diagnosis (90% survival in EPO responders compared to 50% of non-responders) [33]. Zhu [34] successfully conducted a CR patient with refractory anemia with multilineage megaloblastic dysplasia following traditional medicine and erythropoiesis-stimulating agent vitamin B12 and folate growth factor. His peripheral parameters presented pancytopenia (hemoglobin 59g/l, red blood cell count 1.9x1012/l, leukocyte count 2.6x109/l, platelet value 11.8x109/l).

He remained well over 10 years. While another MDS had its unequivocal evidence of disease progression in response to phytohemagglutinin (PHA), inducing the generation of interleukin-2, accelerating the number recovery of CFU-S and initiating DNA synthesis of cells. She had 2.5% blast plus promyelocytes in ~70% cellular marrow before beginning PHA, and 20.7% blast plus promyelocytes in a 90% cellular marrow after ten days (total dosage 250mg) of PHA. Venditt etal [35] conduct that 23 patients with high-risk myelodysplastic syndrome (HRMDS) were treated with a 10 days course of oral ATRA (45mg/m2) and subcutaneous low-dose cytosine arabinoside (LDARAc) given at the dose of 20mg twice a day. In all cases (RAEB9, RAEBt9 and CMML4) [36] bone marrow blasts infiltration was greater than 10% (12-30%). Overall, 5(23%) of 22 patients achieved complete responder and 2(9%) as partial responders. The overall median survival was 8 months (range 1-27months), whereas the median survival of responders was 16months(8-27months), the median duration of response was 11months(2-21months). It seems that the combination of ATRA and LDARA-c may be effective in approximately 30% of HRMDS patients [35].

Valproic acid (VPA) has been used as an anticovulsant for decades. VPA is a potent inhibitor of histone deacetylases (HDAc). It can modify the structure of chromatin allowing recruitment of transcription factors to restore epigenetically suppressed genes. VPA has been shown to posses antiproliferative activity and to overcome the differentiation block in leukemia blast cells [37]. Some clinical trials with VPA monotherapy or in combination with ATRA have been reported in MDS. In a piloty study of Kuendgen and colleagues [38- 40] patients with MDS or AML secondary to MDS were treated with VPA monotherapy or with ATRA later resulting in a 44% of response rate. In the follow-up study of 43 patients, an even higher response rate of 52% was observed in those low-risk MDS patients, while for the patients with excess blasts (RAEB) and CMML response rates were 6% and 0% respectively, which implicate the difference of MDS subtypes. In another trials, Siitonen etal [41] reported that according to IWG criteria,3 patients(16%) of 19 MDS responded to treatment following VPA,13-cis RA and 1,25(OH)2D3 combination. All the responses were hematological improvement. One patient responded to the treatment with an increase in platelet value from 67x109/l to 105x109/l. His peripheral blood and bone marrow blast cells decreased from 4% to 0% and from 19% to 7%, respectively. Furthermore, the disease remained stable in 11 patients but progressed in 5 during treatment. This is encouraging results.

Table 1: Results of Retinoic acid therapy in MDS.

A series of these studies are summaried in (Table 1). While some patients experienced improvement in peripheral blood counts, complete responses were reported in only a small proportion of these studies [42-43]. The sole exception was a patient who presented with 29% marrow blasts and 90% abnormal metaphases with 13-cis RA. He obtained a complete clinical and cytogenetic remission therapy [44-49]. This clinical response to 13-cis RA drug was due to in vivo growth inhibition of malignant monocytoid clone [50]. Continued follow-up of this study in this field will be of interest [51-54] (Table 1).

                     Retinoic Acids in Skin Disease        

Vitamin A is necessary for normal epithelial cell differentiation and maturation [55-57]. Retinoids influence on skin keratocyte proliferation, epidermal differentiation and kerintinisation. Those retinoids including natural and chemically synthesized vitamin A derivatives are common used as systemic and topical treatment of various skin disorders. At present there have well developed three generations: the naturally occurring retinoids (all-trans retinol, Aretinoin, Isotretinoin, Alitretinoin) the monoaromatic retinoid and the polyaromatic retinoid derivatives [58].

Table 2: Results of 13-cis RA in severe acne treatment.

Isotretinoin is an orally active retinoic acid derivative for the treatment of acne (papulo- pustular,nodulo-cystic, conglobata) [59],since it shows an excellent efficacy against severe refractory nodulocystic acne. Peck’s [60] original observation in 1978-79 of the effectives of 13-cis RA in cystic acne has been well supported. In double-blind studies using small doses of 13-cis RA regimen, Farrell [61] in 15 patients, Jones [62] in 76 patients, Plewig [63] in 79 patients and Rapini [64] 150 patients reporting have confirmed this results. A summary study of limited review on 365 affected persons are presented in (Table 2). The drug action involves an inhibition of sebum excretion rate(SER) in sebaceous glands and production rate of free fatty acids[60,61,65-68] through trigerring NGAL (neutrophil gelatinase-associated lipocalin) expression [17] normalise follicular keratinisation [69] and the decrease in colonisation of propionibacterium acnes and associated inflammation in skin surface microflora [70].This response, mediated by toll-like-receptor 2(TLR2), is increased in acne patients due to high expression of TLR2 [71] (Table 2).

