Taurine week #7: Brain

Finishing a week’s worth of 2022 taurine research with two reviews of taurine’s brain effects:

“We provide a overview of brain taurine homeostasis, and review mechanisms by which taurine can afford neuroprotection in individuals with obesity and diabetes. Alterations to taurine homeostasis can impact a number of biological processes such as osmolarity control, calcium homeostasis, and inhibitory neurotransmission, and have been reported in both metabolic and neurodegenerative disorders.

Models of neurodegenerative disorders show reduced brain taurine concentrations. On the other hand, models of insulin-dependent diabetes, insulin resistance, and diet-induced obesity display taurine accumulation in the hippocampus. Given cytoprotective actions of taurine, such accumulation of taurine might constitute a compensatory mechanism that attempts to prevent neurodegeneration.

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Taurine release is mainly mediated by volume-regulated anion channels (VRAC) that are activated by hypo-osmotic conditions and electrical activity. They can be stimulated via glutamate metabotropic (mGluR) and ionotropic receptors (mainly NMDA and AMPA), adenosine A1 receptors (A1R), and metabotropic ATP receptors (P2Y).

Taurine mediates its neuromodulatory effects by binding to GABAA, GABAB, and glycine receptors. While taurine binding to GABAA and GABAB is weaker than to GABA, taurine is a rather potent ligand of the glycine receptor. Reuptake of taurine occurs via taurine transporter TauT.

Cytoprotective actions of taurine contribute to brain health improvements in subjects with obesity and diabetes through various mechanisms that improve neuronal function, such as:

  • Modulating inhibitory neurotransmission, which promotes an excitatory–inhibitory balance;
  • Stimulating antioxidant systems; and
  • Stabilizing mitochondria energy production and Ca2+ homeostasis.”

https://www.mdpi.com/2072-6643/14/6/1292/htm “Taurine Supplementation as a Neuroprotective Strategy upon Brain Dysfunction in Metabolic Syndrome and Diabetes”


A second review focused on taurine’s secondary bile acids produced by gut microbiota:

“Most neurodegenerative disorders are diseases of protein homeostasis, with misfolded aggregates accumulating. The neurodegenerative process is mediated by numerous metabolic pathways, most of which lead to apoptosis. Hydrophilic bile acids, particularly tauroursodeoxycholic acid (TUDCA), have shown important anti-apoptotic and neuroprotective activities, with numerous experimental and clinical evidence suggesting their possible therapeutic use as disease-modifiers in neurodegenerative diseases.

Biliary acids may influence each of the following three mechanisms through which interactions within the brain-gut-microbiota axis take place: neurological, immunological, and neuroendocrine. These microbial metabolites can act as direct neurotransmitters or neuromodulators, serving as key modulators of the brain-gut interactions.

The gut microbial community, through their capacity to produce bile acid metabolites distinct from the liver, can be thought of as an endocrine organ with potential to alter host physiology, perhaps to their own favour. Hydrophilic bile acids, currently regarded as important hormones, exert modulatory effects on gut microbiota composition to produce secondary bile acids which seem to bind a number of receptors with a higher affinity than primary biliary acids, expressed on many different cells.

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TUDCA regulates expression of genes involved in cell cycle regulation and apoptotic pathways, promoting neuronal survival. TUDCA:

  • Improves protein folding capacity through its chaperoning activity, in turn reducing protein aggregation and deposition;
  • Reduces reactive oxygen species production, leading to protection against mitochondrial dysfunction;
  • Ameliorates endoplasmic reticulum stress; and
  • Inhibits expression of pro-inflammatory cytokines, exerting an anti-neuroinflammatory effect.

Although Alzheimer’s disease, Huntington’s disease, Parkinson’s disease, amyotrophic lateral sclerosis (ALS), and cerebral ischemia have different disease progressions, they share similar pathways which can be targeted by TUDCA. This makes this bile acid a potentially strong therapeutic option to be tested in human diseases. Clinical evidence collected so far has reported comprehensive data on ALS only.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9166453/ “Tauroursodeoxycholic acid: a potential therapeutic tool in neurodegenerative diseases”

Taurine week #6: Stress

Two 2022 rodent studies of taurine’s associations with long-term stress, starting with a chronic restraint stress model:

“We show that chronic restraint stress can lead to hyperalgesia accompanied by changes in gut microbiota that have significant gender differences. Corresponding changes of bacteria can further induce hyperalgesia and affect different serum metabolism in mice of the corresponding sex.

Different serum metabolites between pseudo-germ-free mice receiving fecal microbiota transplantation from the chronic restraint stress group and those from the control group were mainly involved in bile secretion and steroid hormone biosynthesis for male mice, and in taurine and hypotaurine metabolism and tryptophan metabolism for female mice.

Effects of gut microbiota transplantation on serum metabolomics of female host: Taurine and hypotaurine metabolism, tryptophan metabolism, serotonergic synapse, arachidonic acid metabolism, and choline metabolism in cancer were the five identified pathways in which these different metabolites were enriched.

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Taurine and hypotaurine play essential roles in anti-inflammation, anti-hypertension, anti-hyperglycemia, and analgesia. Taurine can be used as a diagnostic index for fibromyalgia syndrome and neuropathic pain.

These findings improve our understanding of sexual dimorphism in gut microbiota in stress-induced hyperalgesia and the effect of gut microbiota on blood metabolic traits. Follow-up research will investigate causal relationships between them.”

https://www.sciencedirect.com/science/article/pii/S1043661822000743 “Gut microbiota and its role in stress-induced hyperalgesia: Gender-specific responses linked to different changes in serum metabolites”

Human equivalents:

  • A 7-8 month-old mouse would be a 38-42 year-old human.
  • A 14-day stress period is about two years for humans.

