The soluble receptor for AGEs

July 3, 2022 gettingwell4 4-5 stars Advanced knowledge, Epigenetics, Immune system, Stress Control group, Genetic factors

Two 2022 human studies on sRAGE, starting with one of hypoxia-related diseases:

“The receptor for advanced glycation end products is found on endothelial and inflammatory cell surfaces. It binds to circulating advanced glycation end products, activating a proinflammatory protein cascade that contributes to systemic oxidative stress and inflammation.

sRAGE is the soluble isoform of RAGE and acts as a protective decoy by buffering inflammatory ligands, decreasing inflammatory injury. Therefore, low levels of sRAGE are a biomarker of deficient inflammatory control.

We show that plasma concentrations of the anti-inflammatory molecule sRAGE are reduced in patients with chronic obstructive pulmonary disease (COPD) and in patients with obstructive sleep apnoea (OSA). Overlap of COPD and OSA does not lead to an additive effect.

Effective treatment by continuous positive airway pressure (CPAP) of subjects with obstructive apnoeas (with or without associated COPD) increases the level of sRAGE, while in healthy subjects and COPD without OSA, these levels do not change over time. This is the first study to investigate the effect of CPAP on plasma levels of sRAGE.”

https://respiratory-research.biomedcentral.com/articles/10.1186/s12931-022-02092-9 “Soluble RAGE in COPD, with or without coexisting obstructive sleep apnoea”

A second study introduced sRAGE isoforms:

“We explored associations of circulating levels of soluble RAGE, its endogenous secretory (esRAGE) and cleaved (cRAGE) isoforms, AGEs, and their respective ratios with 15-year all-cause mortality in type 2 diabetes. The potential prognostic value of sRAGE as a marker of disease and occurrence of adverse events seems to be suitable for individuals with chronic disease or multimorbidity, and not for the general population.

Baseline AGEs and sRAGE isoforms concentration were measured by ELISA in 362 patients with type 2 diabetes and in 125 age- and gender-matched healthy control subjects. At an average follow-up of 15 years, 130 deaths [in T2D subjects] were observed.

A nomogram based on age, sex, HbA1c, systolic blood pressure, and the AGEs/cRAGE ratio was built to predict 5-, 10- and 15-year survival in type 2 diabetes. Kaplan-Meier survival function for patients with type 2 diabetes grouped according to quartiles of the nomogram-based mortality risk score:

An increase in the AGEs/cRAGE ratio was accompanied by a higher risk of all-cause mortality in patients with type 2 diabetes. The AGEs/cRAGE ratio led to a significant, albeit modest, improvement in the already established RECODe model of predicting 10-year all-cause mortality in type 2 diabetes based on age, sex, ethnicity, smoking, systolic blood pressure, history of major adverse cardiovascular events (MACE), HbA1c, total cholesterol, HDL-C, serum creatinine, and urinary albumin-to-creatinine ratio.

While none of the parameters was significantly associated with development of any complication in patients without complications at the time of enrollment, sRAGE was associated with the development of MACE over a 15-year follow-up in patients with type 2 diabetes who had no history of MACE at recruitment.”

https://cardiab.biomedcentral.com/articles/10.1186/s12933-022-01535-3 “Circulating levels of AGEs and soluble RAGE isoforms are associated with all-cause mortality and development of cardiovascular complications in type 2 diabetes: a retrospective cohort study”

AGEs in skin

July 3, 2022 gettingwell4 4-5 stars Advanced knowledge, Epigenetics, Stress Control group, Genetic factors, Neurodegenerative disease

Here are two 2022 human studies that non-invasively measured advanced glycation end products in skin, starting with one investigating AGEs, carotenoids, and glaucoma:

“This study is the first to simultaneously estimate AGE and skin carotenoid (SC) levels using fingertip sensors in patients with glaucoma.

Elevated intraocular pressure (IOP) is a major risk factor, and lowering IOP through medication or surgery is the main therapeutic option. Numerous risk factors, such as genetics, inflammation, ocular blood flow, and oxidative stress have been proposed by diverse nonclinical and clinical studies; however, the only reliable parameter used in clinical practice is IOP.

Most carotenoids, such as α- and β-carotenes, β-cryptoxanthin, lycopene, lutein, and zeaxanthin, have a maximal absorption wavelength of around 480 nm; therefore, the carotenoid score reflects the bulk of these carotenoid molecules. Intraocular levels of lutein, (3R,3′R)-zeaxanthin, and meso-(3R,3′S)-zeaxanthin, the only carotenoids present in macular pigment, and their antioxidant activity are difficult to estimate directly.

Although carotenoid levels reflect previous intake of vegetables, this lifestyle factor is also difficult to determine. Given that SC levels were mainly associated with vegetable intake for about 1 month, SC can be a good endpoint to assess roles of carotenoids in various diseases in clinical situations.

