ParActin : Scientific Breakthroughs for Bone, Joint and Muscle Health

ParActin : Scientific Breakthroughs for Bone, Joint and Muscle Health ® An eBook brought to you by Informing and Educating Natural Products Retailer...
Author: Ralph Gilbert
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ParActin : Scientific Breakthroughs for Bone, Joint and Muscle Health ®

An eBook brought to you by

Informing and Educating Natural Products Retailers On Dietary Supplements, Herbs, HABA, Homeopathy, Foods

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Table of Contents

3 Fighting Inflammation, The Body’s Silent Killer    4 NF-kB: The Master Inflammation Switch    4 ParActin : The Natural NF-kB   

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Inhibitor

  

5 Keep Moving! Joint, Bone &

Muscle Health for Everybody

5 ParActin : Healthy Joint Support    8 ParActin : Healthy Bone Support   10 ParActin : Healthy Cartilage Support   12 ParActin : Muscle Health and Recovery   16 ParActin : Masters the Immune Balancing Act   17 ParActin : Organic, Non-GMO, Vegan Choice   18 FAQs   19 References   

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Fighting Inflammation, The Body’s Silent Killer

What’s scarier than the boogeyman you know? The boogeyman you don’t know. Well, chronic inflammation is indeed the boogeyman you don’t know because it isn’t felt until the pain or dysfunction from years of its silent reign inspire physician visits. Cancer. Alzheimer’s. Autoimmune diseases. Depression. What do all these conditions have in common? They have been linked to chronic inflammation. It seems impossible that one thing can be responsible for so many problems, but a growing body of medical research is revealing that long-term, systemic inflammation that occurs when one’s immune system goes into overdrive— sending out cells that attack healthy tissues, along with the unhealthy—may be at the root of many prevalent diseases. The medical and nutraceutical research communities are highly aware how chronic inflammation damages the human organism in many ways. In vivo research has outlined and clarified the cascade of reactions causing unhealthy inflammation. Figure 1: Inflammatory Response

Inflammation, however, is not an unjustified biological response. It is critical for our survival and is the body’s natural mechanism to defend against a diverse variety of pathogens including bacteria, viruses, fungi, tumors and other harmful agents (e.g., chemWhen cells are injured, the mast cells icals, radiation, burns and wounds). Inflamsignal an inflammatory response through a series of biochemical signals. NF-kB is mation is a complex reaction of the body in released and results in the expression of several pro-inflammatory proteins (e.g. COX2 and iNOS) and proresponse to cellular injury (such as a bruise). inflammatory cytokines (e.g. interleukin-2, interferon-gamma) It is marked by tissue swelling, capillary dilation, antihistamine activity, redness, heat and pain. It serves as a mechanism initiating the elimination of noxious agents and of damaged tissue (see Figure 1).

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Two types of inflammation are associated with imbalanced immunity. Classical inflammation is usually associated with pain and may result from an overactive immune system that is constantly “turned on.” This causes the self-attack mode that can lead to several disorders such as irritable bowel syndrome, psoriasis and rheumatoid arthritis, among others. Silent inflammation happens when the immune system continues its self-attack mode at the cellular level, affecting certain organs such as the heart or brain without the individual perceiving pain or discomfort. He or she may experience fatigue, muscle stiffness and headaches, however. As we age, our immune systems go downhill, providing us with an ever-smaller reservoir of cells capable of responding to the increasing amount of damage inside the body and tissues. It’s a sad story. The body hurts itself by trying to fix problems it can’t resolve. Most people reach for common nonsteroidal anti-inflammatory drugs (NSAIDs) like aspirin and ibuprofen to ease aches and pains when we bang up muscles or joints or experience headaches and colds. Unfortunately, NSAIDs can rip the stomach lining and gastrointestinal tract, contributing to even more inflammation in the long run. COX-2-inhibitor drugs were designed to block just the inflammatory functions of the COX-2 enzyme, leaving the stomach-protecting functions of COX-1 intact. However, research has shown an increased risk of heart attack and stroke among users. The current hot theory suggests that depression may be caused by cytokine-driven inflammation in the brain. A study published in JAMA Psychiatry found that people with clinical depression had levels of brain inflammation 30% higher than those in a control group (1). This may be one reason why half of clinically depressed people don’t respond to antidepressants; they cannot tackle inflammation levels.

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NF-kB: The Master Inflammation Switch

Implicated in the onset of 95% of all cancers is a common but under-recognized molecule most people have never heard of: nuclear factor-kappaB (NFkB). Emerging research validates the danger it poses to maturing individuals. NF-kB is a protein that acts as a switch to turn inflammation on and off in the body. Scientists describe NF-kB as a “smoke sensor” that detects dangerous threats like free radicals and infectious agents. In response to these threats, NF-kB “turns on” genes that produce inflammation. As we age, NF-kB expression in the body increases, provoking widespread chronic inflammation and setting the stage for diseases ranging from atherosclerosis and diabetes to Alzheimer’s. Evidence from recent research suggests that by inhibiting NF-kB, a wide range of diseases and conditions in which inflammation plays a critical role can be treated (see Figure 2). Central nervous system: Neurodegeneration