Figure 4: An advanced squamous cell carcinoma of skin before(left) and after(right) isotretinoin [57].

Encouraging results have also been used 13-cis RA in small numbers of patients with rosacea, Gram-negative folliculitis, Darier’s disease, ichthyosis and pityriasis rubra pilaris [72,73]. In the treatment of rosacea, isotretinoins led to a significant reduction of erythemia, papules and pustules in several studies [72,73]. During treatment of rosacea,13-cis RA act as a potent anti-inflammatory and sebum-suppressive agent. Long-lasting remission can be reported for first patient over 12 months [72]. The use of low dose isotretinoin (0.15-0.3mg/kg bw daily) showed high efficacy and was well tolerated. Isotretinoin is only partially effective in psoriasis, in contrast etretinate which is effective in psoriasis but ineffective in severe acne. Promising, some trials have reported with isotretinoin in patients with squamous and basal cell carcinomas [74,75] cutaneous T-cell lymphoma [56] recurrent malignant glioma [76] malignant eccrine poroma [77] and keratoacanthomas [78,79] and xeroderma pigmentosum with squamous cell carcinoma [79]. In literature, there were at least 10 CR patients with squamous cell carcinoma (SCC). Skroza etal [74] reported a CR patient with well-differentiated SCC following the daily dosage of 0.5mg/kg/day for 5 months. Dring 1-year follow up, he remained all in normal range. Using combination chemotherapy and isotretinoin for 4 months, Zaman [80] reported a complete clinical remission of tumors in a case of 15 year old female of xeroderma pigmentosum with SCC. Another collection of four SCC of skin obtained CR through isotretinoin at daily dose of 1mg/ kg/day twice a day for 4 months (Figure 4) [57]. The mechanism may involve the modification of epidermal growth factor receptor (EGFR) and certain protein kinase. At present, It has clearly known the results that amplified (50-fold EGF receptor in SCC relative to normal skin keratinocytes) or mutant EGFR is oncogenic in origin of some SCC [81]. This oncogenic receptor EGFRvIII has also been found in malignant glioma and invasive breast carcinoma [82-89]. Zhu [90] conduct a short CR using chemotherapy and topical 5% Fu of retinoic acid ointment in a 75-year old patient with SCC. She had a 8x5cm rodent ulcer in her left ear and facial area. A shrinkage of irregular and harden marginal valgus converted to flat and superficial red and scar noted after one month treatment. These findings suggest that retinoids may be effective and well-tolerated therapy for advanced epidermoid SCCs in some studies [91-95] (Figure 4) .

       ATRA in patients with gastric cancer (GC)        

Recently [96], two cohorts of group presented ATRA trials on patients with GC. Jin etal presented a better benefits of gastric dysplasia with omeprazole and sucralfate and the addition of ATRA (68% vs 37%) compared to patients treated with omeprazole and sucralfate alone. Hu etal also showed that ATRA significantly prolong overall survival following the combination of conventional chemotherapy. ATRA anticancer mechanisms of action against GC cells included cell cycle blocking and differentiation initiation(p21WAF1/CIP1 induction, decreased ERK/MAPK pathway), decreased expression of HER2 oncogenic receptor in patient’s gastric mucosa, apoptosis initiation and inhibiting CSC(cancer stem cell) properties such as tumorspheres formation and patient derived xenografts(PDX) growth in mice. In GC cells, CD44+ stem/progenitor cells and a high ALDH (aldehyde dehydrogenase, R-ALDH, ALDH1A1 and ALDH1A3) activity could be considered as putative targets to inhibit tumor growth, to overcome resistance to cancer therapy and to improve GC prognosis.

                     The-Structure-of-Retinoic-Acid-Receptors-Molecular-Basis-of-Retinoic-Acid-Action-and-the-RAR-Gene-Transcription RARs structure

The retinoic acid receptors (RAR) belong to the large family of ligand responsive gene regulatory proteins that includes receptors for steroid and thyroid hormones [97]. There are three retinoic acid receptors (RAR), RARα, RARβ and RARγ which are conserved throughout vetebrates encoded by their different RAR (chr 17q21, chr 3p24 and chr12q13) gene, respectively. The RARA contains 462 amino acids(aa) [98,99] RARB consists of 455aa [100] and RARG contains 454aa [101] respectively. The RAR is a type of nuclear receptor which act as a transcription factor that is activated by both all-trans RA and 9-cis RA. The RARs have different functions and may activate distinct target genes. The RARa is expressed in a wide variety of different hematopoietic cells [98,99] the RARβ in a variety of epithelial cells [100] and the RARr in differentiation of squamous epithelia and human skin tissue [101,102]

All RARs contain a variable N-terminal region(A/B), a highly conserved cysteine-rich central domain(C) responsible for the DNA binding activity, and a relatively well-conserved C-terminal half(E) functionally its role in ligand binding and nuclear translocation. These three main domain are separated by a hinge region(D) [12,97,102].The central DNA binding domain(88-153aa) exhibits an array of cysteine residues compatible with the formation of two so-called zinc finger(Miller,1985).Each of them a zinc atom tetrahedrically coordinated to four cysteine and each of the hypothetical zinc finger is encoded by a separate exon of the receptor gene (Figure 5) Zinc finger 1, 88-108aa, Zinc finger 2, 124- 148aa] [97-103].The N-terminal zinc finger of the DNA binding domain confers hormone responsiveness to HREs, determing target gene specificity and responsible for functional discrimination between HREs whereas the C-terminal finger contains the sugarphosphamide backbone of the flanking sequences [103,104] (Figure 5) .

