Posts made by AlphaCog

The role of melatonin in bone regeneration: A review of involved signaling pathways
Abstract
Increasing bone resorption followed by decreasing bone mineralization are hallmarks of bone degeneration, which mostly occurs in the elderly population and post-menopausal women. The use of mesenchymal stem cells (MSCs) has raised many promises in the field of bone regeneration due to their high osteoblastic differentiation capacity and easy availability from abundant sources. A variety of compounds, including growth factors, cytokines, and other internal factors, have been combined with MSCs to increase their osteoblastic differentiation capacity. One of these factors is melatonin, whose possible regulatory role in bone metabolism and formation has recently been suggested by many studies. Melatonin also is a potential signaling molecule and can affect many of the signaling pathways involved in MSCs osteoblastic differentiation, such as activation of PI3K/AKT, BMP/Smad, MAPK, NFkB, Nrf2/HO-1, Wnt, SIRT/SOD, PERK/ATF4. Furthermore, melatonin in combination with other components such as strontium, vitamin D3, and vitamin K2 has a synergistic effect on bone microstructure and improves bone mineral density (BMD). In this review article, we aim to summarize the regulatory mechanisms of melatonin in osteoblastic differentiation of MSCs and underling involved signaling pathways as well as the clinical potential of using melatonin in bone degenerative disorders.
https://www.sciencedirect.com/science/article/abs/pii/S0300908422002127

Melatonin-micronutrients Osteopenia Treatment Study (MOTS): a translational study assessing melatonin, strontium (citrate), vitamin D3 and vitamin K2 (MK7) on bone density, bone marker turnover and health related quality of life in postmenopausal osteopenic women following a one-year double-blind RCT and on osteoblast-osteoclast co-cultures
https://pubmed.ncbi.nlm.nih.gov/28130552/

Results: Ten healthy young women between the ages of 20 and 23 were included in our study after obtaining their consent. The mean age of the participants was 21.63 ± 0.94 years. The average height of our patients was 165.72 ± 3.38 m. the average weight of our patients was 59.45 ± 3.5 kg. Vitamin D levels were significantly higher after taking melatonin (mean 13.6 ± 7.9 ng/ml) than after taking placebo (mean 12.68 ± 5.7 ng/ml) during the follicular phase (P=0.001). Whereas, the increase in vitamin D with the intake of melatonin (mean of 15.8 ± 7.8 ng/ml) compared to the taking of placebo (mean of 14.6 ± 5.7 ng/ml) was not significant during the luteal phase (P=0.7). In addition, there was no significant variation in vitamin D levels between the luteal phase and the follicular phase when taking placebo (P= 0.07) and when taking melatonin (P= 0.25).
https://www.endocrine-abstracts.org/ea/0081/ea0081ep634

Pantethine
Because of pantothenic acid’s role in triglyceride synthesis and lipoprotein metabolism, experts have hypothesized that pantothenic acid supplementation might reduce lipid levels in patients with hyperlipidemia [19].

Several clinical trials have shown that the form of pantothenic acid known as pantethine reduces lipid levels when taken in large amounts [20], but pantothenic acid itself does not appear to have the same effects [1]. A 2005 review included 28 small clinical trials (average sample size of 22 participants) that examined the effect of pantethine supplements (median daily dose of 900 mg for an average of 12.7 weeks) on serum lipid levels in a total of 646 adults with hyperlipidemia [20]. On average, the supplements were associated with triglyceride declines of 14.2% at 1 month and 32.9% at 4 months. The corresponding declines in total cholesterol were 8.7% and 15.1%, and for low-density lipoprotein (LDL) cholesterol were 10.4% and 20.1%. The corresponding increases in high-density lipoprotein (HDL) cholesterol were 6.1% and 8.4%.

A few additional clinical trials have assessed pantethine’s effects on lipid levels since the publication of the 2005 review. A double-blind trial in China randomly assigned 216 adults with hypertriglyceridemia (204–576 mg/dl) to supplementation with 400 U/day CoA or 600 mg/day pantethine [21]. All participants also received dietary counseling. Triglyceride levels dropped by a significant 16.5% with pantethine compared with baseline after 8 weeks. Concentrations of total cholesterol and non-HDL cholesterol also declined modestly but significantly from baseline. However, these declines might have been due, at least in part, to the dietary counseling that the participants received.

Two randomized, blinded, placebo-controlled studies by the same research group in a total of 152 adults with low to moderate cardiovascular disease risk found that 600 mg/day pantethine for 8 weeks followed by 900 mg/day for 8 weeks plus a therapeutic lifestyle change diet resulted in small but significant reductions in total cholesterol, LDL cholesterol, and non-HDL cholesterol compared with placebo after 16 weeks [19,22]. Increasing the amount of pantethine from 600 to 900 mg/day did not increase the magnitude of reduction in the lipid measures.

