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Glutathione and glutathione disulfide – their biomedical and pharmaceutical applications

• Review Article
• Published: 28 July 2023
• Volume 32 , pages 1972–1994, ( 2023 )

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• Xiangming Guan   ORCID: orcid.org/0000-0002-5266-6352   nAff1  

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Glutathione (GSH) is an endogenous tripeptide (Glu-Cys-Gly) and the most abundant endogenous antioxidant. It protects the body against oxidative stress and reactive electrophiles. GSH and its oxidized form glutathione disulfide (GSSG) make up the most important thiol redox buffer in the body, and its homeostasis is critical to many important cellular functions. Dysfunction or disruption of the redox buffer has been implicated in various diseases and the implications make GSH, GSSG, and their related systems valid and effective targets for medicinal chemistry interventions. For example, increased levels of GSH and GSH related systems in cancer have been employed as a basis for anticancer prodrug activation, anticancer drug delivery and anticancer drug development. The enriched GSH transporters in the blood brain barrier has been effectively employed for the design of brain targeting prodrugs and brain drug delivery systems. Further, a glutathione conjugate can serve as a marker for the presence of a reactive electrophile providing valid information for the evaluation of a drug candidate. This review focuses on GSH/GSSG system-based biomedical and pharmaceutical applications with relevant basic and comprehensive background information.

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Xiangming Guan

Present address: Department of Pharmaceutical Sciences, College of Pharmacy & Allied Health Professions, South Dakota State University, Brookings, SD, 57007, USA

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Guan, X. Glutathione and glutathione disulfide – their biomedical and pharmaceutical applications. Med Chem Res 32 , 1972–1994 (2023). https://doi.org/10.1007/s00044-023-03116-9

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Glutathione as a skin whitening agent: Facts, myths, evidence and controversies

Affiliation.

• 1 Skinnocence: The Skin Clinic, Gurgaon, Haryana, India.
• PMID: 27088927
• DOI: 10.4103/0378-6323.179088

Glutathione is a low molecular weight thiol-tripeptide that plays a prominent role in maintaining intracellular redox balance. In addition to its remarkable antioxidant properties, the discovery of its antimelanogenic properties has led to its promotion as a skin-lightening agent. It is widely used for this indication in some ethnic populations. However, there is a dichotomy between evidence to support its efficacy and safety. The hype around its depigmentary properties may be a marketing gimmick of pharma-cosmeceutical companies. This review focuses on the various aspects of glutathione: its metabolism, mechanism of action and the scientific evidence to evaluate its efficacy as a systemic skin-lightening agent. Glutathione is present intracellularly in its reduced form and plays an important role in various physiological functions. Its skin-lightening effects result from direct as well as indirect inhibition of the tyrosinase enzyme and switching from eumelanin to phaeomelanin production. It is available in oral, parenteral and topical forms. Although the use of intravenous glutathione injections is popular, there is no evidence to prove its efficacy. In fact, the adverse effects caused by intravenous glutathione have led the Food and Drug Administration of Philippines to issue a public warning condemning its use for off-label indications such as skin lightening. Currently, there are three randomized controlled trials that support the skin-lightening effect and good safety profile of topical and oral glutathione. However, key questions such as the duration of treatment, longevity of skin-lightening effect and maintenance protocols remain unanswered. More randomized, double-blind, placebo-controlled trials with larger sample size, long-term follow-up and well-defined efficacy outcomes are warranted to establish the relevance of this molecule in disorders of hyperpigmentation and skin lightening.

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• Administration, Intravenous
• Administration, Oral
• Administration, Topical
• Dietary Supplements
• Glutathione / administration & dosage*
• Glutathione / metabolism
• Hyperpigmentation / diagnosis
• Hyperpigmentation / drug therapy*
• Hyperpigmentation / metabolism
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• Skin Pigmentation / drug effects*
• Skin Pigmentation / physiology
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Potential use of antioxidants for the treatment of chronic inflammatory diseases.

• 1 Institute of General Pathology and Pathophysiology, Moscow, Moscow Oblast, Russia
• 2 Institute for Aterosclerosis Research (Russia), Moscow, Russia
• 3 Russian National Research Center of Surgery named after B.V. Petrovsky, Moscow, Moscow Oblast, Russia

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The excessive production of various reactive oxidant species over endogenous antioxidant defense mechanisms leads to the development of a state of oxidative stress, with serious biological consequences. The consequences of oxidative stress depend on the balance between the generation of reactive oxidant species and the antioxidant defense and include oxidative damage of biomolecules, disruption of signal transduction, mutation, and cell apoptosis. Accumulating evidence suggests that oxidative stress is involved in the physiopathology of various debilitating illnesses associated with chronic inflammation, including cardiovascular diseases (CVDs), diabetes, cancer, or neurodegenerative processes, that need continuous pharmacological treatment. Oxidative stress and chronic inflammation are tightly linked pathophysiological processes, one of which can be simply promoted by another. Although, many antioxidant trials have been unsuccessful (some of the trials showed either no effect or even harmful effects) in human patients as a preventive or curative measure, targeting oxidative stress remains an interesting therapeutic approach for the development of new agents to design novel anti-inflammatory drugs with a reliable safety profile. In this regard, several natural antioxidant compounds were explored as potential therapeutic options for the treatment of chronic inflammatory diseases. Several metalloenzymes, such as superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx), are among the essential enzymes that maintain the low nanomolar physiological concentrations of superoxide (O2•-) and hydrogen peroxide (H2O2), the major redox signaling molecules, and thus play important roles in the alteration of the redox homeostasis. These enzymes have become a striking source of motivation to design catalytic drugs to enhance the action of these enzymes under pathological conditions related to chronic inflammation. This review is focused on several major representatives of natural and synthetic antioxidants as potential drug candidates for the treatment of chronic inflammatory diseases.