Lung: Neutrophilic alveolitis Asthma Liver: Hepatitis

Cardiovascular system: Ischemia/reperfusion Septic Shock

Gastrointestinal tract: Inflammatory bowel disease

Kidney: Glomerulonephritis

Articular joint: Rheumatoid arthritis

Figure 2: Inflammatory Diseases

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ParActin®: The Natural NF-kB Inhibitor

ParActin® helps balance and calm over-protective immune cells. Andrographolides in ParActin® can exert their beneficial effects through PPAR gamma activation (i.e., PPAR gamma agonist), which effectively turns off the “master power switch” NF-kB, responsible for exerting the over-reactive inflammatory response. By deactivating NF-kB, the hyperexpression of cytokines, proinflammatory proteins and enzymes such as COX-2, PGE2, interleukin-2 and interferon gamma is reduced (see Figure 3). ParActin® is a patented extract from the plant called Andrographis paniculata, standardized to andrographolide, 14 deoxyandrographolide and neoandrographolide. These naturally occurring phytochemicals in the Andrographis paniculata plant have been shown by researchers to have beneficial actions in supporting healthy joints, bones and muscles; this is so important in today’s active lifestyle. ParActin® was awarded U.S. Patent #8,084,495 B2 (Dec. 27, 2011), titled, “Composition of Labdane Diterpenes Extracted from Andrographis paniculata, Useful for the Treatment of Autoimmune Diseases, and Alzheimer’s Disease by Activation for PPAR-Gamma Receptors.”

Figure 3: PPAR gamma Activation

PPARγ activated

NFκB inhibited

Inflammatory Cytokines reduced (TNFα, IL-6, IL-1β, IL-2)

T Cell deactivation Inflammatory Proteins Deactivated Stat 1 COX2 iNOS

IFNγ

prostaglandins

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NO2

Andrographis has a long and rich history of use in Asia where it is called the “King of Bitters.” In the venerable medicinal systems of Ayurveda and traditional Chinese medicine, practitioners provide or recommend this herb for many maladies and for adaptogenic (i.e., to help the body adapt, balance) support. Interestingly, its traditional uses are what modern medicine now knows as the source of unhealthy inflammatory response. ParActin® is the result of 20 arduous years of research and development. It boasts more than 30 studies, including in vitro, in vivo animal models and human clinical trials. ParActin® has been researched and developed to support healthy NF-kB levels and activity, which, in turn, helps support a healthy and appropriate inflammatory response. As a result, ParActin® is suitable for dietary supplements that support the following condition-specific areas: • Joint Health • Healthy Bones • Healthy Cartilage • Sports Recovery/Muscle Function • Healthy Inflammatory Response • Overall Immune Function

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Keep Moving! Joint, Bone & Muscle Health for Everybody

Typically, most people think about bone and joint health as a concern for the elderly. However, individuals who are younger and love being fit can benefit tremendously from taking a daily supplement with ParActin® to aid flexibility and mobility, ease joint flare-ups, support healthy muscles, set the stage for increasing fitness goals or just have fun. Further, ParActin® is a great choice for those at any age who are dead-set on leaving their couch potato days behind. Intense physical activity can create an undesirable inflammatory response, which in time, impacts joints through swelling and discomfort, causing muscle tearing and increased injury. It would seem somewhat antithetical to exercise for fitness but encounter joints that scream, “Time out!” However, over-expression of inflammation response figures prominently in joint issues and, to a certain extent, muscle pain from overuse. Therefore, doesn’t it make sense to take control by flipping off that master switch? This is where ParActin® comes in and the numerous clinical research trials and patents that demonstrate its power.

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ParActin®: Healthy Joint Support

ParActin® inhibits NF-kB activity and reduces the DNA binding of NF-kB, thereby reducing pro-inflammatory cytokines and enzymes such as COX-2 and prostaglandin that cause pain and inflammation in the body (2). In vitro research has shown ParActin® to be a natural COX-2 inhibitor without causing stomach discomfort or increased risk of heart attack and stroke in users. Rheumatoid arthritis (RA) results from the immune system mistakenly attacking healthy joints for a prolonged period of time, causing a great deal of inflammation. Individuals with RA typically have high levels of C-reactive protein (CRP), which is involved in acute and chronic inflammatory activity in unhealthy joints. Rheumatoid factors (RFs) are antibodies detectable in the blood of approximately 80% of adults with RA. RFs are produced by an immune system that can attack healthy tissue in your body. Tumor necrosis factor-alpha (TNF-α), another key driver of inflammation, is a cytokine that stimulates an acute reaction. Research has found TNF-α to be present in the synovial fluid of RA patients. Andrographolide is known to reduce TNF-α, which leads to a significant reduction in RFs.

