How to Get a Good Looking Body

by: Aquila
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It is often possible to get very near to that amazing body you always have dreamt of. However, it can cost a lot of effort and time to get all the way to the goal. Still you can achieve a lot with less time and cost, as long as you are persistent in your endeavors. Here are some advices to get a better looking body:

You should first plan how you will look. You must decide which body parts you want to be muscular and have round curvatures, and which parts you want to keep slim and gracious.



Most persons will probably feel most well with a balanced body shape: Muscular in the area under the shoulders, strong breast muscles, strong muscles around the shoulders, moderately muscular arms, slim around the mid, firm but not too great belly muscles, round and muscular buttocks, muscular thighs and strong calves.

Other persons will prefer a more v-shaped figure with more muscle mass on the top, and somewhat less at the bottom.

You must also decide if you want changes in you posture, and define these changes. By consistent training you can greatly improve your posture. Your plan must however be realistic. You skeleton sets some limitations of shape and size you cannot surpass.

You must also decide if you want to loose body fat or perhaps gain some fat on your body. You must decide how important it is for you to get a better general condition and gain general wellness, and decide if these goals are more important than improvement in body appearance.

Then you must make a plan for your training, your diet and otherwise for your lifestyle.

The training should contain exercises to gain muscle mass and strength, exercises for your general condition and exercises to get a flexible and agile body. Improvement of posture will result from the combination of stronger muscles and flexibility training.

A repetitive three day's plan with training 45 minutes to one hour each day will give you great results, if the plan is consistently adhered to:

In day one you perform exercises to gain muscular mass and muscular strength, like weight lifting or analogous training methods. You should train all your muscles, but those body parts where you have planned to get must muscles, should be exercised the most.

If you have posture problems, curvatures or bendings in body parts caused by weak muscles or bad habits, these can often be helped for by strengthening the muscles that flex the body parts in the opposite direction. If however, the bending is due to scoliosis or some other disease under progression, the problem need professional treatment.

In day two you do exercises that enhance your general condition, like jogging, swimming, playing ball, and cycling. Choose something that you find funny, and you can also vary between different activities. It is also good to invite some friends to exercise together with you on this day.

In day three you do no hard activities, but stretch out and do exercises to improve your body's flexibility in all natural directions. Yoga exercises are very good to enhance your flexibility and improve your general health. It is also advisable to set out some time for meditation in day three.

The diet is important for achieving and maintaining a good body shape. You must eat 3-5 good meals each day, but do not over-eat.

You need enough proteins. Every meal must have some protein-rich food sources, like: Fish, seafood, lean meat, lean cheese, foul or mushrooms. Also nuts, almonds and sunflower seeds contain protein. These are good food sources, but because of the content of fat, you should not consume too much of them. Eggs are a good protein source, but eat it in moderate amounts to avoid getting too much cholesterol.

In each meal you need some fat from natural sources and you need some carbohydrates. You should however control your consume of fat and sugar. You must not add very much fat or sugar to your food, and you must not eat too much of food with a high content of fat and sugar.

Also vary between different natural fat sources to get all the essential fatty acids you need: Fat fish, nuts, sunflower seeds, almonds, olive oil, rape oil, canola oil, flaxseed oil, marine oils, nut oils and sunflower oil. Do not use only soy oil or corn oil as many people do. Neither use much butter. Do not consume chemically altered fat.

As sources of carbohydrates use mostly full corn bread or cereals, peas, lenses or beans, but also add some sweet fruit.

In order to get enough fiber, vitamins, minerals and anti-oxidants, every meal must have some fruit or vegetables in a natural condition. Supplements of vitamins, minerals and anti-oxidants and special nutrients can be of help.

A training program as depicted combined with a good diet, will often make you loose fat over time. However, if you are heavily over-weight, a more specific slimming regime can be necessary.

About the Author

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Knut Holt is an internet consultant and marketer focusing on health items. At his web-site you can find health advices, training supplements, vitamins, minerals and natural drugs against common diseases, like: Acne and skin problems, over-weight, hypothyroidism, hemorrhoids, heart trouble, joint pain and rheumatism, depression, constipation and digestive trouble, cold, flu, men's and women's problems, and more.