Keywords: ROS, chronic inflammation, Antioxidants, Chronic inflammatory diseases, cellular antioxidant enzymes

Received: 29 Jan 2024; Accepted: 26 Apr 2024.

Copyright: © 2024 Blagov, Summerhill, Sukhorukov, Zhigmitova, Postnov and Orekhov. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Alexander V. Blagov, Institute of General Pathology and Pathophysiology, Moscow, Moscow Oblast, Russia Volha I. Summerhill, Institute for Aterosclerosis Research (Russia), Moscow, Russia Elena B. Zhigmitova, Institute of General Pathology and Pathophysiology, Moscow, Moscow Oblast, Russia Alexander N. Orekhov, Institute of General Pathology and Pathophysiology, Moscow, Moscow Oblast, Russia

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

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Helping women get better sleep by calming the relentless 'to-do lists' in their heads

Yuki Noguchi

Katie Krimitsos is among the majority of American women who have trouble getting healthy sleep, according to a new Gallup survey. Krimitsos launched a podcast called Sleep Meditation for Women to offer some help. Natalie Champa Jennings/Natalie Jennings, courtesy of Katie Krimitsos hide caption

Katie Krimitsos is among the majority of American women who have trouble getting healthy sleep, according to a new Gallup survey. Krimitsos launched a podcast called Sleep Meditation for Women to offer some help.

When Katie Krimitsos lies awake watching sleepless hours tick by, it's almost always because her mind is wrestling with a mental checklist of things she has to do. In high school, that was made up of homework, tests or a big upcoming sports game.

"I would be wide awake, just my brain completely spinning in chaos until two in the morning," says Krimitsos.

There were periods in adulthood, too, when sleep wouldn't come easily, like when she started a podcasting company in Tampa, or nursed her first daughter eight years ago. "I was already very used to the grainy eyes," she says.

Now 43, Krimitsos says in recent years she found that mounting worries brought those sleepless spells more often. Her mind would spin through "a million, gazillion" details of running a company and a family: paying the electric bill, making dinner and dentist appointments, monitoring the pets' food supply or her parents' health checkups. This checklist never, ever shrank, despite her best efforts, and perpetually chased away her sleep.

"So we feel like there are these enormous boulders that we are carrying on our shoulders that we walk into the bedroom with," she says. "And that's what we're laying down with."

By "we," Krimitsos means herself and the many other women she talks to or works with who complain of fatigue.

Women are one of the most sleep-troubled demographics, according to a recent Gallup survey that found sleep patterns of Americans deteriorating rapidly over the past decade.

"When you look in particular at adult women under the age of 50, that's the group where we're seeing the most steep movement in terms of their rate of sleeping less or feeling less satisfied with their sleep and also their rate of stress," says Gallup senior researcher Sarah Fioroni.

Overall, Americans' sleep is at an all time low, in terms of both quantity and quality.

A majority – 57% – now say they could use more sleep, which is a big jump from a decade ago. It's an acceleration of an ongoing trend, according to the survey. In 1942, 59% of Americans said that they slept 8 hours or more; today, that applies to only 26% of Americans. One in five people, also an all-time high, now sleep fewer than 5 hours a day.

Popular myths about sleep, debunked

"If you have poor sleep, then it's all things bad," says Gina Marie Mathew, a post-doctoral sleep researcher at Stony Brook Medicine in New York. The Gallup survey did not cite reasons for the rapid decline, but Mathew says her research shows that smartphones keep us — and especially teenagers — up later.

She says sleep, as well as diet and exercise, is considered one of the three pillars of health. Yet American culture devalues rest.

"In terms of structural and policy change, we need to recognize that a lot of these systems that are in place are not conducive to women in particular getting enough sleep or getting the sleep that they need," she says, arguing things like paid family leave and flexible work hours might help women sleep more, and better.

No one person can change a culture that discourages sleep. But when faced with her own sleeplessness, Tampa mom Katie Krimitsos started a podcast called Sleep Meditation for Women , a soothing series of episodes in which she acknowledges and tries to calm the stresses typical of many women.

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Many grouchy, error-prone workers just need more sleep.

That podcast alone averages about a million unique listeners a month, and is one of 20 podcasts produced by Krimitsos's firm, Women's Meditation Network.

"Seven of those 20 podcasts are dedicated to sleep in some way, and they make up for 50% of my listenership," Krimitsos notes. "So yeah, it's the biggest pain point."

Krimitsos says she thinks women bear the burdens of a pace of life that keeps accelerating. "Our interpretation of how fast life should be and what we should 'accomplish' or have or do has exponentially increased," she says.

She only started sleeping better, she says, when she deliberately cut back on activities and commitments, both for herself and her two kids. "I feel more satisfied at the end of the day. I feel more fulfilled and I feel more willing to allow things that are not complete to let go."

Automated machine learning robot unlocks new potential for genetics research

This technology will save labs time and money while enabling large-scale experiments.

University of Minnesota Twin Cities researchers have constructed a robot that uses machine learning to fully automate a complicated microinjection process used in genetic research.

