High Doses of Saccharin Don’t Lead to Diabetes in Healthy Adults, Study Finds (Medicine)

A new study led by researchers at The Ohio State University Wexner Medical Center and The Ohio State University College of Medicine found the sugar substitute saccharin doesn’t lead to the development of diabetes in healthy adults.

For those trying to live a healthy lifestyle, the choice between sugar and artificial sweeteners such as saccharin can be confusing. A new study led by researchers at The Ohio State University Wexner Medical Center and The Ohio State University College of Medicine found the sugar substitute saccharin doesn’t lead to the development of diabetes in healthy adults as previous studies have suggested.

The study findings are published in the journal Microbiome.

Researchers at The Ohio State University Wexner Medical Center conducted a study expecting to confirm how artificial sweeteners contribute to glucose intolerance, but surprisingly learned that the sweeteners have no adverse effects on healthy adults and do not change metabolic profiles or lead to diabetes. © The Ohio State University Wexner Medical Center

“It’s not that the findings of previous studies are wrong, they just didn’t adequately control for things like underlying health conditions, diet choices and lifestyle habits,” said George Kyriazis, assistant professor of biological chemistry and pharmacology at Ohio State and senior author of the study. “By studying the artificial sweetener saccharin in healthy adults, we’ve isolated its effects and found no change in participants’ gut microbiome or their metabolic profiles, as it was previously suggested.”

Kyriazis collaborated with researchers at Ohio State’s College of Food, Agricultural & Environmental SciencesOhio State’s College of Arts and Sciences, Sanford Burnham Prebys Medical Discovery Institute in California and the Translational Research Institute for Metabolism and Diabetes at Advent-Health in Florida.

Non-caloric artificial sweeteners are often consumed as a substitute for dietary sugars, and saccharin is one of six artificial sweeteners approved by the Food and Drug Administration.

The use of artificial sweeteners has increased dramatically over the past decade due to growing awareness of the negative health outcomes associated with consuming too much sugar, study authors noted.

Kelly Scully uses artificial sweetener in her coffee each day to reduce her sugar intake. A new study by researchers at The Ohio State University Wexner Medical Center finds sugar substitutes do not lead to diabetes in healthy adults as previous studies have suggested. ©×The Ohio State University Wexner Medical Center

“Previous studies elsewhere have suggested that consuming artificial sweeteners is associated with metabolic syndrome, weight gain, obesity and non-alcoholic fatty liver disease. These findings have raised concerns that consuming them may lead to adverse public health outcomes, and a lack of well-controlled interventional studies contributed to the confusion,” said study first author Joan Serrano, a researcher in the department of biological chemistry and pharmacology at Ohio State.

A total of 46 healthy adults ages 18-45 with body mass indexes of 25 or less completed this randomized, double-blind, placebo-controlled study.

Participants ingested capsules that contained the maximum acceptable daily amount of either saccharin, or lactisole (a sweet taste receptor inhibitor, or saccharin with lactisole or placebo every day for two weeks. The maximum acceptable daily amount of saccharin is 400 milligrams per day, which is far more than the average consumer would consume.

The study excluded people with acute or chronic medical conditions or taking medications that could potentially affect metabolic function, such as diabetes, bariatric surgery, inflammatory bowel disease or a history of malabsorption and pregnant or nursing.

Video: Researchers clarify the science by isolating the effects of sugar substitutes from underlying conditions, diet choices and lifestyle habits © The Ohio State University Wexner Medical Center

Researchers also tested for 10 weeks the effects of even higher dose of saccharin in mice that genetically lack sweet taste receptors with the same results: the artificial sweetener didn’t affect glucose tolerance, or cause any significant gut microbiota changes or apparent adverse health effects.

“Sugar, on the other hand, is well-documented to contribute to obesity, heart disease and diabetes,” Kyriazis said. “So when given the choice, artificial sweeteners such as saccharin are the clear winner based on all of the scientific information we currently have.”

Future research will study each FDA-approved sweetener individually to examine if there are any differences in how they’re metabolized. Researchers will study these substances over a longer period of time to ensure they’re safe for daily use.

The National Institutes of Health, the National Institute of Food and Agriculture and Advent-Health institutional funds supported this work.

Reference: Serrano, J., Smith, K.R., Crouch, A.L. et al. High-dose saccharin supplementation does not induce gut microbiota changes or glucose intolerance in healthy humans and mice. Microbiome 9, 11 (2021). https://doi.org/10.1186/s40168-020-00976-w https://microbiomejournal.biomedcentral.com/articles/10.1186/s40168-020-00976-w

Provided by Ohio State Wexner Medical Center

Scientists Study Use of Abundant Enzyme in Tumor Cells to Monitor Cancer Treatment (Medicine)

The abundant presence of an enzyme known as low molecular weight protein tyrosine phosphatase (LMWPTP) in tumor cells has long been considered an indicator of cancer aggressiveness and metastatic potential. It is also known to perform important functions in cells under normal conditions, participating in both the proliferation process and the regulation of intracellular systems. Research continues on its role in cancer progression.

After 14 years studying the action of the enzyme LMWPTP in tumor cells, Brazilian researchers conclude that the molecule is associated with chemotherapy resistance and metastasis (image: tyrosine phosphatase / Wikimedia Commons)

In Brazil, a group of researchers at the University of Campinas’s In Vitro Bioassay and Signal Transduction Laboratory led by Professor Carmen Veríssima Ferreira-Halder are studying the possibility of inhibiting this protein phosphatase to create novel opportunities for monitoring and treatment of cancer and other diseases.