Is Yoga Right for You?

by: James Pendergraf

A lot of women perform yoga exercises not just to lose weight or maintain proper body weight but also because they want to be healthy emotionally and mentally. Yoga is also known to contribute to the decrease of a number of problems during menstruation, pregnancy, and menopause. There is research to prove this, but it’s easy to see the physical, mental, and emotional benefits evident on those women who practice yoga. 

Yoga Helps You Cope with a Busy Lifestyle 

If you are still undecided about yoga, then there are a number of things about it that will help you decide. One of these is its relevance to today’s world, even if it is one of the most ancient practices of all times. 

Yoga is considered as the perfect solution that helps women cope with their busy days and the resulting mental and physical stress. This is especially true if they are working moms who need to deal with the pressures of both work and home. Sitting behind a desk or even driving a car for several hours every day would already result in a woman’s having shoulder and back problems that will not only affect their lives at the office but also at home when they are dealing with the family and household chores. 

Choosing the Best Yoga Style Helps 

Deciding if yoga is really right for you would also require you to choose the yoga style that will fit your lifestyle, personality, and needs. If you are a working mom, your yoga needs might differ from those women who are just working at the office for long hours every day. As such, it is very important to find the perfect teacher or trainer who has the right knowledge about yoga who is not only qualified and accredited but also compassionate and sensitive to what you really need. 

Yoga Styles: 

1)Vini Yoga. This is a personal practice that could be developed through the incorporation of meditation, proper breathing, and posture as well as prayer and rituals. The amount of all these aspects that could be incorporated into your yoga practice will have to be changed though as a woman and her needs change and develop. Therefore, if you are still a student or a young professional, then the physical aspects of yoga might be more important for you, while older women might focus more on the spiritual, mental, and emotional aspects. 

2)Ashtanga Yoga. Also considered as the power yoga, this style is known to be flowing and athletic. Breathing is very important in this yoga style as a woman flows through a series of postures. This is able to generate a lot of sweat and body heat, thus helping women detoxify their bodies. 

3)Ananda Yoga. This yoga style makes use of temperate poses. This is gently meditative and perfect for those who would like to practice a yoga style that helps them to look inwards so they can focus on making their emotions better.

Diet-To-Go

Diet-To-Go is a diet food delivery service that provides whole-day meals that are freshly prepared, tasty, nutritious and conveniently packed for people who are always on-the-go. You might be surprised but Diet-to-Go has been serving its customers for the past 18 years.

Their goal is and has always been for dieters and health conscious individuals to love their meals so much that achieving their goal of losing or maintaining weight or simply improving overall health and well-being becomes even a lot more easier to achieve.

Diet-to-Go has five weeks worth of different diet plans that feature an excellent variety of food items. Moreover, for people who are concerned of their fat or sodium intake or are trying to keep their cholesterol levels in check, two of their plans, the traditional and vegetarian, are both low in fat, sodium and cholesterol.

Diet-to-Go also boasts of having their foods prepared by well-trained chefs and that they strictly adhere to the dietary guidelines issued by the:

* American Heart Association
* American Cancer Society
* American Diabetes Association
* American Dietetic Association

So, how does Diet-to-Go work? Diet-to-Go works closely with its customers. First, they will ask you what your goal is, e.g., are you trying to lose weight, do you want to eat healthier, are you just looking to save time preparing or cooking meals or do you have any other objective you wish to achieve. Then they will need to know if you have any dietary restrictions such as food allergies, taste preferences or if you are on a medically-supervised diet. Based on your responses and any other pertinent diet information you can provide, a Diet-to-Go meal counselor will “recommend” an appropriate and nutritious food plan for you.

I wrote down “recommend” because they do allow you to substitute your pre-planned meal if it does not appeal to your palette. This is for a fee, of course, but Diet-to-Go does give the assurance that they prepare your meal plans with the end-goal of ensuring that you don’t waste your money on food you can’t eat or don’t like. As I’ve mentioned, you can substitute from a list of available dishes. They even give you the option to “double-up” on your favorite foods if it is available during a particular pickup.

If despite the option to substitute or double-up you still feel unhappy with the meals you get, they won’t make you pay for it. The cost of the food or meals you are unhappy about would be credited towards your next purchase.