Figure 5:Amino acid sequence of the DNA binding domain of the hRARa into two putative zinc–binding finger (Figure from George Zhu a feeling for scientific drawing based on Evans RM, Science, 1988, 240:899- 895; Beato M,Cell,1989, 56: 335-344; Giguere V,Nature,1987;330:624-29; Petkovich M, Nature, 1987,330: 444).

    The molecular basis of retinoic acid action and the RAR gene transcription

Retinoic acid (RA) is a lipophilic signal molecule which is able to induce acute and direct activation of the expression of specific genes supports its molecular model of action that resembles that of steroid hormones [105]. The cellular retinoic acid-binding protein (CRABP) may be involved in this transfer [9,10]. In the nucleus, RA receptors (RAR) function as a heterodimer with retinoid X receptors (RXRs) [106-109]. RAR/RXR can bind to DNA motif at RA-response elements (RAREs, also HRE) in the regulatory sequences of target genes in the absence of ligand, thereby interacting with multiple protein complexes that include co-repressors N-CoR [110] SMRT [111] and histone deacetylases (HDACs), and maintaining gene repression. Here, RAREs consist of a direct repeat of a core hexameric sequence 5’ (A/G)G(G/T)TCA-3’ [112] or of the more relaxed 5’-(A/G)G(G/T) (G/T)(G/C)A-3’ motif, separated by 1,2,5 bp [113]. A corepressor represses expression of genes by binding to and activating a repressor transcription factor, the repressor in turn bind to target gene’s operator including RARE sequence, then blocking transcription of that gene (see corepressor-wikipedia). Transcriptional regulation thus drives from the binding of hormone-receptor complexes to RARE sites on target DNA [12,97,103]. In the presence of RA(all-trans RA,9- cis RA),binding of the RA ligand to RAR alter the conformation of the RAR, a conformational change in the DNA-bound receptor leads to the release of co-repressor complexes associated with the RAR/RXR dimer and the recruitment of co-acitivator complexes. These induce chromatin remodeling and facilitate assembly of the transcription pre-initiation complex including RNA polymerase II (Pol II) [114], TATA-binding protein (TBP) and TBP-associated factors (TAFs) [2,12,103,115,116] (Figure 6). Subsequently, transcription of target genes is initiated. This also represent liganddependent transcriptional activation which mediated by nuclear receptors. Like thyroid hormone receptor (THR) [117,118] retinoic acid act as ligand for RARs, converting RARa from transcriptional repressor to activators [2,12,119-122]. Numerous RAR target genes after RA induction have been identified including genes within retinoid pathway, such as RARB,Crbp1/2 (Rbp1/2),Crabp1/2 and CYP26a1.And also, several members of HOX gene family, including HOXa1,HOXb1,HOXb4 and HOXd4,and other genes Tshz1 and Cdx1 [123] the function of which has been demonstrated in vivo in the normal roles of retinoids in patterning vertebrate embryogenesis, early neurogenesis, cell growth and differentiation (Figure 6).

Figure 6:Retinoid receptor-dependent gene regulation [116] & (b): Gene regulation by retinoic acid signalling [2].

                         Molecular Model of the Gene Regulation of Retinoic Acid Action in APL        

Acute promyelocytic leukemia (APL) is a clonal expansion of promyelocytic precursors . Retinoic acid(RA) (initial 13-cis RA, later ATRA and tamibarotene) plus chemotherapy is currently the standard of care [124-131]. APL has a very good prognosis, with long-term survival rates up to near 70%-90% [132]. Molecular analysis has uncovered the facts that approximately 98% of APL, RARa translocates and fuses with the PML gene on chromosome 15 [133-136]. The resulting RAR chimeric genes encode pml/RARa fusion protein, which is specifically expressed in the promyelocytic lineage [20]. In addition to oncogenic receptor derivative pml/RARa [108,137-139] the translocation involves oncogenic TBL1XR1- RARB [140] and NUP98/RARG [141] and oncogenic PML-RARG [142] which share high homolog (90%) of three RAR family that were also detected in APL rare cases.

