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