I’m sure the next thing you would want to know is if guarantee weight loss with their diet food plan. While they don’t offer a money-back guarantee, they do have an amazing track record of helping thousands of busy new mothers, executives, home-based individuals and many others shed unwanted pounds. Furthermore, customers themselves say they lose from 2 to 3 pounds per week while on a full Diet-to-Go meal plan.

If you are worrying about the cost, you don’t have to. The price of their meal plans are extremely flexible because it depends on the number of meals per day that you order, the calorie level you are required to be on (so if you are trying to lose weight, this won’t be a lot), whether or not you want to include snacks, etc. An average customer actually spends only about $90 per week for a full meal plan.

Moreover, Diet-to-go first discuss with the customer their objectives and other considerations before they put a price tag on a meal plan. Plus, they always make sure to mention to customers the specials or any other promotions they are currently offering prior to the purchase.

So what are you waiting for? Start on your very own Diet-to-go . That’s all it takes for you to start eating healthily and lose weight doing it.

Do not deprive yourself. It’s a proven strategy that has worked for thousands of others. It will work for you, too!

Homoeopathy - The Alternative Choice

Homoeopathy is energy medicine, it is a very gentle medicine and is said to have no side effects as there is no physical substance in the remedies. As it treats the whole person, babies and children respond very well to it. As it's known for its 'safe' reputation, pregnant mothers are known to use it quite frequently as well. It works because it looks past your symptoms and listens to you and what you are saying. To help explain what is wrong, Homoeopathy could help your immune system cure your symptoms.

Energy Medicine

Homoeopathic medicine, by a special process of attenuation or dilution, is able to use the vital energy from any substance at all - from plants to animals, to metals to minerals, to the sun and moon and even to music.

In Homoeopathy we then look at the differing characteristics from these substances. For example plants have different likes and dislikes, some like it hot, some like it shady or damp. This helps to make them flower seed and survive as a species. Plants are very sensitive and feel a lot - so do plant people. Many people have heard of Arnica, the flower which grows at the foot of a mountain. It is told to be very good for bruises and accident trauma i.e. falling down a mountain! Nature is kind and supplies us with all our needs.

In Homoeopathy the essential characteristics of the individual person who needs treating are then matched with similar characteristics from one of these individual substances. This is called "like cures like"

Like Cures Like

A classic example of this "like cures like" is the prescription of Allium Cepa (onion) to cure a cold or Hayfever. If you peel an onion you may develop watery eyes, sneeze with discomfort and a woolly head, all symptoms like Hayfever or a cold. If your cold or Hayfever symptoms exactly match the symptoms produced from peeling an onion this remedy will cure you.

Why Energy Medicine?

When we have physical, mental or emotional symptoms our vitality is low and has allowed illness to come in - "the defences are down". This is because we are out of balance or even suffering on an emotional (or energetic) level. This energy depletion needs energy to stimulate a return to health. How often do you hear people say they have no energy or they are depressed?

How do I use Homoeopathy?

Homoeopathy is used in many guises but the best and most dramatic results come from classical Homoeopathic treatment when the person's characteristics are matched with a remedy. This process involves a consultation with your Homoeopath. The first can take 1-2 hours as your Homoeopath tries to understand exactly what your inner disturbance or imbalance is. The result from one dose of a Homoeopathic remedy when prescribed like this can be life changing. You will feel empowered to fulfil your life's purpose as your energy and confidence are increased. As you deal with your past and present life situation your physical symptoms will disappear and you will be able to move on from being stuck and in pain either emotional or physical. A patient once described it as "archiving all her old files."

Your Remedy

Each remedy is carefully selected and then prescribed for you, not for your physical symptoms. A remedy may often be selected on the basis of your physical and emotional reaction to a traumatic situation. For example if you have car accident and have headaches since then, it is the trauma of the accident which needs treating before the headaches will go away.

Downloading Symptoms - Our Biography Becomes Our Biology.

All physical symptoms, whether they are pathological (with tissue changes) or functional (stress related), result from our feelings and how we experience life. When you see your Homoeopath you will realise from your consultation how true this is (often we do not want to admit this!) and that the illness has not just landed on you for no reason at all it has landed because you are vulnerable and often this physical illness if it is acute (like a cold or flu) will just ease you out of the situation. For a while giving you time to rest and recuperate and then be are able to cope again mentally. If you treat your flu or cold Homoeopathically you will get better much quicker as all your symptoms are taken into account including how you felt before you were ill. Downloading is shown when we blush - this is a direct result of acute embarrassment or discomfort in front of other people.