Most studies have shown in APL that oncogenic pml/ RARa act as constitutive transcriptional repressor that blocks neutrophil differentiation at the promyelocyte stage. Without its ligand, retinoic acid (RA), PML-RARA functions as a constitutive transcriptional repressor of RARE-containing target genes, abnormally associating NcoR/HDACs complex and blocking hematopoietic differentiation. In the presence of pharmacological concentration of RA (about 350ng/ml), RA induce the corepressors NcoR/ HDACs dissociation from PML-RARA, thereby activates transcription and stimulate differentiation [11,12,108,139]. In vitro by using a dominant negative RAR construct transfected with interleukin 3(IL-3)-dependent multipotent hematopoietic cell line (FDCP mix A4) and normal mouse bone marrow cells, GM-CSF induced neutrophil differentiation was blocked at the promyelocyte stage. The blocked promyelocytes could be induced to terminally differentiate into neutrophils with supraphysiological concentration of ATRA [143]. Similarly, overexpression of normal RARa transduced cells displayed promyelocyte like morphology in semisolid culture,and immature RARa transduced cells differentiate into mature granulocytes under high dose of RA(10-6M) [144]. Moreover, mutation of the N-CoR binding site abolishes the ability of PML-RARa to block differentiation [145,146]. Therefore, ectopic expression of RAR fusion protein in hematopoietic precursor cells blocks their ability to undergo terminal differentiation via recruiting nuclear corepressor N-CoR/histone deactylase complex and histone methyltransferase SUV39H1 [147]. In vivo, transgenic mice expressing PML-RARA fusion can disrupt normal hematopoiesis, give sufficient time, develop acute leukemia with a differentiation block at the promyelocytic stage that closely mimics human APL (APL-like syndrome, even in its response to RA in many studies. These results are conclusive in vivo evidence that PML/ RARa is indeed oncogenic, and oncogenic pml/RARa is etiology of APL pathogenesis [148-150]. This also represent a steroid receptor in tumorigenesis (Figure 7).

Figure 7: pml/RARa fusion in differentiation block at promyelocytic stage in transgenic mice [149].

Moreover, in Rousselot’s group experiments, HL-60 cells transfected with 15-30ug of PML-RARa fusion in culture show no features of granulocytic differentiation after 7 days of incubation with 10-7,10-6 uM RA (5.5-9.5% of differentiated cells by the NBT test). At 5ug of PML-RARa plasmid concentration, the blockage of RA-dependent myeloid differentiation could be overcomes with high doses(10-6M) of RA (99% of differentiated cells by NBT test) (Figure 8) [151]. The results clearly indicate that PMLRARa mediated transcriptional repression, as well as PML-RARa oncoprotein blocks RA-mediate promyelocyte differentiation. (Figure 8).

Figure 8: Expression of pml-RARa in HL-60 cells blocks ATRA-induced promyelocytic differentiation a(in the presence of 10-7 M RA, top), and transcriptional repressive properties of pml-RARa in human myeloid cells as βRARE-luc assay(bottom) [151].

By using Xenopus oocyte system to uniquely the comparison of the transcriptional properties of RAR and PML-RAR is due to the lack of endogenous nuclear receptors and the opportunity to evaluate the role of chromatin in transcriptional regulation. The results shown in (Figure 9) demonstrated that, indeed, PML-RARA is a stronger transcriptional repressor that is able to impose its silencing effect on chromatin state even in the absence of RXR. Only pharmacological concentration of RA,pml/RARA become transcriptional activator function [139]. (Figure 9).

Figure 9: Shows pml/RARa as a constitutive transcriptional repressor in xenopus oocyte system, as measured by RARE3 CAT and GAL4 assay [139].

In vitro experiments, ATRA induce pml-RARA itself cleavage into a 85-97kd delta PML-RARA product (a truncated pml/RARA form) in RA sensitive NB4 [152-156] (Figure 10). Delta PML-RARa is not formed in ATRA differentiation resistant NB4 subclones [152,155] which indicate the loss of PML/RARa may be directly linked to ATRA-induced differentiation [152,155].This induction of of PML-RARa cleavage and degradation by RA(ATRA,9-cis RA,Am80) involve the proteasome-dependent [152-154] and caspase mediated pathway [155] or independent of proteasome and caspase cleavage[156] and possibly ubiquitin-activating enzyme EI-like(UBEIL) induction in NB4 cells. This is reason that proteasome inhibitor MG-132 and caspase inhibitor ZVAD do not block ATRA-induced pml/RARa cleavage and differentiation whereas this delta pml-RARA is blocked by RARA itself antagonist Ro-41-5253 [156].The proteasome-dependent pml/RARA degradation, by using proteasome inhibitor lactacystin test, allows APL cells to differentiation by relieving the differentiation block [153]. These data suggest a set of multiple molecular mechanisms for restoration by RA induced myeloid differentiation in APL cells. (Figure 10).

Figure 10: Shows delta pml/RARa cleavage products independent of proteasome and caspase in the presence of ATRA(a,b), and pml/RARa act as transcriptional repressor even in the presence of ATRA(0.01uM,1uM) in RARE-tu-luc assay while delta pml/ RARa is less potent activator of RARE-tk-leu activation than wild-type RARa(c) in NB4 cells [155].