“We believe inhibition of LMWPTP could contribute to the treatment of several diseases,” Ferreira-Halder said. “In our case, the focus is on cancer, but research shows it’s also associated with autoimmune diseases and diabetes, among others.”

Ferreira-Halder was principal investigator for the Thematic Project “Low molecular weight protein tyrosine phosphatase in colorectal cancer: from the bench to product generation”, supported by FAPESP and completed in June 2020. 
The phosphatase favors the action of intratumor proteins that help tumors divide, migrate and establish metastasis. “For this reason we say it’s a ‘hub’, in the sense that it controls several processes which together make tumor cells resistant to treatment and able to migrate and establish metastasis,” she said.

A review article by the group published in Cellular and Molecular Life Sciences outlines 14 years of research on LMWPTP and its contribution to cancer treatment. “Our group was one of the first to show that this enzyme contributes to chemotherapy resistance in leukemia cells,” Ferreira-Halder said. “We also found that the more advanced the stage of the tumor, the larger the amount of the enzyme. With these discoveries as a basis, research conducted in collaboration with the group led by Professor Maikel Peppelenbosch at Erasmus University Medical Center in Rotterdam [Erasmus MC, Netherlands] validated the significance of LMWPTP to other types of cancer, such as prostate, colorectal and stomach cancer. This research showed us that LMWPTP not only weakens the response to chemotherapy drugs but is also associated with a greater capacity for metastasis.”

Druggable target

The review article, whose first author is Alessandra Valéria de Sousa Faria, also discusses the available substances that inhibit LMWPTP and the characteristics that make it difficult for drugs to be designed against it. Ferreira-Halder believes it is not yet possible to speak of treatment based on inhibition of LMWPTP, but the strategy can be used for other purposes.

“Our initial aim is to use this enzyme as a biomarker for the purpose of monitoring treatment, and also to use it to classify patients in terms of the severity of disease. In my view this can be done in a relatively short time,” she said. “As for treatment, a lot more work remains to be done. Professor Nunzio Bottini at the University of California San Diego [USA] has filed for a patent on a highly effective inhibitor that can be administered orally. Actually he and his group have synthesized several inhibitors, but they have only published one. Maybe we’re in for a surprise and a drug will be developed faster. Who knows?”

The main challenges to be faced in developing inhibitors are specificity – the drug must act specifically on LMWPTP, which is part of a family of some 100 highly similar phosphatases – and stability, so that the drug remains active in the organism. “Until Bottini and his group filed their patent application, all inhibitors acted on several members of the family,” Ferreira-Halder said.

Some of the substances mentioned in the review were developed for other purposes but also inhibit LMWPTP and could be used to treat cancer, according to Faria, who recently defended her doctoral thesis on how LMWPTP affects platelets, small cell fragments in the bloodstream that play a key role in clotting.

Platelets

Faria’s research on LMWPTP began with its role in colorectal cancer and platelet reaction in this microenvironment. “As our investigation of platelet biology progressed, we realized how much more knowledge of the enzyme’s action on platelets was needed,” she said.

The first part of the study consisted of verifying the action of LMWPTP and the protein tyrosine phosphatase 1B (PTP1B) on platelets, with regard to both metabolism and function. The second focused on the influence of platelets on the expression of LMWPTP in cells.

“The goal was to find out to what extent tumor cells may ‘educate’ platelets to support certain events, such as metastasis, for example, and conversely how far platelets ‘educate’ tumor cells to assure their survival and proliferation,” Faria explained.

For Ferreira-Halder, the relationship appears to be two-way. “However, the action of tumor cells probably predominates. They practically program platelets to work in their favor,” she said.

Collaborations

Ferreira-Halder and her group have collaborated with Peppelenbosch’s since 2004, but work on the Thematic Project completed in June began only 2016, she recalled, adding that experiments conducted by Emanuella Maria Barreto Fonseca and Cláudia de Lourdes Soraggi at Peppelenbosch’s laboratory provided a vitally important foundation for the initial hypotheses. Fonseca was supported by a postdoctoral fellowship from FAPESP. Soraggi was able to attend an overseas training course thanks to support from the University of Campinas (UNICAMP) via its Executive Vice Rectorship for International Relations.

“In our Thematic Project research, we were able to investigate the action of this phosphatase from various angles and validate the hypothesis of its role in other tumors besides chronic myeloid leukemia,” Ferreira-Halder said. “We wanted to uncover the mechanism of its action, and we now have a great deal of information about this action – not just inside but also outside the tumor, because we set out to see if LMWPTP also influenced the tumor’s microenvironment external to the cancer cells.”

Other research interests for the group during the project included: extracellular vesicles (nanometer-sized structures that play an important role in intercellular communication), with Stefano Piatto Clerici supported by FAPESP showing that LMWPTP regulates these vesicles; platelets, studied by Faria, also with a scholarship from FAPESP; and the TGF-beta signaling pathway, which is involved in many cellular processes such as proliferation and differentiation and was studied by Helon Guimarães Cordeiro.

The network of collaborators continued to expand, adding an expert in platelet biology (Sheila Siqueira Andrade at PlateInnove Biotech), and a hematologist and an oncologist at Erasmus MC (Moniek de Maat and Gwenny Fuhler respectively).

According to Ferreira-Halder, the Thematic Project has so far spawned 15 publications (eight articles and two book chapters, as well as five articles under peer review), and several other research fronts. A new project in the same line of research is currently being designed.