Additional studies are needed to determine whether pantethine supplementation has a beneficial effect on hyperlipidemia independently of, and together with, eating a heart-healthy diet. Research is also needed to determine the mechanisms of pantethine’s effects on lipid levels.
https://ods.od.nih.gov/factsheets/PantothenicAcid-HealthProfessional/#h9

@yerrag It's not the calcium amount but the stress-reducing bioactive compounds in tea having a positive effect on metabolism of bone/glucose.

Monitoring fluorine levels in tea leaves from major producing areas in China and the relative health risk
Abstract
The trace element fluoride can exert a preventive function on dental caries at moderate intake levels, but can also lead to skeletal fluorosis and cognitive impairment when consumed in excessive amounts. Tea is a fluoride hyperaccumulator, yet the risks of fluoride intake via tea consumption are yet to be investigated. In this study, we measured fluoride levels in common tea products from major cultivation provinces in China. Fluoride contents ranged from 6 to 808 mg/kg. Of the samples, 15.6% (34/218) demonstrated fluoride contents which exceeded the maximum residue limit of 200 mg/kg. The samples with high fluoride contents mainly represented oolong tea and dark tea. Fluoride contents in tea were significantly varied between producing regions, which is mainly due to different degree of soil acidification and fluoride occurrence in groundwater. Daily fluoride intake via tea consumption among the general population ranged from 0.02 to 2.20 mg/day, which is lower than the tolerable upper fluoride intake level (UL) of 3.50 mg/day based on Chinese Dietary Reference Intakes, but rather close to the UL of 2.50 mg/day set by the European Food Safety Authority. A risk assessment indicated that the consumption of tea was not associated with any significant health risks (hazard quotient ≤ 0.54). However, we found a potential risk for the simultaneous consumption of tea, drinking water, wheat and seafood based on a simulation assessment. Fluoride intake among the high-risk population should be continuously monitored.
https://www.sciencedirect.com/science/article/abs/pii/S0889157523000790

The effects of green tea consumption on metabolic and anthropometric indices in patients with Type 2 diabetes
Conclusion:
Drinking four cups of green tea led to a significant reduction in weight and systolic blood pressure.
https://pmc.ncbi.nlm.nih.gov/articles/PMC3908530/

Shaded Japanese Green Teas
Shaded and unshaded teas refer to how the tea is cultivated in Japan. Shading, or kabuse, is done to reduce the sunlight that the tea plant receives by about 85%, which lowers the plant’s photosynthesis.

To put it succinctly, shading is done to keep the L-theanine content high, and the formation of catechins low. L-theanine is responsible for the umami taste, whereas catechins are responsible for the tea tasting astringent or bitter.

Additionally, shading produces a sweeter leaf because of the higher sugar content. It also tends to create darker and greener leaves due to the plant creating more chlorophyll.

Shading is generally done for a short period (2 to 4 weeks) before the tea leaves are picked. For example, Kabuse Sencha is shaded for 2 weeks, Gyokuro for 3, and finally, Matcha for 4 weeks. Shading is done either directly on the top of the plant or more traditionally with shelf style shading. Shading is also only done in Japan.
https://obubutea.com/comparing-shaded-japanese-green-teas/

Results:
Our study was based on 17 journal articles, including 2 prospective cohort studies, 4 case–control studies, and 11 cross-sectional studies. In the present study, the total OR of osteoporosis for the highest versus the lowest categories of tea consumption was 0.62 (95% CI, 0.46–0.83), with significant heterogeneity among studies (I2 = 94%, P < .01). There was, however, no publication bias of the meta-analysis about tea consumption and osteoporosis. Subgroup analysis showed that tea consumption could reduce the risk of osteoporosis in all examined subgroups.

Conclusion:
In the present study, it can be concluded from the results that tea consumption can reduce the risk of osteoporosis.

https://pmc.ncbi.nlm.nih.gov/articles/PMC5728912/

Ongoing trial:
Efficacy of Nicotine in Preventing COVID-19 Infection (NICOVID-PREV)
https://clinicaltrials.gov/study/NCT04583410

My poll was voted on and I forgot to check:
https://lowtoxinforum.com/threads/oxidized-cholesterol-vs-pufa.28333/

Which one is worse? Oxidized Cholesterol vs Polyunsaturated Fatty Acid

• Oxidized Cholesterol Votes: 2
• Polyunsaturated Fatty Acid Votes: 7

Answered my question from 5 years ago with ChatGPT.
https://lowtoxinforum.com/threads/unsaturated-fat-protects-against-saturated-fat-induced-lipotoxicity.28418/post-427668

GPT-40:
Fasting-induced autophagy and saturated-fat-induced apoptosis are two distinct processes that play crucial roles in cellular health, but they have very different effects and mechanisms.