Next we further examine the pml/RARa three region functions,in vitro deletion of the RARa DNA binding domain decreased the ability of pml/RARa to inhibit vitD3 and TGFinduced the myeloid precursor U937and TF-1 cell differentiation [145]. This is also supported by functional analysis of DNA binding domain mutation in vitro. The RARa zinc finger is a sequencespecific DNA binding through which RARa contacts the RA target genes. Moreover, deletion of PML coiled-coil region also blocked the differentiation capacity of TF-1 cells [145]. The coiled-coil region directs the formation of pml/RARa homodimers tightly interact with the N-CoR/HDACs complex, so that transcriptional derepression cannot occur at RARA target gene promoter even if the presence of ATRA [RA resistant, 12,157]. In vitro, using established subclones of NB4 resistant to both ATRA and 9-cis RA, they were significantly less able to stimulate transcription of a RARE driven CAT-reporter gene induction by ATRA and showed altered DNA binding activaty on a RARE [158]. In the resistant cases, mut PML stabilizes PML-RARa [159]. PML-RARA with ligand-binding domain (LBD) mutation, ligand RA binding with LBD is impaired. These results have clearly shown that PML protein dimerization and RARa DNA binding domain are indispensible for the myeloid precursors differentiation which was blocked by PML/RARA and eventually leukemic transformation.

In accordance,the pml/RARa/RXR target genes is found to block differentiation by consitutively silencing a set of RA-responsive genes in the control of hematopoietic precursor cells. Five major transcription factors, Ap-1 [160] C/EBPepsilon [161,162] Pu.1/ DAPK2 [163] PTEN [164] and p21WAF/CCKN1A [165] directly regulate genes important in myeloid differentiation. PML/RARA fusion is oncogenic transcriptional repressor of five genes. Inhibited expression or functions of these five transcription factors lead to a block in myeloid differentiation, which is a hallmark of APL.

In vitro cotransfection of pml/RARA with plasmid expressing AP-1 of c-Jun and c-fos proteins in MCF-7 cells, by using CAT assay, PML-RARa is a repressor of AP-1 transcriptional activity in the absence of RA while RA treatment converted the chimera into a strong activator [160]. Since high AP-1 activity is associated with differentiation of leukemic cells in several context [160] the stimulatory effects in the presence of RA could be relevance to its reversal by provoking differentiation. Another, in pml/RARacontaining cell lines, a close link exists between induction of differentiation and induction of C/EBP epsilon expression [161]. C/ EBPepsilon knockout mice had a block in myeloid differentiation [162]. In absence of retinoic acid (RA), induction of pml/RARa expression in U937PR9 cells stably transfected with zinc-inducible pml/RARa suppressed the expression of C/EBPepsilon. In contrast to its repression, in the presence of a pharmacologic concentration of RA, pml/RARa significantly increased the level of C/EBPepsilon expression in a time and dose-dependent manner [161]. The findings implicate that C/EBPepsilon is critical downstream target gene in RA-dependent granulocytic differentiation in the treatment of APL [163-165].

Phosphotase and Tensin homolog (PTEN) is a protein and lipid phosphatase, which plays a pivotal dual role in tumor suppression and self-renewal of hematopoietic stem cells as its promoting exhaustion of normal hematopoietic stem cells (HSCs) and generation of leukemia-initiating cells (LICs) [166,167]. PTEN expression is downregulated in APL, while ATRA treatment increases PTEN leves by inducing PU.1 transcriptional activity via pml/RARa degradation, allowing the binding of PU.1 in PTEN promoter, in turn promotes PTEN nuclear re-location and decreases expression of the PTEN target Aurora A kinases. Therefore, PTEN is one of the primary target gene of oncogenic pml/RARa in APL

Importantly, restoring DAPK2 expression in PU.1 knockdown APL cells partially rescued neutrophil differentiation [168]. In addition, DAPK2 interacts with other cyclin- dependent kinase inhibitors such as p15INK4b and p21WAF1/CIP, which is needed for the cell-cycle arrest in terminal differentiation of neutrophils. Moreover, DAPK2 can bind and activate the key autophagy gene beclin-1 [169]. DAPK phosphorylates beclin 1 on Thr 119 located at a crucial position within its BH3 domain and thus promotes the dissociation of beclin 1 from BCL-XL inhibitor and induction of autophagy [169]. Here, beclin 1 was initially identified as a BCL-2- binding protein, which is part of a class III PI3K (phosphatidylinositol -3-kinase) multiprotein complex that participate in autophagosome nucleation. Death- associated protein kinase (DAPK1) is a calcium/ calmodulin (CaM) serine/threonine kinase for mediator of cell death [170]. PU.1, an ETS transcription factor known to regulate myeloid differentiation. Silencing of PU.1 in the adult hematopoietic tissue produces dysfunctional stem cells and impaires granulopoiesis by inducing a maturation block. Overexpression of PU.1 overcomes the differentiation block in SCa 1+/Lin- HSC with transduction of PML/ RARa fusion, as measured by the Gr-1 and Mac-1 expression [171]. Thus, pml/RARa represses PAPK2/PU.1 - mediated transcription of myeloid genes in APL,linking a novel autophagy mechanism of pml/ RARA degradation [172].

Figure 11:Molecular model of the gene regulation of retinoic acid (RA) action (George Zhu, January 1991, revised in 2012, further revised in 2018 and in this paper). Schematic alignment of the receptor protein. The two highly conserved regions, identified as the putative DNA-binding (C) and hormone- binding (E), a hinge region (D) and the non-conserved variable NH4-terminus (A/B) as described above. CAT:CAAT box, CCAAT-enhancer binding proteins(or C/EBPs); GC:GC box; TATA:TATA box. Note: In APLcells, pml/RARa fusion point is located in the first 60 amino acids from the N-terminus(A/B) of RARa [12,182].