Stress

Our body is very clever and knows that we cannot sustain high stress levels for to long without the mind giving in. Thus mental illness is the most disabling form of illness as we cannot communicate properly or function properly in the world as our perception of the world changes. So the mind, to protect itself, downloads symptoms to the physical body.

Once you have a physical symptom you have a reason to go to the doctor or hopefully, now your Homoeopath. Before this you know something is wrong but you cannot put your finger on it, so don't feel able to go to a professional for help. However at this time you could go to your Homoeopath who would be able to listen to how you are feeling and treat you before you have physical symptoms. Too often we wait until we are in physical pain having ignored the emotional pain.

However, once we have physical pain it is easier to go to a doctor and say "I have a terrible pain in the back", the doctor will question and advise further. At this point the back pain is treated but the support the person desperately needs isn't. (It will only go as deep as the pain killers).

If you go to a Homoeopath you can explain about your situation and then perhaps unravel what is the source of the pain. It is likely in the instance of back pain that someone is in such desperate need for some support and that their main body support (their back) is saying it cannot take the strain any longer.

Back pain often occurs when a person's support is lost - for example when a much loved relative or partner has died or left. In this instance too, migraines often occur. This understanding of the situation may help your healing because you have been listened to - but it may not help your pain at all, until you are prescribed a remedy to match your symptoms.

When the Homoeopath hears your story, she or he will be able to prescribe a remedy that will either enable you to find/ask for support or to take on the stress in a different way. You will find that you are empowered to change your life and may often feel as though a weight has been lifted from your shoulders. Your pain will disappear or improve enormously.

It is very difficult to explain the feeling experienced after a good remedy. People are often on an energy high at first and then settle down to a level where they can manage their lives to their best advantage. The best way to experience this is to try Homoeopathy! Even if you feel there is nothing wrong with you can benefit from it to maintain good health.

Homoeopathic remedies are very powerful substances and much like a doctor your Homoeopath has to undergo 4-5 years of structured training and assessment to be able to prescribe accurately. Homoeopathy can deal with pathology as it looks at the individual person not the illness, so all diseases could possibly be helped with Homoeopathy to the extent that it is possible for that person.

Each person's expectation of Homoeopathy will be different and generally expectation is matched by the right improvement and time frame. However, sometimes your improvement can be beyond expectation and a quick and extraordinary process if the remedy picture is clear but often these days the picture is not so clear so you may have to be patient. I always ask patients to see me three times even if they are feeling good, just to ensure that there has been a fundamental change in their constitution that will last.

People often come back for a booster remedy every 6 months or when they feel a bit stuck in their life. The remedy can give them the required energy to create a change. If you see a Homoeopath please ensure that they belong to a registered body such as the Society of Homoeopaths or HMA.

DRINKING WATER ON EMPTY STOMACH

It is popular in Japan today to drink water immediately after waking up every morning. Furthermore, scientific tests have proven its value. We publish below a description of use of water for our readers. For old and serious diseases as well as modern illnesses the water treatment had been found successful by a Japanese medical society as a 100% cure for the following diseases:

Headache, body ache, heart system, arthritis, fast heart beat, epilepsy, excess fatness, bronchitis asthma, TB, meningitis, kidney and urine diseases, vomiting, gastritis, diarrhea, piles, diabetes, constipation, all eye diseases, womb, cancer and menstrual disorders, ear nose.


METHOD OF TREATMENT
1. As you wake up in the morning before brushing teeth, drink 4 x 160ml glasses of water

2. Brush and clean the mouth but do not eat or drink anything for 45 minute

3. After 45 minutes you may eat and drink as normal.

4. After 15 minutes of breakfast, lunch and dinner do not eat or drink anything for 2 hours

5. Those who are old or sick and are unable to drink 4 glasses of water at the beginning may commence by taking little water and gradually increase it to 4 glasses per day.

6. The above method of treatment will cure diseases of the sick and others can enjoy a healthy life.


The following list gives the number of days of treatment required to cure/control/reduce main diseases:

1. High Blood Pressure (30 days)

2. Gastric (10 days)

3. Diabetes (30 days)

4. Constipation (10 days)

5. Cancer (180 days)

6. TB (90 days)

7. Arthritis patients should follow the above treatment only for 3 days in the 1st week, and from 2nd week onwards – daily.