A second study used a chronic social defeat stress model:

“The level of taurine in extracellular fluid of the cerebral medial prefrontal cortex (mPFC) was significantly reduced in mice with chronic social defeat stress (CSDS)-induced depression. We found that taurine supplementation effectively rescued immobility time during a tail suspension assay and improved social avoidance behaviors in CSDS mice.

Male C57BL/6 J mice (∼ 23 g) and male CD-1 mice aged 7–8 months (∼ 45 g) were used. CD-1 mice were screened for aggressive behavior during social interactions for three consecutive days before the start of the social defeat sessions. Experimental C57BL/6 J mice were subjected to physical interactions with a novel CD-1 mouse for 10 min once per day over 10 consecutive days.

We found significant reductions in taurine and betaine levels in mPFC interstitial fluid of CSDS mice compared with control mice.

csds taurine betaine

We additionally investigated levels of interstitial taurine in chronic restraint stress (CRS) mice, another depressive animal model. After 14 days of CRS treatment, mice showed typical depression-like behaviors, including decreased sucrose preference and increased immobility time. mPFC levels of interstitial taurine were also significantly decreased in CRS mice.

Taurine treatment protected CSDS mice from impairments in dendritic complexity, spine density, and proportions of different types of spines. Expression of N-methyl D-aspartate receptor subunit 2A, an important synaptic receptor, was largely restored in the mPFC of these mice after taurine supplementation.

These results demonstrated that taurine exerted an antidepressive effect by protecting cortical neurons from dendritic spine loss and synaptic protein deficits.”

https://link.springer.com/article/10.1007/s10571-022-01218-3 “Taurine Alleviates Chronic Social Defeat Stress-Induced Depression by Protecting Cortical Neurons from Dendritic Spine Loss”

Human equivalents:

  • A 7-8 month-old mouse would be a 38-42 year-old human.
  • A 500 mg/kg taurine dose injected intraperitoneally is (.081 x 500 mg) x 70KG = 2.835 g.
  • A 10-day stress period is about a year and a half for humans.

Don’t think aggressive humans would have to be twice as large to stress those around them. There may be choices other than enduring a year and a half of that.

Taurine week #2: Bile acids

Two papers investigated taurine’s integration into bile acids, starting with a review:

“Bile acids (BAs) are produced from cholesterol in the liver and are termed primary BAs. Primary BAs are conjugated with glycine and taurine in the liver, and stored in the gallbladder. BAs are released from the gallbladder into the small intestine via food intake to facilitate digestion and absorption of lipids and lipophilic vitamins by forming micelles in the small intestine.

After deconjugation by the gut microbiome, primary BAs are converted into secondary BAs. Most BAs in the intestine are reabsorbed and transported to the liver, where both primary and secondary BAs are conjugated with glycine or taurine and rereleased into the intestine.

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Some BAs reabsorbed from the intestine spill into systemic circulation, where they bind to a variety of nuclear and cell-surface receptors in tissues. Some BAs are not reabsorbed and bind to receptors in the terminal ileum.

BAs can affect cell-surface and intracellular membranes, including those of mitochondria and the endoplasmic reticulum. BAs are also hormones or signaling molecules, and can regulate BA, glucose, and lipid metabolism in various tissues, including the liver, pancreas, and both brown and white adipose tissue. BAs also affect the immune system.

BAs can affect the nervous system. More than 20 BAs have been detected in the brain of humans and rodents. The brain communicates with the gut and gut microbiome through BAs.”

https://www.mdpi.com/2076-2607/10/1/68/htm “Physiological Role of Bile Acids Modified by the Gut Microbiome”


Reference 56 was a human study:

“Centenarians (individuals aged 100 years and older) have a decreased susceptibility to ageing-associated illnesses, chronic inflammation, and infectious diseases. Centenarians have a distinct gut microbiome enriched in microorganisms that are capable of generating unique secondary bile acids.

We identified centenarian-specific gut microbiota signatures and defined bacterial species as well as genes and/or pathways that promote generation of isoLCA, 3-oxoLCA, 3-oxoalloLCA, and isoalloLCA. To our knowledge, isoalloLCA is one of the most potent antimicrobial agents that is selective against Gram-positive microorganisms, including multidrug-resistant pathogens, suggesting that it may contribute to maintenance of intestinal homeostasis by enhancing colonization-resistance mechanisms.”

https://www.nature.com/articles/s41586-021-03832-5 “Novel bile acid biosynthetic pathways are enriched in the microbiome of centenarians” (not freely available)


A few more papers will be coming on taurine and bile acids. I haven’t seen one investigate both taurine and glycine treatments to aid bile acid in achieving therapeutic results.

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The misnomer of nonessential amino acids

Three papers, starting with a 2022 review:

“Ideal diets must provide all physiologically and nutritionally essential amino acids (AAs).

Proposed optimal ratios and amounts of true digestible AAs in diets during different phases of growth and production. Because dynamic requirements of animals for dietary AAs are influenced by a plethora of factors, data below as well as the literature serve only as references to guide feeding practices and nutritional research.