The elucidation of the molecular basis of retinoic acid and retinoid pharmacology in APL has been illustrated in several publications [157,173-176] the detail molecular model of gene regulation had also been proposed by Zhu in 1990s [12,177,178]. As an approach to APL treatment, one possible the action of retinoic acid, A consensus sequence (TCAGGTCA motif) has been postulated for thyroid hormone (TRE) and retinoic acid responsive element(RARE)-containing in the promoter region of target genes [112]. High dose of RA-RARE-PML/RARa complexes in intracellular localization appears to relieve repressors from DNA-bound receptor [11,12,117,145,158,179] including the dissociation of corepressor complexes N-CoR, SMRT and HDACs from PML- RARa or partially PML-RARa/RXR [11,12,146,157,179]. Also release PML/RARa -mediated transcription repression [175]. This transcriptional derepression occurs at RARa target gene promoter [12,157,180]. Consquentially, PML-RARa chimera converted receptor from a repressor to a RA-dependent activator of transcription [156,157,160]. Co-activator complexes containing histone acetyltransferase (e.g. p300/CBP) are recruited. The resulting pml-RARA oncoprotein proteolytic degradation occurs through the autophagy- lysosome pathway [172] and the ubiquitin SUMO-proteasome system (UPS) [152-155] as well as caspase 3 [155] or lysosomal protease (cathepsin D) enzyme or/and EI-like ubiquitin-activating enzyme (UBEIL) induction [181]. An effect is to relieve the blockade of pml/RARa-mediated RA dependent promyelocytic differentiation and retinoic acid (9-cid RA, ATRA, Am80) in APL therapy Zhu G, March 1990- January 1991, revised in 2012). Here, RA can overcome the transcriptional repressor activity of pml/RARa [11,12,156,179,182]. The oncogenic pml/ RARa uncover a pathogenic role in leukemogenesis of APL through blocking promyelocytic differentiation. This oncogenic receptor derivative pml/RARa chimera is locked in their “off” regular mode thereby constitutively repressing transcription of target genes or key enzymes (such as AP-1, PTEN, DAPK2, UP.1, p21WAF/CCKN1A) [160-165] that are critical for differentiation of hematopoietic cells. This is first described in eukaryotes (Figure 11).

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Hypervitaminosis A: Symptoms, causes, and treatment

Hypervitaminosis A: Symptoms, causes, and treatment

Welcome to Clinical Records Currently

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Hair Treatment For Hair Fall

"The hair is the most extravagant adornment of ladies." Shimmering brilliant long hair is an indication of a solid individual. It flaunts to the world about our prosperity and imperativeness. Unfortunate hair is one of the initial barely any indications of Mental and additionally Bodily unwell being. As our body requires appropriate sustenance for its development and support, so does our Hair. Thus, eating the right food is the best Protein Treatment For hair fall. So let us have an outline with respect to what are the different supplements required and their job in keeping our Hair solid and forestalling hair fall.

Proteins:

Properly called the structure squares of our body, Proteins comprise up 98% of our hair. This makes proteins one of the most significant supplements for sound hair. It advances sound hair improvement cycles. There are numerous wellsprings of proteins. Of the protein sources nonetheless, the low fat sources like fish, poultry and heartbeats, for example, soy, ragi, and so on are liked. This is on the grounds that high fat eating routine is related with balding. Additionally taking protein in abundance is unfortunate for hair as it counterbalances the corrosive base equalization of the body coming about eventually to balding. It causes lack of minerals like calcium further exacerbating the going bald. People who are consuming less calories or are on a vegetarian diet should keep a tab on their protein allow and recharge themselves suitably.

Nutrients:

Nutrients are a gathering of most significant micronutrients. They must be renewed in our body by dietary methods as it were. One should ensure that he isn't insufficient on nutrients, as it is regular in the current way of life of steady pressure and weights, whereby one can't focus on great and smart dieting propensities. Lack if present will cause general bringing down of wellbeing and hair fall. How about we take a gander at the absolute most significant nutrients that advance hair development.

Nutrient A:

It is a basic supplement for solid hair. Going bald is one of the signs to measure Vitamin An inadequacy. Great Sources of Vitamin An are Yellow and orange hued foods grown from the ground green verdant vegetables like broccoli and Kale. Different sources incorporate liver, egg yolk, milk and spread. Oral Vitamin An enhancements are additionally a hotspot for recharging nutrient A yet one ought to be wary while accepting them as it might cause an overabundance of Vitamin A subsequent in Vitamin A hypervitaminosis.

Nutrient B:

Nutrient B are a gathering of nutrients that are significant for sound hair. Nutrient B lack is an explanations behind Baldness. Of the different nutrients, Biotin is one of the significant ones. Its insufficiency prompts eczematous changes and hair fall. Yeast is perhaps the most extravagant wellspring of Biotin. Nutrients B3 and B5 are significant for hair development. B6 is likewise significant as it helps in handling of the different supplements required for good and solid hair development.

Cell reinforcements:

These are the supplements comprising of nutrients C, E and beta carotene. They can be enhanced by means of a pill or diet.