1. Fasting-Induced Autophagy

• Mechanism: Autophagy is a natural, regulated process of breaking down and recycling damaged or dysfunctional cellular components. When fasting, nutrient availability (particularly glucose and amino acids) drops, activating signaling pathways (e.g., AMPK and mTOR inhibition) that trigger autophagy. Cells then begin to digest damaged proteins, organelles, and other cellular debris, providing energy and essential building blocks for cellular repair and rejuvenation.
• Benefits: Autophagy is associated with various health benefits, including improved metabolic health, protection against neurodegenerative diseases, and potentially increased longevity. By recycling cellular components, autophagy helps cells stay functional and resilient under stress, such as during nutrient scarcity.
• Protective Effects: Autophagy supports cellular survival by removing potentially toxic cellular materials and promoting energy efficiency, acting as a self-preservation mechanism.

2. Saturated-Fat-Induced Apoptosis

• Mechanism: Apoptosis is a programmed cell death pathway that helps eliminate damaged or unneeded cells. Saturated fats, especially when consumed in high amounts, can trigger apoptosis by causing oxidative stress, inflammation, and mitochondrial dysfunction. Excess saturated fats can disrupt the lipid composition of cell membranes and impair cellular function, leading to stress signals that activate apoptosis through pathways like caspase activation and mitochondrial damage.
• Drawbacks: While apoptosis is a healthy and necessary process for removing damaged cells, chronic exposure to saturated fats can increase the rate of cell death in vital tissues like the liver, pancreas, and even certain areas of the brain. This has been linked to insulin resistance, fatty liver disease, and increased cardiovascular risks, particularly in the context of a high-saturated-fat diet with low intake of protective nutrients.
• Potential for Damage: In cases of excessive saturated fat consumption, apoptosis can contribute to tissue damage and inflammation, as dying cells release pro-inflammatory signals, potentially harming healthy surrounding cells.

Summary: Fasting-Induced Autophagy vs. Saturated-Fat-Induced Apoptosis

• Autophagy (from fasting) is a beneficial cellular cleaning and repair process, supporting cellular function and resilience, particularly under nutrient-scarce conditions.
• Apoptosis (from excess saturated fat), while protective in certain contexts, can lead to inflammation and tissue damage when triggered excessively. This can compromise tissue health and overall metabolic stability.

In summary, fasting-induced autophagy supports cellular health and longevity by clearing damaged components, while saturated-fat-induced apoptosis is a response to cellular stress that, when chronic, can contribute to metabolic dysfunction and tissue damage.

Its name comes from the Greek πάντοθεν pantothen, meaning "from everywhere", because pantothenic acid, at least in small amounts, is in almost all foods. Deficiency of pantothenic acid is very rare in humans.
https://en.wikipedia.org/wiki/Pantothenic_acid

From this we infer that people with dementia probably had poor digestion.

Gastrointestinal Diseases, Genetic Risk, and Incident Dementia: A Prospective Cohort Study in 352,463 Middle-Aged Adults
Conclusions and relevance This study found associations of several gastrointestinal diseases with an increased risk of incident dementia, especially early-onset dementia. Our findings imply the great importance of dementia prevention among patients with gastrointestinal diseases.
https://www.medrxiv.org/content/10.1101/2022.11.28.22282820v1.full

Dementia with Lewy bodies (DLB) patients suffer more frequently from gastrointestinal dysfunction
https://wfneurology.org/activities/news-events/archived-news/2017-09-18-wcn-dlb-patients-suffer-more-from-gastrointestinal-dysfunction

Dysbiosis, gut barrier dysfunction and inflammation in dementia: a pilot study
https://bmcgeriatr.biomedcentral.com/articles/10.1186/s12877-020-01644-2

Substantively Lowered Levels of Pantothenic Acid (Vitamin B5) in Several Regions of the Human Brain in Parkinson's Disease Dementia
Abstract
Pantothenic acid (vitamin B5) is an essential trace nutrient required for the synthesis of coenzyme A (CoA). It has previously been shown that pantothenic acid is significantly decreased in multiple brain regions in both Alzheimer's disease (ADD) and Huntington's disease (HD). The current investigation aimed to determine whether similar changes are also present in cases of Parkinson's disease dementia (PDD), another age-related neurodegenerative condition, and whether such perturbations might occur in similar regions in these apparently different diseases. Brain tissue was obtained from nine confirmed cases of PDD and nine controls with a post-mortem delay of 26 h or less. Tissues were acquired from nine regions that show high, moderate, or low levels of neurodegeneration in PDD: the cerebellum, motor cortex, primary visual cortex, hippocampus, substantia nigra, middle temporal gyrus, medulla oblongata, cingulate gyrus, and pons. A targeted ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) approach was used to quantify pantothenic acid in these tissues. Pantothenic acid was significantly decreased in the cerebellum (p = 0.008), substantia nigra (p = 0.02), and medulla (p = 0.008) of PDD cases. These findings mirror the significant decreases in the cerebellum of both ADD and HD cases, as well as the substantia nigra, putamen, middle frontal gyrus, and entorhinal cortex of HD cases, and motor cortex, primary visual cortex, hippocampus, middle temporal gyrus, cingulate gyrus, and entorhinal cortex of ADD cases. Taken together, these observations indicate a common but regionally selective disruption of pantothenic acid levels across PDD, ADD, and HD.
https://pubmed.ncbi.nlm.nih.gov/34564384/

