The complement cascade, membrane attack complex (MAC), and persistent inflammation

Groundbreaking research from Stanford University Medical School has identified a specific type of inflammation that leads to joint pain and cartilage deterioration. Contrary to previous understanding, this research pinpoints the “complement cascade” and resulting Membrane Attack Complex (MAC) as core contributors to joint issues.

What is the complement cascade? It’s one of the body’s standard immune responses to fight off bacteria and viruses, involving over 30 small proteins mostly made by the liver. The cascade triggers proteins sequentially – like a row of dominoes tipping each other over – culminating in a MAC “attack”. In normal circumstances, this process helps protect the body by killing harmful pathogens, then shuts down. But in OA, the complement cascade and MAC continue to stimulate and inflame the synovial fluid in joints like the knee – and even travels around the body – causing cartilage damage and pain in other places. Other research reinforces the link between joint-fluid inflammation – synovitis – and joint pain. In fact, N. Sofat, 2011, found joint fluid inflammation to be a far more potent source of pain than even bone marrow lesions (BMLs): synovitis increases the chances of pain 9.2x, compared to 3.2x for BMLs.

Dr. William H. Robinson, Associate Professor of Medicine at Stanford described the discovery as a significant change in understanding, with the potential to open up new avenues for preventing and treating joint disorders beyond merely alleviating pain. His biography page talks about this paradigm shift in our understanding of OA:

Unlike RA (rheumatoid Arthritis), OA (osteoarthritis) is not an autoimmune disorder and is generally believed to result from “wear and tear”. However, inflammation is emerging as an important component of OA, prompting a reassessment of our understanding of OA pathology. This recent discovery has raised a slew of intriguing questions about the role of inflammation in OA and suggested new possibilities for therapeutic intervention.

As Dr. Robinson notes, this understanding of inflammation contradicts previous teachings that joint pain was mostly caused by age, wear, and tear. And yet, that belief persists among many medical professionals, as you can see in this Cleveland Clinic video which refers to OA as “non-inflammatory, or wear-and-tear arthritis.” The problem: this outdated line of medical thinking leads to the belief that nothing can really be done about your pain and joint discomfort, other than managing it until things gets so bad that the joint needs surgical replacement.

This new understanding opens new avenues for treatment, including plant-based compounds

Traditional approaches for treating OA primarily focus on pain relief, in large part because effective disease-modifying OA drugs (called DMOADs) have yet to be found. Common sense tells us that pharmaceutical interventions (i.e., drugs) that shut down the complement system completely are not an option, because the process is essential for fighting infections.

Instead, many researchers, such as A Haseeb in Clinical Immunology, have advocated for ways to regulate the complement cascade process more naturally, without compromising the body’s natural defense mechanisms. Various plant-derived substances have been shown to help regulate these types of immune responses, and can offer a more nuanced approach, targeting multiple inflammation molecules (such as COX-2, MMP-3, 5-LOX, IL-6, IL-8) without the side effects associated with drugs.

This is exactly the kind of challenge that the Green Valley Naturals product development team was created to solve. Recognized as innovative leaders in the natural supplement industry, Green Valley’s team of world class experts have a deep understanding of the therapeutic properties of natural mineral and plant-based substances from all over the world. Guided by a passion for evidence-based solutions, they apply their encyclopedic knowledge in combination with advanced medical insights – such as the Stanford University discoveries revolutionizing our understanding of OA – to create natural compounds with meaningful wellness benefits.

Triple Joint Relief is an entirely natural product designed to target the root cause of joint problems

There’s an enormous amount of empirical research into the therapeutic properties of natural substances happening around the world. And while many of these authoritative studies are published on sites such as the National Institutes for Health National Center for Biotechnology Information, much of the U.S. medical establishment don’t seem to be interested in the findings. Some think this may be due to influence from the pharmaceutical industry, which seeks to promote more profitable patented drugs. Or, it could be a reflection of how they are trained in U.S. medical schools. But whatever the cause, there is a wealth of valuable scientific knowledge about natural substances that goes largely untapped.

On the other hand, the product development team at Green Valley Natural Supplements eagerly pursues this kind of global knowledge in their quest to develop effective natural compounds. After extensive research and investigation into medical journals worldwide, the team discovered a combination of three unique plant ingredients, Silymarin (from Milk Thistle), Boswellia, and Curcumin, that have shown proof of effectiveness in humans for relieving joint pain and reducing inflammation. These are the active ingredients in the unique Triple Joint Relief compound:

1. Silymarin (milk Thistle)

Triple Joint Relief ingredient insight:Silymarin

After an after extensive drug and plant extract research process, the Green Valley team found silymarin to be the only substance shown in a human trial to reduce joint pain by depressing the complement cascade.

Read on to find out how we combined it with two other powerful substances to further control joint fluid inflammation and pain – and even help revitalize joint cartilage.

The Journal of Advanced Pharmacy Education & Research notes that “Milk thistle seeds have been used for centuries as herbal medicine mainly for the treatment of liver diseases.” It also has “has anti-inflammatory, immunomodulatory, lipid, and biliary effects” as well as “antiviral, antitumor, and other therapeutic properties.” A variety of other academic sources can be found which discuss these properties. The active ingredient -- the one that protects the liver – is known as silymarin, a chemical extracted from the plant’s seeds. Silymarin is actually a group of flavonoids (silibinin, silidianin, and silicristin), which are thought to help repair liver cells damaged by alcohol and other toxins, and help keep new liver cells from being destroyed by these same toxins. It’s also known to reduce inflammation (which is why it is often recommended for people with liver inflammation or hepatitis) and is a strong antioxidant.