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Nutritionists should move beyond the ‘ideal protein’ concept to consider optimum ratios and amounts of all proteinogenic AAs in diets for mammals, birds, and aquatic animals, and, in the case of carnivores, also taurine. This will help formulate effectively low-protein diets for livestock (including swine and high-producing dairy cattle), poultry, fish, and crustaceans, as well as zoo and companion animals.”

https://journals.sagepub.com/doi/10.1177/15353702221082658 “The ‘ideal protein’ concept is not ideal in animal nutrition”


A second 2022 review focused on serine:

“The main dietary source of L-serine is protein, in which L-serine content ranges between 2 and 5%. At the daily intake of ~1 g protein per kg of body weight, the amount of serine obtained from food ranges between 1.4 and 3.5 g (13.2–33.0 mmol) per day in an adult.

Mechanisms of potential benefits of supplementing L-serine include increased synthesis of sphingolipids, decreased synthesis of 1-deoxysphingolipids, decrease in homocysteine levels, and increased synthesis of cysteine and its metabolites, including glutathione. L-serine supplementation has been suggested as a rational therapeutic approach in several disorders, particularly primary disorders of L-serine synthesis, neurodegenerative disorders, and diabetic neuropathy.

Unfortunately, the number of clinical studies evaluating dietary supplementation of L-serine as a possible therapy is small. Studies examining therapeutic effects of L-serine in CNS injury and chronic renal diseases, in which it is supposed that L-serine weakens glutamate neurotoxicity and lowers homocysteine levels, respectively, are missing.”

https://www.mdpi.com/2072-6643/14/9/1987/htm “Serine Metabolism in Health and Disease and as a Conditionally Essential Amino Acid”


A 2021 review subject was D-serine, L-serine’s D-isoform:

“The N-methyl-D-aspartate glutamate receptor (NMDAR) and its co-agonist D-serine are currently of great interest as potential important contributors to cognitive function in normal aging and dementia. D-serine is necessary for activation of NMDAR and in maintenance of long-term potentiation, and is involved in brain development, neuronal connectivity, synaptic plasticity, and regulation of learning and memory.

The source of D-amino acids in mammals was historically attributed to diet or intestinal bacteria until racemization of L-serine by serine racemase was identified as the endogenous source of D-serine. The enzyme responsible for catabolism (breakdown) of D-serine is D-amino acid oxidase; this enzyme is most abundant in cerebellum and brainstem, areas with low levels of D-serine.

Activation of the NMDAR co-agonist-binding site by D-serine and glycine is mandatory for induction of synaptic plasticity. D-serine acts primarily at synaptic NMDARs whereas glycine acts primarily at extrasynaptic NMDARs.

In normal aging there is decreased expression of serine racemase and decreased levels of D-serine and down-regulation of NMDARs, resulting in impaired synaptic plasticity and deficits in learning and memory. In contrast, in AD there appears to be activation of serine racemase, increased levels of D-serine and overstimulation of NMDARs, resulting in cytotoxicity, synaptic deficits, and dementia.”

https://www.frontiersin.org/articles/10.3389/fpsyt.2021.754032/full “An Overview of the Involvement of D-Serine in Cognitive Impairment in Normal Aging and Dementia”


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Coffee improves information’s signal-to-noise ratio

This 2022 rodent study investigated caffeine’s effects:

“A majority of molecular and neurophysiological studies explored the impact of acute rather than repeated exposure to caffeine. We show that, in bulk tissue analysis, chronic caffeine treatment reduced metabolic processes related to lipids, mitochondria, and translation in mouse hippocampus. In sharp contrast to what was observed in bulk tissue, we found that caffeine induced a neuronal autonomous epigenomic response related to synaptic plasticity activation.

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Regular caffeine intake exerts a long-term effect on neuronal activity/plasticity in the adult brain, lowering metabolic-related processes, and simultaneously finely tuning activity-dependent regulations. In non-neuronal cells, caffeine decreases activities under basal conditions, and improves signal-to-noise ratio during information encoding in brain circuits, contributing to bolster salience of information.

Overall, our data prompt the novel concept that regular caffeine intake promotes a more efficient ability of the brain to encode experience-related events. By coordinating epigenomic changes in neuronal and non-neuronal cells, regular caffeine intake promotes a fine-tuning of metabolism in resting conditions.”

https://www.jci.org/articles/view/149371 “Caffeine intake exerts dual genome-wide effects on hippocampal metabolism and learning-dependent transcription”


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Gut microbiota knowledge through 2021

I’ll curate this 2022 review of what’s known and unknown about our trillions of gut microbiota through its topic headings:

“Most microbial taxa and species of the human microbiome are still unknown. Without revealing the identity of these microbes as a first step, we cannot appreciate their role in human health and diseases.

A. Understanding the Microbiome Composition and Factors That Shape Its Diversity
Effect of Diet Composition on the Microbiome Diversity

  • Macronutrients and Microbiome Diversity
  • Nutrient and Mineral Supplements and Microbiome Diversity

Stress

Drugs

Race and Host Genetics

Aging

Lifestyle

  • Exercise
  • Smoking
  • Urbanization

B. Understanding the Microbiome Function and Its Association With Onset and Progression of Many Diseases

Microbiome Association With Inflammatory and Metabolic Disorders

  • Chronic Inflammation in GIT and Beyond
  • Development of Malignant Tumors
  • Obesity
  • Coronary Artery Disease
  • Respiratory Diseases

Microbiome Role in Psychiatric, Behavioral, and Emotional Disorders

C. Understanding the Microbiome Function as Mediated by Secreted Molecules

D. Conclusion and Future Directions – A pioneering study aimed to computationally predict functions of microbes on earth estimates the presence of 35.5 million functions in bacteria of which only 0.02% are known. Our knowledge of its functions and how they mediate health and diseases is preliminary.”

https://www.frontiersin.org/articles/10.3389/fmicb.2022.825338 “Recent Advances in Understanding the Structure and Function of the Human Microbiome”


I took another test last month at the 14-month point of treating my gut microbiota better. Compared with the 7-month top level measurements, what stood out was an increase in relative abundance from 1% to 7% in the Verrucomicrophia phylum that pretty much exclusively comprises species Akkermansia muciniphilia in humans:

top 5 phylum 2-2022

This review termed Akkermansia muciniphilia relative increases as beneficial. Go with the Alzheimer’s Disease evidence didn’t.