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In a 2009 randomized, double-blind and placebo-controlled study published in Clinical Rheumatology, 60 individuals with compromised joints were given 100 mg of ParActin® or placebo in conjunction with methotrexate (MTX), three times a day for 14 weeks (3). MTX, a standard therapy for RA, improves the number of tender and swollen joints, pain and functional status, but longterm use of MTX may cause serious infection and liver damage. ParActin® was effective in reducing the number and total grade of swollen joints, the number and total grade of tender joints, as well as improving scores on HAQ-52, and SF-36 health questionnaires. Its effect was associated with a reduction of RF, creatine kinase, IgA-RF and IgM-RF. IgA and IgM are antibodies made by the body’s immune system in response to a foreign substance attack such as bacteria, viruses and fungus. Patients with RA typically have elevated levels of RF, IgA-RF, IgM-RF and CRP. The reduction in IgA-RF and IgM-RF is beneficial because their excess is positively correlated with cartilage damage. The ParActin® group showed significant improvement compared to the placebo (with MTX) group in the following scores (see Figure 4): • Number of swollen joints: nine in the ParActin® group versus 13 in the placebo group • Total grade of swollen joints: 11 in the ParActin® group versus 16 in the placebo group • Total grade of tender joints: 14 in the ParActin® group versus 17 in the placebo group • HAQ: 19 in the ParActin® group versus 24 in the placebo group • Reduction of RF: 119 in the ParActin® group versus 130 in the placebo group • Reduction in IgA: 293.7 in the ParActin® versus 335 in the placebo group The study concluded that ParActin® is significantly effective at reducing symptoms and serological parameters and therefore is useful as a complementary natural treatment for rheumatoid arthritis. In another human clinical trial published in Innovative Rheumatology, eight individuals with various rheumatoid conditions were given 300 mg of ParActin® daily for four years (4). Supplementation with ParActin® showed significant im-

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Figure 4: Effect of Andrographolide on Joint Comfort Over Time versus Placebo. Table depicts number of patients at risk per group over time. Adapted from Burgos et al. (3).

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provements in the number of swollen joints, total grade of swollen joints, total grade of tender joints and quality of life. Also noted were significant reductions in RF, erythrocytes sedimentation rate and CRP. Furthermore, serum immunological parameters of inflammation were reduced progressively during 48 months of ParActin® supplementation (see Figure 5a). ParActin® may also have additional therapeutic effects over prednisone and MTX in easing pain and fatigue. Research suggests that Andrographolide inhibits the COX-2 enzyme and reduces prostaglandin production tied to pain and inflammation (see Figure 5b). After 24 months of taking ParActin®, six individuals progressed to supplementing with ParActin® as their only therapeutic. No side effects were observed, indicating ParActin® was safe, nontoxic and well tolerated (4) (see Figure 5c).

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Figure 5: Effect of ParActin® in Patients with Chronic Rheumatoid Arthritis. Adapted from Hildalgo et al. (4).

Stiffness (SF-36 scale) Scale 1-4

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ParActin®: Healthy Bone Support

Fluid, comfortable movement isn’t only the job of the joints. It requires bones strong enough to withstand bursts of physical activity or prolonged routine movement. Healthy bones require two coordinated actions: bone formation (by osteoblasts) and bone reabsorption (by osteoclasts). In the process of bone formation, osteoblasts produce a calcium and phosphate-based mineral that is deposited into bones. Almost the entire bone matrix is mineralized by the osteoblasts. An osteoclast is a type of bone cell that resorbs or breaks down bone tissue (see Figure 6). However, this healthy balance of bone formation and bone resorption tends to decline with age, particularly in postmenopausal women. Osteoporosis is the most common bone disorder and is caused by excessive bone resorption by osteoclasts without adequate bone formation by osteoblasts. Increased bone resorption, among other actions, are predominantly caused by the decline of estrogen production in postmenopausal women, who tend to develop porous bones more often than aging men. ParActin® has been shown to help support healthy bone function. In research published in the International Journal of Molecular Sciences, a group of mice whose skeletons mimic postmenopausal osteoarthritis were treated with Figure 6: Osteoclast and Osteoblast Osteoclasts have the function to disrupt the old bone tissue

A proper balance between osteoclasts and osteoblasts is the basis for a normal bone density

OSTEOCLAST

OSTEOBLAST A hyperactivity of osteoclasts is one of the causes of the onset osteoporosis

Osteoblasts have the function to produce the new bone tissue

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NF-kB activation is essential for RANKL (i.e., receptor activator of NF-kB ligand)-induced osteoclast formation. Andrographolide found in ParActin® —a natural NF-kB inhibitor—significantly decreased osteoclast formation in the bone marrow via suppression of RANKL, which are responsible for making osteoclasts (see Figure 8). Figure 7: Micro-CT Scanned 3D Image of Mice Tibias Showing that Andrographolide Inhibits OVX-induced Bone Loss Compared to Vehicle. Adapted from T. Wang et al. (5). Sham

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Figure 8: Effect of Andrographolide on Osteoclasts. Adapted from T. Wang et al. (5).

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Andrographolide (5). The use of these ovariectomized (OVX) animals is a typical experimental model for the investigation of postmenopausal osteoporosis due to estrogen deficiency in women. The ParActin® group showed a significant increase in bone mass, trabecular thickness and number, and a decrease in trabecular separation compared to control mice (see Figure 7).

