Tag Archives: inflammation

Alleviating joint damage and inflammation from arthritis with neutrophil nanosponges

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Assuming you’d be happy with limiting the damage for rheumatoid arthritis, at some point in the future, this research looks promisin. Right now it appears the researchers aren’t anywhere close to a clinical trial. From a Sept. 3, 2018 news item on ScienceDaily,

Engineers at the University of California San Diego [UCSD] have developed neutrophil “nanosponges” that can safely absorb and neutralize a variety of proteins that play a role in the progression of rheumatoid arthritis. Injections of these nanosponges effectively treated severe rheumatoid arthritis in two mouse models. Administering the nanosponges early on also prevented the disease from developing.

A Sept. 3, 2018 UCSD press release (also on EurekAlert), which originated the news item, provides more detail,

“Nanosponges are a new paradigm of treatment to block pathological molecules from triggering disease in the body,” said senior author Liangfang Zhang, a nanoengineering professor at the UC San Diego Jacobs School of Engineering. “Rather than creating treatments to block a few specific types of pathological molecules, we are developing a platform that can block a broad spectrum of them, and this way we can treat and prevent disease more effectively and efficiently.”

This work is one of the latest examples of therapeutic nanosponges developed by Zhang’s lab. Zhang, who is affiliated with the Institute of Engineering in Medicine and Moores Cancer Center at UC San Diego, and his team previously developed red blood cell nanosponges to combat and prevent MRSA infections and macrophage nanosponges to treat and manage sepsis.

neutrophil nanosponge cartoon
Illustration of a neutrophil cell membrane-coated nanoparticle.

The new nanosponges are nanoparticles of biodegradable polymer coated with the cell membranes of neutrophils, a type of white blood cell.

Neutrophils are among the immune system’s first responders against invading pathogens. They are also known to play a role in the development of rheumatoid arthritis, a chronic autoimmune disease that causes painful inflammation in the joints and can ultimately lead to damage of cartilage and bone tissue.

When rheumatoid arthritis develops, cells in the joints produce inflammatory proteins called cytokines. Release of cytokines signals neutrophils to enter the joints. Once there, cytokines bind to receptors on the neutrophil surfaces, activating them to release more cytokines, which in turn draws more neutrophils to the joints and so on.

The nanosponges essentially nip this inflammatory cascade in the bud. By acting as tiny neutrophil decoys, they intercept cytokines and stop them from signaling even more neutrophils to the joints, reducing inflammation and joint damage.

These nanosponges offer a promising alternative to current treatments for rheumatoid arthritis. Some monoclonal antibody drugs, for example, have helped patients manage symptoms of the disease, but they work by neutralizing only specific types of cytokines. This is not sufficient to treat the disease, said Zhang, because there are so many different types of cytokines and pathological molecules involved.

“Neutralizing just one or two types might not be as effective. So our approach is to take neutrophil cell membranes, which naturally have receptors to bind all these different types of cytokines, and use them to manage an entire population of inflammatory molecules,” said Zhang.

“This strategy removes the need to identify specific cytokines or inflammatory signals in the process. Using entire neutrophil cell membranes, we’re cutting off all these inflammatory signals at once,” said first author Qiangzhe Zhang, a Ph.D. student in Professor Liangfang Zhang’s research group at UC San Diego.

To make the neutrophil nanosponges, the researchers first developed a method to separate neutrophils from whole blood. They then processed the cells in a solution that causes them to swell and burst, leaving the membranes behind. The membranes were then broken up into much smaller pieces. Mixing them with ball-shaped nanoparticles made of biodegradable polymer fused the neutrophil cell membranes onto the nanoparticle surfaces.

“One of the major challenges of this work was streamlining this entire process, from isolating neutrophils from blood to removing the membranes, and making this process repeatable. We spent a lot of time figuring this out and eventually created a consistent neutrophil nanosponge production line,” said Qiangzhe Zhang.

In mouse models of severe rheumatoid arthritis, injecting nanosponges in inflamed joints led to reduced swelling and protected cartilage from further damage. The nanosponges performed just as well as treatments in which mice were administered a high dose of monoclonal antibodies.

The nanosponges also worked as a preventive treatment when administered prior to inducing the disease in another group of mice.