We found that low SC levels were associated with:

Male gender;

History of intraocular surgery;

Current smoking status;

Diabetes;

Low vegetable intake score; and

High levels of AGEs.

No significant association with glaucoma type was detected. However, AGE levels were higher in exfoliation glaucoma than primary open-angle glaucoma and controls.”

https://www.mdpi.com/2076-3921/11/6/1138/htm “Fingertip-Measured Skin Carotenoids and Advanced Glycation End Product Levels in Glaucoma”

A second study focused on cardiovascular risk:

“AGEs cause arterial stiffness by two main mechanisms:

Interaction with arterial walls, which cause functional and structural changes that lead to an over production or cross-linking of collagen, and a decreased level of elastin; or

Interacting with receptors for AGEs, thereby activating different signaling pathways, which lead to enhanced production of pro-inflammatory cytokines and vascular adhesion molecules responsible for atherosclerosis.

Our results show that increases in the level of AGEs in Korean patients with type 2 diabetes is associated with arterial pulse wave velocity and vein age, i.e., measures of arterial stiffness. Consequently, subject levels of AGEs were correlated with cardiovascular risk factors. AGE levels can be used as an indicator for CVDs in clinical diagnosis.”

https://www.cell.com/heliyon/fulltext/S2405-8440(22)00859-3 “Skin accumulation of advanced glycation end products and cardiovascular risk in Korean patients with type 2 diabetes mellitus”

Gut microbiota therapy

June 25, 2022 gettingwell4 4-5 stars Advanced knowledge, Brainstem, Dopamine, Epigenetics, Hippocampus, Hypothalamus, Immune system, Limbic system, Lower brain, Memory, Serotonin, Stress Control group, Genetic factors, Neural plasticity, Neurodegenerative disease

This June 2022 review cited twenty 2022 papers for relationships between Parkinson’s disease and gut microbiota:

“Clinical diagnosis of PD is based on typical motor symptoms, and novel diagnostic biomarkers have been developed such as imaging markers, and α-synuclein fluid and tissue markers. Multimorbidity of non-motor disorders heighten the risk of adverse outcomes for patients with PD, which usually appear 20 years before onset of motor symptoms.

The gut microbiota is intimately connected to occurrence, development, and progression of PD, especially in early stages. A better understanding of the microbiota–gut–brain axis in PD can provide an opportunity to monitor an individual’s health by manipulating gut microbiota composition.

Several approaches like administration of probiotics, psychobiotics, prebiotics, synbiotics, postbiotics, FMT, and dietary modifications have been tried to mitigate dysbiosis-induced ill effects and alleviate PD progression.

Epidemiological studies have reported that diet affects (positively or negatively) onset of neurodegenerative disorders. Evidence suggests that diet composition’s effects on brain health is not due to diet-induced inflammatory response, but because of its effects on the gut microbiome.

Dysbiotic gut microbiota (including altered microbial metabolites) may play crucial roles in PD via various mechanisms, such as:

Increased intestinal permeability;

Aggravated intestinal inflammation and neuroinflammation;

Abnormal aggregation of α-synuclein fibrils;

Imbalanced oxidative stress; and

Decreased neurotransmitters production.

Future studies are essential to further elucidate cause-effect relationships between gut microbiota and PD, improved PD therapeutic and diagnostic options, disease progression tracking, and patient stratification capabilities to deliver personalized treatment and optimize clinical trial designs.”

https://www.frontiersin.org/articles/10.3389/fimmu.2022.937555/full “Gut Microbiota: A Novel Therapeutic Target for Parkinson’s Disease”

Taurine week #7: Brain

June 18, 2022January 19, 2025 gettingwell4 4-5 stars Advanced knowledge, Acetylcholine, Amygdala, Anterior cingulate cortex, Brain development, Cerebellum, Cerebrum, Dopamine, Epigenetics, Glutamate, Hippocampus, Hypothalamus, Immune system, Limbic system, Lower brain, Memory, Neurochemicals, Stress, Thalamus Brain neurons, Control group, Embryo development, Genetic factors, Neurodegenerative disease, Prefrontal cortex

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.

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 GABA_A, GABA_B, and glycine receptors. While taurine binding to GABA_A and GABA_B 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.

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

June 17, 2022August 8, 2022 gettingwell4 4-5 stars Advanced knowledge, Cerebellum, Cerebrum, Cortisol, Epigenetics, Glutamate, Hippocampus, Immune system, Limbic system, Lower brain, Neurochemicals, Serotonin, Stress Antidepressants, Brain neurons, Control group, Genetic factors, Neural plasticity, Prefrontal cortex

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.

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.