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The authors concluded that Andrographolide inhibits estrogen deficiency-induced bone loss in mice and may have supplemental potential for osteoarthritis. In an in vitro study published in the European Journal of Pharmacology, Andrographolide from ParActin® inhibited nuclear factors of activated T-cells (NFAT) activity, which regulates the expression of osteoclast genes and is linked to bone erosion (6). In another unpublished study, Andrographolide induced osteoblast mineralization via COX-2 expression, showing a mineralizing effect on the bones with the increase of calcium deposits, thereby suggesting that ParActin® may have other supplemental effects for osteoarthritis (see Figure 9).

Figure 9: Effect of Andrographolide on Calcium Deposits. Adapted from M.D. Carretta et al. (6).

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Figure 10: Joint Anatomy and Cartilage Degradation

Synovial membrane Synovialcytes

Inflammatory cells T-cells B-cells Macrophages

Cartilage degradation and Joint destruction

Chondrocytes Osteoblasts

TIMPs Wnts

Hypertrophic chondrocytes

RANK-L MMPs Aggracanases

IL-1,6,X TNF-α

RANK-L/OPG and cathepsin K

Osteoclasts

Articular cartilage Calcified cartilage and tidemark

Cartilage Bone turnover and bone loss

Bone

ParActin®: Healthy Cartilage Support

Osteoarthritis is characterized by progressive and permanent cartilage degradation. Cartilage erosion can cause inflammation and pain, decreased mobility and reduced athletic performance (see Figure 10). This degradation is caused by Interleukin-1β (IL-1β) cytokines, which trigger the over-production of cartilage-degrading enzymes called matrix metalloproteinases (MMPs) in the synovial cells and the chondrocytes. This leads to a progressive loss of the cartilage matrix, which is composed of biochemicals aggrecan, hyaluronan (HA) and collagen. Recent research has shown that Andrographolide inhibits MMPs in IL-1β-treated human chondrocytes while increasing the natural inhibitors of these enzymes via the NF-kB pathway. A study published in International Scholarly Research Notices found that Andrographolide suppressed MMPs that were induced by IL-1β in equine cartilage (7). Andrographolide further slows cartilage degradation by dramatically reducing the loss of collagen, uronic acid, HA and sulfated-glycosaminoglycans (s-GAGs) caused by IL-1β, a key inducer of cartilage degeneration. The research not only demonstrated the potent cartilage-protecting activities of Andrographolide, but also showed

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the ability of Andrographolide to increase the production of cartilage biomolecules including collagen, aggrecan and HA (see Figure 11). In RA, aggressive fibroblast-like synoviocytes (FLSs) are found in the synovial tissues. These FLSs invade and destroy joints and cartilage by actively releasing pro-inflammatory cytokines. They also produce massive amounts of cartilage-degrading enzymes, especially matrix MMPs, which contribute to the invasive growth of FLSs and subsequent joint destruction. Researchers at the La Jolla Institute for Allergy and Immunology, in collaboration with colleagues from the University of California, San Diego (UCSD), identified FLSs as the target of a potential new RA drug that focuses on cells responsible for the cartilage damage in affected joints. Current RA treatments focus on intercepting the immune system’s misdirected attack on the lining of affected joints to alleviate the debilitating symptoms, reduce inflammation and slow the progression of the disease. “Unfortunately, for around 40% of patients, immune-targeted therapies are not sufficient to bring them into full remission,” says the study’s lead author, Nunzio Bottini, M.D., Ph.D., associate professor at La Jolla Institute and associate professor of medicine at UCSD. “Even if your inflammation is completely under control with the help of current therapies—and they are excellent—the damage to the skeletal structure is not necessarily arrested in the long term because synoviocytes continue to cause damage,” he explains. FLSs secrete proteases that digest cartilage, and they also promote osteoclasts differentiation, which in turn attack the bone and generate erosions. Blocking the action of these synovial fibroblasts will directly protect joints from cartilage destruction (8). In a study published in Cell Biology Toxicology, synovial tissues were collected from 15 RA patients who had undergone a total knee replacement therapy; the cells were treated with Andrographolide for 48 hours (9). The study found that Andrographolide induced cell death in these human RA-FLSs (rheumatoid arthritis fibroblast-like synoviocytes) via cytochrome-C release and caspase-3 activation, which play key roles in cell death. The author suggests that Andrographolide could be a potential therapeutic in supporting against joint destruction in both osteoarthritis and RA.

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s-GAGs level (µ

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A condition called synovial hypoxia frequently occurs in patients with RA, contributing to tendon rupture and perpetual joint destruction. Fifty percent of RA patients also experience inflammation of the synovial tissue surrounding the tendons, which is associated with multiple ruptures and a poor prognosis for longterm joint function. RA patients often have high levels hypoxia-inducible factor-1 alpha (HIF-1α), a chemical linked to inflammation in the synovial tissues. In a study published in Life Sciences, synovial tissue was obtained from 50 RA patients during a knee joint arthroscopy (10). The researchers found that Andrographolide significantly decreased the cartilage-degrading enzymes MMPs, induced by hypoxia. Andrographolide inhibited the migration, prevented the invasion of RA-FLS and increase of MMPs in RA-FLSs via the inhibition of HIF-1α signaling. Hypoxia causes RA-FLS migration and invasion. Andrographolide inhibited hypoxia-induced migration and RA-FLS invasion, thus suggesting the potential for Andrographolide in benefiting those with joint degeneration. 19