This treatment method has no side effects, however at the commencement of treatment you may have to urinate a few times.

It is better if we continue this and make this procedure as a routine work in our life. Drink Water and Stay healthy and Active.

This makes sense ..

The Chinese and Japanese drink hot tea with their meals ..not cold water. Maybe it is time we adopt their drinking habit while eating!!! Nothing to lose, everything to gain...

For those who like to drink cold water, this article is applicable to you.
It is nice to have a cup of cold drink after a meal. However, the cold water will solidify the oily stuff that you have just consumed. It will slow down the digestion.

Once this "sludge" reacts with the acid, it will break down and be absorbed by the intestine faster than the solid food. It will line the intestine.
Very soon, this will turn into fats and lead to cancer. It is best to drink hot soup or warm water after a meal.

A serious note about heart attacks:

· Women should know that not every heart attack symptom is going to be the left arm hurting,

· Be aware of intense pain in the jaw line.

· You may never have the first chest pain during the course of a heart attack.

· Nausea and intense sweating are also common symptoms.

· 60% of people who have a heart attack while they are asleep do not wake up.

· Pain in the jaw can wake you from a sound sleep. Let's be careful and be aware. The more we know, the better chance we could survive...

A cardiologist says if everyone who read this, tell it to everyone they know, you can be sure that we'll save at least one life.

A TRAIL in liver diseas

The molecular mechanisms underlying cholestatic liver disease, which is caused by disrupted bile flow, are relatively unknown.¹ A paper in the Proceedings of the National Academy of Sciences

now points to a proapoptotic pathway in the liver involving death receptor 5 and tumor necrosis factor–related apoptosis-inducing ligand that potentially could be targeted to help treat the disease or prevent progression to liver failure.

At least two companies are developing antibodies that agonize death receptor 5 (DR5) to treat cancer. However, researchers polled by SciBX warned that targeting the pathway to interfere with apoptosis in the liver requires caution, and they suggested other approaches to restore bile acid homeostasis and to combat fibrosis associated with the disease.

Autoimmunity and bacterial infection are two potential causes of bile duct deterioration that can lead to cholestasis (bile duct blockage). Although cholestatic liver disease is less frequent than disease resulting from alcohol abuse or chronic hepatitis infection, a direct consequence of cholestasis is the accumulation of toxic levels of bile acid in the liver. Over time, this can lead to liver fibrosis, cirrhosis and end-stage liver disease.^{2, 3}

Two of the best studied cholestatic liver diseases are primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC). Urso ursodiol, a bile acid derivative marketed by Axcan Pharma Inc. in North America, is the only drug approved to treat PBC. There are no approved drugs for PSC, which is also associated with significant risk for cholangiocarcinoma or cancer of the bile ducts.

In the PNAS paper, researchers from Japan and Australia reported that activating a death receptor–dependent apoptotic pathway in mouse liver induced bile duct inflammation and blockage, suggesting the pathway might play an important role in cholestatic liver disease.⁴

"Hepatocyte injury is likely due to a combination of death signaling mechanisms activated by TNF and FasL [Fas ligand] as well as TRAIL."

Rebecca Pruss
Trophos S.A.

In wild-type mice, intraperitoneal administration of antibodies that target and agonize DR5 elicited severe jaundice and increased serum levels of bilirubin and alkaline phosphatase—two established biomarkers of liver dysfunction—compared with administration of control IgG antibody.

Histological examination of mice that received the anti-DR5 mAb revealed hardening of the extra-hepatic bile duct from fibrosis and inflammatory cell infiltration.

In murine ligation models of cholestatic liver disease, knocking out DR5 or its ligand tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) delayed onset of hepatocyte damage and inflammation compared with what was seen in wild-type controls. In the same models, TRAIL and DR5 knockout also led to significantly better survival rates than those of wild-type counterparts (p<0.001).

Finally, an examination of serum samples from PSC patients revealed that TRAIL expression on cholangiocytes was substantially higher than that seen on cholangiocytes in healthy controls (p<0.05).>

The authors proposed, "TRAIL/DR5-mediated signaling may be involved in the pathogenesis and pathological features of chronic cholestatic diseases in human beings, particularly in the diseases with progressive destruction of the bile ducts."