Professor Liangfang Zhang cautions that the nanosponge treatment does not eliminate the disease. “We are basically able to manage the disease. It’s not completely gone. But swelling is greatly reduced and cartilage damage is minimized,” he said.

The team hopes to one day see their work in clinical trials.

Here’s a link to and a citation for the paper,

Neutrophil membrane-coated nanoparticles inhibit synovial inflammation and alleviate joint damage in inflammatory arthritis by Qiangzhe Zhang, Diana Dehaini, Yue Zhang, Julia Zhou, Xiangyu Chen, Lifen Zhang, Ronnie H. Fang, Weiwei Gao, & Liangfang Zhang. Nature Nanotechnology (2018) DOI: https://doi.org/10.1038/s41565-018-0254-4 Published 03 September 2018

This paper is behind a paywall.

Hallucinogenic molecules and the brain

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Psychedelic drugs seems to be enjoying a ‘moment’. After decades of being vilified and  declared illegal (in many jurisdictions), psychedelic (or hallucinogenic) drugs are once again being tested for use in therapy. A Sept. 1, 2017 article by Diana Kwon for The Scientist describes some of the latest research (I’ve excerpted the section on molecules; Note: Links have been removed),

Mind-bending molecules

© SEAN MCCABE

All the classic psychedelic drugs—psilocybin, LSD, and N,N-dimethyltryptamine (DMT), the active component in ayahuasca—activate serotonin 2A (5-HT2A) receptors, which are distributed throughout the brain. In all likelihood, this receptor plays a key role in the drugs’ effects. Krähenmann [Rainer Krähenmann, a psychiatrist and researcher at the University of Zurich]] and his colleagues in Zurich have discovered that ketanserin, a 5-HT2A receptor antagonist, blocks LSD’s hallucinogenic properties and prevents individuals from entering a dreamlike state or attributing personal relevance to the experience.12,13

Other research groups have found that, in rodent brains, 2,5-dimethoxy-4-iodoamphetamine (DOI), a highly potent and selective 5-HT2A receptor agonist, can modify the expression of brain-derived neurotrophic factor (BDNF)—a protein that, among other things, regulates neuronal survival, differentiation, and synaptic plasticity. This has led some scientists to hypothesize that, through this pathway, psychedelics may enhance neuroplasticity, the ability to form new neuronal connections in the brain.14 “We’re still working on that and trying to figure out what is so special about the receptor and where it is involved,” says Katrin Preller, a postdoc studying psychedelics at the University of Zurich. “But it seems like this combination of serotonin 2A receptors and BDNF leads to a kind of different organizational state in the brain that leads to what people experience under the influence of psychedelics.”

This serotonin receptor isn’t limited to the central nervous system. Work by Charles Nichols, a pharmacology professor at Louisiana State University, has revealed that 5-HT2A receptor agonists can reduce inflammation throughout the body. Nichols and his former postdoc Bangning Yu stumbled upon this discovery by accident, while testing the effects of DOI on smooth muscle cells from rat aortas. When they added this drug to the rodent cells in culture, it blocked the effects of tumor necrosis factor-alpha (TNF-α), a key inflammatory cytokine.

“It was completely unexpected,” Nichols recalls. The effects were so bewildering, he says, that they repeated the experiment twice to convince themselves that the results were correct. Before publishing the findings in 2008,15 they tested a few other 5-HT2A receptor agonists, including LSD, and found consistent anti-inflammatory effects, though none of the drugs’ effects were as strong as DOI’s. “Most of the psychedelics I have tested are about as potent as a corticosteroid at their target, but there’s something very unique about DOI that makes it much more potent,” Nichols says. “That’s one of the mysteries I’m trying to solve.”

After seeing the effect these drugs could have in cells, Nichols and his team moved on to whole animals. When they treated mouse models of system-wide inflammation with DOI, they found potent anti-inflammatory effects throughout the rodents’ bodies, with the strongest effects in the small intestine and a section of the main cardiac artery known as the aortic arch.16 “I think that’s really when it felt that we were onto something big, when we saw it in the whole animal,” Nichols says.

The group is now focused on testing DOI as a potential therapeutic for inflammatory diseases. In a 2015 study, they reported that DOI could block the development of asthma in a mouse model of the condition,17 and last December, the team received a patent to use DOI for four indications: asthma, Crohn’s disease, rheumatoid arthritis, and irritable bowel syndrome. They are now working to move the treatment into clinical trials. The benefit of using DOI for these conditions, Nichols says, is that because of its potency, only small amounts will be required—far below the amounts required to produce hallucinogenic effects.