HA

ParActin®: Muscle Health and Recovery

Muscles are susceptible to damage, just like other bodily tissues. Trauma, infections, certain medications or strenuous exercise can cause varying degrees of muscle injury. As the saying goes, “No pain, no gain.” But if you’re over the age of 40, no pain is actually a good thing. If you find yourself in the discomfort zone, your body may be trying to tell you something. By the age of 40, the body has endured years of wear and tear, and is more susceptible to repetitive stress that can cause injury. While you may feel strong and ready to take on any physical activity, your bones, muscles and joints could be more delicate than you realize. As we age, our musculoskeletal system (i.e., bones, joints, tendons, ligaments and muscles) changes by gradually losing muscle mass, connective tissues (i.e., tendons, ligaments, cartilage and other support structures), flexibility and the resilience that was present at a younger age. And in addition to the loss of elasticity and resilience, low bone density conditions such as osteopenia and osteoporosis can further complicate matters. Skeletal muscle injuries constitute the majority of sports-related injuries. Injured skeletal muscle undergoes the healing phases of degeneration, inflammation, regeneration and fibrosis (see Figure 12). The body heals damaged tissue fibers by laying down new soft tissue fibers as part of the secondary

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Figure 12:

Muscle Laceration Injury

Fibrosis

Degeneration Inflammation

Proteases TGF-β1 Growth Factors

Regeneration 7 days

Regeneration 5 days

phase of the inflammatory process. This occurs in bones, muscles, tendons, ligaments, joint capsules and cartilage. Healthy new fibers are essential to healing and pain relief as they replace the torn and damaged ones. In a pivotal study published in Skeletal Muscle, mdx mice (i.e., mice studied for muscle degeneration and regeneration) were treated with ParActin® for three months (11). ParActin® was shown to promote muscle health and recovery, making it ideal for those engaged in regular fitness routines, hard labor or athletic participation. Three positive effects were observed in this study, as follows: 1. ParActin® reduced inflammation in the skeletal muscle via NF-kB inhibition. Prostaglandins (PGEs) have been identified and implicated as major factors in tissue inflammation. Many PGEs are synthesized by cyclooxygenase enzyme and are largely produced during the inflammatory phase after muscle injury. Aspirin and other NSAIDs inhibit PGE synthesis, and are typically recommended to be taken in the first few days after injury to limit inflammation and pain. However, long-term use of these NSAIDs may cause stomach discomfort. Multiple studies have demonstrated the effectiveness of selective COX-2 inhibitors in the reduction of joint and muscle pain with gastrointestinal safety. In the study, supplementation with ParActin® reduced

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Total NFκB positive nuclei

Figure 13: Effect of ParActin® on NF-kB and COX-2. Adapted from Cabrera et al. (11).

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the number of nuclei positive for NF-κB and reduced COX-2 enzyme, which in turn reduces PGE concentrations that causes pain and inflammation (see Figure 13). 2. ParActin® reduced fibrosis and pro-fibrotic factor. Transforming growth factor type beta (TGF-β1) and connective tissue growth factor (CTGF) have been shown to inhibit skeletal muscle regenerative processes. They replace scarred connective tissue that is composed of fibronectin, as well as type-I and type-III collagen. While this fibrotic tissue provides early support for damaged skeletal muscle, these new fibers do not arrange in the same direction the original fibers were oriented. This results in scarring (fibrosis) in the injured muscle that often causes stiffness, abnormal joint function, nerve pain and restricts the regenerative process. Recurring injury and loss of muscle strength after muscle injuries may be attributable to TGF-ß1–induced fibrosis within the muscle. ParActin® administration significantly decreased fibronectin, collagen I and collagen III levels in the mdx mice. In addition, the ParActin® treatment group 22

CTGF mRNA relativelevels/GAPDH

TGF-β1 mRNA relativelevels/GAPDH

Figure 14: Effect of ParActin® on TGF-β and CTGF. Adapted from Cabrera et al. (11).

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saw reduced TGF-β1 and CTGF, two pro-fibrotic factors that contribute to fibrosis and prevent proper muscle regeneration process. By blocking TGF-ß1 and thus reducing scar tissue, ParActin® can facilitate improved muscle function recovery (see Figure 14). 3. ParActin® reduced muscle damage and lowered serum creatine kinase. Strenuous exercise and overtraining can lead to structural damage to muscle cells, triggering white blood cell activity to increase after muscle soreness, thus leading to the inflammatory response. This has been noted especially in marathon runners whose muscle fibers revealed remarkable damage after both training and marathon competition. The muscle damage causes calcium to leak out of the muscle, further leading to the activation of enzymes that break down cellular proteins in the muscle. These proteins then cause an inflammatory response by the immune system, which then leads to swelling (water retention at the site of injury) and pain.

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mN/mm2

Figure 15: Effect of Andrographolide on Muscles. Adapted from Cabrera et al. (11).