Localized Pantothenic Acid (Vitamin B5) Reductions Present Throughout the Dementia with Lewy Bodies Brain
Abstract
Background: Localized pantothenic acid deficiencies have been observed in several neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease dementia (PDD), and Huntington's disease (HD), indicating downstream energetic pathway perturbations. However, no studies have yet been performed to see whether such deficiencies occur across the dementia with Lewy bodies (DLB) brain, or what the pattern of such dysregulation may be.

Objective: Firstly, this study aimed to quantify pantothenic acid levels across ten regions of the brain in order to determine the localization of any pantothenic acid dysregulation in DLB. Secondly, the localization of pantothenic acid alterations was compared to that previously in AD, PDD, and HD brains.

Methods: Pantothenic acid levels were determined in 20 individuals with DLB and 19 controls by ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) across ten brain regions. Case-control differences were determined by nonparametric Mann-Whitney U test, with the calculation of S-values, risk ratios, E-values, and effect sizes. The results were compared with those previously obtained in DLB, AD, and HD.

Results: Pantothenic acid levels were significantly decreased in six of the ten investigated brain regions: the pons, substantia nigra, motor cortex, middle temporal gyrus, primary visual cortex, and hippocampus. This level of pantothenic acid dysregulation is most similar to that of the AD brain, in which pantothenic acid is also decreased in the motor cortex, middle temporal gyrus, primary visual cortex, and hippocampus. DLB appears to differ from other neurodegenerative diseases in being the only of the four to not show pantothenic acid dysregulation in the cerebellum.

Conclusions: Pantothenic acid deficiency appears to be a shared mechanism of several neurodegenerative diseases, although differences in the localization of this dysregulation may contribute to the differing clinical pathways observed in these conditions.

Plain language summary
Decreases in a molecule called pantothenic acid (also known as vitamin B5) have been observed in several areas of the brain in multiple dementia disease, including Alzheimer’s disease, Parkinson’s disease dementia, and Huntington’s disease. However, it is unknown whether such changes also occur in another dementia disease, dementia with Lewy bodies, which shows many of the same symptoms and molecular changes as these conditions. As such, this study was performed in order to determine if and where changes in pantothenic acid occur throughout the dementia with Lewy bodies brain. Using a methodology called liquid chromatography–mass spectrometry, which is able to measure pantothenic acid levels in a highly precise manner in brain tissues, we found that several regions of the dementia with Lewy bodies brain show decreases in pantothenic acid, including some involved in movement such as the substantia nigra and motor cortex, as well as regions associated with cognition and memory such as the hippocampus—looking most similar to the pattern of changes already seen in Alzheimer’s disease. It is possible that these changes contribute to the progression of dementia with Lewy bodies; however, further studies need to be performed to determine at what point these changes happen during the disease and how they may contribute to the development of symptoms.

https://pubmed.ncbi.nlm.nih.gov/38820022/

Could Alzheimer’s disease be a maladaptation of an evolutionary survival pathway mediated by intracerebral fructose and uric acid metabolism?

Although biological effects of fructose metabolism and its byproduct, intracellular uric acid, appear critical for the survival of many animals in nature, including our ancestors, in modern society, it appears to be overengaged, increasing the risk for metabolic syndrome, obesity, diabetes, and other conditions
...
uric acid translocatess NADPH oxidase (nicotinamide adenine dinucleotide phosphate oxidase) to the mitochondria, leading to oxidative stress that blocks the citric acid cycle (via inhibition of aconitase) and fatty acid β-oxidation. As mitochondrial function slows, glycolysis takes over, while uric acid inhibits AMP-activated protein kinase, reducing the ability to recover ATP. The effect is a reduction in ATP in the cell, activating a survival switch that includes hunger, thirst, foraging, fat accumulation, and insulin resistance.
...
Uric acid translocates NADPH oxidase (nicotinamide adenine dinucleotide phosphate oxidase) to the mitochondria, where it causes oxidative stress, reducing fatty acid oxidation (blocking enoyl CoA hydratase) while inhibiting aconitase in the citric acid cycle
...
In nature, dietary fructose from excessive intake of fruit provides a major pathway to activate this survival response, much like what occurs in the autumn when bears prepare for hibernation. However, fructose is also produced in the body via the polyol pathway, in which glucose is converted to fructose. The rate-limiting enzyme in the polyol pathway is aldose reductase, and its activity is stimulated during times of stress, such as when nutrient delivery is impaired (hypoxia or ischemia), when water supplies are low (dehydration, hyperglycemia, and hyperosmolarity), or when uric acid levels are high (reflecting degradation of nucleotides and ATP, suggestive of an energy crisis)