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 #5: Blood

June 16, 2022June 16, 2022 gettingwell4 4-5 stars Advanced knowledge, Cortisol, Epigenetics, Neurochemicals, Serotonin, Stress Control group, Genetic factors, Neurodegenerative disease

Two 2022 papers investigated taurine’s effects in blood, starting with a review of platelets:

“Taurine is the most abundant free amino acid in the human body, with a six times higher concentration in platelets than any other amino acid. It is highly beneficial for the organism, has many therapeutic actions, and is currently approved for heart failure treatment in Japan. Only the lack of large-scale phase 3 clinical trials restricts taurine use as a therapeutic agent in several other pathologies for treatment of which it has been shown to be effective (hypertension, atherosclerosis, stroke, neurodegenerative diseases, metabolic diseases, e.g., diabetes mellitus, and others).

Because taurine was seen as a non-patentable nutrient, the pharmaceutical industry has not shown much interest in its research. Considering that taurine and its analogues display permissible side effects, along with the need of finding new, alternative antithrombotic drugs with minimal side effects and long-term action, the potential clinical relevance of this fascinating nutrient and its derivatives requires further consideration.”

https://www.mdpi.com/2077-0383/11/3/666/htm “Taurine and Its Derivatives: Analysis of the Inhibitory Effect on Platelet Function and Their Antithrombotic Potential”

Figure 1 provided details of taurine and its derivatives’ effects on various processes involved in platelet activation and aggregation.

A second paper was a rodent study:

“To evaluate chronic effects of taurine on cholesterol levels, we analyzed mice fed a taurine-rich diet for 14–16 weeks. Long-term feeding of taurine lowered plasma cholesterol and bile acids without significantly changing other metabolic parameters, but hardly affected these levels in the liver.

Taurine upregulates transcriptional activity of Cyp7a1 by suppressing FGF21 production in the liver. Bile acids are converted from blood cholesterol by CYP7A1, and more efficiently enter enterohepatic circulation via taurine conjugation.

This study shows that long-term feeding of taurine lowers both plasma cholesterol and bile acids, reinforcing that taurine effectively prevents hypercholesterolemia.”

https://www.mdpi.com/1422-0067/23/3/1793/htm “Long-Term Dietary Taurine Lowers Plasma Levels of Cholesterol and Bile Acids”

A human equivalent of this male C57BL/6J mouse 16-week taurine intervention is roughly 17 years. That strain’s male maximum lifespan is around 800 days, and human maximum lifespan is currently 122.5 years.

Taurine week #4: Muscles

June 15, 2022November 7, 2022 gettingwell4 4-5 stars Advanced knowledge, Epigenetics, Stress Control group

Two 2022 papers investigated taurine and skeletal muscles, starting with a rodent study of endurance exercise:

“This study examined effects of taurine on dynamics of blood glucose concentration (BGC) during endurance exercise in rats.

Blood was collected every 10 min from the jugular vein via cannulation.

Exercise period was divided by every 40 min into four phases.

Individual exhaustion time is indicated by arrows (white: CON group [n = 12], black: TAU group [n = 10]) under the X-axis.

120-min point is the approximate median where there were significant differences in BGC between groups at exercise point every 10 min (80–150 min).

†P < 0.05 and #P < 0.05 show significant difference to respective starting points (0 min) in TAU and CON groups.

Arrow with two heads (↔) shows a significant difference at P < 0.05 between groups at each point.

Observation of BGC confirmed that taurine supplementation delayed the decline in once-elevated BGC during endurance exercise.

Significantly higher levels of free fatty acid in plasma as well as acetyl-carnitine and N-acetyltaurine in skeletal muscle at the 120-min point suggested that taurine supplementation shifted the priority of energy substrate utilization in skeletal muscles to fatty acid oxidation during endurance exercise. Consequent sparing effect of taurine on BGC might contribute to enhancing exercise performance.”

https://link.springer.com/article/10.1007/s00726-021-03110-8 “Taurine supplementation enhances endurance capacity by delaying blood glucose decline during prolonged exercise in rats”

A second rodent study focused on injured muscle:

“We evaluated whether taurine administration in old mice counteracts physiopathological effects of aging in skeletal muscle.

Type I slow-twitch oxidative fibers (expressing the slow isoform of the myosin heavy chain, slow MHC) are more resistant to damage and a variety of atrophic conditions than type IIb fast-twitch glycolytic fibers. In several muscle pathologies, including sarcopenia, the fastest muscle phenotype is more severely compromised when compared with slow-twitch muscles.

Tibialis anterior (TA) muscles of old mice expressed very low levels of slow-MHC isoform compared to young muscles. Slow-MHC expression increased in muscles of taurine-treated mice.

Analysis of the fast-MHC isoform revealed that, in the presence of taurine, its expression was significantly upregulated compared to what was observed in TA muscles of old mice that did not receive taurine.