Reference: Faria, A.V.S., Fonseca, E.M.B., Cordeiro, H.G. et al. Low molecular weight protein tyrosine phosphatase as signaling hub of cancer hallmarks. Cell. Mol. Life Sci. (2020). https://link.springer.com/article/10.1007/s00018-020-03657-x https://doi.org/10.1007/s00018-020-03657-x

Provided by FAPESP

Study of Flowers With Two Types of Anthers Solves Mystery that Baffled Darwin (Botany)

Some flowers use a clever strategy to ensure effective pollination by bees, doling out pollen gradually from two different sets of anthers.

Most flowering plants depend on pollinators such as bees to transfer pollen from the male anthers of one flower to the female stigma of another flower, enabling fertilization and the production of fruits and seeds. Bee pollination, however, involves an inherent conflict of interest, because bees are only interested in pollen as a food source.

A Hesperapis regularis bee visits a flower of Clarkia cylindrica at Pinnacles National Park. © Tania Jogesh

“The bee and the plant have different goals, so plants have evolved ways to optimize the behavior of bees to maximize the transfer of pollen between flowers,” explained Kathleen Kay, associate professor of ecology and evolutionary biology at UC Santa Cruz.

In a study published December 23 in Proceedings of the Royal Society B, Kay’s team described a pollination strategy involving flowers with two distinct sets of anthers that differ in color, size, and position. Darwin was mystified by such flowers, lamenting in a letter that he had “wasted enormous effort over them, and cannot yet get a glimpse of the meaning of the parts.”

For years, the only explanation put forth for this phenomenon, called heteranthery, was that one set of anthers is specialized for attracting and feeding bees, while a less conspicuous set of anthers surreptitiously dusts them with pollen for transfer to another flower. This “division of labor” hypothesis has been tested in various species, and although it does seem to apply in a few cases, many studies have failed to confirm it.

The new study proposes a different explanation and shows how it works in species of wildflowers in the genus Clarkia. Through a variety of greenhouse and field experiments, Kay’s team showed that heteranthery in Clarkia is a way for flowers to gradually present their pollen to bees over multiple visits.

“What’s happening is the anthers open at different times, so the plant is doling out pollen to the bees gradually,” Kay said.

Close-up photos of Clarkia unguiculata and Clarkia cylindrica flowers show the two types of anthers, a conspicuous inner whorl and an outer whorl that blends in with the petals. © Kay et al., PRSB 2020

This “pollen dosing” strategy is a way of getting the bees to move on to another flower without stopping to groom the pollen off their bodies and pack it away for delivery to their nest. Bees are highly specialized for pollen feeding, with hairs on their bodies that attract pollen electrostatically, stiff hairs on their legs for grooming, and structures for storing pollen on their legs or bodies.

“If a flower doses a bee with a ton of pollen, the bee is in pollen heaven and it will start grooming and then go off to feed its offspring without visiting another flower,” Kay said. “So plants have different mechanisms for doling out pollen gradually. In this case, the flower is hiding some anthers and gradually revealing them to pollinators, and that limits how much pollen a bee can remove in each visit.”

There are about 41 species of Clarkia in California, and about half of them have two types of anthers. These tend to be pollinated by specialized species of native solitary bees. Kay’s team focused on bee pollination in two species of ClarkiaC. unguiculata (elegant clarkia) and C. cylindrica (speckled clarkia).

In these and other heterantherous clarkias, an inner whorl of anthers stands erect in the center of the flower, is visually conspicuous, and matures early, releasing its pollen first. An inconspicuous outer whorl lies back against the petals until after the inner anthers have opened. The outer anthers then move toward the center of the flower and begin to release their pollen gradually. A few days later, the stigma becomes erect and sticky, ready to receive pollen from another flower.

“In the field, you can see flowers in different stages, and using time-lapse photography we could see the whole sequence of events in individual flowers,” Kay said.

The division of labor hypothesis requires both sets of anthers to be producing pollen at the same time. Kay said she decided to investigate heteranthery after observing clarkia flowers at a field site and realizing that explanation didn’t fit. “I could see some flowers where one set was active, and some where the other set was active, but no flowers where both were active at the same time,” she said.

In C. cylindrica, the two sets of anthers produce pollen with different colors, which enabled the researchers to track where it was going. Their experiments showed that pollen from both sets of anthers was collected for food and was also being transferred between flowers, contradicting the division of labor hypothesis.

“The color difference was convenient, because otherwise it’s very hard to track pollen,” Kay said. “We showed that bees are collecting and transporting pollen from both kinds of anthers, so they are not specialized for different functions.”

Kay said she didn’t realize how much time Darwin had spent puzzling over heteranthery until she started studying it herself. “He figured out so many things, it’s hard to find a case where he didn’t figure it out,” she said. Darwin might have been on the right track, though. Shortly before his death, he requested seeds of C. unguiculata to use in experiments.

In addition to Kay, the coauthors of the paper include postdoctoral scholar Tania Jogesh and two UCSC undergraduates, Diana Tataru and Sami Akiba. Both students completed senior theses on their work and were supported by UCSC’s Norris Center for Natural History.

Reference: Kathleen M. Kay, Tania Jogesh, Diana Tataru and Sami Akiba, “Darwin’s vexing contrivance: a new hypothesis for why some flowers have two kinds of anther”, Royal Society Publishing, 2020. https://royalsocietypublishing.org/doi/10.1098/rspb.2020.2593 https://doi.org/10.1098/rspb.2020.2593

Provided by University of California Santa Cruz

Enlightening Dark Ions (Physics)

Physicists get closer to examining the symmetries underlying our Universe.

Every field has its underlying principles. For economics it’s the rational actor; biology has the theory of evolution; modern geology rests on the bedrock of plate tectonics.