...
However, the studies that evaluated the differences between fructose and glucose in cerebral metabolism using BOLD MRI were performed early (∼15 min), thus making it more likely to reflect true differences between fructose and glucose. The striking finding from these studies was that fructose reduced blood flow to the posterior cingulate cortex, the hippocampus, the thalamus, and the occipital cortex; however, blood flow increased to the area of the visual cortex associated with food reward. Cortical blood flow also decreased. Fructose administration also stimulated hunger and desire for food. These responses are consistent with a stimulation of the foraging response. In contrast, glucose inhibited blood flow to the hypothalamus, thalamus, insula, anterior cingulate, and striatum while stimulating blood flow to the cortex. These responses are expected to inhibit not only the foraging response but also responses involving appetite and reward.
...
The brain can generate and metabolize fructose
Our hypothesis suggests that local fructose generation and metabolism may be the critical factor for how fructose induces AD because under normal circumstances, only 1%–2% of ingested fructose reaches the brain. Indeed, the brain is capable of producing fructose. As mentioned earlier, simply raising blood glucose levels increases brain fructose levels in healthy humans. Raising serum osmolality in mice by dehydration or salty food also stimulates fructose production in the brain (hypothalamus). Dietary fructose may also increase fructose production in the brain, possibly by raising uric acid levels in the brain. For example, acutely raising serum uric acid increases uric acid in both the hypothalamus and the hippocampus in association with local inflammation. In turn, uric acid stimulates fructose production and metabolism.
...
Fructose is elevated in the brain of patients with AD
Sorbitol and fructose levels (both components of the polyol pathway) were significantly elevated, averaging 3–5-fold higher in all regions of the brain studied, including the hippocampus, entorhinal cortex, middle temporal gyrus, cingulate cortex, sensory and motor cortex, and cerebellum.
...
Numerous studies have reported that subjects with AD have low serum uric acid levels, suggesting that this might be important to the pathogenesis. However, although serum uric acid may reflect fructose metabolism, it also is a general marker of nutrition status. Clinical manifestations of AD are often preceded by significant weight loss. Which may account for the lower serum uric acid levels on presentation of AD. This may also explain why obesity predicts AD in midlife but actually protects from AD late in life
...
https://www.sciencedirect.com/science/article/pii/S0002916523000047

@LucH Thanks for the link. I'm curious regarding the interpretation of Beta-Amyloid and Tau Proteins by various parties. The behaviour of the proteins seemed to have commonality with Uric Acid.

Metformin prevents p-tau and amyloid plaque deposition and memory impairment in diabetic mice
Abstract
Insulin deficiency or resistance can promote dementia and hallmarks of Alzheimer's disease (AD). The formation of neurofibrillary tangles of p-TAU protein, extracellular Aβ plaques, and neuronal loss is related to the switching off insulin signaling in cognition brain areas. Metformin is a biguanide antihyperglycemic drug used worldwide for the treatment of type 2 diabetes. Some studies have demonstrated that metformin exerts neuroprotective, anti-inflammatory, anti-oxidant, and nootropic effects. This study aimed to evaluate metformin's effects on long-term memory and p-Tau and amyloid β modulation, which are hallmarks of AD in diabetic mice. Swiss Webster mice were distributed in the following experimental groups: control; treated with streptozotocin (STZ) that is an agent toxic to the insulin-producing beta cells; STZ + metformin 200 mg/kg (M200). STZ mice showed significant augmentation of time spent to reach the target box in the Barnes maze, while M200 mice showed a significant time reduction. Moreover, the M200 group showed reduced GFAP immunoreactivity in hippocampal dentate gyrus and CA1 compared with the STZ group. STZ mice showed high p-Tau levels, reduced p-CREB, and accumulation of β-amyloid (Aβ) plaque in hippocampal areas and corpus callosum. In contrast, all these changes were reversed in the M200 group. Protein expressions of p-Tau, p-ERK, pGSK3, iNOS, nNOS, PARP, Cytochrome c, caspase 3, and GluN2A were increased in the parietal cortex of STZ mice and significantly counteracted in M200 mice. Moreover, M200 mice also showed significantly high levels of eNOS, AMPK, and p-AKT expression. In conclusion, metformin improved spatial memory in diabetic mice, which can be associated with reducing p-Tau and β-amyloid (Aβ) plaque load and inhibition of neuronal death.
https://pubmed.ncbi.nlm.nih.gov/34283253/