Preventing human infections with dietary fibers inferred that insufficient dietary fiber may disproportionately increase abundance of this species. But I already eat much more fiber than our human ancestors’ estimated 100 grams of fiber every day, so lack of fiber definitely didn’t cause this relative increase.

Resistant starch therapy observed:

“Relative abundances of smaller keystone communities (e.g. primary degraders) may increase, but appear to decrease simply because cross-feeders increase in relative abundance to a greater extent.”

I’ll wait for further evidence while taking responsibility for my own one precious life.

Didn’t agree with this review’s statements regarding microbial associations with fear. These reviewers framed such associations as if gut microbiota in the present had stronger influences on an individual’s fear responses than did any of the individual’s earlier experiences. No way.

I came across this review by it citing The microbiome: An emerging key player in aging and longevity, which was Reference 25 of Dr. Paul Clayton’s blog post What are You Thinking?

Also didn’t agree with some of the doctor’s post:

  • Heterochronic parabiosis of young and old animals is wildly different from fecal transfer. Can’t really compare them to any level of detail.
  • Using a rodent young-to-old fecal microbiota transplant study to imply the same effects would happen in humans? Humans don’t live in controlled environments, so why would a young human individual’s gut microbiota necessarily have healthier effects than an old individual’s?
  • Another example was the penultimate paragraph: “By adding a mix of prebiotic fibers to your diet and maintaining a more youthful and less inflammatory microbiome you will have less inflammation, less endotoxaemia and less inflammageing. You will therefore live healthier and longer.” I’m okay with the first sentence. Equivalating the first sentence to both healthspan and lifespan increases in the second sentence wasn’t supported by any of the 45 cited references.

Signaling pathways and disordered proteins

This 2022 review explored the title subject:

“Cell signaling imposes many demands on proteins that comprise these pathways, including abilities to form active and inactive states, and to engage in multiple protein interactions. Signaling often requires amplifying signals, regulating or tuning responses to signals, combining information sourced from multiple pathways, all while ensuring process fidelity.

Sensitivity, adaptability, and tunability are possible, in part, due to inclusion of intrinsically disordered regions in many proteins involved in cell signaling.  This review highlights the critical role of intrinsically disordered proteins for signaling:

  • In widely diverse organisms (animals, plants, bacteria, fungi);
  • In every category of cell signaling pathway (autocrine, juxtacrine, intracrine, paracrine, and endocrine); and
  • At each stage (ligand, receptor, transducer, effector, terminator) in the cell signaling process.

Function of the glucocorticoid receptor is regulated in part by its intrinsically disordered C-terminal tail. Prior to activation, the glucocorticoid receptor resides in cytosol:

glucocorticoid receptor

Intrinsic disorder in the glucocorticoid receptor not only enables multiple allosteric regulatory interactions to impact function, but also allows deployment of different surfaces of the protein to enable binding to many different sets of macromolecules, and regulation of these interactions via mRNA splicing and phosphorylation.

Combinations of alternative translation initiation and alternative mRNA splicing result in production of multiple glucocorticoid receptor isoforms from one gene. Various isoforms exhibit distinctive tissue distribution patterns and altered transcriptional regulatory profiles.

Greater than 90% of transcription factors either contain intrinsically disordered regions of proteins or are entirely intrinsically disordered. The many advantages conferred by disorder to cell signaling cascades means that:

  1. Understanding signaling required definition of roles disorder plays in each pathway;
  2. Many more examples of disordered proteins in cell signaling pathways are likely to be discovered; and
  3. More mechanisms by which disorder functions remain to be elucidated.”

https://biosignaling.biomedcentral.com/articles/10.1186/s12964-022-00821-7 “Intrinsically disordered proteins play diverse roles in cell signaling”


Cells in vivo seldom act on their own impetus. I would have liked discussion – or at least mention – of bidirectional signals between genes / cells / tissues / organs / organism / environment. This review’s topic of cell signaling pathways excluded “interactions of complex, interconnected systems spanning hierarchical levels” as explored in An environmental signaling paradigm of aging.

Eat broccoli sprouts for depression, Part 2

Here are three papers that cited last year’s Part 1. First is a 2021 rodent study investigating a microRNA’s pro-depressive effects:

“Depressive rat models were established via chronic unpredicted mild stress (CUMS) treatment. Cognitive function of rats was assessed by a series of behavioral tests.

Nrf2 CUMS

Nrf2 was weakly expressed in CUMS-treated rats, whereas Nrf2 upregulation alleviated cognitive dysfunction and brain inflammatory injury.

Nrf2 inhibited miR-17-5p expression via binding to the miR-17-5p promoter. miR-17-5p was also found to limit wolfram syndrome 1 (Wfs1) transcription.