Knowing this, the Green Valley development team performed an extensive review of worldwide literature and found two studies of particular note:

• Silymarin found to provide exceptional levels of joint pain relief - IT Numan, 2007

  A double-blind clinical study showed that silymarin, when used alone or in combination with two common NSAID pain relievers resulted in significant improvement in the components of KOOS Pain Test, and significantly higher than that produced by the pain relievers when each used alone.

  KOOS is a sophisticated test designed to assess knee injury and pain on a scale of 1-100, with zero representing extreme knee problems and 100 representing no knee problems. The higher the score, the better the test subjects feel. Here’s a summary of the findings over the course of the trial:

  Week 0 32.7: “Severe or extreme symptoms of pain” at start of studyWeek 1 71: Real pain relief in 7 daysWeek 2 83.4Week 4 96Week 8 98: Virtually no pain at the end of the study

• Silymarin significantly reduces key proteins in the complement cascade - SA Hussein, 2009

  This follow-up study analyzed before and after blood serum samples from the 2009 IT Numan study to find the mechanism of action responsible for such significant results. Of particular note: At the end of eight weeks, silymarin was found to reduce a number of known inflammatory molecules, including IL-8 and IL-1alpha, which were reduced by 58% and 56% respectively. More importantly, two of the nine proteins in the complement cascade were also impacted:

  Complement cascade protein C3 reduced by 81%Complement cascade protein C4 reduced by 45%

  In other words, silymarin substantially reduces two proteins – C3 and C4 – early in the complement cascade sequence, which helps to brake completion of the process. Going back to the dominoes analogy, it’s like putting 9 domino tiles in a row, taking out the third and fourth pieces, then trying to tip over what’s left. You won’t succeed very often.

2. Boswellia

Triple Joint Relief ingredient insight:Boswellia

There are many boswellia supplements on the market, but it’s not the same substance that’s been proven to work in clinical trials. Triple Joint Relief uses 100 mg of ApresFlex, which is the brand name for the Aflapin boswellia extract used in these studies. The standard 30% AKBA extract found in most boswellia supplements isn’t as easily absorbed into the circulatory system, and can’t be counted on to deliver results.

Also known as frankincense, boswellia is one of the best researched and most effective inflammation-fighting plants. Long used in traditional medicine, scientists have been intrigued by its broad anti-inflammatory capabilities. Research has identified gum resin extracts of Boswellia serrata containing 3-O-acetyl-11-keto-β-boswellic acid (AKBA) for its “promising potential as therapeutic interventions against inflammatory diseases such as osteoarthritis (OA)” (Sengupta, 2011). In particular, it has been found to reduce inflammatory molecules in joint fluid and throughout the body – the synovitis that travels around the body and increases pain perception 9.2 x.

When taken orally, standard boswellia has poor “bioavailability” – meaning only a limited amount of AKBA is absorbed into the body, curbing its effect. However, a relatively new form of boswellia extract enriched with non-volatile oil portions of the plant, called Aflapin, has been found to increase bioavailability by 52%, delivering significant benefits in a number of studies. Of note, the 2011 Sungupta study, V Karlapudi 2023 and others have cited a number of significant effects including:

• TNF alpha: Reduced this biomarker of inflammation at day 30 by one third – 29%
• 5-LOX: Blocks this pain-causing enzyme
• C-Reactive Protein: Reduced this common measure of inflammation by 24%
• MMP3: Turns down enzyme, which degrades joint cartilage, by 46.33%, helping protect cartilage from progressing to bone-on-bone
• Collagen and glycosaminoglycans: Increases synthesis of these healthy components of cartilage

But the more important question is, do these results translate into significant improvement in the lives of real people? A key, and widely cited, clinical trial (AA Vishal, 2011) found that that after 30 days, Aflapin “conferred clinically and statistically significant improvements in pain scores and physical function scores” based on the Western Ontario and McMaster Universities Arthritis Index – also called the WOMAC Index – a widely accepted clinical measure hip and knee pain, function, and stiffness.

3. Curcumin

Triple Joint Relief ingredient insight:Curcumin

Curcumin is a powerful compound, with many uses. In Triple Joint Relief, it helps boost the effectiveness of the primary silymarin and boswellia ingredients. But scientific literature will tell you that standard extracts have problems with solubility, absorption, and bioavailability – and likely won’t work as required.

Curcumin, the anti-inflammatory component of the spice turmeric, is one of the most well-known and recommended joint-relief products in the world. Per S Khalife, 2011, it targets a phenomenal number of inflammatory molecules:

• IL-1beta
• Prostaglandin E2
• COX-2
• IL-6
• IL-8
• MMP-3
• MMP-9
• JNK
• NF-kB

Research performed in vitro (i.e., in a lab dish) and in vivo (in living organisms) also shows that curcumin helps protect human cartilage from breakdown by IL-1beta and MMP3, and blocks cartilage degradation by other molecules, such as NF-kB – making it the ideal complement to silymarin and boswellia for comprehensive joint relief.

That’s why Triple Joint Relief uses only patented Curcumin C3 Complex, a unique compound of three extracts – curcumin, demethoxycurcumin, and bisedemethoxycurcumin – derived from the rhizomes (roots) of the plant Curcuma longa. This unique formulation makes Curcumin C3 Complex far more absorbable in the gastrointestinal tract. In fact, due to its consistency, quality, and integrity, Curcumin C3 Complex is the most clinically-studied natural anti-inflammatory and antioxidant at research institutions around the world.