In the mdx mouse study, the administration of ParActin® reduced necrosis and cumulative muscle damage compared with control mdx mice (see Figure 15). Creatine kinase (CK) is a type of enzyme found within your muscles, including the heart and brain. Serum CK indicates the overall health of the muscles within the body and if a serum CK test shows elevated levels, it indicates muscle strain that may have been caused by simply heavy exercise or something as serious as a heart attack. Muscle inflammation and other skeletal muscle damage are associated with an elevated CK level. Depending upon muscle damage severity, some may have CK levels that are as much as 100 times normal levels. Serum CK levels were significantly decreased in ParActin®-treated mdx mice compared with control mdx mice, with an approximately 50% recovery score (see Figure 16).

10000

Figure 17: Effect of ParActin® on Muscles. Adapted from Cabrera et al. (11).

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mN/mm2

Serum Creatine Kinase Activity (UI/L)

Figure 16: Effect of Andrographolide on Creatine Kinase. Adapted from Cabrera et al. (11).

8000 6000

C57 + Vehi C57 + PAR mdx + PAR mdx + Veh

*, #

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Frequency (pps) C57 + Vehicle C57 + PARACTIN® mdx + PARACTIN® mdx + Vehicle

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*

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id

m

m

dx

dx

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dr og

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icl

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e

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ol ra dr og

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% twitch force, Recovery score = 50.3%

ph

# set backs in the threadmill

e id

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rce, Recovery score = 50.3%

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% twitch force, Recovery score = 50.3%

% of specific isometric force

*

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# of set backs, Recovery score = 45.5%

4. ParActin® improved skeletal muscle strength and exercise performance. ParActin®-administrated mdx mice showed improved skeletal muscle strength and enhanced exercise performance. ParActin®-administrated mdx mice showed a significant increase in the generation of isometric force (see Figure 17); an increase twitch and tetanic force in the Tibialis anterior (TA) muscle (in front of the shin); and a significant decrease in the number of fall back in the treadmill running protocol, with a recovery score of 45.5% (see Figure 18). The author concludes that the supplement group exhibited less severe muscular dystrophy, performed better in an exercise endurance test and had improved muscle strength compared to control mdx mice. 25

# set backs in the threadmill

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W T m dx + m Ve dx hi m + cle dx Ve + hi cle m An dx dr + og An ra dr ph og ol raide ph ol id e

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T

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150

Peak twitch force (mN/mm2)

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% Peak tetanic force

% Peak tetanic force

Figure 18: ParActin® Improves Functional Capacity. Adapted from Cabrera et al. (11).

ParActin®: Masters the Immune Balancing Act

Just like the famous Wallenda brothers, when your immune system is balanced and calibrated, it can keep you safe and healthy during times when you feel like you are walking on a tightrope high above the ground. Stressors— environmental, mental/emotional and physical—all conspire to hamper the immune system’s effective functioning, creating an imbalance that may result in colds, flu and exacerbated allergies. Cold and flu can reach epidemic proportions during the winter months. There are more than 95 million flu cases in the United States annually, according to the Centers for Disease Control and Prevention, and more than 62 million cases of the common cold. When the immune system is balanced and healthy, it launches a series of events to engage in battle with an invading virus. Interferon gamma plays an important role in the first line of defense against viral infections; they are part of the non-specific immune system and are induced at an early stage in viral infections such as in influenza—before the specific immune system has had time to respond. Interferon-gamma is produced by certain activated T-cells and NK cells and is made in response to viral antigens or when stimulated by

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lymphocytes. Interferons are responsible for reacting to conditions like colds, fever, shivers, migraines and gastrointestinal disorders. Interferon gamma interacts with other interleukin molecules such as interleukin-2 and others to form a complex, lymphokine regulatory network. Think of it this way, when your immune system is unbalanced, it’s like being a ship that’s listing to one side or stuck in the doldrums. ParActin® can help right the ship and move it forward for smooth sailing. In a randomized, double-blind placebo-controlled study, 109 healthy students were given either 25 mg per day of ParActin® or placebo for three months (12). During the first month, there was no significant change between the groups, evaluated for the presence or absence of common colds. However, during months two and three, there was significantly less incidence of common cold in the ParActin® group (30%) compared to the placebo group (62%). In another randomized, double-blind placebo-controlled study of 158 adults already with common cold symptoms, 200 mg of ParActin® per day for five days were shown to significantly decrease the intensity of symptoms compared to the placebo group (13). According to ParActin® researcher Dr. Juan Hancke, at a low dosage (50 mg), ParActin® stimulates natural defense mechanisms by activating NF-kB, thereby increases the production of cytokines such as interferon gamma and interleukin-2 to help boost the immune response in winter. Once an individual begins to feel under the weather, 300 mg of ParActin® inhibits NF-kB, thereby reducing the production of pro-inflammatory cytokines such as interferon gamma and interleukin-2 to help produce a better sense of wellness. The immune and inflammation balancing properties of ParActin® may assist the body to help fight a viral antigen while reducing the overload of cytokines (14).