These results suggest that the positive effect of taurine on skeletal muscle homeostasis of aged mice may be mediated by stimulation of the PGC1-α/MEF2C pathway, favoring a possible metabolic shift of myofibers towards the oxidative phenotype, and preserving more susceptible glycolytic fibers.

In injured muscle, taurine enhances the regenerative process by downregulating inflammatory response and preserving muscle fiber integrity. Taurine attenuates ROS production in aged muscles by maintaining a proper cellular redox balance, acting as an antioxidant molecule.

These data demonstrate that taurine administration ameliorates the microenvironment, allowing an efficient regenerative process, and attenuation of catabolic pathways related to onset of sarcopenia.”

https://www.mdpi.com/2076-3921/11/5/1016/htm “Taurine Administration Counteracts Aging-Associated Impingement of Skeletal Muscle Regeneration by Reducing Inflammation and Oxidative Stress”

A human equivalent to each daily mouse taurine dose administered over five weeks was (.081 x 100 mg) x 70 kg = .567 g.

Taurine week #3: Organs

June 15, 2022January 19, 2025 gettingwell4 4-5 stars Advanced knowledge, Epigenetics, Immune system, Stress Control group, Genetic factors

Three 2022 papers investigated taurine’s effects on organs, starting with a rodent study of sepsis:

“Sepsis usually causes multiple organ dysfunctions and high mortality. Pathogenesis of sepsis is thought to be driven by hyperactive inflammation following pathogen invasion. If the immune system fails to eradicate pathogens, immune homeostasis is disturbed, leading to an overwhelming inflammation accompanied by immunosuppression.

Metabolomic analysis showed large amounts of taurine in neutrophils and monocytes and a dramatic decrease in taurine levels after lipopolysaccharides (LPS) exposure:

Cecal ligation and puncture (CLP) model mice and CLP plus taurine mice were injected intraperitoneally with saline (200 μl) or taurine (200 mg/kg, in 200 μl) respectively at 6, 24, and 48 h after the operation. Taurine protected septic mice from death, improving tissue injuries in the lung, liver, and kidney by reducing neutrophil infiltration and TNF-α production.

Our data indicate that a supplement with taurine might be a promising therapeutic strategy for sepsis to reduce hyperactive inflammation and improve multiple organ dysfunctions.”

https://www.sciencedirect.com/science/article/abs/pii/S0008874922000272 “Mechanism of taurine reducing inflammation and organ injury in sepsis mice” (not freely available) Thanks to Dr. Liuluan Zhu for providing a copy.

Taurine demonstrated the only decrease in 17 amino acids measured in monocytes above. It was the same story for those amino acids and neutrophils.

A human equivalent to each of three mouse taurine doses administered over two days was (.081 x 200 mg) x 70 kg = 1.134 g. A second dose given at the 12-hour point may have improved treated subjects’ survival, as half of them died before the study’s 24-hour point of a second dose.

A second rodent study was on liver injury:

“We investigated the beneficial effects of taurine on fatty liver injury in vivo induced by tunicamycin, a chemical endoplasmic reticulum (ER) stressor.

The unfolded protein response (UPR) is a protein homeostasis-maintaining system that monitors ER conditions by sensing inadequacy in ER protein folding capacity. The ER is both a protein homeostasis-maintaining system and the primary site of lipid metabolism. The UPR plays vital roles in maintaining metabolic and lipid homeostasis.

Glutathione (GSH), a final byproduct of sulfur-containing amino acid metabolism, is not only a powerful antioxidant, but also a principal redox buffer in the ER. Depletion of reduced glutathione can cause additional oxidative stress.

Cysteine, the metabolic precursor of GSH, is also an essential substrate for taurine synthesis. Utilization of cysteine to generate GSH and taurine is competitive.

In this study, availability of cysteine is favored for GSH synthesis due to sufficient taurine supply. Taurine supplementation restored GSH levels, which were attenuated by tunicamycin treatment, by increasing expression of GCLC, an enzyme mediating GSH synthesis.

The protective effect of taurine on tunicamycin-induced hepatic injury results from its concurrent mitigation of both ER and oxidative stress.”

https://www.mdpi.com/2075-1729/12/3/354/htm “Taurine Ameliorates Tunicamycin-Induced Liver Injury by Disrupting the Vicious Cycle between Oxidative Stress and Endoplasmic Reticulum Stress”

This study provided further evidence for an idea in Treating psychopathological symptoms will somehow resolve causes? that:

“Such positive effects of taurine on glutathione levels may be explained by the fact that cysteine is the essential precursor to both metabolites, whereby taurine supplementation may drive metabolism of cysteine towards GSH synthesis.”