One potential approach to targeting TRAIL and DR5 would be to use a soluble DR5 that binds TRAIL before it can interact with DR5 on liver cells. Indeed, a soluble DR5 decoy receptor has previously been shown to inhibit TRAIL-mediated apoptosis in multiple cancer cell lines.⁵

However, because TRAIL can bind other receptors besides DR5, and because the binding interactions between TRAIL and DR5 are quite complex, this approach would require further in vivo testing, said Shelia Violette, VP of research at Stromedix Inc., a developer of fibrosis therapeutics.

Violette told SciBX that an alternative strategy might be to develop an antagonist anti-DR5 mAb that does not trigger DR5 oligomerization and subsequent apoptosis, as potentially occurs with agonist anti-DR5 antibodies like the one used in the paper.

At least two biotechs are developing antibodies that agonize death receptors. Lexatumumab (HGS-ETR2), an antibody from Human Genome Sciences Inc. that agonizes DR5 (TRAIL-R2), is in Phase I testing for cancer. The company's mapatumumab (HGS-ETR1) antibody that agonizes DR4 (TRAIL-R1) is in Phase II testing for cancer.

AMG 655, an mAb from Amgen Inc. that agonizes DR5, is in Phase Ib/II trials for multiple cancers.

In a Phase I trial of lexatumumab in patients with advanced solid malignancies, the highest dose of the antibody was associated with asymptomatic elevation of liver enzymes.⁶

Targeting components of the apoptotic pathway downstream from DR5 could be an effective strategy in liver disease, said Gregory Gores, professor of medicine and physiology and chair of the Division of Gastroenterology and Hepatology at the Mayo Clinic.

In murine bile duct ligation models, Gores and colleagues have shown that a broad-spectrum small molecule caspase inhibitor (IDN-6556) lowered hepatocyte apoptosis, liver injury and hepatic fibrogenesis compared with what was seen in saline-treated controls.⁷

Pfizer Inc. gained IDN-6556 when it acquired Idun Pharmaceuticals Inc. in 2005. At that time, the compound was in two Phase II trials in liver transplantation and HCV. According to Pfizer's 2008 pipeline report, the compound (renamed PF-3491390) is in Phase II testing in liver fibrosis.

However, Scott Friedman, professor of medicine and chief of the Division of Liver Diseases at Mount Sinai School of Medicine, warned that the general strategy of inhibiting apoptosis in cholestatic liver disease might inadvertently promote cancer.

"Caspase inhibitors may block apoptosis in liver cells. However, by so doing, they might also increase the likelihood that cancer appears, so caution is warranted as we move forward with these agents," he said. "This particularly applies to patients with primary sclerosing cholangitis, which is consistently associated with increased risk for bile duct cancer. Consequently, we have to be careful with how we use this strategy in some forms of cholestatic liver disease."

Top of page

Timing is everything

Even if more animal data confirm that TRAIL and DR5 interactions underlie cholestatic liver disease, the question remains how early in the disease treatment should begin. Once major bile duct damage has occurred, potential therapies like anti-TRAIL antibodies may be too late to the party.

Additional studies in mouse models and larger animals should provide a better understanding of how and when it is most effective to inhibit bile duct damage, said Mark Smyth, a principal investigator on the PNAS paper and head of the Cancer Immunology Program at Peter MacCallum Cancer Centre.

At Stromedix, Violette said there is a clear rationale for considering the company's STX-100 mAb in cholestatic and fibrotic liver diseases, such as PSC and biliary atresia, because its target, integrin _v6, is upregulated in fibrotic liver disease as a result of biliary injury.

For example, in separate studies of murine bile duct ligation models, a small molecule inhibitor of integrin _v6 and an anti–integrin _v6 antibody lowered progression of biliary fibrosis.^{8, 9}

STX-100 is in a Phase I safety trial in healthy volunteers, with plans to begin a Phase IIa trial next year in patients with chronic allograft nephropathy (CAN), Violette said. Stromedix in-licensed the compound from Biogen Idec Inc.

Intercept Pharmaceuticals Inc. is looking at targeting stages of cholestatic liver disease that generally occur prior to cirrhosis. "Our strategy in testing farnesoid X receptor agonists in cholestatic diseases like primary biliary cirrhosis has been to exploit their hepato-protective regulation of bile homeostasis," said Mark Pruzanski, president and CEO.