Nutrient E:

Nutrient E is another significant supplement for solid hair. It has barely any veggie lover sources like green verdant vegetables including spinach, mustard green, parsley and so forth; entire grains, nuts like sunflower seeds and almonds. Additional virgin olive oil, avocados and so on.

Nutrient C:

The principle wellsprings of nutrient C includes a wide range of citrus products of the soil vegeables like tomato. Tomato likewise has Lycopene which additionally upgrades the skin and secures it structure UV beams.

Fundamental Fatty Acids:

One of the most significant fundamental unsaturated fats undoubtedly is Omega 3 unsaturated fats. They are chiefly present in ocean nourishments like salmon, fish and halibut. Veggie lover hotspots for omega 3 unsaturated fats are nuts like Flax Seeds, and pecan.

Minerals:

There are sure minerals that are critical to us as Micro just as Macro Nutrients. Model being Zinc, Silica, Selenium, Sulfur, Manganese. These are significant for improving the hair quality. These minerals are found in food sources like egg, chicken, egg, meat, cheddar, milk, pumpkin seeds and so forth.

Iron:

Iron is a significant mineral for enlarging the hair wellbeing. Its insufficiency prompts balding. Lack of iron prompts lower Hemoglobin levels consequently prompting drowsy blood dissemination and lower oxygen flexibly to the scalp. This thus prompts lessened supplements that are provided to the hair follicles, prompting hair fall.

Iodine:

Iodine is a miniaturized scale supplement mineral and is answerable for conferring solidarity to the hair. It is seen that individuals experiencing Hypothyroidism, which is caused because of lower levels of iodine in our body, have a high frequency of balding. The hotspots for iodine are Sea food like salmon, Potatoes, molasses, Lima beans, eggs, watercress, garlic and ocean growth. Likewise these days, normal salt is invigorated with iodine to manage iodine inadequacy in our day by day diet.

The current situation where the way of life has gotten unpleasant with our bustling timetables and work pressures, the rate of going bald is on a high. Lion's share of these can be dealt with essentially by fusing a sound dietary routine whereby we remember all the supplements for our ordinary dinners in a fair way. The significance of diet as a preventive and helpful device for enhancing our heads with wonderful and sound looking hair and as the best hair treatment for hair fall, can't be thought little of.

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Ken Jeong Answers Medical Questions From Twitter

hi this is dr. ken Jeong of dr. ken and welcome to Doc's support hey first question from Ashley at queasy big how do I know if I have the stomach flu or a hangover well honey did you drink last night mmm glug glug did you have food or did you have alcohol the Internet is not for stupidity ma'am the Internet is for smart established doctors like me and my friend Luis here think before you tweet okay another question okay Kellie underscore Sheridan one finally a great question how much vitamin C is too much yes sometimes too much vitamins is too much you always get these things on medical shows go on like should I take this supplement should I take this supplement and honestly you can get hypervitaminosis like if you go to G and C or some other stories they'll say like oh this you get like 2,000 percent of the recommended daily allowance of vitamin you know C you can actually get side effects and symptoms or GI symptoms from too much vitamins so it's probably good just to get like a hundred percent of the recommended daily allowance that's really all you need great question kelly sheridan i'm not supposed to pick favorites they told me not to the producer but you're my favorite bat petit macaron so it's like a weird skin tag under my eye that hurts when i rip it off what's up with that skin tag is a call to skin polyp in real life is render it can be anywhere along your body i think to rip off any lesion that you don't know about right under your eye I mean honestly I can't think of a more ill-advised stupid move than that they can numb up the area clip it off I've actually when I practice medicine someone had skin tags on their arm or extremities you could always freeze it off with liquid nitrogen and it doesn't hurt I highly recommend that you have a professional remove it professionally at captain handlebar ass now can we address the knee reflex tests at the doctor's office this has to be useless right no it's not useless we're not monkeys that use these just for props we're not the carrot top of doctors here and I can just show you right here this is a knee there's a tendon that connects the knee to the leg bone okay called the tibia there's a 10 in here you want to check the reflex of this you go oh let me just check that and what that does it's actually it checks really your whole nervous system in many ways to see that if your reflexes are intact low thyroid levels in your body which is very common called hypothyroidism you actually will be hyporeflexia and you would not be able to elicit much of a reflex so this sucker is very important okay don't mock our tools okay we're pros and we're sensitive emotionally mm-hmm-hmm busy so to ask how do you check your pulse good check it here you check it here even check it here on your leg a baby could tell you how to check a pulse oh no no you can't you can't ask any question on Twitter just don't defend shut up I'm sorry I see that it's just me Lois gotten the whole thing whatever okay moving on roogey Okubo says do I really need both my kidneys you know what that's part of the whole area of like kidney transplantation we've heard of people donating kidneys to other people in need who have kidney failure technically one can survive with just one kidney if it's as long as this normally functioning really good question hope I have more questions like this at Haley Nesbitt one says why do I always get cramps or spasms in my full leg newly every day hashtag ouch hashtag doctor help no sleep for me that I would definitely get checked out leg pain or leg spasm can be due to a multitude of things instead of saying what those hundred things are you actually need to see a physician for that to determine is it neurological a nation in nature is an inner penological in nature it can be do a lot of different things okay good question okay at hice underscore SCI underscore EHS quick what are the three parts of the brainstem first one to reply with the correct answer can surprise study test tomorrow smiley emoji with glasses okay so three parts of the brainstem are the medulla the pons and the midbrain and the medulla I believe control the breathing and the pons links the cerebellum to the cerebrum and the midbrain rudimentary vision and hearing all for me didn't have to look it up I'm a smart man shut up I forget all right I've been busy doing hangover movies asshole at Wigan underscore Stephen ask any doctors on here can I drink alcoholic substances while taking a rhythmic pet antibiotics hashtag doctor help hashtag doctors you know what actually that's a great question erythromycin which is what erythro pet is a trademarked name for it can upset the stomach and also is metabolized in the liver so I would check with your doctor see exactly how much you know biotics are taken i generally discourage any taken any alcohol level on antibiotics because a lot of antibiotics are metabolized in the liver you don't want to like overload them with too much things that can be toxic to your liver alright they sing 14s what's the part of the brain that's going to deal with my emotional breakdown tomorrow a hashtag AP psych there's many parts of brain that's gonna be dealing with kind of stress to take a test so i wish you the best of luck and i know you'll do well alright that's do bunny ask if anyone has any ideas for how to do a sinus headache and pressure I'm open to hearing if it's been going on for weeks at a time I would actually consider antibiotics I would consider going to your general practice doctor or even your nose throat doctor an ENT doctor to get treatment at dr. Claire Kane says help need emergency hiccup cure before clinic starts in approximately five minutes ah Saints care Jim all right at lice the pits why is my eye twitching oh my god stop first of all probably stop using words like oh my gosh stop maybe get some more sleep drink less caffeine alright next at CD 101 I wan burp but why can't I I don't know I'm not your diaphragm at cbs- 540 my kidneys hurt it's drinking a lot of water a bad thing any doctors on here actually drinking too much water can lead to some problems I would actually go see a general practice doctor get your sodium level checked because you don't want to have too much hyponatremia anyway this doctor supported I'm dr. ken Jeong if dr. Ken and I would like to thank some of you on Twitter for your amazing questions and the others you suck you really do shut up Louis they do