A third rodent study investigated lung pneumonia:

“We evaluated anti-inflammatory effects of taurine derivative N-chlorotaurine (also known as taurine chloramine; TauCl) against LPS-induced pneumonia in obese mice maintained on a high fat diet.

Taurine is present in immune system cells such as macrophages and neutrophils. When an organism is infected by pathogens, immune cells produce hypochlorous acid to kill pathogens. Taurine reacts with excessive hypochlorous acid to produce TauCl, which reduces high levels of hypochlorous acid and its toxicity to surrounding host cells.

Intraperitoneal TauCl suppressed excessive immune response in lungs. TauCl treatment attenuates acute pneumonia-related pulmonary and systemic inflammation, including muscle wasting.”

https://www.mdpi.com/2218-1989/12/4/349/htm “N-Chlorotaurine Reduces the Lung and Systemic Inflammation in LPS-Induced Pneumonia in High Fat Diet-Induced Obese Mice”

Taurine week #1: Biomarkers

June 13, 2022January 19, 2025 gettingwell4 4-5 stars Advanced knowledge, Epigenetics, Stress Control group, Genetic factors

It’s been a while since I curated taurine research. Read at least a week’s worth of 2022 papers last weekend.

Let’s start with two studies that didn’t supplement with taurine, but found it was a biomarker. The first was a rodent study that treated a high fat diet with blood pressure medicine:

“Non-alcoholic fatty liver disease (NAFLD) is a main form of chronic liver disease, and has been the leading cause of liver transplantation. Epidemiological evidence uncovered bidirectional and causal relationships between NAFLD and hypertension.

Evidence suggests that gut dysbiosis can be a driving force for NAFLD and hypertension, despite pathogenesis of NAFLD and hypertension fundamental differences, as they often present similar aberrant microbiota. We found that amlodipine besylate and amlodipine aspartate:

Exerted their hepatoprotective activities through modulating fatty acid metabolism without influencing oxidative and endoplasmic reticulum stress;

Decreased serum transaminases, hepatic fat deposits, and liver inflammation, and showed improvements in plasma lipid profiles; and

Gut microbiota had higher abundance of functional genes involved in taurine and hypotaurine metabolism.

Overall, these results led us to propose that targeting gut microbiota and the taurine and hypotaurine metabolism pathway may be a feasible preventive strategy for patients with NAFLD and hypertension.”

https://bpspubs.onlinelibrary.wiley.com/doi/10.1111/bph.15768 “Amlodipine, an anti-hypertensive drug, alleviates non-alcoholic fatty liver disease by modulating gut microbiota”

A second rodent study investigated garlic compounds’ effects on a high fat diet:

“Garlic organosulfur compounds (OSCs) have been shown to be major components responsible for garlic’s health benefits. However, the composition and function of garlic OSCs are damaged due to various processing and cooking methods during food preparation.

In this study garlic alliinase was deactivated to obtain stable garlic OSCs. We made two preparations of alliinase-free garlic powders based on their OSCs and fructan contents. OSCs concentrations of alliinase-free garlic powder 1 (G1) and alliinase-free garlic powder 2 (G2) differ by approximately 2-fold, 20.889 mg/g and 43.869 mg/g, respectively.

Mice fed with lipid and glucose metabolic disorder-inducing Western diet (WD) revealed that stable garlic OSCs prevented the disorder by increasing relative abundance of gut Bacteroides acidifaciens. Both G1 and G2 significantly increased fecal levels of taurine, with G2 being significantly better than G1.

Garlic OSCs inhibited dyslipidemia and fatty liver by increasing taurine and subsequently promoting hepatic fatty acid β-oxidation. Results of this study demonstrate that the preventive effect of garlic OSCs on WD-induced metabolic disorder is attributed to enhanced growth of Bacteroides acidifaciens and consequent increase in taurine.”

https://pubs.acs.org/doi/10.1021/acs.jafc.2c00555 “Natural Garlic Organosulfur Compounds Prevent Metabolic Disorder of Lipid and Glucose by Increasing Gut Commensal Bacteroides acidifaciens” (not freely available) Thanks to Dr. Hisham R. Ibrahim for providing a copy.

Betaine and diabetes

June 5, 2022January 19, 2025 gettingwell4 4-5 stars Advanced knowledge, Epigenetics, Hippocampus, Hypothalamus, Immune system, Limbic system, Stress Control group, DNA methylation, Genetic factors, Neurodegenerative disease

Two 2022 papers on betaine’s effects, starting with a review:

“Rodent studies provide evidence that betaine effectively limits many diabetes-related disturbances.

Betaine therapy improves glucose tolerance and insulin action, which is strongly associated with changes in insulin-sensitive tissues, such as skeletal muscle, adipose tissue, and liver.

Betaine supplementation positively affects multiple genes, which expression is dysregulated in diabetes.