Metformin attenuates Alzheimer's disease-like neuropathology in obese, leptin-resistant mice
Abstract
Diabetes increases the risk of Alzheimer's disease (AD). The pathological hallmarks for AD brains are extracellular amyloid plaques formed by β-amyloid peptide (Aβ) and intracellular neurofibrillary tangles consisting of hyperphosphorylated tau protein. This study was designed to determine AD-like brain changes in mice modeling for type 2 diabetes. The effects of metformin on these changes also were studied. Seven-week old male db/db mice received intraperitoneal injection of 200 mg kg− 1 d− 1 metformin for 18 weeks. They were subjected to Barnes maze at an age of 21 weeks and fear conditioning at an age of 24 weeks to assess their cognitive functions. Hippocampus was harvested after these tests for biochemical evaluation. The db/db mice had more tau phosphorylated at S396 and total tau in their hippocampi than their non-diabetic control db + mice. Activated/phosphorylated c-jun N-terminal kinase (JNK), a tau kinase, was increased in the db/db mouse hippocampus. Metformin attenuated the increase of total tau, phospho-tau and activated JNK. The db/db mice had increased Aβ levels. Metformin attenuated the reduction of synaptophysin, a synaptic protein, in the db/db mouse hippocampus. Metformin did not attenuate the impairments of spatial learning and memory as well as long-term hyperglycemia in the db/db mice. Our results suggest that the db/db mice have multiple AD-like brain changes including impaired cognitive functions, increased phospho-tau and Aβ as well as decreased synaptic proteins. Activation of JNK may contribute to the increased phospho-tau in the db/db mice. Metformin attenuates AD-like biochemical changes in the brain of these mice.
https://www.sciencedirect.com/science/article/abs/pii/S0091305712000640

Gout risk in adults with pre-diabetes initiating metformin
Conclusions: Metformin use was associated with a reduced risk of gout among adults with pre-diabetes, suggesting that metformin may be important in lowering gout risk in individuals with pre-diabetes.
https://ard.bmj.com/content/early/2024/05/15/ard-2024-225652

Metformin Lowers Serum Urate Levels but Not Gout Risk
https://www.rheumatologyadvisor.com/news/metformin-lowers-serum-urate-but-not-gout-risk/

Effect of metformin use on clinical outcomes and serum urate in gout patients with diabetes mellitus: a retrospective cohort study
In conclusion we could not confirm a clinically relevant anti-inflammatory or urate lowering effect of metformin in patients starting ULT treatment and receiving usual care flare prophylaxis.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9153141/

Metformin Initiation Cuts Gout Risk in Prediabetes
Metformin use lowers the risk for gout by 32% in individuals with prediabetes; however, the treatment doesn't change serum urate or C-reactive protein levels.
https://www.medscape.com/viewarticle/metformin-initiation-cuts-gout-risk-prediabetes-2024a1000a4j

Metformin ameliorates high uric acid-induced insulin resistance in skeletal muscle cells
https://www.sciencedirect.com/science/article/abs/pii/S0303720716305482

Metformin protects against insulin resistance induced by high uric acid in cardiomyocytes via AMPK signaling pathways in vitro and in vivo
https://www.biorxiv.org/content/10.1101/2021.01.29.428905v1

Fasting enhances extinction retention and prevents the return of fear in humans

Fear is prone to return following extinction that is the basis of exposure therapy for fear-related disorders. Manipulations that enhance the extinction process can be beneficial for treatment. Animal studies have shown that fasting or caloric restriction can enhance extinction and inhibit the return of fear. The present study examined the effects of fasting on fear acquisition, extinction, and the return of fear in humans. One hundred and twenty-five male participants were randomized into a fasting group and food group and exposed to a Pavlovian fear conditioning paradigm. Changes in plasma cortisol and ghrelin levels were examined using enzyme-linked immunosorbent assays. One-night fasting had no effect on fear acquisition but enhanced fear extinction retention and prevented the return of fear, and this effect persisted for at least 6 months. This procedure was also effective for remote fear memory. Plasma ghrelin levels were elevated after fasting and had a negative relationship with the fear response in spontaneous recovery test. However, overnight fasting did not affect cortisol levels. These findings indicate that fasting enhances extinction retention and prevents the return of fear, without influencing fear memory formation. We propose that this novel procedure may open new avenues for promoting extinction-based therapies for fear-related disorders.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6177454/

The Association of Posttraumatic Stress Disorder with Fast Food and Soda Consumption and Unhealthy Weight Loss Behaviors Among Young Women
Results
PTSD symptoms were associated with an increased frequency of consumption of fast food and soda as well as unhealthy dieting behaviors but not with increased body mass index (BMI).
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3153863/

Youtube - Fighting cancer cells with Calcium Carbonate

Mind-body practices lower blood sugar levels in people with type 2 diabetes
All practices achieve significant reductions in blood sugar levels

The team analyzed data from randomized controlled trials conducted across the globe between 1993 and 2022. They found 28 trials in which people with type 2 diabetes began a mind-body practice in addition to receiving medication and compared their results with people who only received medication to reduce their blood sugar levels.