https://youtu.be/9oFQzvPUzeU

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Advantages and Disadvantages of Alternative Medicine

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There are reasons why people chose alternative medicine and reasons why they avoid it, preferring conventional medicine. Alternative medicine is safer than standard health treatments and usually works. It's true that it can't be used in severe conditions like car accidents or other severe emergencies, but be that as it may, there are enough situations in which alternative medicine is recommended. When it comes to emotional and spiritual needs, non-conventional medicine may come up with the solution. Furthermore, it's better for preventing illnesses than standard medicine. More and more physicians nowadays agree upon the benefits of alternative medicine and also even advise their clients to choose the best natural treatment for them.

One of the advantages of alternative medicine is that it encompasses a broad range of therapies, treatments and products, thus the search for obtaining positive results doesn't flow on a narrow path at all. A pretty important disadvantage states the idea that, even though the expenses of using acupuncture or chiropractic are sometimes covered by health insurances, the majority of alternative treatments are not reimbursed.

There are certain risks that come along with the usage of natural remedies. Despite the use of herbs throughout the years and even ancient times, not all of them have been studied regarding their safety and efficiency. There are issues concerning their purity and their possible interaction with other substances related to conventional therapies. The majority of information regarding herbs have been perpetuated throughout history and with the help of tradition. Many people assume that herbal medicines are better than synthetic drugs simply because, well, they are natural and not synthetic, therefore present no risk. But they are not risk free; they can do more harm than good if taken without having the details of their effects over the body.

People might abuse of natural medicines the same way as they do it in the case of synthetic drugs. They have the misconception that if unconventional medicine consists of herbal products which are natural, then there is no harm done if they triple the dosage or more. This is totally wrong and can have serious consequences. Take vitamins for example. They are just vitamins, right? They can't possibly do any damage inside the body. But they do. Vitamin overdosing or vitamin toxicity can lead to unpleasant effects depending on the vitamin that has been taken one too many times. Vitamin A over dosage can cause liver problems, osteoporosis, hair loss and other dangerous effects and Hypervitaminosis D leads to dehydration, vomiting, anorexia and even kidney stones.

An advantage of using herbal remedies concerns the effectiveness related with chronic health issues that don't respond well or even at all to traditional medicines. If long term medication is needed, then herbs are pretty much safer than conventional drugs. The alternative medicine industry takes advantage from this and keeps evolving and developing due to the constant need for natural remedies.

Another advantage is the low cost of herbal products compared to synthetic drugs which are highly priced for the simple reason that researching and testing the products is expensive. Furthermore, herbal products can be bought without a prescription and are easy to procure. The availability of natural remedies is outstanding; chamomile for example can be easily picked out from a nearby field.

The advantages of using herbal medicines are numerous, but so are the disadvantages. The best idea would be to consider modern medicine according to the severity of the illness, to consult a physician upon the proper medication and dosage and if you do chose the alternative medicine, try to gather enough information upon both kinds of treatments, natural or synthetic, so you may reassure yourself that you took the right decision to balance your health situation.

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