Researchers have found that compounds in the edible Lions’ Mane mushroom (Hericium erinaceus), already used in herbal medicine for stomach complaints, can promote nerve growth and boost memory. Their findings are published in The Journal of Neurochemistry.
The compounds are neurotrophins – a family of proteins associated with the growth, functioning and maintenance of neurons. In mammals, brain-derived neurotrophic factor (BDNF) is highly expressed in central nervous system neurons. Because BDNF pathway impairment is associated with several diseases, including schizophrenia, Alzheimer’s disease, Rett syndrome, and Huntington’s disease, experimental treatments for neurological and neurodegenerative disorders often target neutrophins.
So far, such treatments have run into problems with crossing the blood-brain barrier and off-target effects. H. erinaceus is high in neutrophins, though it has traditionally been used in herbal medicine to treat stomach complaints and cancer. It is also known for promoting peripheral nerve regeneration.
Two of the biologically active types of compounds, hericenones and erinacines, can successfully cross the the blood-brain barrier and confer neuroprotective effects.
The researchers tested crude and purified H. erinaceus extracts and found that they exhibited BDNF-like neurotrophic activity in both in vitro cultured hippocampal neurons and in mouse models of hippocampal memory. The extracts also promoted neurite outgrowth and improved memory.
They concluded that Hericene A acts through a novel signalling pathway, giving rise to improved cognitive performance. These findings however will need to be validated by future research.
Changing the structure of a dietary fibre commonly found in a range of food products has been found to promote healthy gut bacteria and reduce gas formation, a finding that could help people with intolerances to fibre and irritable bowel conditions. The findings have been published in Food Hydrocolloids.
A team of scientists from the University of Nottingham, Quadram Institute Biosciences and the University of East Anglia examined psyllium, a type of natural dietary fibre that is used in a range of products including cereals and yoghurts. They showed that the physical state of the fibre has a major impact on gas production which often is linked to bowel discomfort.
The team performed in vitro fermentation experiments seeded with human stool. They conducted analysis of fermentation products and evaluated the impact of different structures on the broad categories of microorganisms.
Dr Gleb Yakubov, Associate Professor in Food Physics at the University of Nottingham was one of the lead researchers on the study, he explains: “Although fibre is an important part of any diet, for many people it can cause bowel discomfort and for people with IBS or IBD fibre can be a trigger. This is because some foods cause bacterial interactions in the gut that create gas that can lead to pain or discomfort. Our study shows that the physical state of the fibre has a major impact on gas production by creating beneficial compounds that promote the creation of the good bacteria in the gut.”
Psyllium fibre comes from the seeds of Plantago ovata plants, known by many common names such as blond plantain. These seeds produce a jelly-like material called mucilage, which comes in a variety of shapes and forms and these feature long-chain sugars, called polysaccharides. It is these polysaccharides that lead to the production of beneficial short-chain fatty acids that contribute positively to gut health and systemic metabolism. This study shows that different physical states of fibre impact the way dietary fibre breaks down and that microbes ‘colonise fibre’ during fermentation.
Professor Yakubov continues: “These findings show that there are new opportunities for designing targeted structures using psyllium, either through seed processing or selective breeding, to achieve new fibre materials with clear clinical benefit above that of unrefined psyllium powders aiding in the treatment of gastrointestinal discomfort.”
Research is already underway to create and test psyllium-mimicking materials as medical nutrition which could provide a source of fibre for people with some bowel conditions.
A new study published in Science Advances shows that female and male hearts respond differently to the stress hormone noradrenaline. The study in mice may have implications for human heart disorders like arrhythmias and heart failure and how different sexes respond to various drugs.
Using fluorescence imaging, the researchers were able to see in real time and in vivo how a mouse heart responds to hormones and neurotransmitters, including noradrenaline.
The results reveal that male and female mouse hearts respond uniformly at first after exposure to noradrenaline. However, some areas of the female heart return to normal more quickly than the male heart, producing differences in the heart’s electrical activity.
“The differences in electrical activity that we observed are called repolarisation in the female hearts. Repolarisation refers to how the heart resets between each heartbeat and is closely linked to some types of arrhythmias,” said Jessica L. Caldwell, first author of the study.
“We know that there are sex differences in the risk for certain types of arrhythmias. The study reveals a new factor that may contribute to different arrhythmia susceptibility between men and women,” Caldwell said.