An unknown molecular ion is depicted in a trap with two radium ions. The radium ions’ fluorescence provides a measurement of the mystery ion’s mass, identifying it as RaOCH3+ via the method introduced by Fan and his colleagues. Photo Credit:  MAX LADABAUM

Physics has conservation laws and symmetries. For instance, the law of conservation of energy – which holds that energy can neither be created nor destroyed — has guided research in physics since antiquity, becoming more formalized as time went on. Likewise, parity symmetry suggests that switching an event for its mirror image shouldn’t affect the outcome.

As physicists have worked to understand the truly bizarre rules of quantum mechanics, it seems that some of these symmetries don’t always hold up. Professor Andrew Jayich focuses on investigating these symmetry violations in an effort to shed light on new physics. He and his lab members have just published a paper in Physical Review Letters reporting progress on synthesizing and detecting ions that are among the most sensitive measures for time (T) symmetry violations.

Time symmetry implies that the laws of physics look the same when time runs forward or backward. “For example, the path of a pool ball on a table simply retraces its course if the arrow of time is reversed,” Jayich said. But that does not hold for all physical interactions.

Andrew Jayich Photo Credit:  UC SANTA BARBARA

Understanding when and why T symmetry breaks down could provide answers to some of the biggest open questions in physics, such as why the Universe is full of matter and lacks antimatter. “The laws of physics as we know them treat matter and antimatter on equal footing,” Jayich said, “yet events in the early moments of the Universe favored matter over antimatter.” These are tough problems to crack, with close to a century of work behind them.

To address these questions, Jayich and his team have controllably synthesized, trapped and cooled radioactive molecules, RaOCH3+ and RaOH+, that provide large improvements in sensitivity to T symmetry violation. First author Mingyu Fan, a doctoral student in Jayich’s lab, discovered a technique to detect dark ions in their electromagnetic trap. These particles don’t scatter light, which means the researchers can’t detect them with a camera.

Mingyu Fan
Photo Credit: 
UC SANTA BARBARA

While adjusting some of the experimental parameters, Fan noticed the trapped ions, which normally sit very still, were oscillating rapidly at a large yet fixed amplitude. He figured out that this behavior provides a strong signal for detecting these elusive ions. “This controlled amplification of the motion allows us to measure the ion’s motional frequency, and thus its mass precisely and quickly,” Fan said.

Jayich and Fan reported their success in laser cooling radium ions in a previous study, which was the first to achieve this feat for the heavy element. The lab’s recent breakthrough brings them closer to their ultimate goal of using radioactive molecules to test time symmetry violations.

The researchers used radium-226, which has 138 neutrons and no nuclear spin, in their recent work. They plan to use the slightly lighter isotope, radium-225, which has the necessary nuclear spin, in their planned symmetry violation experiments. Other members of the lab are working on efforts to laser cool and trap radium-225 ions and perform optical spectroscopy on the radioactive molecules that contain it.

“These results are a clear breakthrough for our planned ‘big’ experiments,” said Jayich. “We have made these incredibly sensitive detectors, where a single molecule has the sensitivity to set new limits on T-violation. This opens up a new paradigm for measuring T-violation.”

Reference: M. Fan, C. A. Holliman, X. Shi, H. Zhang, M. W. Straus, X. Li, S. W. Buechele, and A. M. Jayich, “Optical Mass Spectrometry of Cold RaOH+ and RaOCH3+”, Phys. Rev. Lett. 126, 023002 – Published 11 January 2021. https://journals.aps.org/prl/abstract/10.1103/PhysRevLett.126.023002

Provided by UC Santa Barbara

SARS-CoV-2 Can Infect Neurons and Damage Brain Tissue (Neuroscience)

Using both mouse and human brain tissue, researchers at Yale School of Medicine have discovered that SARS-CoV-2 can directly infect the central nervous system and have begun to unravel some of the virus’s effects on brain cells. The study, published today in the Journal of Experimental Medicine (JEM), may help researchers develop treatments for the various neurological symptoms associated with COVID-19.

An image of a human brain organoid shows numerous dying cells (green) surrounding neurons (gray) that have been infected by SARS-CoV-2 (red). © 2021 Song et al. Originally published in Journal of Experimental Medicine.

Though COVID-19 is considered to primarily be a respiratory disease, SARS-CoV-2 can affect many other organs in the body, including, in some patients, the central nervous system, where infection is associated with a variety of symptoms ranging from headaches and loss of taste and smell to impaired consciousness, delirium, strokes, and cerebral hemorrhage.

“Understanding the full extent of viral invasion is crucial to treating patients, as we begin to try to figure out the long-term consequences of COVID-19, many of which are predicted to involve the central nervous system,” says Akiko Iwasaki, a professor at Yale School of Medicine.

Many questions remain to be answered, including whether SARS-CoV-2 can infect neurons or other types of brain cells. To address this question, a team led by Iwasaki and co-senior author Kaya Bilguvar, an associate professor at Yale School of Medicine, analyzed the ability of SARS-CoV-2 to invade human brain organoids, miniature 3D organs grown in the lab from human stem cells. The researchers found that the virus was able to infect neurons in these organoids and use the neuronal cell machinery to replicate. The virus appears to facilitate its replication by boosting the metabolism of infected cells, while neighboring, uninfected neurons die as their oxygen supply is reduced.

SARS-CoV-2 enters lung cells by binding to a protein called ACE2, but whether this protein is present on the surface of brain cells is unclear. The Yale team determined that the ACE2 protein is, in fact, produced by neurons and that blocking this protein prevents the virus from human brain organoids.

