Easy to overdose on paracetamol if you’re selenium deficient, says research

A lack of the mineral selenium in the diet puts people at risk of paracetamol overdose, even when the painkiller is taken at levels claimed to be safe on the packaging, according to collaborative research emerging from the University of Bath and Southwest University in China.

Paracetamol (also called Tylenol) is best known for relieving mild pain and fever, and is a leading cause of liver failure when taken at dangerous levels. For adults, the recommended maximum daily dosage is 4g (amounting to two 500mg tablets taken four times). However, the team from Bath and Chongqing has found that the micronutrient selenium affects the speed at which the painkiller is flushed from the body. As a result, taking 4g of the medication in a given day can be dangerous for people with low levels of selenium in their bodies.

“People with a selenium deficiency can struggle to eliminate the drug fast enough to keep their livers healthy,” explained Dr. Charareh Pourzand who led the collaborative research from the University of Bath’s Department of Pharmacy and Pharmacology. “They can overdose even when they follow dosage guidelines.”

A huge amount of Paracetamol is consumed around the world, with an average person in the UK popping 70 tablets (or 35 grams) every year. Dr. Pourzand said: “For most people, paracetamol is safe up to the stated dose. But if you are frail, malnourished or elderly, your levels of selenium are likely to be somewhat depleted, and for these people I think it’s a bad idea to take paracetamol at the maximum level currently considered safe.”

It is thought that insufficient selenium intake affects up to 1 billion people worldwide—or one in seven of the globe’s population. It may be tempting to boost selenium levels through supplements, but based on the results of this study, Dr. Pourzand advises against this course of action, as an excess of the micronutrient can be just as dangerous to the body as a deficiency.

“There is a rather limited dose range for the beneficial effects of selenium,” she said. “Both mild selenium deprivation in the body and excess supplementation increase the severity of liver injury after you’ve taken paracetamol.”

She added: “This study shows that the link between selenium status in the diet and paracetamol toxicity is very important. I hope people pay attention to these findings, given everyone has paracetamol in their home. And now with people falling ill with COVID-19, paracetamol is being taken more than ever.”

Selenium helps maintain a healthy redox balance in the body within antioxidant enzymes called selenoproteins (selenium-containing proteins). Redox balance describes the mechanism by which each cell maintains a subtle balance between antioxidant and pro-oxidant levels (where some atoms gain electrons and others lose them, becoming free radicals). When the body’s selenium levels fall out of the beneficial range, antioxidant enzyme activities are decreased and too many free radicals are formed in liver—the main organ where paracetamol is metabolized. This results in damage both to an individual’s DNA and to their proteins.

Dr. Pourzand emphasizes the importance of a good diet in keeping selenium levels within the recommended range. “A healthy, balanced diet is especially important if you take paracetamol on a regular basis, for instance for chronic pain,” she said.

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Pseudoislet system expected to advance pancreas and diabetes research

The multicellular, 3-D structure of human pancreatic islets—the areas of the pancreas containing hormone-producing or endocrine cells—has presented challenges to researchers as they study and manipulate these cells’ function, but Vanderbilt University Medical Center researchers have now developed a pseudoislet system that allows for much easier study of islet function.

A pancreatic islet is composed primarily of beta cells, alpha cells and delta cells, but also includes many supporting cells, such as endothelial cells, nerve fibers and immune cells, which act in concert as a mini organ to control blood glucose through hormone secretion. Insulin, secreted from beta islet cells, lowers blood glucose by stimulating glucose uptake in peripheral tissues, while glucagon, secreted from alpha islet cells, raises blood glucose through its actions in the liver.

Dysfunction of these islet cells is a primary component of all forms of diabetes, and a better understanding of this dysfunction can lead to improved treatment and management of the disease. Vanderbilt scientists and others around the world have identified potential targets for diabetes using both mouse models and human tissue, however the lack of a system to manipulate these pathways in human islet cells has limited the field.

The VUMC team led by Marcela Brissova, Ph.D., research professor of Medicine and director of the Islet Procurement and Analysis Core of the Diabetes Research and Training Center, began attempting a protocol for the pseudoislet system in 2016, performing countless trials. In late 2017, Rachana Haliyur, then a Vanderbilt MD/Ph.D. student, combined media containing factors that support vascular cells and endocrine cells into what the group named the Vanderbilt Pseudoislet Media. The team watched as the cells began reaggregating, or organizing themselves in a way that resembled native islets.

“A lot of things in science happen serendipitously, and this was one of those,” said Brissova. “We tried and failed many times, and basically it came down to the media we used for our cells. In our recent publication, we have provided all experimental details and our protocol so others can make the media and create pseudoislets in their own laboratories.”

Because of the complex structure of the human islet, it is difficult to introduce and manipulate cells past the first cell-layer of the islet sphere. The pseudoislet system allows investigators to separate the pancreatic islet into single cells, introduce a virus into the cells which allows genetic manipulation and then combine the cells back together again into a pseudoislet. This allows researchers to target certain cell types or replicate changes happening in disease and study them in the 3-D environment of the islet.

John “Jack” Walker, an MD/Ph.D. student in the Powers & Brissova Research Group, continued to refine the pseudoislet system protocol and was co-first author on a recent study based on the system published in JCI Insight, an open access journal published by the American Society for Clinical Investigation (ASCI).

