Depriving Deadly Brain Tumors Of Cholesterol , parasites need cholesterol

Depriving Deadly Brain Tumors Of Cholesterol May Be Their Achilles’ Heel

Summary: Depriving glioblastoma brain cancer cells of cholesterol caused tumor regression and prolonged survival in mouse models of the disease, a new study reports.

Source: UCSD.

In mouse models, alternative approach proves promising against hard-to-treat cancer.

Researchers at University of California San Diego School of Medicine, Ludwig Institute for Cancer Research and The Scripps Research Institute, with colleagues in Los Angeles and Japan, report that depriving deadly brain cancer cells of cholesterol, which they import from neighboring healthy cells, specifically kills tumor cells and caused tumor regression and prolonged survival in mouse models.

The findings, published in the online October 13 issue of Cancer Cell, also present a potential alternative method for treating glioblastomas (GBM), the most common and most aggressive form of brain cancer. GBMs are extremely difficult to treat. The median survival rate is just over 14 months, with few treated patients living five years or more past diagnosis.

Adult brain cancers are almost universally fatal, in part because of the biochemical composition of the central nervous system (CNS) and the blood-brain barrier, which selectively and protectively limits the passage of molecules from the body into the brain, but which also blocks most existing chemotherapies, contributing to treatment failure.

This includes blocking small molecule inhibitors that target growth factor receptors, which have not proven to be effective with brain cancers, possibly due to their inability to get past the blood-brain barrier and achieve sufficiently high levels in the central nervous system.

“Researchers have been thinking about ways to deal with this problem,” said senior author Paul S. Mischel, MD, a member of the Ludwig Cancer Research branch at UC San Diego and professor in the UC San Diego School of Medicine Department of Pathology. “We have been challenged by the fact that GBMs are among the most genomically-well characterized forms of cancer, with clear evidence of targetable driver oncogene mutations but this information has yet to benefit patients, at least in part, because the drugs designed to target these oncogenes have difficulty accessing their targets in the brain. We have been trying to find an alternative way to use this information to develop more effective treatments.

“One such approach stems from the observation that oncogenes (mutated genes) can rewire the biochemical pathways of cells in ways that make them dependent on proteins that are not themselves encoded by oncogenes. Targeting these ‘oncogene-induced co-dependencies’ opens up a much broader pharmacopeia, including the use of drugs that aren’t traditionally part of cancer drug pipelines but have better pharmacological properties.”

In previous research, Mischel and others had noted GBM cells cannot synthesize cholesterol, which is vital to cell structure and function, particularly in the brain. Instead, GBM cells derive what they need from brain cells called astrocytes, which produce cholesterol in abundance. Roughly 20 percent of total body cholesterol is found in the brain.

When normal cells have sufficient cholesterol, they convert some of it into molecules called oxysterols, which activate a receptor in the cell’s nucleus — the liver X receptor (LXR) — to shut down the uptake of cholesterol.

“So when normal cells get enough cholesterol, they stop making it, stop taking it up and start pumping it out,” said Mischel. “We found that in GBM cells, this mechanism is completely disrupted. They’re like parasites of the brain’s normal cholesterol system. They steal cholesterol and don’t have an off switch. They just keep gobbling the stuff up.”

Image shows an MRI brain scan of a glioblastoma patient.

GBM cells ensure their cholesterol supply by suppressing the production of oxysterols, the researchers said, ensuring cells’ LXRs remain inactive.

The research team, including Andrew Shaiu and Tim Gahman of Ludwig’s Small Molecule Development team at UC San Diego, identified an experimental metabolic disease drug candidate named LXR-623 that activates LXRs.

In mouse models, LXR-623 easily crossed the blood-brain barrier to bind with LXRs in normal cells, stimulating the production of oxysterols and the reduction of cholesterol. There was no effect upon healthy neurons and other brain cells, the scientists found, but GBM cells were deprived of vital cholesterol, resulting in cell death and tumor regression.

“Disrupting cholesterol import by GBM cells caused dramatic cancer cell death and shrank tumors significantly, prolonging the survival of the mice,” said Mischel. “The strategy worked with every single GBM tumor we looked at and even on other types of tumors that had metastasized to the brain. LXR-623 also had minimal effect on astrocytes or other tissues of the body.”

Mischel suggested the GBM strategy could be implemented in clinical trials using drug-candidates under development or in early trials.