In their experiments, the researchers were able to use this automated robot to manipulate the genetics of multicellular organisms, including fruit fly and zebrafish embryos. The technology will save labs time and money while enabling them to more easily conduct new, large-scale genetic experiments that were not possible previously using manual techniques

The research is featured on the cover of the April 2024 issue of GENETICS , a peer-reviewed, open access, scientific journal. The work was co-led by two University of Minnesota mechanical engineering graduate students Andrew Alegria and Amey Joshi. The team is also working to commercialize this technology to make it widely available through the University of Minnesota start-up company, Objective Biotechnology.

Microinjection is a method for introducing cells, genetic material, or other agents directly into embryos, cells, or tissues using a very fine pipette. The researchers have trained the robot to detect embryos that are one-hundredth the size of a grain of rice. After detection, the machine can calculate a path and automate the process of the injections.

"This new process is more robust and reproducible than manual injections," said Suhasa Kodandaramaiah, a University of Minnesota mechanical engineering associate professor and senior author of the study. "With this model, individual laboratories will be able to think of new experiments that you couldn't do without this type of technology."

Typically, this type of research requires highly skilled technicians to perform the microinjection, which many laboratories do not have. This new technology could expand the ability to perform large experiments in labs, while reducing time and costs.

"This is very exciting for the world of genetics. Writing and reading DNA have drastically improved in recent years, but having this technology will increase our ability to perform large-scale genetic experiments in a wide range of organisms," said Daryl Gohl, a co-author of the study, the group leader of the University of Minnesota Genomics Center's Innovation Lab and research assistant professor in the Department of Genetics, Cell Biology, and Development.

Not only can this technology be used in genetic experiments, but it can also help to preserve endangered species through cryopreservation, a preservation technique conducted at ultra-low temperatures.

"You can use this robot to inject nanoparticles into cells and tissues that helps in cryopreservation and in the process of rewarming afterwards," Kodandaramaiah explained.

Other team members highlighted other applications for the technology that could have even more impact.

"We hope that this technology could eventually be used for in vitro fertilization, where you could detect those eggs on the microscale level," said Andrew Alegria, co-lead author on the paper and University of Minnesota mechanical engineering graduate research assistant in the Biosensing and Biorobotics Lab.

• Medical Devices
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• Medical Imaging
• Educational Technology
• Artificial Intelligence
• Robot calibration
• Computational neuroscience
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Materials provided by University of Minnesota . Note: Content may be edited for style and length.

Journal Reference :

• Andrew D Alegria, Amey S Joshi, Jorge Blanco Mendana, Kanav Khosla, Kieran T Smith, Benjamin Auch, Margaret Donovan, John Bischof, Daryl M Gohl, Suhasa B Kodandaramaiah. High-throughput genetic manipulation of multicellular organisms using a machine-vision guided embryonic microinjection robot . GENETICS , 2024; 226 (4) DOI: 10.1093/genetics/iyae025

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Strange & offbeat.

Breaking ice, and helicopter drops: winning photos of working scientists

Nature ’s annual photography competition attracted stunning images from around the world, including two very different shots featuring the polarstern research vessel..

By Jack Leeming

23 April 2024

This article is also available as a pdf version .

Scientists often take images from their work – whether they produce medical scans, microscopic captures, or computer screenshots of tricky pieces of code during the course of their work. By continuing our Working Scientist photography competition, we aim to celebrate and highlight the very best images created by our audience in the pursuit of research.

We received more than 200 entries this year from researchers working around the world. The winner and the four runners-up were selected by a jury of Nature staff, including three of the journal’s picture editors. All will receive a prize of £500 (US$620), in the form of Amazon vouchers or a donation to charity, as well as a year’s subscription to Nature .

This image, taken on top of the icebreaker research vessel Polarstern , shows the delicate process of retrieving an instrument called a CTD (short for conductivity, temperature, depth) that had become trapped under sea ice off the coast of northeastern Greenland.

CTDs, which are anchored to the sea floor, measure how ocean properties such as salinity and temperature vary with depth. At some point, the sea ice had closed over the top of this one, forcing the Polarstern to skirt carefully around the equipment, breaking the ice to rescue it from the freezing ocean.

Credit: Richard Jones

“You’re crashing into ice and breaking through it. So it wasn’t particularly calm sailing for the majority of the trip,” remembers Richard Jones, who took the image in September 2017 and is the winner of Nature ’s 2024 Working Scientist photography competition. His research aims to improve estimates of the rate at which ice is being lost from the world’s glacial ice sheets.

Jones, a glaciologist at Monash University in Melbourne, Australia, highlights the photographic contrast between icebreaker and ice that he’d become used to in his five weeks aboard the Polarstern . “All you really see is blue and white. And sometimes that might feel pretty monotonous, but the colours from the CTD instrument and the orange of the crane contrast the scene and also complement it quite nicely.”

Here are the rest of the winning images from the competition.

Credit: Ryan Wagner

Reaching the beak

Conservation biologist Ryan Wagner snapped this photo of field biologist Sonia Vallocchia feeding a recently caught kiwikiu ( Pseudonestor xanthophrys ), in January this year. It was taken on Haleakalā volcano on the Hawaiian island of Maui. Wagner, a PhD student at Washington State University Vancouver, was on an expedition to the island as a science communicator, hoping to raise awareness of the plight of the endangered birds.