In addition to opening the door to a new class of diseases that could benefit from psychedelics-inspired therapy, Nichols’s work suggests “that there may be some enduring changes that are mediated through anti-inflammatory effects,” Griffiths [Roland Griffiths, a psychiatry professor at Johns Hopkins University] says. Recent studies suggest that inflammation may play a role in a number of psychological disorders, including depression18 and addiction.19

“If somebody has neuroinflammation and that’s causing depression, and something like psilocybin makes it better through the subjective experience but the brain is still inflamed, it’s going to fall back into the depressed rut,” Nichols says. But if psilocybin is also treating the inflammation, he adds, “it won’t have that rut to fall back into.”

…

If it turns out that psychedelics do have anti-inflammatory effects in the brain, the drugs’ therapeutic uses could be even broader than scientists now envision. “In terms of neurodegenerative disease, every one of these disorders is mediated by inflammatory cytokines,” says Juan Sanchez-Ramos, a neuroscientist at the University of South Florida who in 2013 reported that small doses of psilocybin could promote neurogenesis in the mouse hippocampus.20 “That’s why I think, with Alzheimer’s, for example, if you attenuate the inflammation, it could help slow the progression of the disease.”

For anyone who was never exposed to the anti-hallucinogenic drug campaigns, this turn of events is mindboggling. There was a great deal of concern especially with LSD in the 1960s and it was not entirely unfounded. In my own family, a distant cousin, while under the influence of the drug, jumped off a building believing he could fly.  So, Kwon’s story opening with a story about someone being treated successfully for depression with a psychedelic drug was surprising to me . Why these drugs are being used successfully for psychiatric conditions when so much damage was apparently done under the influence in decades past may have something to do with taking the drugs in a controlled environment and, possibly, smaller dosages.

Curcumin gel for burns and scalds

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The curcumin debate continues (see my  Jan. 26, 2017 posting titled: Curcumin: a scientific literature review concludes health benefits may be overstated for more about that). In the meantime, scientists at the University of California at Los Angeles’ (UCLA) David Geffen School of Medicine found that curcumin gel might be effective as a treatment for burns. From a March 14, 2017 Pensoft Publishers news release on EurekAlert (Note: Links have been removed),

What is the effect of Topical Curcumin Gel for treating burns and scalds? In a recent research paper, published in the open access journal BioDiscovery, Dr. Madalene Heng, Clinical Professor of Dermatology at the David Geffen School of Medicine, stresses that use of topical curcumin gel for treating skin problems, like burns and scalds, is very different, and appears to work more effectively, when compared to taking curcumin tablets by mouth for other conditions.

“Curcumin gel appears to work much better when used on the skin because the gel preparation allows curcumin to penetrate the skin, inhibit phosphorylase kinase and reduce inflammation,” explains Dr Heng.

In this report, use of curcumin after burns and scalds were found to reduce the severity of the injury, lessen pain and inflammation, and improve healing with less than expected scarring, or even no scarring, of the affected skin. Dr. Heng reports her experience using curcumin gel on such injuries using three examples of patients treated after burns and scalds, and provides a detailed explanation why topical curcumin may work on such injuries.

Curcumin is an ingredient found in the common spice turmeric. Turmeric has been used as a spice for centuries in many Eastern countries and gives well known dishes, such as curry, their typical yellow-gold color. The spice has also been used for cosmetic and medical purposes for just as long in these countries.

In recent years, the medicinal value of curcumin has been the subject of intense scientific studies, with publication numbering in the thousands, looking into the possible beneficial effects of this natural product on many kinds of affliction in humans.

This study published reports that topical curcumin gel applied soon after mild to moderate burns and scalds appears to be remarkably effective in relieving symptoms and improved healing of the affected skin.

“When taken by mouth, curcumin is very poorly absorbed into the body, and may not work as well,” notes Dr. Heng. “Nonetheless, our tests have shown that when the substance is used in a topical gel, the effect is notable.”