ABOUT THIS NEUROSCIENCE RESEARCH ARTICLE

Co-authors of this paper include: first author Genaro R. Villa, Yuchao Gu, Xin Rong, Cynthia Hong, Timothy F. Cloughesy, UCLA; Jonathan J. Hulce, Kenneth M. Lum, Michael Martini and Benjamin F. Cravatt, TSRI; Ciro Zanca, Junfeng Bi, Shiro Ikegami, Gabrielle L. Cahill, Huijun Yang, Kristen M. Turn, Feng Liu, Gary C. Hon, David Jenkins, Aaron M. Armando, Oswald Quehenberger, Frank B. Furnari, and Webster K. Cavenee, UC San Diego; and Kenta Masui and Peter Tontonoz, Tokyo Women’s Medical University.

Funding: Funding for this research came, in part, from the National Cancer Institute (F31CA186668), the National Institute for Neurological Diseases and Stroke (NS73831, NS080939), the Defeat GBM Program of the National Brain Tumor Society, the Ben and Catherine Ivy Foundation, the Ziering Family Foundation and the National Institutes of Health (CA132630).

Source: Scott LaFee – UCSD
Image Source: NeuroscienceNews.com image is credited A. Christaras.
Original Research: The study will appear in Cancer Cell.


All parasites may be metabolising cholesterol

The requirement of cholesterol for internalization of eukaryotic pathogens like protozoa (Leishmaniasis, Malaria and Toxoplasmosis) and the exchange of cholesterol along with other metabolites during reproduction in Schistosomes (helminths) under variable circumstances are poorly understood. In patients infected with some other helminthes, alterations in the lipid profile have been observed. Also, the mechanisms involved in lipid changes especially in membrane proteins related to parasite infections remain uncertain. Present review of literature shows that parasites induce significant changes in lipid parameters, as has been shown in the in vitro study where substitution of serum by lipid/cholesterol in medium and in experimental models (in vivo). Thus changes in lipid profile occur in patients having active infections with most of the parasites. Membrane proteins are probably involved in such reactions. All parasites may be metabolising cholesterol, but the exact relationship with pathogenic mechanism is not clear. So far, studies suggest that there may be some factors or enzymes, which allow the parasite to breakup and consume lipid/cholesterol.

Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1142336/

Study reveals role of specific lipids in accelerating or curbing bacterial infection

Study reveals role of specific lipids in accelerating or curbing bacterial infection

Lipids appear to play an important role in infections. According to researchers from the University of Maastricht in Maastricht, The Netherlands, and the University of Maryland, Baltimore (UMB) in Baltimore, Md., USA, specific lipids can greatly accelerate bacterial infection.

With the help of mass spectrometry imaging (MSI), researchers showed that specific mammalian lipids could also provide protection against the same infection. Their discovery offers hope for future treatment of vulnerable patients in hospitals or development of preventative treatments for travellers to risk areas in certain parts of the world.

The findings of the research team, led by American researchers Robert Ernst and Alison Scott at UMB and Maastricht University Distinguished Professor Ron Heeren, were published Nov. 6 in the journal, Proceedings of the National Academy of Sciences (PNAS).

Mass Spectrometry Imaging
Mass spectrometry imaging is an imaging technique in which molecular maps of a pathological tissue section can be compiled from a single experiment. Researchers use the technique to determine exactly where certain molecules are located and how their distribution is affected by pathogenic bacteria, for instance. “This technique enables us to analyse thousands of molecules with a single measurement,” Heeren explains. “What is special about our research is that we were able to use this method in order to capture for the first time the molecular changes which occur during a bacterial infection, mainly revealing the role of lipids in the further evolution of such an inflammation. This result means that we’ll be able in future to determine the severity of an infection accurately within half an hour. Based on the type of lipid, we’ll also know how the inflammation will behave in a patient.”

Protect or accelerate
To test their ability to use MSI to track disease progression, the scientists injected a healthy mouse with the highly pathogenic bacteria Francisella novicida (Fn). Through MSI, the researchers were then able to create an accurate molecular map of the infection’s evolution, predominantly based on lipids. In doing so, it became clear that certain lipids significantly accelerated the infection, although these lipids should never be seen as separate from their spatial context in the tissue. “The distribution of lipids in the host – the patient – appears to have a tremendous effect on the immune system. For this reason, lipids are a strong determining factor in the aggressiveness of a bacterial infection,” Heeren concludes. “It is now important to establish a kind of library, in which we can precisely identify which lipids play a role in accelerating infection and which lipids have a positive effect on the immune response.”