This study, the first to analyze a range of mind-body practices including meditation, qigong, yoga and mindfulness-based stress reduction and their effect on blood glucose levels, revealed that all mind-body practices led to significant reductions in blood sugar levels.

Taken as a whole, the mind-body practices averaged a .84% reduction in hemoglobin A1c, a measure of the average blood glucose level for the past 3 months. Yoga, the most-studied modality, provided the largest benefit, about a 1% reduction in hemoglobin A1c. The authors noted that a 1% reduction is particularly notable because metformin, the most prescribed diabetes drug, reduces hemoglobin A1c in people with type 2 diabetes by 1.1% on average.

“What is important about this study is that the effect is very strong and that it is on top of the standard of care,” said Richard M. Watanabe, PhD, professor of population and public health sciences and physiology and neuroscience at the Keck School of Medicine, noting that the research revealed that mind-body practices helped participants achieve reductions in blood glucose levels on top of the reductions they were getting from medication.
https://keck.usc.edu/news/mind-body-practices-lower-blood-sugar-levels-in-people-with-type-2-diabetes/

Effect of 6 Months of Meditation on Blood Sugar, Glycosylated Hemoglobin, and Insulin Levels in Patients of Coronary Artery Disease
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5934947/

Effects of Buddhist walking meditation on glycemic control and vascular function in patients with type 2 diabetes
Results
After 12 weeks, maximal oxygen consumption increased and fasting blood glucose level decreased significantly in both groups (p < 0.05). Significant decrease in HbA1c and both systolic and diastolic blood pressure were observed only in the WM group. Flow-mediated dilatation increased significantly (p < 0.05) in both exercise groups but arterial stiffness was improved only in the WM group. Blood cortisol level was reduced (p < 0.05) only in the WM group.

Conclusion
Buddhist walking meditation exercise produced a multitude of favorable effects, often superior to traditional walking program, in patients with type 2 diabetes.
https://www.sciencedirect.com/science/article/abs/pii/S0965229916300346

Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase
https://www.nature.com/articles/nature13270

The ‘Jekyll and Hyde’ of Gluconeogenesis: Early Life Adversity, Later Life Stress, and Metabolic Disturbances
The physiological response to a psychological stressor broadly impacts energy metabolism. Inversely, changes in energy availability affect the physiological response to the stressor in terms of hypothalamus, pituitary adrenal axis (HPA), and sympathetic nervous system activation. Glucocorticoids, the endpoint of the HPA axis, are critical checkpoints in endocrine control of energy homeostasis and have been linked to metabolic diseases including obesity, insulin resistance, and type 2 diabetes. Glucocorticoids, through the glucocorticoid receptor, activate transcription of genes associated with glucose and lipid regulatory pathways and thereby control both physiological and pathophysiological systemic energy homeostasis. Here, we summarize the current knowledge of glucocorticoid functions in energy metabolism and systemic metabolic dysfunction, particularly focusing on glucose and lipid metabolism. There are elements in the external environment that induce lifelong changes in the HPA axis stress response and glucocorticoid levels, and the most prominent are early life adversity, or exposure to traumatic stress. We hypothesise that when the HPA axis is so disturbed after early life adversity, it will fundamentally alter hepatic gluconeogenesis, inducing hyperglycaemia, and hence crystalise the significant lifelong risk of developing either the metabolic syndrome, or type 2 diabetes. This gives a “Jekyll and Hyde” role to gluconeogenesis, providing the necessary energy in situations of acute stress, but driving towards pathophysiological consequences when the HPA axis has been altered.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8037741/

Association between Metformin Treatment and Improved Symptoms of Post-Traumatic Stress Disorder
https://diabetesjournals.org/diabetes/article/69/Supplement_1/174-LB/56254

Metformin Use Associated with Decreased PTSD Symptoms in Diabetic Veterans
https://www.hcplive.com/view/metformin-associated-with-decreased-ptsd-symptoms-in-diabetic-veterans

Metformin ameliorates stress-induced depression-like behaviors via enhancing the expression of BDNF by activating AMPK/CREB-mediated histone acetylation
https://pubmed.ncbi.nlm.nih.gov/31521867/

To counteract possible lactic acidosis induced by metformin, simply add a teaspoon of calcium carbonate to your favourite beverage:
Increased intake of calcium reverses vitamin B12 malabsorption induced by metformin
Abstract
Objective: Of patients who are prescribed metformin, 10-30% have evidence of reduced vitamin B12 absorption. B12-intrinsic factor complex uptake by ileal cell surface receptors is known to be a process dependent on calcium availability Metformin affects calcium-dependent membrane action. The objective of this study was to determine the magnitude and mechanism of the reduction in serum vitamin B12 after metformin administration.