“Only 130 of these birds remain on Earth,” explains Wagner. “Their numbers have crashed due to avian malaria, which is spread by invasive mosquitoes. As climate change warms the island, mosquitoes have advanced upslope into the high-elevation refuges where native birds survive. A single mosquito bite can kill a kiwikiu.”

He hopes that ornithologists such as Vallocchia, who works for the Maui Forest Birds Recovery Project in Makawao, will help to save these birds by bringing some of them (by helicopter) to the Maui Bird Conservation Center, also in Makawao. There, they will be treated for malaria and join a captive breeding programme, he says.

Credit: Luiz L. Saldanha/Kimberly P. Castro

Library of leaves

PhD student Kim Castro took this photo of her colleague, postdoctoral researcher Luiz Leonardo Saldanha, in a herbarium that they both work in regularly. It’s shared between the University of Zurich and the Swiss Federal Institute of Technology (ETH) in Zurich. Both Castro and Saldanha investigate the medicinal plants of the Amazon at the Department of Systematic and Evolutionary Botany at the University of Zurich, although the two have very different approaches: whereas Saldanha investigates their chemical diversity, Castro looks at how the plants are perceived by Indigenous communities in the Amazon, specializing in how the plants smell.

A herbarium, Saldanha says, is “like a library — but instead of books, there are plants here”. Saldanha posed with this particular sample ( Palicourea corymbifera , collected in 1977) because it comes from his home country, Brazil, but is used by the Indigenous Desano people in Colombia as a medicinal herb. “So it creates a commonality between South American countries,” he says.

Credit: Herton Escobar/University of São Paulo Images

Mountain drop-off

In this dramatic image, taken from below the still-spinning, deafening blades of a military helicopter, scientists shelter with their equipment after being dropped off at the top of a remote mountain in northern Amazonia. They are taking part in a biodiversity-research expedition to Serra Imeri, an isolated mountain range that rises through the forest canopy near the border of Brazil and Venezuela, in November 2022.

“A total of 14 scientists and dozens of military support personnel took part in the expedition, which lasted for 11 days and resulted in the discovery of several new species of amphibians, reptiles, birds and plants,” says photographer Herton Escobar, a science journalist who works with the scientists pictured, at the University of São Paulo in Brazil.

Credit: Emiliano Cimoli

Go with the floe

Emiliano Cimoli, a remote-sensing scientist at the Institute for Marine and Antarctic Studies at the University of Tasmania, Australia, took the second photograph featuring the research vessel Polarstern in this year’s collection of winning images. Here, Carolin Mehlmann and Thomas Richter, mathematicians at the University of Magdeburg, Germany, are measuring the depth of snow across a giant ice floe drifting in the middle of the Arctic Ocean.

The image was taken during a two-month voyage organized by the Alfred Wegener Institute, based in Bremerhaven, Germany, in August 2023. The goal of the expedition was to evaluate interactions between the ice physics, biology, hydrography, biogeochemistry and biodiversity of the Arctic ecosystem, from the sea ice to the sea floor.

Nature 628 , 919-921 (2024)

doi: https://doi.org/10.1038/d41586-024-01181-7

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Journal of Materials Chemistry B

Nitrodopamine modified mno 2 ns-mos 2 qds hybrid nanocomposite for the extracellular and intracellular detection of glutathione †.

* Corresponding authors

a Department of Chemistry, Faculty of Engineering and Technology, SRM Institute of Science and Technology (SRMIST), Kattankulathur, Tamil Nadu-603203, India E-mail: [email protected]

b School of Physical Sciences, Jawaharlal Nehru University, New Delhi-110067, India E-mail: [email protected]

We have developed a highly sensitive and reliable fluorescence resonance energy transfer (FRET) probe using nitro-dopamine (ND) and dopamine (DA) coated MnO 2 nanosheet (ND@MnO 2 NS and DA@MnO 2 NS) as an energy acceptor and MoS 2 quantum dots (QDs) as an energy donor. By employing surface-modified MnO 2 NS, we can effectively reduce the fluorescence intensity of MoS 2 QDs through FRET. It can reduce MnO 2 NS to Mn 2+ and facilitate the fluorescence recovery of the MoS 2 QDs. This ND@MnO 2 NS@MoS 2 QD-based nanoprobe demonstrates excellent sensitivity to GSH, achieving an LOD of 22.7 nM in an aqueous medium while exhibiting minimal cytotoxicity and good biocompatibility. Moreover, our sensing platform shows high selectivity to GSH towards various common biomolecules and electrolytes. Confocal fluorescence imaging revealed that the nanoprobe can image GSH in A549 cells. Interestingly, the ND@MnO 2 NS nanoprobe demonstrates no cytotoxicity in living cancer cells, even at concentrations up to 100 μg mL −1 . Moreover, the easy fabrication and eco-friendliness of ND@MnO 2 NS make it a rapid and simple method for detecting GSH. We envision the developed nanoprobe as an incredible platform for real-time monitoring of GSH levels in both extracellular and intracellular mediums, proving valuable for biomedical research and clinical diagnostics.

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Nitrodopamine modified MnO 2 NS-MoS 2 QDs hybrid nanocomposite for the extracellular and intracellular detection of glutathione

G. Sivakumar, A. Gupta, A. Babu, P. K. Sasmal and S. Maji, J. Mater. Chem. B , 2024, Advance Article , DOI: 10.1039/D3TB03068G

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Glutathione!