Alison Scott PhD, research associate professor at the University of Maryland School of Dentistry (UMSOD) and guest researcher at Maastricht University, hopes that this knowledge will help develop drugs that could be used to treat vulnerable patients and help them form the right lipids in the right places to dampen infection.

Applicability of this study
Although the researchers specifically used MSI to track Fn infection in this study, the techniques could be applied to a wide range of diseases. “The methodology underlying the study is relevant to any infection and positions us to expand work in the field of the role of lipids in both the bacteria and the host. It allows researchers to identify host-based pathways for therapeutic treatment to control bacterial infection and inflammation. I hope to start looking at airway infections such as pseudomonas,” says Scott.

This kind of research is only made possible by collaborations across disciplines. “This study shows the value of highly collaborative projects bringing together microbiologists and mass spectrometry experts to define the finite interactions between a bacteria and a host,” says Robert “Bob” Ernst, PhD, the senior investigator involved in the study and professor and vice chair of the Department of Microbial Pathogenesis at UMSOD and an adjunct professor at the University of Maryland School of Medicine (UMSOM).

The research presented here opens up many research avenues, both into the applicability of MSI for disease studies and the development of therapeutics that target lipids to treat infection, according to Ernst and colleagues, who include Kari Ann Shirey, PhD, assistant professor in UMSOM’s Department of Microbiology and Immunology.

Healthy fiber and Antibiotics, the good and bad

One of my senior client who is 91 yrs old loves pork and have a gout. He walks well and appears healthy but with lots of medications.  He has a problem with digesting fats and was put in low salt diet by his doctor. So, I added more fiber in his diet, added pinch of sea salt in his soup and ensured that he is not over medicated especially with antibiotics.

Healthy fiber can help all of us in losing weight as it encapsulates the fat and sugar out of our bodies.

From Dr Mercola:

Your gut microbiome also exerts a powerful influence on your weight. Gut microbes known as Firmicutes have been detected in higher numbers in obese individuals, who also may have 90 percent less of a bacteria called bacteroidetes than lean people.7 In a Medscape interview8 published in April, 2015, Dr Martin Blaser, who heads up the Human Microbiome Center at New York University, discussed the links between your gut microbiome, obesity, and chronic disease.

As noted by Dr. Blaser:

“The basic idea is that the microbiome is ancient. The organisms that we carry are not random; they have been selected over eons of evolution. They are important for our physiology, and there is a lot of evidence for that. My big point is that they are changing. As a result of the change, there are health consequences …

I believe that there is a general paradigm that we are losing important organisms early in life, and that is fueling some of the diseases that are epidemic today.”

In his book, “Missing Microbes: How the Overuse of Antibiotics Is Fueling Our Modern Plagues,” Dr. Blaser attributes rising obesity and disease rates to factors that have altered the microbial composition of our microbiome. This includes:

  • Increased rates of C-sections
  • Excessive use of antibiotics in medicine
  • Inappropriate use of antibiotics in food production. As noted by Dr. Blaser: Farmers found that they could increase the growth of their livestock by giving them low doses of antibiotics … the earlier in life they gave the antibiotics, the more profound the effect—and that is what we are doing to our kids”
  • Dietary changes, switching to diets low in fat and high in carbohydrates
  • Switching from breast milk to infant formula. This dietary change, he believes, is the most adverse of all

Moreover, he believes the effects are “cumulative over time and cumulative across generations,” noting that:“We’ve done studies in mice in which we can show that giving mice antibiotics early in life makes them fat. Putting mice on a high-fat diet makes them fat, and putting them on both together makes them very fat, suggesting the idea of additive risk.”

How Gut Bacteria Helps Regulate Your Appetite

Recent research has shed even more light on the links between gut bacteria and weight problems. Here, the researchers decided to investigate the possibility that bacterial proteins might act directly on appetite-controlling pathways. The hypothesis was that since bacterial survival depends on maintaining a stable environment, the bacteria must have some way of communicating their nutritional needs to the host.

Indeed, this is what they discovered. In essence, it appears gut bacteria play a role in appetite regulation by multiplying in response to nutrients, and stimulating the release of satiety hormones. The research also suggests bacteria produce proteins that can linger in your blood for a longer period of time, thereby modulating satiety pathways in your brain.