We found that Nrf2 inhibited miR-17-5p expression and promoted Wfs1 transcription, thereby alleviating cognitive dysfunction and inflammatory injury in rats with depression-like behaviors. We didn’t investigate the role of Nrf2 in other depression models (chronic social stress model and chronic restraint stress model) and important brain regions other than hippocampus, such as prefrontal cortex and nucleus accumbens. Accordingly, other depression models and brain regions need to be designed and explored to further validate the role of Nrf2 in depression in future studies.”

https://link.springer.com/article/10.1007/s10753-021-01554-4 “Nrf2 Alleviates Cognitive Dysfunction and Brain Inflammatory Injury via Mediating Wfs1 in Rats with Depression‑Like Behaviors” (not freely available)

This study demonstrated that activating the Nrf2 pathway inhibited brain inflammation, cognitive dysfunction, and depression. Would modulating one microRNA and one gene in vivo without Nrf2 activation achieve similar results?


A 2021 review focused on the immune system’s role in depression:

“Major depressive disorder is one of the most common psychiatric illnesses. The mean age of patients with this disorder is 30.4 years, and the prevalence is twice higher in women than in men.

Activation of inflammatory pathways in the brain is considered to be an important producer of excitotoxicity and oxidative stress inducer that contributes to neuronal damage seen in the disorder. This activation is mainly due to pro-inflammatory cytokines activating the tryptophan-kynurenine (KP) pathway in microglial cells and astrocytes.

Elevated levels of cortisol exert an inhibitory feedback mechanism on its receptors in the hippocampus and hypothalamus, stopping stimulation of these structures to restore balance. When this balance is disrupted, hypercortisolemia directly stimulates extrahepatic enzyme 2,3-indolimine dioxygenase (IDO) located in various tissues (intestine, placenta, liver, and brain) and immune system macrophages and dendritic cells.

Elevation of IDO activities causes metabolism of 99% of available tryptophan in the KP pathway, substantially reducing serotonin synthesis, and producing reactive oxygen species and nitrogen radicals. The excitotoxicity generated produces tissue lesions, and activates the inflammatory response.”

https://academic.oup.com/ijnp/article/25/1/46/6415265 “Inflammatory Process and Immune System in Major Depressive Disorder”

This review highlighted that stress via cortisol and IDO may affect the brain and other parts of the body.


A 2022 review elaborated on Part 1’s findings of MeCP2 as a BDNF inhibitor:

“Methyl-CpG-binding protein 2 (MeCP2) is a transcriptional regulator that is highly abundant in the brain. It binds to methylated genomic DNA to regulate a range of physiological functions implicated in neuronal development and adult synaptic plasticity.

Ability to cope with stressors relies upon activation of the hypothalamic–pituitary–adrenal (HPA) axis. MeCP2 has been shown to contribute to early life stress-dependent epigenetic programming of genes that enhance HPA-axis activity.

We describe known functions of MeCP2 as an epigenetic regulator, and provide evidence for its role in modulating synaptic plasticity via transcriptional regulation of BDNF or other proteins involved in synaptogenesis and synaptic strength like reelin. We conclude that MeCP2 is a promising target for development of novel, more efficacious therapeutics for treatment of stress-related disorders such as depression.”

https://www.mdpi.com/2073-4409/11/4/748/htm “The Role of MeCP2 in Regulating Synaptic Plasticity in the Context of Stress and Depression”


Osprey lunch

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CD38 and balance

I’ll highlight this 2022 review’s relationships between inflammation and cluster of differentiation 38:

“We review the nicotinamide adenine dinucleotide (NAD) catabolizing enzyme CD38, which plays critical roles in pathogenesis of diseases related to infection, inflammation, fibrosis, metabolism, and aging.

NAD is a cofactor of paramount importance for an array of cellular processes related to mitochondrial function and metabolism, redox reactions, signaling, cell division, inflammation, and DNA repair. Dysregulation of NAD is associated with multiple diseases. Since CD38 is the main NADase in mammalian tissues, its contribution to pathological processes has been explored in multiple disease models.

CD38 is upregulated in a cell-dependent manner by several stimuli in the presence of pro-inflammatory or secreted senescence factors or in response to a bacterial infection, retinoic acid, or gonadal steroids. CD38 is stimulated in a cell-specific manner by lipopolysaccharide, tumor necrosis factor alpha, interleukin-6, and interferon-γ.

dysregulated inflammation

CD38 plays a critical role in inflammation, migration, and immunometabolism, but equally important is resolution of the inflammatory response which left unchecked leads to loss of self-tolerance, tissue infiltration of lymphocytes, and circulation of autoantibodies.

  • Depending upon context, CD38 can either promote or protect against an autoimmune response.
  • Chronic mucosal inflammation and tissue damage characteristic of inflammatory bowel disease predisposes IBD patients to development of colorectal cancer, and the risks increase with duration, extent, and severity of inflammation.
  • Pulmonary fibrosis occurs in the presence of unresolved inflammation and dysregulated tissue repair, and results from an array of injurious stimuli including infection, toxicant exposure, adverse effects of drugs, and autoimmune response.
  • Modulating CD38 and NAD levels in kidney disease may provide therapeutic approaches for prevention of inflammatory conditions of the kidney.
  • Inflammation as well as evidence of senescence are present in pathophysiology of chronic liver diseases that progress to cirrhosis.
  • Inflammation-associated metabolic diseases impair vascular function. Chronic inflammation can lead to vascular senescence and dysfunction.

One cause of NAD decline during aging is due to increase of NAD breakdown in the presence of increased CD38 expression and activity on immune cells, thus linking inflammaging with tissue NAD decline. Other sources of NAD decline include increased DNA-damage requiring PARP1 activation, and decreased NAMPT levels leading to diminished NAD synthesis through the salvage pathway.

Inflammation is among the major risk factors that predispose organisms to age-associated diseases. During aging, accumulation of senescent cells creates an environment rich in proinflammatory signals, leading to ‘inflammaging.’ Metabolically active cells lose their replicative capacity by entering an irreversible quiescent state, and are considered both a cause and a consequence of inflammaging.