The pseudoislet system allowed the VUMC investigators to more clearly examine intracellular signaling pathways, allowing genetic manipulation of those pathways to change their function and better understand how insulin and glucagon secretion are altered with that manipulation. They determined that activation of Gi protein signaling reduced insulin and glucagon secretion while activation of Gq protein signaling stimulated glucagon secretion but had both stimulatory and inhibitory effects on insulin secretion.

In addition, this approach allowed the scientists to introduce biosensors into the islet cells to measure intercellular signaling events within the cells and better understand how those are linked to hormone secretion.

Another advance was the combination of the pseudoislet system with a unique microfluidic device, developed by co-authors Matthew Ishahak and Ashutosh Agarwal, Ph.D., from the University of Miami, that allowed the investigators to simultaneously document the changes in both calcium ions and hormone secretion.

“The exciting thing about this approach is that we both deconstruct the islet for our manipulation and reconstruct it to understand functional consequences at a larger level,” Walker said. “Since we put the islet cells back together, we can look at both insulin and glucagon secretion, but in a coordinated manner. Both of the secretion profiles measured are reflective of intra-islet interactions that are happening as well.”

This work greatly benefited from the research environment and infrastructure at Vanderbilt, particularly the National Institutes of Health (NIH)-funded Diabetes Research and Training Center (DRTC) and the Vanderbilt Cell Imaging Shared Resource.

“Another research direction will be creating pseudoislets that replicate a specific disease state, such as pseudo-islets that look like native islets from an individual with type 1 diabetes,” Haliyur said.

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It’s not just Alzheimer’s disease: Research highlights form of dementia

The long-running study on aging and brain health at the University of Kentucky’s Sanders-Brown Center on Aging Alzheimer’s Disease Center has once again resulted in important new findings—highlighting a complex and under-recognized form of dementia. The work was recently published in the Journal of the American Medical Association (JAMA): Neurology.

“One of the things that we’ve learned in the last decade or so is that a lot of people that we think have dementia from Alzheimer’s disease, actually don’t. There are other brain diseases that cause the same kind of symptoms as Alzheimer’s, including some that we only recently figured out existed,” said Erin Abner an associate professor at the University of Kentucky’s Sanders-Brown Center on Aging (SBCoA) and College of Public Health, who helped lead the recent study.

Abner collaborated with several of her colleagues at SBCoA for the study, which used brain autopsy data from 375 older adults within the University of Kentucky Alzheimer Disease Center Brain Bank. This work builds on the work done last year by Dr. Pete Nelson and his team to discover another form of dementia caused by TDP-43 proteinopathy now known as LATE.

Abner refers to misfolded TDP-43 protein, which was discovered in 2006, as the “newest brain bad guy.” She says although TDP-43 exists normally in a non-disease causing form, it is seen in multiple debilitating diseases in addition to LATE, including ALS and frontotemporal dementia. She says as she and the team at SBCoA reviewed clinical and brain autopsy data for research participants, they noticed there were significantly more people than expected that had not only Alzheimer’s pathology but also pathology indicating Lewy bodies (alpha synuclein), and the ‘newest brain bad guy’—TDP-43.

“They had every neurodegeneration causing pathology that we know about. There was not a name for this, so we came up with one: quadruple misfolded proteins, or QMP,” stated Abner.

The group then obtained more data to conduct a study of how often QMP occurred and what that meant for the participant with QMP. The study found that about 20% of the participants with dementia had QMP, and their dementia was the most severe.

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Diet, gut microbes affect effectiveness of cancer treatment, research reveals

What we eat can affect the outcome of chemotherapy—and likely many other medical treatments—because of ripple effects that begin in our gut, new research from the University of Virginia suggests.

Scientists found that diet can cause microbes in the gut to trigger changes in the host’s response to a chemotherapy drug. Common components of our daily diets (for example, amino acids) could either increase or decrease both the effectiveness and toxicity of the drugs used for cancer treatment, the researchers found.

The discovery opens an important new avenue of medical research. It could have major implications for predicting the right dose and better controlling the side effects of chemotherapy, the researchers report. The finding also may help explain differences seen in patient responses to chemotherapy that have baffled doctors until now.

“The first time we observed that changing the microbe or adding a single amino acid to the diet could transform an innocuous dose of the drug into a highly toxic one, we couldn’t believe our eyes,” said Eyleen O’Rourke of UVA’s College of Arts & Sciences, the School of Medicine’s Department of Cell Biology and the Robert M. Berne Cardiovascular Research Center. “Understanding, with molecular resolution, what was going on took sieving through hundreds of microbe and host genes. The answer was an astonishingly complex network of interactions between diet, microbe, drug and host.”

How diet affects outcomes

Doctors have long appreciated the importance of nutrition on human health, but the new discovery highlights how what we eat affects not just us, but the microorganisms within us.

The changes that diet triggers on the microorganisms can increase the toxicity of a chemotherapeutic drug up to 100-fold, the researchers found using the new lab model they created with roundworms. “The same dose of the drug that does nothing on the control diet kills the [roundworm] if a milligram of the amino acid serine is added to the diet,” said Wenfan Ke, a graduate student and lead author of a new scientific paper outlining the findings.

Further, different diet and microbe combinations change how the host responds to chemotherapy. “The data show that single dietary changes can shift the microbe’s metabolism and, consequently, change or even revert the host response to a drug,” the researchers report in their paper published in Nature Communications.

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