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ParActin®: Organic, Non-GMO, Vegan Choice

Yes, there are quite a few choices out there to keep you healthy and preserve free movement. Before you reach for the old standby, here’s why ParActin® (a specialized and patented extract of the abundant herb Andrographis paniculata) may be your best choice. As a botanical, ParActin® has nothing undesirable in it that typically comes from bovine or other animal sources (eggshells and seafood shells). As more and more Americans are discovering they have food sensitivities and/or allergies, ParActin® is a clean ingredient. It is also non-GMO, cultivated without pesticides (wild-crafted) and also available in an organic version. ParActin® is attractive for any consumer from vegans to omnivores; there is no limit to potential consumers. ParActin® is: • No bovine (chondroitin), BSE-Free • Shellfish-free (for those concerned about shellfish allergies/vegans) • Eggshell-free (for those concerned about eggshell allergies/vegans) • Non-GMO • Vegan • Wild-crafted • Non-irradiated, TSE free • Certified kosher and halal • Available in organic and conventional Botanical Source: Andrographis paniculata Countries of Origin: India, China, Southeast Asia Part Used: Stems and leaves Shelf Life: 3 years Active Ingredients: Not less than 50% patented extract of bioactive andrographolides, 14-deoxyandrographolide, neoandrographolide. Applications: Nutritional supplements targeted for: sports nutrition, and support of bone, joint, muscle, relief of aches and discomfort, and immune health.

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FAQs about HP Ingredients and ParActin®

What claims can be made for ParActin®? Multiple human clinical studies allow for the following claims:* • Supports Healthy Inflammatory Response • Supports Healthy Joint Function • Strengthens Joints and Eases Joint Flare-ups • Improves Flexibility and Mobility • Maintains Bone Mass and Strength • Supports Muscle Health • Supports Healthy Immune Response • Supports Healthy Cartilage What are the dosage amounts for ParActin®? Typical dosage recommendations, based on traditional use and on the available scientific evidence in humans, are 300 mg daily, which may be taken in 150 mg doses twice daily. Those seeking optimum support may take as much as 600 mg daily. Is ParActin® patented? Yes. ParActin® has U.S. Patent #8,084,495 B2, Composition and Use: “Composition of Labdane Diterpenes Extracted From Andrographis Paniculata, Useful For The Treatment Of Autoimmune Diseases, And Alzheimer’s Disease By Activation of PPAR-Gamma Receptors.” For joint health, what are the mechanisms or mode of action of ParActin®? • Inhibits NF-κB binding to DNA • Inhibits IKKβ • Inhibits COX-2 and reduces PGE2 • Inhibits NFAT—bone erosion • Stimulates osteoblasts and calcium deposition • Decreases Rheumatoid Factor—TNF-α • Reduces IgA and IgM: cartilage damage • Reduces C-Reactive Protein • Promotes regulatory T cell (Treg), CD4+CD25+ • Reduces AP-1 and STAT3 in synovial tissue

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Where is ParActin® grown and processed? Andrographis paniculata is widely cultivated in India, China and Southeastern Asia. ParActin® is sustainably harvested and is processed in a GMP-certified and ISO 9001-2008-certified Quality Management Systems facility. Is ParActin® GRAS (Generally Recognized As Safe?) It is not GRAS for food products, but it is allowed for use in dietary supplements. Who is HP Ingredients (HPI)? HP Ingredients (HPI) is a fast-growing research-based botanical company that offers unique, innovative, science-based, clinically proven, patented, safe and natural ingredients to the nutraceutical industry. HPI’s ingredients address today’s most common chronic health conditions; they help support optimal joint, bone and muscle health, as well as testosterone, energy, heart, blood sugar, cholesterol, weight management, brain and memory health. *These statements have not been evaluated by the Food and Drug Administration. This product is not intended to treat, cure or prevent any disease. What’s HPI’s mission? HPI was founded in 2001 by Annie Eng with the goal of bringing nature and science together. Today, HP Ingredients is an innovative nutraceutical company dedicated to providing cutting-edge, science-based nutraceuticals that addresses cholesterol, blood glucose control, weight management, joint health, andropause and healthy aging. HPI believes in ongoing research and development for its premier ingredients. Working with top scientists from around the world, HPI is dedicated to providing ongoing research on its proprietary ingredients in a qualitative manner similar to pharmaceutical products. The company believes in supporting its products with proven science, bringing well-researched, patented plant extracts to the nutraceutical industry. The material presented in this piece is for industry education only. It is not intended to serve as medical advice. Dietary supplements do not cure, treat or prevent any diseases.

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References   1.

E. Setiawan et al., “Role of Translocator Protein Density, a Marker of Neuroinflammation, in the Brain During Major Depressive Episodes,” JAMA Psychiatry 73 (1), 87–88 (2016).