Recent findings uncover a major role of CD38 in inflammation and senescence, showing that age-related NAD+ decline and the sterile inflammation of aging are partially mediated by a senescence / senescence associated secretory phenotype (SASP)-induced accumulation of CD38+ inflammatory cells in tissues. Given the clear association between the phenomenon of inflammaging, senescence, and CD38, as well as the impact of CD38 on degradation of NAD and the NAD precursor NMN, future studies should focus on CD38 as a druggable target in viral illnesses.”

https://journals.physiology.org/doi/abs/10.1152/ajpcell.00451.2021 “The CD38 glycohydrolase and the NAD sink: implications for pathological conditions” (not freely available). Thanks to Dr. Julianna Zeidler for providing a copy.


We extend good-vs.-bad thinking to nature. Does that paradigm explain much, though?

All pieces of a puzzle are important. Otherwise, evolution would have eliminated what wasn’t necessary for its purposes.

Restoring balance to an earlier phenotype suits my purposes. Don’t want to eliminate inflammatory responses, but instead, calm them down so that they’re evoked appropriately.

Immune system aging

This 2021 review by three coauthors of Take responsibility for your one precious life – Trained innate immunity cast a wide net:

“Non-specific innate and antigen-specific adaptive immunological memories are vital evolutionary adaptations that confer long-lasting protection against a wide range of pathogens. However, these mechanisms of memory generation and maintenance are compromised as organisms age.

This review discusses how immune function regulates and is regulated by epigenetics, metabolic processes, gut microbiota, and the central nervous system throughout life. We aimed to present a comprehensive view of the aging immune system and its consequences, especially in terms of immunological memory.

aging immune system

A comprehensive strategy is essential for human beings striving to lead long lives with healthy guts, functional brains, and free of severe infections.”

https://link.springer.com/article/10.1007/s12016-021-08905-x “Immune Memory in Aging: a Wide Perspective Covering Microbiota, Brain, Metabolism, and Epigenetics”


Attempts to cover a wide range of topics well are usually uneven. For example, older information in the DNA Methylation In Adaptive Immunity section was followed by a more recent Histone Modifications in Adaptive Immunity section.

This group specializes in tuberculosis vaccine trained immunity studies, and much of what they presented also applied to β-glucan trained immunity. A dozen previously curated papers were cited.

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Saving bees by regulating epigenetics

This 2021 study investigated an epigenetic treatment for bees forgetting about their hives:

“Over the last few decades, numbers of both wild and managed bee pollinators have been declining. Although reasons for this decline are under debate, it is highly likely that a combination of multiple stressors is to blame, in particular, deformed wing virus (DWV).

Histone deacetylase inhibitors (HDACi) are a class of compounds which prevent deacetylation of histones and therefore increase gene expression. The present study found that HDACi sodium butyrate (NaB) significantly increased survival and reversed the learning / memory impairment of DWV-infected bees. We demonstrated the mechanism of how epigenetic regulation can resume honeybees’ memory function.

bee survival rates

  • When bees were infected with DWV, 50% of bees died by the end of day 2 and only 10% survived to the end of day 5.
  • When NaB was added to the diet prior to DWV infection, survival rate of DWV-infected bees (N/D group) remained >90% after 5 days.
  • Under laboratory rearing conditions, around 30% of control bees died over a period of 5 days.
  • When NaB was included in uninfected bees’ diet, less than 15% of bees died.

These results indicate that feeding bees with NaB could significantly increase survival with or without DWV infection.”

https://www.cell.com/iscience/fulltext/S2589-0042(21)01024-5 “Real-time monitoring of deformed wing virus-infected bee foraging behavior following histone deacetylase inhibitor treatment”


Interesting that these researchers didn’t attempt to eliminate either the virus cause of bee behavior or parasitical mites that carried the virus. They mainly depended on bees’ endogenous systems providing beneficial responses when stimulated.

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Remembering encounters provides future benefits

Two 2021 papers on trained immunity, with the first a review:

“Effective memory immune responses rely on interaction between innate and adaptive immune cells. While activation of innate immunity provides the first line of defense against infections, it also primes the adaptive immune response.

Adaptive immunity can enhance antimicrobial machinery of innate cells, making them more effective at clearing pathogenic microorganisms. An additional layer of complexity adds to this network of interactions, with innate cells adopting a memory phenotype, which used to apply to only adaptive immunity. Furthermore, non-immune cells can develop some features of this memory-like phenotype.

fimmu-12-745332-g001

Cell subsets in which trained immunity has been described. Different stimuli including Bacillus Calmette Guerin (BCG), β-glucan, cytokines, cytomegalovirus (CMV), and bacterial components can induce a trained immunity phenotype. A common hallmark of trained immunity in these cases is H3K4me3 in promoters of genes encoding for different cytokines.