AMP-activated protein kinase is thought to play a central role in the mechanism underlying anti-diabetic betaine action.

Studies with animal models of type 2 diabetes have shown that betaine exerts anti-inflammatory and anti-oxidant effects, and also alleviates endoplasmic reticulum stress.

These changes contribute to improved insulin sensitivity and better blood glucose clearance. Results of animal studies encourage exploration of therapeutic betaine efficacy in humans with type 2 diabetes.”

https://www.sciencedirect.com/science/article/pii/S0753332222003353 “The anti-diabetic potential of betaine. Mechanisms of action in rodent models of type 2 diabetes”

Reference 31 was a human study:

“Few studies on humans have comprehensively evaluated intake composition of methyl-donor nutrients choline, betaine, and folate in relation to visceral obesity (VOB)-related hepatic steatosis (HS), the hallmark of non-alcoholic fatty liver diseases.

Total choline intake was the most significant dietary determinant of HS in patients with VOB.

Combined high intake of choline and betaine, but not folate, was associated with an 81% reduction in VOB-related HS.

High betaine supplementation could substitute for choline and folate to normalize homocysteine levels under methyl donor methionine-restriction conditions.

Preformed betaine intake from whole-grain foods and vegetables can lower obesity-increased choline and folate requirements by sparing choline oxidation for betaine synthesis and folate for methyl donor conversion in one-carbon metabolism.

Our data suggest that combined dietary intake of choline and betaine reduces the VOB-related HS risk in a threshold-dependent manner.”

https://www.mdpi.com/2072-6643/14/2/261/htm “Optimal Dietary Intake Composition of Choline and Betaine Is Associated with Minimized Visceral Obesity-Related Hepatic Steatosis in a Case-Control Study”

Increasing betaine intake to lower choline and folate requirements was similar to an idea in Treating psychopathological symptoms will somehow resolve causes? that:

“Such positive effects of taurine on glutathione levels may be explained by the fact that cysteine is the essential precursor to both metabolites, whereby taurine supplementation may drive metabolism of cysteine towards GSH synthesis.”

I came across this first paper by it citing All about the betaine, Part 2:

“This review focuses on biological and beneficial effects of dietary betaine (trimethylglycine), a naturally occurring and crucial methyl donor that restores methionine homeostasis in cells. Betaine is endogenously synthesized through metabolism of choline, or exogenously consumed through dietary intake.

Human intervention studies showed no adverse effects with 4 g/day supplemental administration of betaine in healthy subjects. However, overweight subjects with metabolic syndrome showed a significant increase in total and LDL-cholesterol concentrations. These effects were not observed with 3 g/day of betaine administration.

Betaine exerts significant therapeutic and biological effects that are potentially beneficial for alleviating a diverse number of human diseases and conditions.”

https://www.mdpi.com/2079-7737/10/6/456/htm “Beneficial Effects of Betaine: A Comprehensive Review”

The oligosaccharide stachyose

June 4, 2022 gettingwell4 4-5 stars Advanced knowledge, Cortisol, Epigenetics, Hippocampus, Hypothalamus, Immune system, Limbic system, Memory, Neurochemicals, Stress Brain neurons, Control group, Genetic factors, Neural plasticity

Two 2022 stachyose papers to follow on to Don’t take Beano if you’re stressed, which studied raffinose. Stachyose is in the raffinose oligosaccharide group with similar characteristics, and its content is usually larger in legumes. First is a rodent study:

“Stress can activate the hypothalamic–pituitary–adrenal (HPA) axis and elevate glucocorticoids in the body (cortisol in humans and corticosterone in rodents). Glucocorticoid receptors are abundant in the hippocampus, and play an important role in stress-induced cognition alteration.

Corticosterone is often used to model cognitive impairment induced by stress. Long-term potentiation (LTP) deficit and cognitive impairment always coexist in stress models, and LTP impairment is often considered as one mechanism for stress-induced cognitive deficits.

N-methyl-D-aspartate (NMDA) receptors play critical roles both in normal synaptic functions and excitotoxicity in the central nervous system. D-serine, a coactivator of NMDA receptors, plays an important role in brain function.

In this study, we focused on effects of stachyose, on LTP impairment by corticosterone, gut flora, and the D-serine pathway.

Data in this study showed that 7-consecutive-day intragastric (i.g.) administration of stachyose had protective effect. There was little effect via intracerebroventricular (i.c.v.) and intraperitoneal (i.p.) administration.

To disturb gut flora, a combination of non-absorbable antibiotics (ATB) were applied. Results showed that ATB canceled the protective effect of stachyose without affecting LTP in control and corticosterone-treated mice, suggesting that stachyose may display its protective effects against LTP impairment by corticosterone via gut flora.