SARS-CoV-2 was also able to infect the brains of mice genetically engineered to produce human ACE2, causing dramatic alterations in the brain’s blood vessels that could potentially disrupt the organ’s oxygen supply. Central nervous system infection was much more lethal in mice than infections limited to the lungs, the researchers found.

Finally, the researchers analyzed the brains of three patients who succumbed to COVID-19. SARS-CoV-2 was detected in the cortical neurons of one of these patients, and the infected brain regions were associated with ischemic infarcts in which decreased blood supply causes localized tissue damage and cell death. Microinfarcts were detected in the brain autopsy of all three patients.

“Our study clearly demonstrates that neurons can become a target of SARS-CoV-2 infection, with devastating consequences of localized ischemia in the brain and cell death,” Bilguvar says. “Our results suggest that neurologic symptoms associated with COVID-19 may be related to these consequences, and may help guide rational approaches to the treatment of COVID-19 patients with neuronal disorders.”

“Future studies will be needed to investigate what might predispose some patients to infections of the central nervous system and to determine the route of SARS-CoV-2 invasion into the brain and the sequence of infection in different cell types within the central nervous system that will help validate the temporal relationship between SARS-CoV-2 and ischemic infarcts in patients,” Iwasaki adds.

Reference: Eric Song, Ce Zhang, Yile Dai et al., “Neuroinvasion of SARS-CoV-2 in human and mouse brain”, Journal of Experimental Medicine, 2020. https://doi.org/10.1084/jem.20202135 https://apps.crossref.org/pendingpub/pendingpub.html?doi=10.1084%2Fjem.20202135

Provided by Rockefeller University Press

About the Journal of Experimental Medicine

The Journal of Experimental Medicine (JEM) features peer-reviewed research on immunology, cancer biology, stem cell biology, microbial pathogenesis, vascular biology, and neurobiology. All editorial decisions are made by research-active scientists in conjunction with in-house scientific editors. JEM makes all of its content free online no later than six months after publication. Established in 1896, JEM is published by the Rockefeller University Press. For more information, visit jem.org.

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Texas A&M Research Explores How Melanoma Grows And Spreads (Medicine)

A study found that disrupting the metabolic pathway in the initiation, growth and progression of melanoma could lead to development of new treatments.

The first step in treating cancer is understanding how it starts, grows and spreads throughout the body. A relatively new cancer research approach is the study of metabolites, the products of different steps in cancer cell metabolism, and how those substances interact.

Melanoma cancer cells shown under a microscope. New Texas A&M research focuses on the metabolites involved in the growth and spread of melanoma, a rare but deadly type of skin cancer. © Getty Images

To date, research like this has focused mostly on cancerous tissues; however, normal tissues that surround tumors, known as the extratumoral microenvironment (EM), may have conditions favorable for tumor formation and should also be studied.

In a new study published in the journal PLoS One, researchers investigated the metabolites involved in the growth and spread of melanoma, a rare but deadly type of skin cancer. The study, led by Nicholas Taylor, assistant professor in the Department of Epidemiology and Biostatistics at the Texas A&M University School of Public Health, analyzed frozen tissue samples from melanoma patients at the H. Lee Moffitt Cancer Center and Research Institute in Tampa, Florida. These included samples of primary melanoma and matching EM tissues as well as unmatched metastatic melanoma tissues (melanoma that had spread to other parts of the body).

Differences in the types and amounts of metabolites in these tissues could tell more about how melanoma grows and spreads and whether EM tissues are truly normal or more favorable for tumor development.

Taylor and colleagues noted 824 significant differences in metabolite amounts between matched primary melanoma and EM tissues and 1,118 differences between metastatic melanoma and EM samples. The researchers then analyzed some of the chains of chemical reactions, known as metabolic pathways, involved in melanoma initiation and growth.

Their pathway-level analysis found that malignant and EM tissues had significantly different amounts of certain metabolites, such as lactate. They also found that both primary and metastatic melanoma showed similar metabolite differences from EM tissues. The amounts of a metabolite involved mainly in the spread, or metastasis, of cancer would differ between primary and metastatic melanoma. Thus, the metabolites analyzed are likely responsible for tumor initiation and maintenance and not for metastasis.

In addition, Taylor and colleagues observed differences in metabolite amounts across tumors that point to the reversal of a phenomenon common in cancer cells in which lactate is produced through a metabolic pathway that does not need large amounts of oxygen. This phenomenon is beneficial for cancer cells growing in low-oxygen environments, such as inside tumors. The reversal of this phenomenon is supported in this study by evidence that lactate was produced using a different oxygen-dependent pathway. The researchers note that this evidence agrees with other recent studies that suggest the existence of the reversed effect.

This knowledge can help with the development of new ways to treat melanoma, such as new experimental therapies that disrupt the oxygen-dependent metabolic pathway observed in this study. Because that metabolic pathway can help supply energy for growing cancer cells, disrupting the pathway could help slow or stop tumor growth. The findings of this study also serve as a starting point for additional research into the metabolism of both cancer cells and surrounding tissues.

Reference: Taylor NJ, Gaynanova I, Eschrich SA, Welsh EA, Garrett TJ, Beecher C, Sharma R, Koomen JM, Smalley KSM, Messina JL, Kanetsky PA. Metabolomics of primary cutaneous melanoma and matched adjacent extratumoral microenvironment. PLoS One. 2020 Oct 27;15(10):e0240849. doi: 10.1371/journal.pone.0240849. PMID: 33108391; PMCID: PMC7591037.