My awareness of the importance of glutathione in health began with the brilliant commentary on oceanic disease ( IMCJ 7.1) by associate editor Sid Baker, md . 1 Since then, as I have studied detoxification, mitochondrial function, and healthy aging, the critical role of adequate glutathione to health has become ever more apparent. I have now mentioned glutathione in several previous editorials: protection from oxidative stress ( IMCJ 8.3), 2 protection from mercury and other toxic metals ( IMCJ 8.2, 9.3, 10.4), 3 – 5 protection from alcohol ( IMCJ 11.6), 6 and protection from persistent organic pollutants (POPs) ( IMCJ 12.2). 7 This resulted in my creating a 60-slide lecture on glutathione, which I gave for the first time at the October 2013 Restorative Medicine Conference in San Diego, California. As several attendees told me it was one of the most important lectures they had ever heard, I decided to make glutathione the topic of this editorial.

Glutathione Physiology, Production, and Recycling

Glutathione is a tripeptide (cysteine, glycine, and glutamic acid) found in surprisingly high levels—5 millimolar—concentrations in most cells. As can be seen in Figure 1 , this is the same concentration in cells as glucose, potassium, and cholesterol! Considering the high level of metabolic activity required to produce glutathione, such a high level underlines its importance.

Concentration of Molecules in Cells

Glutathione exists in cells in 2 states: reduced (GSH) and oxidized (GSSG). As can be seen in Figure 2 , oxidized glutathione is actually 2 reduced glutathiones bound together at the sulfur atoms.

Balance Between GSH and GSSG

The ratio of GSH to GSSG determines cell redox status of cells. Healthy cells at rest have a GSH/GSSG ratio >100 while the ratio drops to 1 to 10 in cells exposed to oxidant stress. Glutathione is also recognized as a thiol buffer maintaining sulfhydryl groups of many proteins in their reduced form. Glutathione is produced exclusively in the cytosol and actively pumped into mitochondria. GSH is made available in cells in 3 ways:

• De novo synthesis via a 2-step process catalyzed by the enzymes glutamate cysteine ligase (GCL) and glutathione synthetase (requires ATP).
• Regeneration of oxidized GSSG to reduced GSH by glutathione reductase (requires NADPH).
• Recycling of cysteine from conjugated glutathione via GGTP (requires NADPH).

Notice that all 3 require energy. The rate of synthesis, regeneration, and recycling is determined primarily by 3 factors 8 :

• De novo glutathione synthesis is primarily controlled by the cellular level of the amino acid cysteine, the availability of which is the rate-limiting step.
• GCL activity is in part regulated by GSH feedback inhibition.
• If GSH is depleted due to oxidative stress, inflammation, or exposure to xenobiotics, de novo synthesis of GSH is upregulated primarily by increasing availability of cysteine through recycling of GSSG.

These 3 methods for producing glutathione can be seen in Figure 3 .

Synthesis and Recycling of Glutathione 9

Critical Role of Glutathione in Detoxification, Inflammation, and So Much More

It is hard to overstate the importance of glutathione, key roles of which are summarized in Table 1 . It plays a crucial role in shielding cellular macromolecules from endogenous and exogenous reactive oxygen and nitrogen species. While it directly quenches some free radicals, of perhaps greater importance is that it deals directly with the causes of oxidative stress such as mercury and POPs.

The Critical Roles of Glutathione

Glutathione is involved in the detoxification of both xenobiotic and endogenous compounds. It facilitates excretion from cells (Hg), facilitates excretion from body (POPs, Hg) and directly neutralizes (POPs, many oxidative chemicals). Glutathione facilitates the plasma membrane transport of toxins by at least 4 different mechanisms, the most important of which is formation of glutathione S-conjugates. Low levels of glutathione and/or transferase activity are also associated with chronic exposure to chemical toxins and alcohol, cadmium exposure, AIDS/HIV, macular degeneration, Parkinson’s disease, and other neurodegenerative disorders.

Glutathione directly scavenges diverse oxidants: superoxide anion, hydroxyl radical, nitric oxide, and carbon radicals. Glutathione catalytically detoxifies: hydroperoxides, peroxynitrites, and lipid peroxides. 11 Another way glutathione protects cells from oxidants is through recycling of vitamins C and E as shown in Figure 4 . 10

Glutathione Protection via Recycling 10

Abbreviations: APx = ascorbate peroxidase; CAT = catalase; DHA = dehydroascorbate; DHAR = dehydroascorbate reductase; MDHA = monodehydroascorbate; MDHAR = monodehydroascorbate reductase; GR = glutathione reductase; GSH = reduced glutathione; GSSG = glutathione disulphide; SOD = superoxide dismutase.

Another indication of the key roles of glutathione in health is that the accumulation of GSSG due to oxidative stress is directly toxic to cells, inducing apoptosis by activation of the SAPK/MAPK pathway. 12 Glutathione depletion triggers apoptosis, although it is unclear whether it is mitochondrial or cytosol pools of GSH that are the determining factor. 13

Perhaps the best indicator of the importance of glutathione is that its cellular and mitochondrial levels directly are highly associated with health and longevity.

Clinical Applications

As shown in Table 2 , depletion of GSH has been implicated in many chronic degenerative diseases.