Methods
The novel imaging system uses a genetically modified ‘CAMPER’ mouse to emit light during a very specific chemical reaction in the heart: cAMP binding.
The cAMP molecule (an abbreviation of cyclic adenosine 3′,5;-monophosphate) is an intermediate messenger that turns signals from hormones and neurotransmitters, including noradrenaline, into action from heart cells.
The light signals from the CAMPER mouse are transmitted by a biosensor that uses a fluorescence signal that can be picked up at high speed and high resolution by a new imaging system specially designed for hearts. This allows the researchers to record the heart’s reaction to noradrenaline in real time, along with changes in electrical activity.
This new imaging approach revealed the differences in the breakdown of cAMP in female and male mice and the associated differences in electrical activity.
Including female mice leads to discoveries
The researchers had not planned to study sex-based responses, according to Crystal M. Ripplinger, senior author of the study. But the researchers started seeing a pattern of different reactions, which led them to realise the differences were sex-based.
When Ripplinger started her lab at the UC Davis School of Medicine over a decade ago, she exclusively used male animals. That was the norm for most research at the time. But several years ago, she began including male and female animals in her studies.
“Sometimes the data between the two sexes is the same. But if the data start to show variation, the first thing we do is look at sex differences. Using both male and female mice has revealed clues into differences we would never have suspected. Researchers are realising you can’t extrapolate to both sexes from only studying one,” Ripplinger said.
She notes that with the current study, it’s not clear what the differences in cAMP and electrical activity may mean.
“The response in the female mice may be protective – or it may not. But simply documenting that there is a measurable difference in the response to a stress hormone is significant. We are hoping to learn more in future studies,” Ripplinger said.
One early indicator of Parkinson’s disease (PD) is isolated REM-sleep behaviour disorder. Researchers have shown that a greater concentration of α-synuclein aggregates can be detected in the stool samples of patients. In the scientific journal npj Parkinson’s Disease, they now present a method for detecting these aggregates.
There are two forms of PD. In 70% of cases, it originates in the central nervous system. However, in around 30% of cases it originates in the nervous system of the intestine (“enteric nervous system”). The latter form is referred to as “body-first Parkinson’s disease” (for short: body-first PD) and the characteristic deposits of aggregates of the body’s own α-synuclein protein are formed in the neurons in the intestine.
A preliminary form of body-first PD is the so-called isolated REM-sleep behaviour disorder (for short: iBRD). It causes in part complex movements during REM-sleep insofar as the patient experiences vivid and disturbing dreams. These movements can endanger the sufferer themselves or others.
A research team headed by Professor Erdem Gültekin Tamgüney from the Institute of Physical Biology at HHU now reports that it is possible to detect an elevated level of α-synuclein aggregates in the stool samples of patients. To achieve this, the team used a new surface-based fluorescence intensity distribution analysis (sFIDA) to detect and quantify individual particles of α-synuclein aggregates.
Professor Tamgüney: “We are the first to prove the presence of α-synuclein aggregates in stool samples. Our results show a significantly higher level of α-synuclein aggregates in iRBD patients compared with healthy individuals or patients with Parkinson’s. These findings could lead to a non-invasive diagnostic tool for prodromal synucleinopathies — including Parkinson’s — which could in turn enable therapies to be initiated at an early stage before symptoms occur.” However, more research is required before the process can find its way into clinical practice, for example investigation into why the level is lower in Parkinson’s patients.
The study was conducted in a collaboration to establish a biobank with stool samples from patients and control subjects, and to develop the test procedure and conduct the tests on the samples, and to eventually commercialise the technique.
Background
In body-first PD, the deposits of fibrils of the body’s own α-synuclein protein, which are characteristic of Parkinson’s, are first formed in the neurons of the enteric nervous system, which serves the gastrointestinal tract. The aggregates then spread to the central nervous system in a way similar to prions, i.e. an existing aggregate combines individual α-synuclein proteins in its vicinity into further aggregates in a nucleation process; these aggregates then spread further through the body.
The influence of what happens in the gastrointestinal tract on the brain is referred to as the “gut-brain axis.” The gastrointestinal tract is exposed to the environment and it is possible that harmful substances such as chemicals, bacteria or viruses ingested directly with food or via interaction with the microbiome of the gastrointestinal tract may trigger the pathological formation of α-synuclein aggregates.