Bile acids regulate their own biosynthesis and transport by binding to and activating the farnesoid X receptor (FXR). Activation of FXR initiates transcription of genes that decrease the concentration of bile acids within hepatocytes.

"The rationale for agonizing the farnesoid X receptor is twofold—first, to downregulate transcription factors that drive bile synthesis, and second, to upregulate bile transporters in hepatocytes and thus help cells clear out excess accumulated bile acids that can cause toxicity," Pruzanski said.

Intercept's FXR agonist INT-747, a semisynthetic bile acid derivative, is in two ongoing Phase II trials to treat primary biliary cirrhosis in pre-cirrhotic patients—one trial as a monotherapy and the other in combination with ursodiol. The primary endpoint of the trials is a reduction in serum alkaline phosphatase.

Rebecca Pruss, CSO of Trophos S.A., noted that other tumor necrosis factor (TNF) superfamily ligands besides TRAIL might also have to be targeted to adequately treat liver disease.

Even if TRAIL and DR5 signaling is found to be an initiating event leading ultimately to liver failure, "hepatocyte injury is likely due to a combination of death signaling mechanisms activated by TNF and FasL [Fas ligand] as well as TRAIL," she said. "Therefore, all of these pathways may need to be addressed in treating more common types of hepatic toxicity due to bile duct occlusion, hepatitis C and nonalcoholic steatohepatitis."

Trophos' TRO19622, a small molecule with a cholesterol-like structure that interacts with the mitochondrial permeability transition pore (MPTP), is in a Phase IIa trial to treat nonalcoholic steatohepatitis (NASH).

Indeed, targeting inflammation upstream of fibrosis and cirrhosis could potentially limit the need for antifibrotic therapeutics.

"We know that an inflammatory stage typically occurs prior to onset of liver fibrosis. Moreover, even though this stage is asymptomatic in most patients, it could nevertheless be detectable during routine blood tests as an abnormal elevation of liver enzymes," said Friedman. "In such instances, administering an efficacious anti-inflammatory could potentially block or at least slow onset of fibrosis. Perhaps this wouldn't rule out the use of antifibrotic agents, but it could improve their efficacy in some form of a combination therapy."

Next steps

Smyth said another useful next step to better understand the role of TRAIL and DR5 signaling in cholestatic liver disease would be to identify potential mutations and polymorphisms in the relevant genes in patients with PSC.

Gores wanted to see additional proof that the models used in the PNAS paper were actually developing PSC. "At the moment, there are no good animal models of PSC," he said. "The mice used in the paper could thus potentially help fill this gap. However, I would like to see some additional readouts—in particular, a longer observation period to confirm that the animals develop biliary cirrhosis and proof of cholangiographic features of PSC."

Cholangiography is a way of imaging the bile duct, most commonly using X-rays or MRI.

In PSC and PBC, Pruss said, "autoimmunity may lead to the production of agonist DR5 autoantibodies, and this possibility should be explored in order to block these antibodies from activating DR5" and triggering apoptosis.

A second possibility, she said, is that "factors such as cytokines or bile acids may contribute to increased TRAIL expression in cholangiocytes." Thus, inhibiting these factors rather than targeting TRAIL or DR5 directly could offer other therapeutic strategies.

Violette emphasized the importance of additional in vivo work to determine the differential effects of TRAIL and DR5 blockade on cell types within the liver.

DR5 is also expressed on hepatic stellate cells, for which inducing apoptosis could be beneficial to the treatment of fibrosis. This is directly opposite to what's seen in the PNAS paper with cholangiocytes, where apoptosis can trigger biliary injury and subsequent fibrosis. Thus, Violette said, additional in vivo studies in liver fibrosis models may be useful to better understand the consequences of TRAIL and DR5 blockade in the liver.

Friedman suggested that similar next steps could even include humans.

"High-resolution confocal microscopy of immunostained tissue from patient liver explants or biopsies would be important to determine the relative expression of DR5 on hepatic stellate cells and cholangiocytes," he said. "These expression levels could then potentially guide the choice of a proper dosing regimen for antagonists of TRAIL/DR5 apoptotic signaling, since stellate cells may also be sensitive to these agents."