Diseases Associated with GSH Depletion 14

GSH depletion has been strongly associated with the diseases and loss of function with aging. A representative study of community-dwelling elderly found that higher glutathione levels were associated with higher levels of physical health, fewer illnesses, and higher levels of self-rated health. 15 As might be expected, then, GSH status has been found to parallel telomerase activity, an important indicator of lifespan. 16 This depletion of GSH also shows up as progressive loss of mitochondrial function due to accumulation of damage to mtDNA. 17 The ability of animal species to protect their mtDNA is directly proportional to longevity. 18

GGT as Measure of Glutathione Need

GGT (gamma-glutamyl transferase) is upregulated in proportion to the need for glutathione such as for the detoxification of POPs. 19 It provides the rate-limiting cysteine through a catabolic “salvage pathway.” Increases in GGT correlate with many diseases: metabolic syndrome, both fatal and nonfatal coronary heart disease (CHD) events, atherosclerosis, fatty liver, diabetes, cancer, hypertension, and carotid intima-media thickness. 20 – 22 Of particular note, these are elevations of GGT within the supposedly “normal” range. For example, men with a GGT of 40 to 50 have a 20-fold increased risk of diabetes. 23 Research also shows a GGT 30 to 40—well within the normal range—is associated with a doubling of the risk of all-cause mortality. 24 (For a more comprehensive discussion of the remarkable correlations between GGT and disease risks, please see my editorial in IMCJ 8.3). 2

Ways to Increase Intracellular Glutathione

Considering how important glutathione is to health, many researchers have looked for ways to increase intracellular and intramitochondrial levels. The good news is that there are several effective strategies. The first, of course, is to decrease the need for glutathione, which means decreasing toxic load. The most obvious is limiting alcohol consumption (see my editorial in IMCJ 11.6). 6 , 25 Less obvious is decreasing exposure to POPs, the primary source of which are conventionally grown foods. (See my editorial in IMCJ 12.2.) 7 Another strategy is to provide other antioxidants to decrease oxidative stress. A good example is α-lipoic acid, supplementation of which increases mitochondrial glutathione levels even though ALA is not used in the synthesis or recycling of glutathione. 26

The obvious strategy is to directly administer glutathione. This can be done orally, topically, intravenously, intranasally, or in nebulized form. Glutathione administered intravenously, inhaled, and ingested intranasally increases systemic levels. 27 IV glutathione has a short half-life but has shown at least short-term efficacy in several diseases. Oral administration is controversial; while most research shows that oral glutathione does not increase RBC glutathione, there are a few studies that show efficacy. 28 My opinion is that unmodified oral glutathione is unlikely to consistently elevate cellular levels. Oral and transdermal liposomal glutathione show promise, but research is early. 29

Finally, we can provide specific nutrients to promote glutathione production. As noted above, cysteine availability is the rate-limiting step in the de novo production of glutathione. While oral cysteine does not make it through the digestive track, supplemental cysteine in the form of whey or N -acetylcysteine (NAC) is effective at raising levels. While there is substantial variation, 1000 mg/d of NAC will substantially increase glutathione in virtually all patients. 30 For the rare patient who reacts to NAC, SAMe can be used. 31 Do not use methionine as it will increase homocysteine. Interestingly, supplementing with NAC (600 mg/d for 4 wk) decreases GGT 25%, suggesting that increasing de novo synthesis decreases the need for GGT recycling. 32

For those looking for a nonsupplemental solution, 500 mL of alcohol-free beer per day raises RBC glutathione 29%! 33 There are many other examples of foods that increase glutathione. For example, 83 g/d of almonds increases glutathione in smokers by 16% and decreases their DNA damage by 29%. 34

Finally, there is meditation—practitioners have 20% higher levels of glutathione. 35

Clinical Application

Direct administration and promotion of production of glutathione have been used effectively in a wide range of diseases: Parkinson’s, peripheral obstructive arterial disease, cystic fibrosis, emphysema, COPD, preterm infants autism, contrast-induced nephropathy, chronic otitis media, lead exposure, nail biting(!), nonalcoholic fatty liver disease, exercise-induced fatigue—the list is long and surprisingly diverse. 36 – 46

Clearly, adequate availability of glutathione is critical for maintaining health, protecting the body from toxins, and promoting longevity. Fortunately, there is much we can do to optimize glutathione levels: primarily decrease toxin exposure (including alcohol) and promote production with regular consumption of whey or NAC. I think we are just scratching the surface of the clinical benefits that can be achieved through enhancing intracellular and intramitochondrial glutathione. (I hope you, my dear reader, enjoy these editorials as much as do in writing them.)

In This Issue

I have been intrigued for quite some time by the surprising efficacy and diversity of mushrooms in the promotion of health and treatment of disease. Why would mushrooms produce substances helpful for humans? What was our adaptation as we evolved as a species that facilitated this benefit? The questions are many. Alena G. Guggenheim, nd ; Kirsten M. Wright, bs ; and Heather L. Zwickey, p h d , provide us an excellent review article on how immune modulation by mushrooms can be beneficial in integrated cancer care. I invited Paul Stamets, ds c, and Heather Zwickey, p h d , to write a commentary on mushrooms to help us better understand these very interesting agents.

Our original research this issue is a randomized, controlled trial of the use of pranayam for treatment of chronic obstructive pulmonary disease. Anupama Gupta, md ; Rajesh Gupta, md ; Sushma Sood, md ; and Mohammad Arkham, bnys , show us that even chronic conditions respond to nonpharmacological interventions.