  • Mechanisms Underlying Establishment of Trained Immunity
  • Trained Immunity in Neutrophils
  • Trained Immunity in Monocytes and Macrophages: General Features
  • Metabolic Pathways Involved in Training of Monocytes and Macrophages
  • Hormonal Control of Trained Immunity Responses in Monocytes and Macrophages
  • Trained Immunity on Alveolar Macrophages and Involvement of Resident Cells
  • Trained Immunity in NK Cells
  • Trained Immunity in Innate Lymphoid Cells
  • Trained Immunity on Hematopoietic Stem Cells
  • Trained Immunity in Bronchial Epithelial Cells
  • Trained Immunity in Skin Stem Cells
  • Trained Immunity in the Gastrointestinal Tract
  • Immunity Training Against Protozoan-Mediated Pathologies
  • Trained Immunity in Non-Infectious Pathologies

Many gaps of knowledge remain in this field. For example, how long changes associated to trained immunity last, and if, in addition to epigenetic modulation, there are other post-translational modifications on proteins relevant for induction of trained immunity.”

https://www.frontiersin.org/articles/10.3389/fimmu.2021.745332/full “Molecular and Cellular Mechanisms Modulating Trained Immunity by Various Cell Types in Response to Pathogen Encounter”


This second paper was a human study cited for its glutathione findings as follows:

  • “Plasma concentration of IL-1β from BCG-vaccinated individuals are positively associated with serum glutathione concentrations.
  • Trained immunity up-regulates expression of genes involved in glutathione metabolism, suggesting an increase in glutathione synthesis and a higher glutathione recycling rate.
  • Single nucleotide polymorphisms in these genes are associated with changes in pro-inflammatory cytokine production after in vitro training by β-glucan and BCG.

Enzymes whose activities are dependent on glutathione could be used as novel targets to modulate trained immunity.”

IL-1β production

“We found a positive association between plasma glutathione concentration and ex vivo IL-1β production 90 days after BCG vaccination upon in vitro exposure to heterologous stimulus Staphylococcus aureus. Up-regulation of IL-1β production by BCG vaccination was also positively associated with circulating concentrations of other metabolites involved in glutathione metabolism, such as methionine, cysteine, glutamate, and glycine.

GSH metabolism was associated with trained immunity traits in 278 healthy individuals. Trained immunity mechanisms that are shaped by GSH metabolism remain to be further explored.”

https://www.mdpi.com/2073-4409/10/5/971/htm “Glutathione Metabolism Contributes to the Induction of Trained Immunity”


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Broccoli sprout compounds and gut microbiota

Two 2021 reviews from one institution, with this first focused on aliphatic glucosinolates’ (GLS) metabolism to isothiocyanates (ITCs) like sulforaphane:

“Human clinical trials examining efficacy of whole food interventions on cancer prevention targets have shown high levels of inter-individual variation in both absorption and excretion of ITCs. We discuss how consumption of cruciferous vegetables may alter the microbiome, and in turn, influence ITC absorption.

Bioavailability of ITCs from GLS has been shown to be greatly impacted by processing before ingestion. When ITCs are given preformed, they possess the greatest level of bioavailability and are readily absorbed by humans.

Studies have indicated that without plant-derived myrosinase, the gut microbiome is essential for conversion of GLS to ITCs. Without conversion to ITCs, GLS are biologically inert.

There are two different intervals in time when GLS metabolism occurs in the large intestine:

  1. Metabolism of GLS directly following consumption when GLS are not absorbed in the small intestine; and
  2. When GLS are absorbed in the small intestine and go through enterohepatic circulation, returning as GLS in the gut where factors influencing microbial metabolism (such as food matrix, pH, and other compounds present) may be different from the first interval.

This list of bacterial genera altered by cruciferous vegetable consumption focuses on studies completed in healthy individuals and animal models:

Metabolic Fate of Dietary Glucosinolates and Their Metabolites:

Clinical trials have shown that consumption of a diet rich in cruciferous vegetables, compared to a cruciferous vegetable devoid diet, significantly alters composition of the gut microbiome. Each individual responded uniquely to cruciferous vegetable consumption, suggesting that basal microbiome composition may impact outcome.

Understanding the gut microbiome’s role in GLS metabolism, specifically GLS conversion to ITCs, is important to understanding drivers of inter-individual variation . Translating chemopreventative properties of cruciferous vegetables from the lab bench to the clinic requires addressing factors that drive high variability in ITC absorption and excretion observed in clinical trials.”

https://www.frontiersin.org/articles/10.3389/fnut.2021.748433/full “Metabolic Fate of Dietary Glucosinolates and Their Metabolites: A Role for the Microbiome”


Discussion of indole-3-carbinol (I3C) and 3,3′-diindolylmethane (DIM) was passed over to this second review:

“Hydrolysis of glucobrassicin GLS by plant or bacterial myrosinase produces multiple indoles, predominantly I3C. Yield of I3C from glucobrassicin is about 20%.

In the stomach, I3C undergoes extensive condensation to yield predominately DIM. Ingestion of I3C results in 20–40% conversion to DIM.

DIM has multiple mechanisms of action, the most well-characterized is modulation of aryl hydrocarbon receptor (AHR) signaling. The DIM-intestinal AHR-microbiome axis is an important component for future development of a personalized nutraceutical approach to achieving optimal health.”

https://www.frontiersin.org/articles/10.3389/fnut.2021.734334/full “Indoles Derived From Glucobrassicin: Cancer Chemoprevention by Indole-3-Carbinol and 3,3′-Diindolylmethane”


DIM estimates in this second review were too high with respect to clinical trial findings of Eat broccoli sprouts for DIM. Using the trial’s 21.61 μmol of average glucobrassicin intake, this review’s 20% I3C yield would be 4.32 μmol. This review’s lowest 20% DIM yield from I3C would be 0.86 μmol, representing a 4.0% DIM bioavailability from glucobrassicin intake.

The trial’s lowest average DIM (in postmenopausal women) after 35 days of eating broccoli sprouts measured 0.5544 μmol, representing an average 2.57% DIM bioavailability from glucobrassicin intake. One of the trial’s coauthors officially reviewed this second review, but he didn’t insist on better human in vivo estimates, although 4.0 / 2.57 is more than 50% too high for the review’s lowest DIM estimate.