Provided by Texas A&M

New Treatment Allows Some People With Spinal Cord Injury to Regain Hand and Arm Function (Medicine)

Almost 18,000 Americans experience traumatic spinal cord injuries every year. Many of these people are unable to use their hands and arms and can’t do everyday tasks such as eating, grooming or drinking water without help.

Using physical therapy combined with a noninvasive method of stimulating nerve cells in the spinal cord, University of Washington researchers helped six Seattle area participants regain some hand and arm mobility. That increased mobility lasted at least three to six months after treatment had ended. The research team published these findings Jan. 5 in the journal IEEE Transactions on Neural Systems and Rehabilitation Engineering.

“We use our hands for everything — eating, brushing our teeth, buttoning a shirt. Spinal cord injury patients rate regaining hand function as the absolute first priority for treatment. It is five to six times more important than anything else that they ask for help on,” said lead author Dr. Fatma Inanici, a UW senior postdoctoral researcher in electrical and computer engineering who completed this research as a doctoral student of rehabilitation medicine in the UW School of Medicine.

“At the beginning of our study,” Inanici said, “I didn’t expect such an immediate response starting from the very first stimulation session. As a rehabilitation physician, my experience was that there was always a limit to how much people would recover. But now it looks like that’s changing. It’s so rewarding to see these results.”

Fatma Inanici applies small patches that will deliver electrical currents to the injured area on a participant’s neck. Note: This photo was taken in 2018.Marcus Donner/Center for Neurotechnology

After a spinal cord injury, many patients do physical therapy to help them attempt to regain mobility. Recently, a series of studies have shown that implanting a stimulator to deliver electric current to a damaged spinal cord could help paralyzed patients walk again.

The UW team, composed of researchers from the Center for Neurotechnology, combined stimulation with standard physical therapy exercises, but the stimulation doesn’t require surgery. Instead, it involves small patches that stick to a participant’s skin like a Band-Aid. These patches are placed around the injured area on the back of the neck where they deliver electrical pulses.

The researchers recruited six people with chronic spinal cord injuries. All participants had been injured for at least a year and a half. Some participants couldn’t wiggle their fingers or thumbs while others had some mobility at the beginning of the study.

To explore the viability of using the skin-surface stimulation method, the researchers designed a five-month training program. For the first month, the researchers monitored participants’ baseline limb movements each week. Then for the second month, the team put participants through intensive physical therapy training, three times a week for two hours at a time. For the third month, participants continued physical therapy training but with stimulation added.

“We turned on the device, but they continued doing the exact same exercises they did the previous month, progressing to slightly more difficult versions if they improved,” Inanici said.

Participants progressed to more difficult versions of the training exercises (for example, going from picking up a ping pong ball to picking up a tiny bead, shown here) as they improved. Note: This photo was taken in 2019.Marcus Donner/Center for Neurotechnology

For the last two months of the study, participants were divided into two categories: Participants with less severe injuries received another month of training alone and then a month of training plus stimulation. Patients with more severe injuries received the opposite — training and stimulation first, followed by only training second.

The researchers designed a five-month training program that included month-long regimens of training alone or training with stimulation. Inanici et. al, IEEE Transactions on Neural Systems and Rehabilitation Engineering

While some participants regained some hand function during training alone, all six saw improvements when stimulation was combined with training.

“Both people who had no hand movement at the beginning of the study started moving their hands again during stimulation, and were able to produce a measurable force between their fingers and thumb,” said senior author Chet Moritz, a UW associate professor of electrical and computer engineering, rehabilitation medicine and physiology and biophysics. “That’s a dramatic change, to go from being completely paralyzed below the wrists down to moving your hands at will.”

In addition, some participants noticed other improvements, including a more normal heart rate and better regulation of body temperature and bladder function.

The team followed up with participants for up to six months after training and found that these improvements remained, despite no more stimulation.

“We think these stimulators bring the nerves that make your muscles contract very close to being active. They don’t actually cause the muscle to move, but they get it ready to move. It’s primed, like the sprinter at the start of a race,” said Moritz, who is also the co-director of the Center for Neurotechnology. “Then when someone with a spinal cord injury wants to move, the few connections that might have been spared around the injury are enough to cause those muscles to contract.”

Chet Moritz (left) and Fatma Inanici (center) observe as a participant (right) measures grip strength (by squeezing the device in his hand). The participant has sensors on his arms (black cases) to measure his arm muscle activity during the task. Note: This photo was taken in 2019. Marcus Donner/Center for Neurotechnology

The research is moving toward helping people in the clinic. The results of this study have already informed the design of an international multi-site clinical trial that will be co-led by Moritz. One of the lead sites will be at the UW.

“We’re seeing a common theme across universities — stimulating the spinal cord electrically is making people better,” Moritz said. “But it does take motivation. The stimulator helps you do the exercises, and the exercises help you get stronger, but the improvements are incremental. Over time, however, they add up into something that’s really astounding.”

Lorie Brighton, a research scientist at the UW; Soshi Samejima, a UW doctoral student in rehabilitation medicine; and Dr. Christoph Hofstetter, an associate professor of neurological surgery in the UW School of Medicine, are co-authors on this paper. This research was funded by the Center for Neurotechnology, the Washington State Spinal Cord Injury Consortium and the Christopher and Dana Reeve Foundation.