My first introductions to the importance of nutrition to health and the destructiveness of the Western diet was reading the works of Weston A. Prince, dds , and Francis M. Pottenger, Jr, md . If you have not had the chance to see the Pottenger cats movie—please do so. 47 It is available through the Price-Pottenger Nutrition Foundation. The results are stunning. After my daughter Raven earned her MS/RD in nutrition she was considering a PhD in anthropology. I suggested she make her PhD thesis repeating Price’s work 100 years later. She decided to go into clinical nutrition practice instead, so I hope someone else will follow up this insightful work. IMCJ is delighted to be providing an interview highlighting the important Foundation.

As nutritional medicine becomes more established with research, clinical training, and public acceptance, the reactionary forces have become ever more strident. Books, magazine and newspaper articles, and television and radio interviews—we seem to see some critique of nutritional medicine every week. We all need to be proactive to help ensure the public is not misinformed. An excellent example is Thomas G. Guilliams, p h d , who addresses the many deficiencies in “The Case is Closed: Editorial Bias Prevents Reasonable Evaluation of Dietary Supplements.” I fully support one of his key points that evaluating supplements with drug study protocols as single agents is not scientifically valid for most nutrients. Virtually all nutrients are a part of complex systems. Research designs for agents that poison single enzymes make little sense when studying nutrients.

We continue with our new feature interviewing a keynote speaker from an upcoming conference of one of our affiliate professional associations. This issue features my long time friend, Patrick Hanaway, md , who will be emcee at the Institute for Functional Medicine (IFM) conference on food and nutrition May 29–31, 2014, in San Francisco. These annual IFM educational programs are in my top 5 conferences each year. Congratulations to Patrick on his new position as director of medical education for the Institute for Functional Medicine.

Apparently living in a distant land has not impaired John Weeks’s connection to everything integrative medicine. One of the few (very few) positive provisions of the Affordable Care Act (aka, Obamacare) is that it included health care provider nondiscrimination. It is frustrating to see the efforts to repeal this provision. Perhaps one of the worst aspects of the Affordable Care Act is that the individual mandate has not only eliminated health care plans for millions of Americans, but it has also eliminated the high-deductible plans that are so favored by our patients who choose to prioritize integrative medicine for their primary care. Yet another “unintended consequence” of government overreach. On the other hand, good to see Tracy Gaudet, md , providing such innovative leadership for the VA. Our troops truly need fully integrated medicine. Very interesting to see the American Herbal Products Association calling for a voluntary national standard for the disclosure of GMOs. I shudder to think that our medicinal herbs might be becoming so modified without our even knowing about it.

BackTalk by Bill Benda, md —ouch, this one hurt.

Joseph Pizzorno, nd , Editor in Chief

moc.mhnoisivonni@onrozziprd

http://twitter.com/drpizzorno

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Researchers detect a new molecule in space

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New research from the group of MIT Professor Brett McGuire has revealed the presence of a previously unknown molecule in space. The team's open-access paper, “ Rotational Spectrum and First Interstellar Detection of 2-Methoxyethanol Using ALMA Observations of NGC 6334I ,” appears in April 12 issue of The Astrophysical Journal Letters .

Zachary T.P. Fried , a graduate student in the McGuire group and the lead author of the publication, worked to assemble a puzzle comprised of pieces collected from across the globe, extending beyond MIT to France, Florida, Virginia, and Copenhagen, to achieve this exciting discovery. 

“Our group tries to understand what molecules are present in regions of space where stars and solar systems will eventually take shape,” explains Fried. “This allows us to piece together how chemistry evolves alongside the process of star and planet formation. We do this by looking at the rotational spectra of molecules, the unique patterns of light they give off as they tumble end-over-end in space. These patterns are fingerprints (barcodes) for molecules. To detect new molecules in space, we first must have an idea of what molecule we want to look for, then we can record its spectrum in the lab here on Earth, and then finally we look for that spectrum in space using telescopes.”

Searching for molecules in space

The McGuire Group has recently begun to utilize machine learning to suggest good target molecules to search for. In 2023, one of these machine learning models suggested the researchers target a molecule known as 2-methoxyethanol. 

“There are a number of 'methoxy' molecules in space, like dimethyl ether, methoxymethanol, ethyl methyl ether, and methyl formate, but 2-methoxyethanol would be the largest and most complex ever seen,” says Fried. To detect this molecule using radiotelescope observations, the group first needed to measure and analyze its rotational spectrum on Earth. The researchers combined experiments from the University of Lille (Lille, France), the New College of Florida (Sarasota, Florida), and the McGuire lab at MIT to measure this spectrum over a broadband region of frequencies ranging from the microwave to sub-millimeter wave regimes (approximately 8 to 500 gigahertz). 

The data gleaned from these measurements permitted a search for the molecule using Atacama Large Millimeter/submillimeter Array (ALMA) observations toward two separate star-forming regions: NGC 6334I and IRAS 16293-2422B. Members of the McGuire group analyzed these telescope observations alongside researchers at the National Radio Astronomy Observatory (Charlottesville, Virginia) and the University of Copenhagen, Denmark. 

“Ultimately, we observed 25 rotational lines of 2-methoxyethanol that lined up with the molecular signal observed toward NGC 6334I (the barcode matched!), thus resulting in a secure detection of 2-methoxyethanol in this source,” says Fried. “This allowed us to then derive physical parameters of the molecule toward NGC 6334I, such as its abundance and excitation temperature. It also enabled an investigation of the possible chemical formation pathways from known interstellar precursors.”

Looking forward

Molecular discoveries like this one help the researchers to better understand the development of molecular complexity in space during the star formation process. 2-methoxyethanol, which contains 13 atoms, is quite large for interstellar standards — as of 2021, only six species larger than 13 atoms were detected outside the solar system , many by McGuire’s group, and all of them existing as ringed structures.  