The author of the study believes that the effectiveness of curcumin gel on the skin – or topical curcumin – is related to its potent anti-inflammatory activity. Based on studies that she has done both in the laboratory and in patients over 25 years, the key to curcumin’s effectiveness on burns and scalds is that it is a natural inhibitor of an enzyme called phosphorylase kinase.

This enzyme in humans has many important functions, including its involvement in wound healing. Wound healing is the vital process that enables healing of tissues after injury. The process goes through a sequence of acute and chronic inflammatory events, during which there is redness, swelling, pain and then healing, often with scarring in the case of burns and scalds of the skin. The sequence is started by the release of phosphorylase kinase about 5 mins after injury, which activates over 200 genes that are involved in wound healing.

Dr. Heng uses curcumin gel for burns, scalds and other skin conditions as complementary treatment, in addition to standard treatment usually recommended for such conditions.

Caption: These are results from 5 days upon application of curcumin gel to burns, and results after 6 weeks. Credit: Dr. Madalene Heng

Here’s a link to and a citation for the paper,

Phosphorylase Kinase Inhibition Therapy in Burns and Scalds by Madalene Heng. BioDiscovery 20: e11207 (24 Feb 2017) https://doi.org/10.3897/biodiscovery.20.e1120

This paper is in an open access journal.

Arbro Pharmaceuticals and its bioavailable curcumin

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Curcumin (a constituent of the spice turmeric) is reputed to have health benefits and has been used in traditional medicine in Asia (notably India) for millenia. Recently scientists have been trying to render curcumin more effective which means increasing its bioavailability (my Nov. 7, 2014 posting features some of that research). According to an April 29, 2016 Arbro Pharmaceuticals press release, the goal of increased bioavailability has been reached and a product is now available commercially,

Arbro Pharmaceuticals has launched SNEC30, a patented highly bioavailable self-nanoemulsifying curcumin formulation in the dosage of 30mg.

Curcumin is the active ingredient of turmeric or haldi, which has been widely used in traditional medicine and home remedies in India for hundreds of years.

Clinical research conducted over the last 25 years has shown curcumin to be effective against various diseases like cancer, pain, inflammation, arthritis, ulcers, psoriasis, arteriosclerosis, diabetes and many more pro-inflammatory conditions.

Despite its effectiveness against so many medical conditions, scientists have come to believe that curcumin’s true potential has been limited by its poor bioavailability which is caused by the fact that it has poor solubility and extensive pre-systemic metabolism.

Arbro Pharmaceuticals partnered with Jamia Hamdard University to carry out research and develop a novel formulation, which can overcome curcumin’s poor bioavailability. The development project was jointly funded by Arbro and the Department of Science and Technology, Government of India under its DPRP (Drug and Pharmaceutical Research Programme) scheme.

SNEC30 is the outcome of this joint research and is based on a novel self-nanoemulsifying drug delivery systems (SNEDDS) for which patents have been filed and the US patent has been granted.

“There has been tremendous interest in the therapeutic potential of curcumin but its poor bioavailability was a limiting factor, our research group together with Arbro took the challenge and applied nanotechnology to overcome this limitation and achieve highest ever bioavailability for curcumin,” said Dr. Kanchan Kohli, Asst. Prof, Faculty of Pharmacy, Jamia Hamdard University, who is one of the main developers of the formulation.

Nanotechnology is the engineering of functional systems at the molecular scale (CRN – Centre for Responsible Nanotechnology). The name stems from the fact that the structures are in the nano-metre (10-9 mm) in range. In pharmaceutics, nano-formulations are used for targeted drug-delivery, particularly in cancer therapy. It also finds numerous other applications in medicine.

“Just 30mg of curcumin that is contained in one capsule of SNEC30 has shown higher blood levels than what can be achieved by consuming the curcumin content of 1kg of raw haldi or turmeric,” said Mr. Vijay Kumar Arora, Managing Director, Arbro Pharmaceuticals.

About Arbro Pharmaceuticals:

Arbro Pharmaceuticals is a 30-year-old research oriented company with its own research and development, testing and manufacturing facilities. Arbro has been manufacturing and exporting hundreds of formulations under its own brand name to more than 10 countries.

I am not endorsing this product but if you are interested the SNEC30 website is here. I believe Arbro Pharmaceuticals’ headquarters, the company which produces SNEC30, are located in India.

