2 questions i asked chat open AI mostly beyond my understanding but might be of interest to some of you :)

[JustJeff]

Q1 Which drugs could be re purposed to stimulate autophagy?

ChatGPT

Autophagy is a natural cellular process through which the body cleans out damaged cells and regenerates new, healthy ones. It plays a crucial role in maintaining cellular health and has been implicated in various diseases including neurodegenerative disorders, cancer, and metabolic diseases.

Several drugs and compounds have been studied for their potential to stimulate autophagy. It's important to note that while some of these compounds have shown promise in preclinical studies, their effectiveness and safety in humans are still being investigated, and they should only be used under the guidance of a qualified healthcare professional. Here are some compounds that have been studied for their potential to stimulate autophagy:

Rapamycin and Rapalogs: Rapamycin is an immunosuppressant drug that has been shown to induce autophagy. Several rapalogs (compounds related to rapamycin) are also being studied for their autophagy-inducing properties.

Metformin: This commonly prescribed drug for type 2 diabetes has been investigated for its potential to induce autophagy. Some studies suggest that metformin may activate AMP-activated protein kinase (AMPK), which in turn can stimulate autophagy.

Resveratrol: Found in red grapes and some other plants, resveratrol is a natural compound that has been studied for its potential to induce autophagy. It is believed to activate AMPK and SIRT1, which are involved in autophagy regulation.

Trehalose: This natural disaccharide has been investigated for its ability to induce autophagy. It is thought to enhance the clearance of aggregate-prone proteins.

Spermidine: This polyamine compound found in foods like wheat germ and soybeans has been shown to induce autophagy. It may work by inhibiting histone acetyltransferases.

Urolithin A: This compound is derived from ellagic acid, which is found in foods like pomegranates and nuts. Urolithin A has been studied for its potential to induce mitophagy, a specific type of autophagy that targets damaged mitochondria.

Nicotinamide adenine dinucleotide (NAD+): NAD+ is a coenzyme involved in various cellular processes, including autophagy. Some compounds that boost NAD+ levels, like nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN), have been studied for their potential to stimulate autophagy.

Chloroquine and Hydroxychloroquine: These drugs, traditionally used to treat malaria, have been investigated for their autophagy-modulating properties. They inhibit the later stages of autophagy and are being studied in various diseases, including cancer.

Trehalose Analogues: Some modified versions of trehalose have been developed and studied for their potential to enhance autophagy more effectively than natural trehalose.

Q2 Which drugs could be re purposed to remove or unfold the misfolded alpha synuclein from the brain

ChatGPT

Misfolded alpha-synuclein is a protein implicated in neurodegenerative disorders like Parkinson's disease. While there is no definitive cure for these conditions, there is ongoing research to find drugs that can target misfolded alpha-synuclein or promote its clearance. Some potential candidates include:

Small Molecules:

Anle138b: An experimental compound that has shown promise in animal studies for targeting alpha-synuclein aggregates.

NPT200-11: Another experimental small molecule that has demonstrated the ability to reduce alpha-synuclein aggregation in preclinical studies.

Immunotherapies:

PRX002/RG7935: An antibody designed to target and clear misfolded alpha-synuclein. It is being studied in clinical trials.

AFFITOPE® PD01A: A peptide vaccine targeting alpha-synuclein that is under investigation for its potential to induce an immune response against misfolded forms of the protein.

Gene Therapies:

LTI-291: This experimental therapy aims to increase the production of normal, soluble alpha-synuclein to potentially outcompete the misfolded forms.

Chaperone Molecules:

Cyclophilin inhibitors: Some studies have suggested that cyclophilin inhibitors may help stabilize alpha-synuclein and prevent its misfolding.

Proteasome Enhancers:

Raloxifene: This FDA-approved drug, traditionally used for osteoporosis, has shown some promise in preclinical studies for enhancing proteasomal degradation of misfolded alpha-synuclein.

Heat Shock Protein Inducers:

Arimoclomol: This experimental drug aims to induce heat shock proteins, which are involved in protein folding and degradation. It's being investigated for its potential to clear misfolded proteins, including alpha-synuclein.

Enhancing Autophagy:

As mentioned in the previous response, drugs and compounds that stimulate autophagy (like rapamycin) may indirectly assist in the clearance of misfolded proteins.

LRRK2 Inhibitors:

While primarily targeted for Parkinson's disease related to LRRK2 mutations, LRRK2 inhibitors are being studied for their potential to modulate alpha-synuclein pathology.

[hercules957]

Remarquable AI response. Thanks for sharing.

[enjoy2013]

Well done. Great initiative.

It is interesting though that it didn't mention Ambroxol for autophagy, or mannitol for alphasynuclein.

[MarionP]

The trouble with ai, especially with ChatGPT, is that you can't know when it's lying. And it will lie to you rather than say nothing, it is programmed to respond with something rather than "I don't know," and it's language model is all about statistics and correlations between words, not thought and perception and judgment. It is no more logical than when say Donald Trump says to inject yourself with bleach and forces his doctors at the FDA to not object or counter.

You're much better off looking into ways to stimulate autophagy naturally, such as some of the fasting routines that are added on to keto diets, although you need not be doing a keto diet to do the fasting routine. It's also something you can do right now. For actual discussion on how that works, see Dr Annette bosworth, who is on YouTube as "DR Boz", she and her husband who was also way physician have a very good approach and rationale which I think can survive critical examination, and that is something most approaches cannot.