Further study is needed to uncover the relation between gut flora and the D-serine metabolic pathway.”

https://www.frontiersin.org/articles/10.3389/fphar.2022.799244/full “Stachyose Alleviates Corticosterone-Induced Long-Term Potentiation Impairment via the Gut–Brain Axis”

One of this study’s references was Eat oats and regain cognitive normalcy.

A stachyose clinical trial is expected to complete this month:

“In the stachyose intervention group, each person took 5 g of stachyose daily before breakfast. Administration method was 100 ml of drinking water dissolved and taken orally for two months. Each person in the placebo control group took the same amount of maltodextrin daily. Stool samples of the 36 subjects were collected weekly.

Primary outcome measures:

Expression of microRNA; and

Structure of gut microbiota.”

https://clinicaltrials.gov/ct2/show/NCT05392348 “Regulatory Effect of Stachyose on Gut Microbiota and microRNA Expression in Human”

The misnomer of nonessential amino acids

June 4, 2022June 4, 2022 gettingwell4 4-5 stars Advanced knowledge, Amygdala, Brain development, Brainstem, Cerebellum, Cerebrum, Epigenetics, Glutamate, Hippocampus, Immune system, Limbic system, Lower brain, Memory, Neurochemicals, Stress Control group, Embryo development, Neural plasticity, Neurodegenerative disease, Prefrontal cortex

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.

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”

Food combination effects

May 25, 2022May 25, 2022 gettingwell4 4-5 stars Advanced knowledge, Stress Neurodegenerative disease

Two 2022 studies, starting with “Increasing bound antioxidant compounds through their reaction with soluble phenolic compounds”:

“Wheat, oat, rye, and rice bran samples were reacted with different concentrations of beverages (green tea infusion, black tea infusion, espresso, and red wine) rich in various soluble phenolic compounds.

Green tea infusion was found to be the most effective beverage.

pH rather than time and temperature had significant effects on the reaction.

Neutral or slightly alkaline conditions (pH 7.0-7.9) and mild temperature (at about 50 °C) were found to be optimum to increase antioxidant capacity of cereal bran samples.

Total antioxidant capacity of oat bran treated with green tea infusion at optimum conditions (53.3 °C, pH 7.4, 60.0 min) reached 226.42±0.88 mmol.

Free amino groups in cereal bran were also found to decrease 32–95% after treatment.”

https://onlinelibrary.wiley.com/doi/10.1002/jsfa.12017 “Optimization of reaction conditions for the design of cereal based dietary fibers with high antioxidant capacity” (not freely available)

Hadn’t thought about purposely combining oats with green tea before. I eat whole oats, though, not oat bran.

The same coauthors earlier used an in vitro digestion procedure to investigate combinations of 20 foods purchased from local markets:

“Individual antioxidant capacity of a single compound is not adequate to assess antioxidant potential of food or human plasma. Compounds always present as natural mixtures, and may possess similar, overlapping, or different but complementary effects.

Certain types of foods co-existing in daily diet were investigated in terms of their combined total antioxidant capacity (TAC) determined by the QUENCHER method, which allows physiological evaluation without any extraction procedure. Hydroxyl radical scavenging capacity was also determined in bioaccessible fractions of foods.

Interaction types were determined at each step:

Synergism refers to a greater overall effect in the combination of two samples compared to simple addition of their individual effects, which means that TAC_measured is greater (p < 0.05) than TAC_estimated.

The phenomenon in which a lower (p < 0.05) net interactive effect than the sum of their individual effects (TAC_measured < TAC_estimated), is known as antagonism.

Additive interaction occurs when a net interactive antioxidant effect is as same (p > 0.05) as the sum of individual effects.

Seeds and nuts interacted antagonistically with other foods due to the pro-oxidant potential of transition metals on lipid rich system.

Protein-phenol interactions masking TACs of phenol-rich foods before digestion could stabilize and regenerate phenolic compounds under gastrointestinal digestion conditions, providing a synergistic interaction.

Intestinal conditions promoting reaction between antioxidant compounds and radicals resulted in increases in TACs of foods.

Enzymatic colonic digestion caused significant increases in TACs of certain foods.

These findings provide a basis to increase antioxidant activity in daily diet and new food formulations.”

https://www.sciencedirect.com/science/article/pii/S2665927122000351 “Effect of food combinations and their co-digestion on total antioxidant capacity under simulated gastrointestinal conditions”

View this second study as representative or hypothesis-generating, but not specifically definitive. No research group will use its resources to investigate even the 190 pairwise combinations of 20 foods, much less all 616,645 combinations.

Also, since food is digested all in the same place and time, contexts for each combination’s synergistic, antagonistic, or additive activities may be influenced by other combinations’ results. See the second study of Dietary contexts matter for a similar investigation.

