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/

Bird poop , ALS and health problems

HEALTH HAZARDS ASSOCIATED WITH BIRD AND BAT DROPPINGS


Human Health Dangers of Bird Droppings Associated with HVAC …


Enteroviral Infection: The Forgotten Link to Amyotrophic Lateral … – NCBI


Mar 12, 2018 – Amyotrophic lateral sclerosis (ALS) is a devastating ….. such as exosomes (Bird et al., 2014; Robinson et al., 2014; Chen et al., ….. in respiratory and feces samples of the patients with Hand-Foot-Mouth Disease after recovery.

Bats and human health – Health conditions directory


conditions.health.qld.gov.au/HealthCondition/condition/14/…/bats-and-human-health

A Survey of the Aerobic Bacteria in the Feces of Captive Raptors – jstor


Feces of 47 captive raptors belonging to the order Falconiformes or Strigi- … the second most common isolate, was cultured from 30 birds. …… Thanks are als.

Psittacosis in Birds and People | Mass.gov


Burn bird poop instead of coal to save the planet, Israeli scientists …


https://www.haaretz.com › Science & Health

Nazis a ‘speck of bird poop’ on Germany’s ‘successful’ history, far-right …


Does Glyphosate Acting as a Glycine Analogue Contribute To ALS?


Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease … in the human gut, reaching a density of more than 1010 bacteria per gram of feces. …. Remarkably, a paralytic disease that has afflicted multiple bird species in …

Unsterilized milk

Raw (Unpasteurized) Milk | Features | CDC


Raw Milk Questions and Answers | Raw Milk | Food Safety | CDC


The Dangers of Raw Milk: Unpasteurized Milk Can Pose a Serious – FDA


Drinking Raw Milk: Benefits and Dangers – Healthline


The Dangers of Drinking Raw Milk


THE FACTS ABOUT REAL RAW MILK – A Campaign for Real MilkA …


Drinking Raw Milk Is Worth The Risk, Advocates Say : NPR


Jul 19, 2010 – Selling raw milk across state borders is banned because of the risk that it could be contaminated with dangerous bacteria. Some people insist …

Raw milk – Wikipedia


3 Things You Should Know About Raw Milk – Pharmacy Times


Raw Milk – North Dakota Department of Health


Mycobacteria,  schizophrenic, epileptic and Osteomyelitis

Immunoelectrophoresis – Semantic Scholar

Cell extracts from four species of mycobacteriaMycobacterium tuberculosis (four strains), M. bovis strain BCG, M. scrofulaceum, and M. phlei, were assayed by 2D-IEPwith four …… alized chronic schizophrenic and epileptic patients. J. Neurol.

Species Identification of Mycobacteria by PCR-Restriction Fragment …


by H Lee – ‎2000 – ‎Cited by 288 – ‎Related articles

Currently, identification of clinical isolates of mycobacteria to the species level …. M. asiaticum; 8, M. chelonae; 9, M. moriokaese; 10, M. phlei; 11, M. pulveris; 12, ….. of microRNA-181b in regulating the schizophrenia susceptibility gene EGR3.

Web results

Osteomyelitis caused by mycobacterium fortuitum – Springer


Zusammenfassung: Osteomyelitis durch Mycobacterium /or- tuitum. Eine Osteomyelitis … A twenty-five year old man with schizophrenia was admit- ted to another …. growth 3–4 weeks. Fast-growing. M. phlei growth within 5 days. M. fortuitum.

Johne’s Disease, Inflammatory Bowel Disease, and Mycobacterium …


Oct 13, 2004 – An extract of Mycobacterium phlei allowed in vitro growth of the microorganisms present in animal tissues by providing mycobactin, …

Periventricular diffuse pinealoma: Report of a case with clinical …


… diffuse pinealoma: Report of a case with clinical features of catatonic schizophrenia. … to Infection by a Crude Cell Wall Preparation from Mycobacterium phlei.

(PDF) Use of DNA probes to identify and classify mycobacteria


Use of DNA probes to identify and classify mycobacteria … 8 (lane 7), 11 (lane 8), 27 (lane 9) M . kansasii (lane lo), M. chelonei (lane 11) and M . phlei (lane 12). … . Two-dimensional PAGE analysis of translation products ,from schizophrenic …

Alzheimer’s gut bacteria, virus and iron dysregulation

Researchers Identify Virus and Two Types of Bacteria as Major Causes of Alzheimer’s

A worldwide team of senior scientists and clinicians have come together to produce an editorial which indicates that certain microbes – a specific virus and two specific types of bacteria – are major causes of Alzheimer’s Disease. Their paper, which has been published online in the highly regarded peer-reviewed journal, Journal of Alzheimer’s Disease, stresses the urgent need for further research – and more importantly, for clinical trials of anti-microbial and related agents to treat the disease.

This major call for action is based on substantial published evidence into Alzheimer’s. The team’s landmark editorial summarises the abundant data implicating these microbes, but until now this work has been largely ignored or dismissed as controversial – despite the absence of evidence to the contrary. Therefore, proposals for the funding of clinical trials have been refused, despite the fact that over 400 unsuccessful clinical trials for Alzheimer’s based on other concepts were carried out over a recent 10-year period.