“Continued observations of large molecules and subsequent derivations of their abundances allows us to advance our knowledge of how efficiently large molecules can form and by which specific reactions they may be produced,” says Fried. “Additionally, since we detected this molecule in NGC 6334I but not in IRAS 16293-2422B, we were presented with a unique opportunity to look into how the differing physical conditions of these two sources may be affecting the chemistry that can occur.”

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In Tight Presidential Race, Voters Are Broadly Critical of Both Biden and Trump

3. feelings about the 2024 race for president, table of contents.

• The state of the 2024 presidential race
• Other findings: Biden’s job approval ticks up, Trump’s election-related criminal charges
• Educational differences in candidate support
• What are 2020 voters’ preferences today?
• How Biden’s supporters view his personal traits
• How Trump’s supporters view his personal traits
• Views of Biden’s presidency and retrospective evaluations of Trump’s time in office
• Attention to the candidates
• Does it matter who wins?
• What if voters could change the presidential ballot?
• How important is it for the losing candidate to publicly acknowledge the winner?
• 4. Joe Biden’s approval ratings
• Acknowledgments
• The American Trends Panel survey methodology
• Validated voters

• About half of voters (49%) say they have given a lot of thought to the candidates who are running in the 2024 presidential election – nearly identical to the share saying this at a similar point four years ago (51%).
• But the share who say “it really matters who wins” in November is 5 percentage points lower than it was in April 2020.
• And most voters say that if it were up to them, they would replace at least one of the two likely nominees (Joe Biden and Donald Trump). About half say they’d replace both Biden and Trump on the ballot.

Today, Trump and Biden supporters are about equally likely to say they’ve given a lot of thought to the presidential candidates. About half of Trump’s and Biden’s supporters say they have given a lot of thought to their options.

In April 2020, about half of voters said they had given “a lot” of thought to the candidates. But Biden’s supporters – fresh off the heels of a competitive primary – were more likely than Trump’s supporters to say they had thought a lot about the candidates (58% vs. 48%).

Today, 69% of voters say “it really matters who wins” the presidential election. Just 8% say it doesn’t really matter who wins, and roughly a third fall somewhere in between. However, the share of voters who say it really matters is 5 points lower than it was in April 2020, when 74% of voters said it really mattered. Both Trump and Biden supporters are lower on this measure today than four years ago.

Though both Biden and Trump have received enough delegates in the 2024 presidential primaries to secure their respective party’s nominations for president , most voters say they would like to replace at least one of them on the ballot.

• 49% of voters say that, if they had the ability to decide the major party candidates for the 2024 presidential election, they would replace both Trump and Biden with different candidates.
• 16% say they would keep Biden but replace Trump with a different Republican.
• A similar share (18%) say they would keep Trump but replace Biden with a different Democrat.
• Another 15% of voters say they would keep the contest as is.

Demographic and political differences

There are demographic differences in desired changes to the ballot. To some extent, these are associated with voting preferences.

Biden supporters are much more likely than Trump supporters to say they’d replace both candidates if they could (62% of Biden’s supporters say this, compared with 35% of Trump’s). In contrast, Trump’s voters are much more likely than Biden’s to say they’d keep both(27% of Trump supporters vs. 4% of Biden supporters). Roughly similar shares (about a third each) of each candidate’s supporters say they would keep only their candidate and replace the other.

Younger voters are more likely than older voters to desire ballot changes. Roughly two-thirds of voters under 30 say they would replace both Biden and Trump on the 2024 ballot. This compares with a narrower majority of those ages 30 to 49 (54%) and smaller shares of those 50 to 64 (46%) and those 65 and older (40%).

The gap between younger and older voters is far wider among Biden’s backers:

• Nearly three-quarters of Biden supporters under 50 (73%) say they would replace both candidates. Among Biden supporters ages 50 and older, about half say they would replace both Biden and Trump (53%). In both age groups, most of those who do not want to replace both candidates say they would keep only Biden.
• Among Trump supporters, 38% of those under 50 would replace both, compared with 33% of those 50 and older. Older Trump supporters are roughly twice as likely as younger Trump supporters to say they’d keep both candidates on the ballot (32% vs. 18%). Older Trump backers are more likely than younger ones to say they’d keep Trump but replace Biden (41% vs. 33%).

Among each candidate’s supporters, those with a four-year college degree are more likely than those with less education to say they would replace both candidates if they could.

Most voters continue to say it is at least somewhat important for the losing candidate to publicly acknowledge the winner as the legitimate president of the country.

Over the past eight years, a majority of voters – regardless of who they supported for president – have said it was at least somewhat important that the losing candidate in a presidential race acknowledge the winner.

But the degree to which Trump’s supporters have said this is important has shifted over the past eight years.  As the 2016 presidential election neared, Trump’s supporters became less likely to say it was important for the losing candidate to concede than they were earlier in the fall: The share who said it was very important for the loser to acknowledge the winner as the legitimate president declined by 20 percentage points between October 2016 and the eve of the November 2016 election.

In the spring of 2020, as Trump ran for reelection, 66% said this was very important.

Today, 44% of Trump’s supporters say it is very important for the losing candidate to concede. This compares with 77% of Biden’s supporters.

While there have been shifts among Clinton and Biden supporters during the same period, these changes have been much more modest. Majorities have said it is very important for the losing candidate to acknowledge the winner.

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