Inflammation isn’t all bad but sometimes you need to reduce it with nanomedicines

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Researchers from Brigham and Women’s Hospital (BWH), Columbia University Medical Center, Icahn School of Medicine at Mount Sinai, and Massachusetts Institute of Technology (MIT) have published about a study about their use of nano-sized particles to release therapeutic drugs that are designed to relieve chronic inflammation. From the Mar. 18, 2013 news release on EurekAlert,

Inflammation is the body’s natural defense mechanism against invading organisms and tissue injury. In acute inflammation, the pathogen or inflammatory mediators are cleared away and homeostasis is reached, however in chronic inflammatory states, this resolving response is impaired, leading to chronic inflammation and tissue damage. It is now widely believed that an impaired resolution of inflammation is a major contributing factor to the progression of a number of devastating diseases such as atherosclerosis, arthritis, and neurodegenerative diseases, in addition to cancer. Since the level of inflammation in these diseases is very high—targeted therapeutic solutions are required to help keep inflammation contained.

A new study from researchers at Brigham and Women’s Hospital (BWH), Columbia University Medical Center, Icahn School of Medicine at Mount Sinai, and Massachusetts Institute of Technology presents the development of tiny nanomedicines in the sub 100 nm range (100,000 times smaller than the diameter of a human hair strand) that are capable of encapsulating and releasing an inflammation-resolving peptide drug. The authors showed that these nanoparticles are potent pro-resolving nanomedicines, capable of selectively homing to sites of tissue injury in mice, and releasing their therapeutic payload in a controlled manner over time. Uniquely, these nanoparticles are designed to target the extracellular microenvironment of inflamed tissues. The particles then slowly release their potent inflammation-resolving payload such that it can diffuse through the inflamed tissue. There the drug binds to receptors on the plasma membrane of activated white blood cells and causes them to become more quiescent.

The research will be published some time this week (week of Mar. 18, 2013) by the Proceedings of the National Academy of Science. The news release offers more detail about the work,

“The beauty of this approach is that it takes advantage of nature’s own design for preventing inflammation-induced damage, which, unlike many other anti-inflammatory strategies, does not compromise host defense and promotes tissue repair,” said Ira Tabas, MD, PhD, physician-scientist at Columbia University Medical Center and co-senior author of this study.

“The development of self-assembled targeted nanoparticles which are capable of resolving inflammation has broad application in medicine including the treatment of atherosclerosis,” said Omid Farokhzad, MD, physician-scientist at BWH, and a co-senior author of this study.

Polymers consisting of three chains attached end-to-end were developed as building blocks for the engineering of self-assembled targeted nanoparticles; one chain enabled the entrapment and controlled release of the therapeutic payload, in this case a peptide which mimics the pro-resolving properties of the Annexin A1 protein. Another chain conferred stealth properties to the nanoparticles, enabling their long-circulation after systemic administration. Yet a third chain gave homing capability to the nanoparticles to target the collagen IV protein to the vascular wall. As such these nanoparticles are capable of selectively sticking to injured vasculature allowing their therapeutic anti-inflammatory cargo to be released where it is needed to effectively promote inflammation resolution in a deliberate and targeted manner.

“These targeted polymeric nanoparticles are capable of stopping neutrophils, which are the most abundant form of white blood cells, from infiltrating sites of disease or injury at very small doses. This action stops the neutrophils from secreting further signaling molecules which can lead to a constant hyper-inflammatory state and further disease complications,” said Nazila Kamaly, PhD, a postdoctoral fellow at BWH and co-lead author of this study.

“Nanoparticles that selectively bind to injured vasculature could have a profound impact in prevalent diseases, such as atherosclerosis, where damaged or comprised vasculature underlie the pathology. This work offers a novel targeted nanomedicine to the burgeoning field of inflammation-resolution, a field previously pioneered by BWH’s Dr. Charles Serhan,” said Gabrielle Fredman, PhD, a post-doctoral fellow at Columbia University Medical Center and co-lead author of this study.

These new developments have led the researchers to start investigating the potential of these pro-resolving nanomedicines for their effects on shrinking atherosclerotic plaques, and these studies are currently underway.

This news release does not offer any information as to what type of studies might be underway. My guess is that we are still years away from human clinical trials. Azonano also features this work in a Mar. 19, 2013 news item.