Opposition to the microbial concepts resembles the fierce resistance to studies some years ago which showed that viruses cause certain types of cancer, and that a bacterium causes stomach ulcers. Those concepts were ultimately proved valid, leading to successful clinical trials and the subsequent development of appropriate treatments.

Professor Douglas Kell of The University of Manchester’s School of Chemistry and Manchester Institute of Biotechnology is one of the editorial’s authors. He says that supposedly sterile red blood cells were seen to contain dormant microbes, which also has implications for blood transfusions.

“We are saying there is incontrovertible evidence that Alzheimer’s Disease has a dormant microbial component, and that this can be woken up by iron dysregulation. Removing this iron will slow down or prevent cognitive degeneration – we can’t keep ignoring all of the evidence,” Professor Douglas Kell said.

Image shows an old lady looking out of a window.

Professor Resia Pretorius of the University of Pretoria, who worked with Douglas Kell on the editorial, said “The microbial presence in blood may also play a fundamental role as causative agent of systemic inflammation, which is a characteristic of Alzheimer’s disease – particularly, the bacterial cell wall component and endotoxin, lipopolysaccharide. Furthermore, there is ample evidence that this can cause neuroinflammation and amyloid-β plaque formation.”

The findings of this editorial could also have implications for the future treatment of Parkinson’s Disease, and other progressive neurological conditions.

ABOUT THIS ALZHEIMER’S DISEASE RESEARCH

Source: University of Manchester
Image Credit: The image is adapted from the University of Manchester press release.
Original Research: Full open access editorial for “Microbes and Alzheimer’s Disease” by Itzhaki, Ruth F.; Lathe, Richard; Balin, Brian J.; Ball, Melvyn J.; Bearer, Elaine L.; Bullido, Maria J.; Carter, Chris; Clerici, Mario; Cosby, S. Louise; Field, Hugh; Fulop, Tamas; Grassi, Claudio; Griffin, W. Sue T.; Haas, Jürgen; Hudson, Alan P.; Kamer, Angela R.; Kell, Douglas B.; Licastro, Federico; Letenneur, Luc; Lövheim, Hugo; Mancuso, Roberta; Miklossy, Judith; Lagunas, Carola Otth; Palamara, Anna Teresa; Perry, George; Preston, Christopher; Pretorius, Etheresia; Strandberg, Timo; Tabet, Naji; Taylor-Robinson, Simon D.; and Whittum-Hudson, Judith A. in Journal of Alzheimer’s Disease. Published online March 8 2016 doi:10.3233/JAD-160152


Abstract

Microbes and Alzheimer’s Disease

We are researchers and clinicians working on Alzheimer’s disease (AD) or related topics, and we write to express our concern that one particular aspect of the disease has been neglected, even though treatment based on it might slow or arrest AD progression. We refer to the many studies, mainly on humans, implicating specific microbes in the elderly brain, notably herpes simplex virus type 1 (HSV1), Chlamydia pneumoniae, and several types of spirochaete, in the etiology of AD. Fungal infection of AD brain [5, 6] has also been described, as well as abnormal microbiota in AD patient blood. The first observations of HSV1 in AD brain were reported almost three decades ago]. The ever-increasing number of these studies (now about 100 on HSV1 alone) warrants re-evaluation of the infection and AD concept.

AD is associated with neuronal loss and progressive synaptic dysfunction, accompanied by the deposition of amyloid-β (Aβ) peptide, a cleavage product of the amyloid-β protein precursor (AβPP), and abnormal forms of tau protein, markers that have been used as diagnostic criteria for the disease. These constitute the hallmarks of AD, but whether they are causes of AD or consequences is unknown. We suggest that these are indicators of an infectious etiology. In the case of AD, it is often not realized that microbes can cause chronic as well as acute diseases; that some microbes can remain latent in the body with the potential for reactivation, the effects of which might occur years after initial infection; and that people can be infected but not necessarily affected, such that ‘controls’, even if infected, are asymptomatic

“Microbes and Alzheimer’s Disease” by Itzhaki, Ruth F.; Lathe, Richard; Balin, Brian J.; Ball, Melvyn J.; Bearer, Elaine L.; Bullido, Maria J.; Carter, Chris; Clerici, Mario; Cosby, S. Louise; Field, Hugh; Fulop, Tamas; Grassi, Claudio; Griffin, W. Sue T.; Haas, Jürgen; Hudson, Alan P.; Kamer, Angela R.; Kell, Douglas B.; Licastro, Federico; Letenneur, Luc; Lövheim, Hugo; Mancuso, Roberta; Miklossy, Judith; Lagunas, Carola Otth; Palamara, Anna Teresa; Perry, George; Preston, Christopher; Pretorius, Etheresia; Strandberg, Timo; Tabet, Naji; Taylor-Robinson, Simon D.; and Whittum-Hudson, Judith A. in Journal of Alzheimer’s Disease. Published online March 8 2016 doi:10.3233/JAD-160152