The trial and its parent trial also weren’t cited by either review. Aren’t human clinical trials measuring sulforaphane, sulforaphane metabolites, and DIM bioavailability relevant to “Metabolic Fate of Dietary Glucosinolates and Their Metabolites” and “Indoles Derived From Glucobrassicin”?

Something else was missing from both papers. They had academic suggestions for future studies, but neither one continued on to say “and here’s what we’re sponsored to do to fill these gaps.”

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Gut microbiota and critical development periods

This 2021 rodent study focused on global histone acetylation as a model to understand roles of microbially produced short-chain fatty acids in liver function:

“Despite the utility of germ-free mice in probing complex interactions between gut microbiota and host physiology, germ-free mice are developmentally, physiologically, and metabolically unique when compared with their conventionally housed counterparts. We sought to determine whether antibiotic-mediated microbiota depletion would affect global hepatic histone acetylation states through SCFA-dependent mechanisms, as previously observed in germ-free mice.

The inability of antibiotic-mediated microbiota depletion to recapitulate findings observed in germ-free mice suggests that the transition from a germ-free to a colonized mouse leads to resilient alterations in hepatic histone acetylation states that cannot be altered by further modulating the microbial environment. This finding is distinct from other germ-free phenotypes that are considered to be partially reversible, with clear alterations in their function observed after antibiotic treatment.

histone acetylation

Comparing antibiotic-treated and untreated mice that both received CCl4 at 24 and 48 hours after injury, there were almost no histone acetylation differences. This demonstrates that hepatic injury leads to a global shift in histone acetylation that is primarily independent of gut microbiota.

Major chromatin reorganization driven by histone acetylation leads to markers of differentiation, and addition of targeted differentiation signals induces events to stabilize these histone acetylation patterns – a key feature of embryonic development and terminal cellular differentiation. Differences in histone acetylation patterns seen between germ-free and conventionally raised mice may be a developmental-like effect of hepatocytes not yet exposed to microbial by-products.

Results suggest that microbial and dietary modifications to the gut microbiome in conventionally raised mice are not a means to modulate global hepatic histone acetylation. Microbiota-dependent landscaping of the hepatic epigenome appears static in nature, while the hepatic transcriptome is responsive to alterations in the gut microbiota, yet independent of global histone acetylation.

Findings underscore significant differences between these model systems that should be taken into account when considering their relevance to human biology.”

https://aasldpubs.onlinelibrary.wiley.com/doi/10.1002/hep.32043 “Global Microbiota-Dependent Histone Acetylation Patterns Are Irreversible and Independent of Short Chain Fatty Acids” (not freely available) Thanks to Dr. Elliot S. Friedman for providing a copy.


1. By describing “a key feature of embryonic development,” this study provided a gut microbiota-liver analogy of critical periods. If developmental events don’t happen when they are required, it’s probable that their window is missed, and won’t reopen later for a second chance at normalizing.

2. Many studies used a germ-free animal model, such as:

This study provided evidence for a limitation of this model, especially when extrapolating germ-free animal results to humans without similarly testing humans.


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Natural products vs. neurodegenerative diseases

I was recently asked about taking rapamycin for its effects on mTOR. I replied that diet could do the same thing. Here’s a 2021 review outlining such effects:

“As common, progressive, and chronic causes of disability and death, neurodegenerative diseases (NDDs) significantly threaten human health, while no effective treatment is available. Recent studies have revealed the role of phosphoinositide 3-kinase (PI3K)/Akt (Protein kinase B)/mammalian target of rapamycin (mTOR) in some diseases and natural products with therapeutic potentials.

Growing evidence highlights the dysregulated PI3K/Akt/mTOR pathway and interconnected mediators in pathogenesis of NDDs. Side effects and drug-resistance of conventional neuroprotective agents urge the need for providing alternative therapies.

1-s2.0-S0944711321002075-ga1_lrg

Polyphenols, alkaloids, carotenoids, and terpenoids have shown to be capable of a great modulation of PI3K/Akt/mTOR in NDDs. Natural products potentially target various important oxidative/inflammatory/apoptotic/autophagic molecules/mediators, such as Bax, Bcl-2, p53, caspase-3, caspase-9, NF-κB, TNF-α, GSH, SOD, MAPK, GSK-3β, Nrf2/HO-1, JAK/STAT, CREB/BDNF, ERK1/2, and LC3 towards neuroprotection.

This is the first systematic and comprehensive review with a simultaneous focus on the critical role of PI3K/Akt/mTOR in NDDs and associated targeting by natural products.”

https://www.sciencedirect.com/science/article/abs/pii/S0944711321002075 “Natural products attenuate PI3K/Akt/mTOR signaling pathway: A promising strategy in regulating neurodegeneration” (not freely available) Thanks to Dr. Sajad Fakhri for providing a copy.


Natural products mentioned in this review that I eat in everyday foods are listed below. The most effective ones are broccoli and red cabbage sprouts, and oats and oat sprouts:

  • Artichokes – luteolin;
  • Blackberries – anthocyanins;
  • Blueberries – anthocyanins, gallic acid, pterostilbene;
  • Broccoli and red cabbage sprouts – anthocyanins, kaempferol, luteolin, quercetin, sulforaphane;
  • Carrots – carotenoids;
  • Celery – apigenin, luteolin;
  • Green tea – epigallocatechin gallate;
  • Oats and oat sprouts – avenanthramides;
  • Strawberries – anthocyanins, fisetin;
  • Tomatoes – fisetin.

Four humpback whales

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