Reference: F. Inanici, L. N. Brighton, S. Samejima, C. P. Hofstetter and C. T. Moritz, “Transcutaneous spinal cord stimulation restores hand and arm function after spinal cord injury,” in IEEE Transactions on Neural Systems and Rehabilitation Engineering.
doi: 10.1109/TNSRE.2021.3049133 URL: http://ieeexplore.ieee.org/stamp/stamp.jsp?tp=&arnumber=9314097&isnumber=4359219

Provided by University of Washington

Hope for Children With Rare Heart Condition: Novel Stem Cell Therapy to Save the Day (Medicine)

Researchers put forward a safe and efficient new stem cell therapy for regenerating cardiac function in pediatric patients.

Dilated cardiomyopathy (DCM) is a condition caused by the weakening of the heart muscle, affecting the ventricles (chambers in the heart that push blood around the body as it contracts). If allowed to progress unchecked, DCM can lead to heart failure and death, especially in children. The only cure, at present, is a heart transplant, which comes with its own challenges: long waiting times to secure a suitable donor heart, the possibility of organ rejection, long hospitalizations and recovery times, among others.

In this study, exosomes were isolated from patient-derived cardiospheres and visualized using transmission electron microscopy. © Okayama University Hospital

In recent decades, stem cells have become the cornerstone of regenerative medicine, allowing medical professionals to treat damaged organs and reverse the course of several diseases that were previously deemed irrevocable. Scientists have turned to “cardiosphere-derived cells” (CDCs), a type of cardiac stem cells known to have beneficial effects in adults suffering from specific heart conditions. By developing (“differentiating”) into heart tissue, CDCs can reverse the damage inflicted by diseases. However, little is known about their safety and therapeutic benefit in children.

To address this problem, Professor Hidemasa Oh led an interdepartmental team of scientists at Okayama University, Japan, to launching the first steps to assess this therapy in children suffering from DCM. In a study published in Science Translational Medicine, the team not only showed the effectiveness of CDCs in replenishing damaged tissues in DCM but also revealed how this happens. Prof Oh explains the motivation, “I have been working on cardiac regeneration therapy since 2001. In this study, my team and I assessed the safety and efficacy of using CDCs to treat DCM in children .”

The first step of any trial when testing a new drug or therapy is to use animal models who react similarly to humans, which shows us whether the treatment is safe and has the intended effect. Thus, to begin with, the researchers tested this method in pigs, inducing cardiac symptoms similar to DCM and treating them with different doses of CDCs or a placebo. In those given the stem cell treatment, the scientists noticed quick improvements in cardiac function. The heart muscle thickened, allowing more blood to be pumped around the body. This effectively reversed the damage induced in the pigs’ hearts, an encouraging result leading them to progress to small, controlled human trials.

Their phase 1 trial involved five young patients suffering from DCM. The scientists now had a better idea of the suitable dose of CDCs to give their young patients, thanks to the pre-clinical trials in animals. One year after injection, the patients showed no sign of severe side effects from the treatment, but most importantly, there were encouraging signs of improved heart function. The authors are cautious: based on the small population size of their study, they cannot establish a strong conclusion. However, they are satisfied that CDC treatment appears sufficiently safe and effective to progress to a larger clinical trial. As Prof Oh explains, “We intend to move these results into a randomized phase 2 trial to obtain a pharmaceutical approval of this therapy in Japan .”

Another important finding was the mechanism through which CDCs actually lead to improved cardiac function. Indeed, their analyses revealed that transplanted cells secrete small vesicles called “exosomes,” which are enriched with proteins called “microRNAs” that initiate a whole cascade of molecular interactions. These microRNA-enriched exosomes have two effects. First, it blocks the damage-inducing cells from causing further harm to the heart tissue. Secondly, it induces the differentiation of stem cells into fully functioning cardiac cells (“cardiomyocytes”), starting the regenerative process. This generates hope that injecting these exosomes alone might be enough to reverse this type of heart damage in patients, bypassing the need for CDCs in the first place.

Looking back on their research, the scientists are hopeful that a phase 2 trial will confirm their suspicions, and what this could mean for future patients. Prospective transplant patients sometimes wait for years for a donor heart to become available. This type of therapy could allow them to live relatively normal lives, and even prevent the need for a transplant altogether for patients who have not yet reached such a critical stage.

Reference: Kenta Hirai, Daiki Ousaka, Yosuke Fukushima, Maiko Kondo, Takahiro Eitoku, Yusuke Shigemitsu, Mayuko Hara, Kenji Baba, Tatsuo Iwasaki, Shingo Kasahara, Shinichi Ohtsuki, Hidemasa Oh, “Cardiosphere-derived exosomal microRNAs for myocardial repair in pediatric dilated cardiomyopathy”, Science Translational Medicine  09 Dec 2020: Vol. 12, Issue 573, eabb3336 DOI: 10.1126/scitranslmed.abb3336 https://stm.sciencemag.org/content/12/573/eabb3336

Provided by Okayama University

Rotten Egg Gas Could Guard Against Alzheimer’s Disease (Medicine)

Typically characterized as poisonous, corrosive and smelling of rotten eggs, hydrogen sulfide’s reputation may soon get a face-lift thanks to Johns Hopkins Medicine researchers. In experiments in mice, researchers have shown the foul-smelling gas may help protect aging brain cells against Alzheimer’s disease. The discovery of the biochemical reactions that make this possible opens doors to the development of new drugs to combat neurodegenerative disease.

A ribbon model of a sulfhydrated GSK3β that would inhibit its activity. Oxygen atoms are shown in red, sulfur in yellow and nitrogen in blue. Credit: Bindu Paul and Johns Hopkins Medicine

The findings from the study are reported in the Jan. 11 issue of the Proceedings of the National Academies of Science.