Young gut, young eyes

May 17, 2022May 17, 2022 gettingwell4 4-5 stars Advanced knowledge, Cerebrum, Epigenetics, Hippocampus, Hypothalamus, Immune system, Limbic system, Memory, Stress Brain neurons, Control group, Corpus callosum, Genetic factors, Neural plasticity, Neurodegenerative disease

I’ll highlight this 2022 rodent study findings of effects on eye health:

“We tested the hypothesis that manipulating intestinal microbiota influences development of major comorbidities associated with aging and, in particular, inflammation affecting the brain and retina. Using fecal microbiota transplantation, we exchanged intestinal microbiota of young (3 months), old (18 months), and aged (24 months) mice.

Transfer of aged donor microbiota into young mice accelerates age-associated central nervous system inflammation, retinal inflammation, and cytokine signaling. It promotes loss of key functional protein in the eye, effects which are coincident with increased intestinal barrier permeability.

These detrimental effects can be reversed by transfer of young donor microbiota.

We provide the first direct evidence that aged intestinal microbiota drives retinal inflammation, and regulates expression of the functional visual protein RPE65. RPE65 is vital for maintaining normal photoceptor function via trans-retinol conversion. Mutations or loss of function are associated with retinitis pigmentosa, and are implicated in age-related macular degeneration.

Our finding that age-associated decline in host retinal RPE65 expression is induced by an aged donor microbiota, and conversely is rescued by young donor microbiota transfer, suggests age-associated gut microbiota functions or products regulate visual function.”

https://microbiomejournal.biomedcentral.com/articles/10.1186/s40168-022-01243-w “Fecal microbiota transfer between young and aged mice reverses hallmarks of the aging gut, eye, and brain”

Exercise substitutes?

May 16, 2022September 11, 2022 gettingwell4 2-3 stars Required further work, Cerebrum, Epigenetics, Hippocampus, Immune system, Limbic system, Memory, Stress Brain neurons, Control group, Genetic factors, Infants, Neurodegenerative disease

Two papers, starting with a 2022 abstract of an ongoing in vitro study with rodent cells:

“Exercise mimetics may target and activate the same mechanisms that are upregulated with exercise administration alone. This is particularly useful under conditions where contractile activity is compromised due to muscle disuse, disease, or aging.

Sulforaphane and Urolithin A represent our preliminary candidates for antioxidation and mitophagy, respectively, for maintaining mitochondrial turnover and homeostasis. Preliminary results suggest that these agents may be suitable candidates as exercise mimetics, and set the stage for an examination of synergistic effects.”

https://faseb.onlinelibrary.wiley.com/doi/10.1096/fasebj.2022.36.S1.R3745 “Exercise mimicry: Characterization of nutraceutical agents that may contribute to mitochondrial homeostasis in skeletal muscle” (study not available)

A second 2022 paper reviewed what’s known todate regarding urolithins:

“Urolithins (Uros) are metabolites produced by gut microbiota from the polyphenols ellagitannins (ETs) and ellagic acid (EA). ETs are one of the main groups of hydrolyzable tannins. They can occur in different plant foods, including pomegranates, berries (strawberries, raspberries, blackberries, etc.), walnuts, many tropical fruits, medicinal plants, and herbal teas, including green and black teas.

Bioavailability of ETs and EA is very low. Absorption of these metabolites could be increased by co-ingestion with dietary fructooligosaccharides (FOS).

Effects of other experimental factors: post-intake time, duration of administration, diet type (standard and high-fat), and ET dosage (without, low, and high ET intake) in ETs metabolism were evaluated in blood serum and urine of rats consuming strawberry phenolics. Highest concentrations were obtained after 2–4 days of administration.

Various crucial issues need further research despite significant evolution of urolithin research. Overall, whether in vivo biological activity endorsed to Uros is due to each specific metabolite and(or) physiological circulating mixture of metabolites and(or) gut microbial ecology associated with their production is still poorly understood.

Ability of Uros to cross the blood-brain barrier and the nature of metabolites and concentrations reached in brain tissues need to be clarified.

Specific in vivo activity for each free and conjugated Uro metabolite is unknown. Studies on different Uro metabolites and their phase-II conjugates are needed to understand their role in human health.

Evidence on safety and impact of Uros on human health is still scarce and only partially available for Uro-A.

It is unknown whether there are potential common links between gut microbial ecologies of the two unambiguously described metabotypes so far, i.e., equol (isoflavones) and Uros (ellagitannins).

Gut microbes responsible for producing different Uros still need to be better identified and characterized, and biochemical pathways and enzymes involved.”

https://onlinelibrary.wiley.com/doi/10.1002/mnfr.202101019 “Urolithins: a Comprehensive Update on their Metabolism, Bioactivity, and Associated Gut Microbiota”