As reported by Medical News Today:9

“The researchers studied the growth dynamics of E. coli K12 … when exposed to regular nutrient supply …After 20 minutes of consuming nutrients and expanding numbers, it was found that E. coli bacteria from the gut produce different kinds of proteins than they do before feeding. The 20-minute mark coincides with the time taken for a person to begin feeling full or tired after a meal …

[T]he researchers began to profile the bacterial proteins before and after feeding … ‘Full’ bacterial proteins were found to stimulate the release of … a hormone associated with feeling full while “hungry” bacterial hormones did not …

The investigators next tested for the presence of one of the ‘full’ bacterial proteins, called ClpB. Levels of CLpB in mice and rats 20 minutes after eating … did correlate with ClpB DNA production in the gut, suggesting a mechanism linking gut bacterial composition with the host control of appetite.

The researchers also found that ClpB increased production of appetite-reducing neurons. Evidently, bacterial proteins produced by satiated E. coli influence the release of gut-brain signals, as well as activating appetite-regulated neurons in the brain.”

Another recent study10 found that probiotics helped protect against weight gain. The probiotic product in question was a commercial product simply referred to as VSL#3, containing multiple bacterial strains, includingLactobacillus acidophilus and Bifidobacterium longum. After four weeks, men who consumed this probiotic mix gained less weight and fat compared to those who received a placebo.

A Course of Antibiotics Can Alter Your Gut Microbiome for Up to a Year

It’s really important to understand the impact antibiotics have on your overall health, as they’re indiscriminate killers, wiping out not just the disease-causing bacteria but the beneficial bacteria too. Recent research demonstrates that when you take a course of antibiotics, your gut microbiome may be adversely affected for up to a year afterwards, depending on the antibiotic you’re taking.

Such dramatic shifts in your microbiome can also allow pathogens such as the deadly Clostridium difficile to gain a strong foothold, as evidenced in a recent animal study.11 This is a significant reason for limiting antibiotics to severe infections only, as a healthy gut microbiome is part of your immune function, serving as a primary defense against all disease.

The randomized, placebo-controlled clinical trial,12,13,14,15 which took place in Sweden and Great Britain, evaluated the effects of four commonly-prescribed antibiotics: clindamycin, ciprofloxacin, minocycline, and amoxicillin.

The bacteria in the participants’ oral and gut microbiomes were analyzed before the experiment, right after finishing the one-week long course of antibiotics, and again one, two, four, and 12 months afterward. While the oral microbiome normalized fairly quickly, the gut microbiome typically did not.

As reported by The Atlantic:16

“People who took clindamycin and ciprofloxacin saw a decrease in types of bacteria that produce butyrate, a fatty acid that lowers oxidative stress and inflammation in the intestines.

The reduced microbiome diversity for clindamycin-takers lasted up to four months; for some who took ciprofloxacin, it was still going on at the 12-month check-up. Amoxicillin, on the plus side, seemed to have no significant effect on either the oral or gut microbiome, and minocycline-takers were back to normal at the one-month check-up.”

Antibiotics Also Raise Your Risk of Antibiotic-Resistant Disease

But that’s not all. The study also demonstrated that when you take an antibiotic, you may also raise your risk of antibiotic-resistant disease. Antibiotic resistance genes were found in both British and Swedish participants at the outset of the study, although the British had on average a 1.13-times-higher load of antibiotic resistance genes than the Swedes.

The authors speculate that this may be a result of the fact that Sweden has significantly decreased use of antibiotics over the past 20 years, due to the Swedish Strategic Program for the Rational Use of Antimicrobial Agents and Surveillance of Resistance (STRAMA), launched in 1994. After exposure to antibiotics, the antibiotic resistance gene load increased across the board.

According to the authors:

“Among the antibiotics tested, exposure to amoxicillin resulted in the least discernible effects on the microbiome composition, while these samples had the highest number with antibiotic resistance-associated genes and the most classes that were increased in the predicted metagenomes and in the full metagenomes, respectively, a week after the exposure …

Clearly, even a single antibiotic treatment in healthy individuals contributes to the risk of resistance development and leads to long-lasting detrimental shifts in the gut microbiome.”