Research design and methods: A comparative study design was employed using 2 groups (metformin and control). A total of 21 patients with type 2 diabetes received sulfonylurea therapy; 14 of these 21 patients were switched to metformin. Monthly serum total vitamin B12 measurements and holotranscobalamin (holoTCII) (B12-TCII) were performed. After 3 months of metformin therapy, oral calcium supplementation was administered.

Results: Serial serum vitamin B12 determinations revealed a similar decline in vitamin B12 and holoTCII. Oral calcium supplementation reversed the metformin-induced serum holoTCII depression.

Conclusions: Patients receiving metformin have diminished B12 absorption and low serum total vitamin B12 and TCII-B12 levels because of a calcium-dependent ileal membrane antagonism, an effect reversed with supplemental calcium.
https://pubmed.ncbi.nlm.nih.gov/10977010/

The successful application of honey in wound care management has been achieved due to honey’s potent antibacterial effects, characterised by its multifactorial action. Impressive clinical efficacy has ignited its further use in diverse clinical disciplines, including stomatology. Indeed, there is increasing usage of honey in dental medicine as a preventive or therapeutic remedy for some periodontal diseases mainly associated with bacteria, such as dental caries, gingivitis and mucositides. Dental caries is undoubtedly a major oral health problem worldwide, with an increasing tendency of incidence. The purpose of this perspective review is to describe the recent progress in the laboratory and clinical use of honey in the prevention of dental caries, with emphasis on the antibacterial and antibiofilm effects of honey. The role of honey in the cariogenic process is also discussed. In addition, the quality of honey and the urgent in vitro evaluation of its antibacterial/antibiofilm properties before clinical use are highlighted. Findings based on data extracted from laboratory studies demonstrate the pronounced antibacterial effect of different honeys against a number of periodontal pathogens, including Streptococcus mutans. Although the promising antibiofilm effects of honey have been reported mainly against S. mutans, these results are limited to very few studies. From a clinical point of view, honey significantly reduces dental plaque; however, it is not superior to the conventional agent. Despite the positive in vitro results, the clinical effectiveness of honey in the prevention of dental caries remains inconclusive since further robust clinical studies are needed.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9455747/

Abstract
Importance: Supporting healthy aging is a US public health priority, and gratitude is a potentially modifiable psychological factor that may enhance health and well-being in older adults. However, the association between gratitude and mortality has not been studied.

Objective: To examine the association of gratitude with all-cause and cause-specific mortality in later life.

Design, Setting, and Participants: This population-based prospective cohort study used data from self-reported questionnaires and medical records of 49 275 US older female registered nurses who participated in the Nurses’ Health Study (2016 questionnaire wave to December 2019). Cox proportional hazards regression models estimated the hazard ratio (HR) of deaths by self-reported levels of gratitude at baseline. These models adjusted for baseline sociodemographic characteristics, social participation, physical health, lifestyle factors, cognitive function, and mental health. Data analysis was conducted from December 2022 to April 2024.

Exposure: Gratitude was assessed with the 6-item Gratitude Questionnaire, a validated and widely used measure of one’s tendency to experience grateful affect.

Main Outcomes and Measures: Deaths were identified from the National Death Index, state statistics records, reports by next of kin, and the postal system. Causes of death were ascertained by physicians through reviewing death certificates and medical records.

Results: Among the 49 275 participants (all female; mean [SD] age at baseline, 79 [6.16] years), 4608 incident deaths were identified over 151 496 person-years of follow-up. Greater gratitude at baseline was associated with a lower hazard of mortality in a monotonic fashion. For instance, the highest tertile of gratitude, compared with the lowest tertile, was associated with a lower hazard of all-cause deaths (HR, 0.91; 95% CI, 0.84-0.99) after adjusting for baseline sociodemographic characteristics, social participation, religious involvement, physical health, lifestyle factors, cognitive function, and mental health. When considering cause-specific deaths, death from cardiovascular disease was inversely associated with gratitude (HR, 0.85; 95% CI, 0.73-0.995).

Conclusions and Relevance: This study provides the first empirical evidence suggesting that experiencing grateful affect is associated with increased longevity among older adults. The findings will need to be replicated in future studies with more representative samples.

https://jamanetwork.com/journals/jamapsychiatry/fullarticle/2820770

Abstract
Estrogens (estron: E1; estradiol: E2; estriol: E3) are major water pollutants. For the removal of estrogens, activated carbon (AC) and ozone treatments were employed, and the chemical oxygen demand (COD) and pH of a single solution and multiple solution systems were investigated. The removal of estrogens increased with the amount of AC. The percentage of removed estrogens by AC in the single solution system was greater than that in the ternary solution system. The estrogens were completely removed using ozone, which also reduced COD and pH. The removal of estrogens increased the water quality and decreased the amount of organic carbon.
https://pubmed.ncbi.nlm.nih.gov/22123241/