[3KJP in reply to MarionP]

My Husband takes Rapamycin now post Kidney transplant 2 years ago. It is a nightmare for him, but it keeps his creatinine low. He gets mouth ulcers that cause him incredible pain into his facial bones. His labs are done every 2 months and his numbers are very good, and it's not dehydration. This is not the case for everyone though.

I agree with looking into fasting, with your Dr. knowing. My Sister in Law has been doing it for 2 years now just for weight loss, not illness, and even the cellulite on her legs has gone away.

Best of luck to you.

( ChatGPT is not just - not human, it is anti human. From my observations)

[MarionP]

Essential reading. Also fun! Attorneys in a New York Court sanctioned and fined by the court for accepting and submitting into evidence phony case law provided by ChatGPT.

apnews.com/article/artifici...

[chartist]

JJ,

ChatGPT uses data that is not current, so you don't get the latest studies in their replies. Their most current data is from September 2021.

Regarding autophagy, melatonin can stimulate autophagy as needed by the body, while potently inhibiting reactive oxygen species (ROS) which damages mitochondria in PD and other disease states as well as damaging dopaminergic neurons as discussed here :

ncbi.nlm.nih.gov/pmc/articl....

Here is a relevant quote from the review :

' Melatonin can increase autophagy and reduce amyloid production partly through the regulation of reactive oxygen species (ROS) and inflammation [191]. The uncontrolled, continued production of ROS in cells could damage mitochondrial proteins, lipids, and DNA, resulting in increased autophagy [193]. Recent studies showed that both mitochondria and ER play a key role in the formation of autophagosomes [194,195]. It was well-established that melatonin could regulate many targets involved in the ER stress process such as increasing the Bcl-2/Bax ratio, restoring catalase, Cu/Zn-SOD, Mn-SOD, and COX-2. Through this interaction, melatonin could affect autophagy and apoptosis [196]. Melatonin exhibits a beneficial effect on mitochondria by reducing the oxygen consumption rate, oxygen flux, membrane potential, and ultimately suppressing the production of superoxide anions and hydrogen peroxide [190]. '

Melatonin has already proven itself useful for PD in at least 3 PwP/melatonin studies in recent years.

Regarding LRRK2, melatonin has shown itself useful :

ncbi.nlm.nih.gov/pmc/articl....

Here is a relevant quote from the review :

' Genetically, mutations of the leucine-rich repeat kinase 2 (LRRK2) gene associated with sleep disorders and PD were significantly decreased when melatonin was administered (Sun et al., 2016). '

On a related note melatonin has a very good safety profile and reduces alpha synuclein aggregation. Not so much for Rapamycin :

drugs.com/sfx/rapamune-side...

These are just the common serious side effects, not all of the side effects :

Serious side effects of Rapamune

Along with its needed effects, sirolimus (the active ingredient contained in Rapamune) may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking sirolimus:

More common

Accumulation of pus

anxiousness, unexplained

backache

black or red, tarry stools

bleeding from the gums or nose

blurred vision

body aches or pain

bone pain

bruising

burning or stinging of the skin

burning while urinating

burning, dry, or itching eyes

burning, tingling, numbness, or pain in the hands, arms, feet, or legs

change in mental status

changes in skin color

chest pain

chills

confusion

cough

dark or bloody urine

deafness

decreased urine output

decreased vision

difficulty with breathing or swallowing

dilated neck veins

discharge from the eyes

dizziness

drowsiness

dry mouth

earache

excessive tearing

eye pain

facial hair growth in females

faintness or lightheadedness when getting up from lying or sitting position

fast, slow, or irregular heartbeat

fever

flushing or redness of the skin, especially on the face and neck

general feeling of discomfort or illness

increased hunger

increased menstrual flow or vaginal bleeding

itching, pain, redness, swelling, tenderness, or warmth on the skin

lack or loss of appetite

large, flat, blue, or purplish patches in the skin

loss of sexual ability, desire, drive, or performance

loss of voice

muscle pain

nasal congestion

nausea or vomiting

numbness or tingling around the lips, hands, or feet

pain in the chest, groin, or legs, especially the calves

painful cold sores or blisters on the lips, nose, eyes, or genitals

pale skin

prolonged bleeding from cuts

rapid heartbeat

rash

red or dark brown urine

redness or swelling in the ear

redness, pain, or swelling of the eye, eyelid, or inner lining of the eyelid

ringing in the ears

runny nose

seizures

sensation of pins and needles

severe constipation

severe vomiting

severe, sudden headache

slurred speech

sore throat

sores or white spots on the lips or in the mouth

stomach cramps, pain, or upset

sudden decrease in the amount of urine

sudden loss of coordination

sudden, severe weakness or numbness in the arm or leg

sweating

swollen, painful, or tender lymph glands in the neck, armpit, or groin

tenderness, pain, swelling, warmth, skin discoloration, and prominent superficial veins over affected area

tremor

ulcers on the lips or in the mouth

unusual tiredness or weakness

vision changes

weakness or heaviness of the legs

white patches in the mouth or on the tongue

yellow skin and eyes

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Art