Antibiotics in Infancy Increases Risk for Obesity, Asthma, and Allergies

Similar research done on infants show that antibiotic treatment alters your baby’s gut microbiome for 2 months or longer, and shifts the balance to allow the potentially disease-causing Proteobacteria to become dominant. The study also found that treated infants had an increased risk for developing obesity, asthma, and allergies. As reported by the American Society for Microbiology:17

“In the study, 9 infants were treated with intravenous ampicillin/gentamicin within 48 hours of birth, and over the 2 month study period, their gastrointestinal flora were compared to that in 9 control infants. At 4 weeks, bacteria from the beneficial genera, the Bifidobacteria and the Lactobacilli, were significantly reduced, and although the numbers bounced back by the study’s end, the species diversity did not …

“This research suggests that the merits of administering broad spectrum antibiotics—those that kill many bacterial species—in infants should be reassessed, to examine the potential to use more targeted, narrow-spectrum antibiotics, for the shortest period possible,” says [co-author Catherine]Stanton.

Healthy Sources of Fiber

It’s easy to be fooled when it comes to fiber. Most processed grain products claim to supply you with fiber, but breads and cereals are far from ideal. Not only do cereal grains promote insulin and leptin resistance, which is at the heart of obesity and chronic disease, most are also contaminated with glyphosate.

For example, about 15 years ago, farmers began dousing non-organic wheat with glyphosate just before harvest—a process known as desiccation—which increases yield and kills rye grass.

As a result, most of the non-organic wheat supply is now heavily contaminated with glyphosate, which has been linked to celiac disease and other gut dysfunction. Needless to say, this is the exact converse of what you’re trying to achieve by adding fiber to your diet. Instead, focus on eating more vegetables, nuts, and seeds.

The following whole foods, for example, contain high levels of soluble and insoluble fiber. Psyllium in particular has been shown to improve glycemic control in people at risk for Type 2 diabetes.18

Organic psyllium seed husk, flax hemp, and chia seeds Berries Vegetables such as broccoli and Brussels sprouts
Root vegetables and tubers, including onions, sweet potatoes, and jicama Raw almonds Peas
Green beans Cauliflower Beans

Healthy Fiber Provides Fodder for Beneficial Gut Microbes

As you can see, many of the health benefits associated with fiber involve its impact on the microorganisms in your gut. Not only does soluble fiber serve as a prebiotic but it is also converted to short-chain fatty acids that are then converted to healthy ketones that feed your tissues.

Alterations of the human microbiome through inappropriate and unnatural diet changes (especially reverting away from breastfeeding infants, and avoiding fresh vegetables and other fiber-rich whole foods) appear to be part and parcel of rising disease rates. In essence, we’ve strayed too far from our natural diet, which promotes a healthy gut flora.

A major culprit is food processing, which removes many of the vital nutrients. Add to that the use of agricultural chemicals such as glyphosate, and decimated soil nutrients secondary to industrial agriculture , and it should be clear that what we’re eating today is very far indeed from what our ancestors ate even two or three generations ago. As a result, our microbiome is changing, and it’s changing for the worse.

Soluble fibers, such as psyllium, are ideal nourishment for beneficial bacteria that assist with digestion and absorption of your food, and play a significant role in your immune function. Opting for an organic version of psyllium will prevent exposure to pesticides, herbicides and chemical fertilizers that are present in nearly all commercial psyllium products.

I also recommend choosing one that does not contain additives or sweeteners, as these tend to have a detrimental effect on your microbiome. Sugar feed potentially pathogenic microorganisms, which is the converse of what you’re trying to achieve.

Brain neurons can be stimulated to create more networks, re-hydrate brain by sleeping

What stops our brain from having this balance all the time?

  1. Injury
  2. Medications, including alcohol
  3. Fatigue
  4. Emotional distress
  5. Pain
  6. Stress

These 6 types of problems tend to create a pattern in our brain’s activity that is hard to shift.

In chaos theory, we would call this pattern a “chaotic attractor”. Getting “stuck” in a specific kind of brain behaviour is like being caught in an attractor.

Even if you aren’t into chaos theory, you know being “stuck” doesn’t work – it keeps us in a place we likely don’t want to be all the time and makes it harder to dedicate our energies to something else -> Flexibility and Resilience.

Neurofeedback

Next, let’s take a closer look at how neurofeedback can be used to change brain activity.

Rehydrate the brain by SLEEPING and detox waste from brain by getting better sleep.