A Bloomberg investigation has revealed that Glaxo, which went on to form pharmaceutical giant GSK, was aware of the possible carcinogenic content of its popular heartburn drug Zantac for over 40 years.
The once-popular heartburn drug Zantac (ranitidine) was developed in the 1970s by the then-small British pharmaceutical company Glaxo. It was marketed as better and safer than Tagamet (cimetidine) and it soon outsold it and became one of the company’s best-selling drugs.
NDMA belongs to a class of compounds known as nitrosamines, came to light in cancer research when it was found that nitrites could combine with amines in the stomach, giving rise to cancer-causing compounds. This led to calls for restrictions of sodium nitrites, found in various cured foods, but the food industry has resisted this.
This all came to an end in 2019, when Zantac was found to be contaminated by the chemical N-Nitrosodimethylamine (NDMA), a pale yellow liquid at room temperature. NDMA is a known carcinogen at high concentrations and a possible one at low concentrations. This contamination was not due to a manufacturing error, however: NDMA can form from other reactions and in this case came from within the drug itself. Around the world, Zantac was pulled from shelves, and in 2020 the drug was banned by the FDA. NDMA currently is only produced in small amounts to induce cancer in rats. Whether it is carcinogenic at very low levels is still a matter of debate, but Zantac products contained NDMA at levels which could increase over time.
According to Bloomberg, Glaxo was aware of this, as the possibility of ranitidine being converted in the stomach to nitrosamines being raised in 1980. Tests with human subjects taking ranitidine showed this. Even though NDMA is widely held to be a carcinogen in humans, it is difficult to prove that a particular chemical is responsible for mutations leading to cancers. Glaxo simply took the view that ranitidine did not cause cancer in rodent studies, and that any possible cancer risk was minimised by short exposure. In fact, users would take Zantac for extended periods, even years or decades.
The company was thus warned over 40 years by its own scientists as well as independent researchers, with thousands of pages of documentation seen by Bloomberg for the first time. One 1981 Lancet study showed that Zantac mixed with nitrite in the stomach (as from a meal) would produce nitrosamines. Glaxo scientists countered by saying that the nitrite levels in the study were far above those found in a human stomach, a defence which would become their standard response.
While Glaxo was preparing for FDA approvals in 1982, another study came to their attention. Concerned, Glaxo asked one of their scientists, Richard Tanner, to replicate it and he found that some samples contained 232 000ng of NDMA – the FDA approved limit for each drug was 96ng, though with lower nitrite levels, no NDMA was detected. The daily FDA exposure limit from all sources for NDMA is 190ng, which includes NDMA from all sources, including other medications (which may produce their own NDMA over time) as well as biological processes.
This report would remain secret for more than 40 years. More trouble came from the fact that NDMA could be formed from exposure to either heat or humidity. When it went through the FDA approval process, it did not mention the Tanner report and the notion of storage was glossed over: approved in 150mg doses for eight weeks, storage requirements were listed as a dry place at a temperature no higher than 86°F (30°C).
Zantac surged in popularity, turning the company into a multi-billion dollar enterprise, though the FDA took action over Glaxo’s claims. An over-the-counter 75mg version was launched in 1996. It was coloured pink due to issues of discolouration with white pills turning yellow or brown over time.
While discolouration issues were briefly investigated, it was only in 2019 when there were concerns over NDMA contamination, spurred by recalls of a blood pressure drug, valsartan. A private laboratory warned the FDA over NDMA discovery in Zantac and ranitidine generics, and after the FDA conducted its own tests, the company that was now GSK turned over its documentation.
Within a month, distribution of ranitidine was halted nearly worldwide, and the FDA took the drastic further stop of ordering its production halted. Shortly afterward, the FDA stated that the evidence for NDMA in ranitidine was inconclusive, and clarified that the NDMA concerns were from contamination being produced during its storage, not production in the stomach.
For GSK, the damages from the thousands of plaintiffs may range from US$5 to 17 billion, but damages are likely to be reduced and previous lawsuits of this type have struggled to prove that the relevant compound caused cancer. For Zantac, however, this will be less of an obstacle as NDMA is almost universally accepted as a carcinogen.