  2. M.A. Hidalgo et al., “Andrographolide interferes DNA binding of NF-KB in HL- 60/Neutrophils cells,” Br. J. Pharmacol. 144 (5), 680-686 (2005).   3. R.A. Burgos et al., “Efficacy of an Andrographis paniculata Composition for the Relief of Rheumatoid Arthritis Symptoms: A Prospective Randomized Placebo-Controlled Trial,” Clinical Rheumatol. 28 (8), 931–946 (2009).   4. M  . Hidalgo et al., “Andrographolide a New Potential Drug for the Long Term Treatment of Rheumatoid Arthritis Disease,” Innovative Rheumatology, 256–259 (2013).   5. T  . Wang et al., “Andrographolide Inhibits Ovariectomy-Induced Bone Loss via the Suppression of RANKL Signaling Pathways,” Int. J. Mol. Sci. 16 (11), 27470–27481 (2015).   6. M.D. Carretta et al., “Andrographolide Reduces IL-2 Production in T-Cells by Interfering with NFAT and MAPK Activation,” Eur. J. Pharmacol. 602(2-3), 413–421 (2009).   7. S. Tangyuenyong, et al., “Andrographolide Exerts Chondroprotective Activity in Equine Cartilage Explant and Suppresses Interleukin-1β-Induced MMP-2 Expression in Equine Chondrocyte Culture,” International Scholarly Research Notices 1–8 (2014).   8. K.M. Doody, et al., “Targeting Phosphatase-Dependent Proteoglycan Switch for Rheumatoid Arthritis Therapy,” Sci. Transl. Med. 7 (288), (2015).   9. J. Yan et al., “Andrographolide Induced Cell Cycle Arrest and Apoptosis in Human Rheumatoid Arthritis Fibroblast-Like Synoviocytes,” Cell Biol. Toxicol. 28 (1), 47–56 (2012). 10. L. Guo-feng et al., “Andrographolide Inhibits the Migration, Invasion and Matrix Metalloproteinase Expression Of Rheumatoid Arthritis Fibroblast-Like Synoviocytes via Inhibition of HIF-1α Signaling,” Life Sci. 136, 67–72 (2015). 11. D. Cabrera et al., “Andrographolide Attenuates Skeletal Muscle Dystrophy In Mdx Mice And Increases Efficiency of Cell 3 Therapy by Reducing Fibrosis,”Skelet. Muscle 4 (6), (2014). 12. D.D. Cáceres et al., “Prevention of Common Colds with Andrographis paniculata Dried Extract: A Pilot Double Blind Trial,” Phytomed. 4 (2), 101-104 (1997). 13. JL. Hancke et al., “A Double Blind Study with a New Monodrug: Kan Jang Decrease of Symptoms and Enhancement of Resistance to Common Colds,” Phytother. Res. 9: 559562, 1995. 14. R.A. Burgos et al., “Andrographolide Inhibits Infγ and IL-2 Cytokine Production and Protects against Cell Apoptosis,” Planta Medica. 71 (5), 429-434 (2005).

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Glossary of Terms

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AP-1: Activator protein 1 is involved in cellular proliferation, transformation and death. CD4 + CD25: Two types of regulatory T-cells that control the burst of superantigen-induced cytokine production. COX-2: Cyclooxygenase-2 is an enzyme responsible for the formation of prostaglandins, prostacyclins and thromboxanes, which are involved in the inflammatory response. C-reactive protein: An acute phase reactant, meaning that its levels will rise in response to inflammation. IgM and IgA: Immunoglobins M and A are two types of antibodies in the blood that primarily protect individuals from infections inside the body’s tissue, organs and blood. IKKβ: An IRF5 kinase that instigates inflammation. IL-2: Interleukin-2 is a type of cytokine-signaling molecule in the immune system and a protein that regulates the activities of white blood cells that are responsible for immunity. IL-6: Interleukin-6 acts as both a pro-inflammatory cytokine and an anti-inflammatory myokine. NFAT: Nuclear factor of activated T-cells is a general name applied to a family of transcription factors shown to be important for immune response. NF-kB: Nuclear factor-kappa B is a protein complex that controls transcription of DNA, cytokine production and cell survival. PGE2: Prostaglandin E2 is a prostaglandin that ultimately induces fever. It also suppresses T-cell receptor signaling and may play a role in the resolution of inflammation. PPAR-γ: Peroxisome proliferator-activated receptor gamma is a nuclear receptor that binds peroxisome proliferators such as hypolipidemic drugs and fatty acids. STAT3: Signal transducer and activator of transcription 3 is a protein-coding gene that has been found to play a fundamental role in converting normal cells to cancerous cells. Synovial membrane: The soft tissue found between the articular capsule (joint capsule) and the joint cavity of synovial joints. TNF-α: Tumor necrosis factor alpha is a cell-signaling protein (cytokine) involved in systemic inflammation and is one of the cytokines that make up the acute phase reaction.

HP Ingredients Corp. 707 24th Ave. West Bradenton, FL 34205 Toll-free: (877)437-2234 Tel: (941)749-7066 Fax: (866)278-2874 www.hpingredients.com [email protected] Key Personnel Annie Eng, President Hame K. Persaud, Executive Vice President Dr. Juan Hancke, Chief Scientific Director This publication is brought to you by WholeFoods Magazine. For more information, see www.hpingredients.com. Copyright ©2016. All rights reserved. WHOLE FOODS (ISSN 0193-1504) (USPS 405-710) is published monthly, with May Source Directory issue, in the interest of the health/natural products industry by WHOLE FOODS Magazine, WFC, Inc., 51 Cragwood Road, Ste. 100, South Plainfield, NJ 07080, telephone (908)769-1160, FAX (908)769-1171. WholeFoodsMAGAZINE has no affiliation with Whole Foods Market. WholeFoodsMAGAZINE is published by WFC, Inc.