“Our new data firmly link aging, neurodegeneration and cell signaling using hydrogen sulfide and other gaseous molecules within the cell,” says Bindu Paul, M.Sc., Ph.D., faculty research instructor in neuroscience in the Solomon H. Snyder Department of Neuroscience at the Johns Hopkins University School of Medicine and lead corresponding author on the study.

The human body naturally creates small amounts of hydrogen sulfide to help regulate functions throughout the body, from cell metabolism to blood vessel dilation. The rapidly burgeoning field of gasotransmission shows that gases are major cellular messenger molecules, with particular importance in the brain. However, unlike conventional neurotransmitters, gases can’t be stored in vesicles. Thus, gases act through very different mechanisms to rapidly facilitate cellular messaging. In the case of hydrogen sulfide, this entails the modification of target proteins by a process called chemical sulfhydration, which modulates their activity, says Solomon Snyder, D.Phil., D.Sc., M.D., professor of neuroscience at the Johns Hopkins University School of Medicine and co-corresponding author on the study.

Studies using a new method have shown that sulfhydration levels in the brain decrease with age, a trend that is amplified in patients with Alzheimer’s disease. “Here, using the same method, we now confirm a decrease in sulfhydration in the AD brain,” says collaborator Milos Filipovic, Ph.D., principal investigator, Leibniz-Institut für Analytische Wissenschaften – ISAS.

For the current research, the Johns Hopkins Medicine scientists studied mice genetically engineered to mimic human Alzheimer’s disease. They injected the mice with a hydrogen sulfide-carrying compound called NaGYY, developed by their collaborators at the University of Exeter in the United Kingdom, which slowly releases the passenger hydrogen sulfide molecules while traveling throughout the body. The researchers then tested the mice for changes in memory and motor function over a 12-week period.

Behavioral tests on the mice showed that hydrogen sulfide improved cognitive and motor function by 50% compared with mice that did not receive the injections of NaGYY. Treated mice were able to better remember the locations of platform exits and appeared more physically active than their untreated counterparts with simulated Alzheimer’s disease.

The results showed that the behavioral outcomes of Alzheimer’s disease could be reversed by introducing hydrogen sulfide, but the researchers wanted to investigate how the brain chemically reacted to the gaseous molecule.

A series of biochemical experiments revealed a change to a common enzyme called glycogen synthase β (GSK3β). In the presence of healthy levels of hydrogen sulfide, GSK3β typically acts as a signaling molecule, adding chemical markers to other proteins and altering their function. However, the researchers observed that in the absence of hydrogen sulfide, GSK3β is overattracted to another protein in the brain called Tau.

When GSK3β interacts with Tau, Tau changes into a form that tangles and clumps inside nerve cells. As Tau clumps grow, the tangled proteins block communication between nerves, eventually causing them to die. This leads to the deterioration and eventual loss of cognition, memory and motor function that is characteristic of Alzheimer’s disease.

“Understanding the cascade of events is important to designing therapies that can block this interaction like hydrogen sulfide is able to do,” says Daniel Giovinazzo, M.D./Ph.D. student, the first author of the study.

Until recently, researchers lacked the pharmacological tools to mimic how the body slowly makes tiny quantities of hydrogen sulfide inside cells. “The compound used in this study does just that and shows by correcting brain levels of hydrogen sulfide, we could successfully reverse some aspects of Alzheimer’s disease,” says collaborator on the study Matt Whiteman, Ph.D., professor of experimental therapeutics at the University of Exeter Medical School.

The Johns Hopkins Medicine team and their international collaborators plan to continue studying how sulfur groups interact with GSK3β and other proteins involved in the pathogenesis of Alzheimer’s disease in other cell and organ systems. The team also plans to test novel hydrogen sulfide delivery molecules as part of their ongoing venture.

Other researchers involved in this study include Biljana Bursac, Thubaut Vignana and Milos Filipovic of the Leibniz-Institut für Analytische Wissenschaften – ISAS and Juan Sbodio, Sumedha Nalluru, Adele Snowman, Lauren Albacarys and Thomas Sedlak of the Johns Hopkins University School of Medicine.

This work was supported by the U.S. Public Health Service Grant (DA044123), the American Heart Association, the Allen Initiative in Brain Health and Cognitive Impairment, the Medical Research Council of the United Kingdom (MR/S002626/1), the Brian Ridge Scholarship, and the European Research Council under the European Union’s Horizon 2020 research and innovation programme (864921).

The Johns Hopkins researchers declare no competing financial interests.

Reference: Jasmina Zivanovic, Emilia Kouroussis, Joshua B. Kohl, Bikash Adhikari, Biljana Bursac, Sonia Schott-Roux, Dunja Petrovic, Jan Lj. Miljkovic, Daniel Thomas-Lopez, Youngeun Jung, Marko Miler, Sarah Mitchell, Verica Milosevic, Jose Eduardo Gomes, Moran Benhar, Bruno Gonzalez-Zorn, Ivana Ivanovic-Burmazovic, Roberta Torregrossa, James R. Mitchell, Matthew Whiteman, Guenter Schwarz, Solomon H. Snyder, Bindu D. Paul, Kate S. Carroll, Milos R. Filipovic, Selective Persulfide Detection Reveals Evolutionarily Conserved Antiaging Effects of S-Sulfhydration, Cell Metabolism, Volume 30, Issue 6, 2019, Pages 1152-1170.e13, ISSN 1550-4131, https://doi.org/10.1016/j.cmet.2019.10.007. (http://www.sciencedirect.com/science/article/pii/S1550413119305625)

Provided by John Hopkins Medicine