Naringin inhibition of adenosine deaminase (ADA) + Ghrelin activation

cs3000

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This enzyme breaks down adenosine to inosine, Naringin was shown to moderately inhibit this enzyme, but would high intakes of OJ lead to increased adenosine levels / decreased inosine levels?

(they used cordycepin as it mimicks adenosine. in a rat study it increases NREM stage of sleep, but at doses practically too high to get from cordyceps)

"As cordycepin exhibits a wide range of biological functions including anticancer effects, derivatives of adenosine could be a promising candidate for a new drug. However, to protect the molecules from the rapid degradation by ADA, noncytotoxic but effective ADA inhibitors need to be coadministered"

"Inhibition assays revealed that naringin exhibited an inhibitory effect against the deamination of cordycepin. Strong inhibition of ADA activities by potent ADA inhibitors such as pentostatin or deficiency of ADA1 gene can cause immune deficiency (Kraut et al. 1990; Ozsahin et al. 1997).
[inosine increases immune cell function so too much inhibition giving too little inosine conversion probably plays a part] Meanwhile, the inhibitory effect of naringin was moderate, suggesting that severe adverse reactions such as immune deficiency would not occur with naringin."


also https://www.pnas.org/doi/abs/10.1073/pnas.0505414102
"Here we show in humans that a genetic variant of adenosine deaminase, which is associated with the reduced metabolism of adenosine to inosine, specifically enhances deep sleep and SWA during sleep"


another interesting thing Naringin exhibits in vivo prokinetic activity via activation of ghrelin receptor in gastrointestinal motility dysfunction rats - PubMed is that naringin activates the Ghrelin receptor in vitro & in vivo. oral bioavailability 11%.
[another study below mentions this was from 50mg/kg orally]
^ it helped increase gut motility, better orally than IV
"it turned out that intravenous administration of naringin led to a lower prokinetic effect than when administrated orally to rats, indicating that naringin prefers to act on the intestinal wall rather than getting absorbed into the systemic circuit"

and ghrelin has increased slow wave sleep in humans Ghrelin promotes slow-wave sleep in humans - PubMed (prolactin also plays a role)



Active orally in mice at 50mg/kg ~ 250mg human dose & stimulated hippocampal neurogenesis Naringin Mediates Adult Hippocampal Neurogenesis for Antidepression via Activating CREB Signaling

Ng-treated mice were orally administrated with Ng at the dosage of 50 mg/kg/d
Overall, those results indicate that naringin is an ideal drug candidate for antidepression treatment. A previous study suggests the safety profile of naringin even used at the dosage up to 500 mg/kg body weight per day and continuously used for 3 and 6 consecutive months

Naringin treatment (50 mg/kg/d) increased BrdU+/NeuN+ cells in the hippocampus of the CORT-induced depressant mice. Naringin treatment remarkably increased the density of DCX+ fibers and the DCX+ dendritic fibers expanding to molecular layer. Thus, we remark that naringin could induce neuronal differentiation and the maturation of NSPCs for hippocampal neurogenesis.

[but may be act as estrogenic only in high doses]
?


The oral no observed adverse effect level of naringin is approximately 200 mg/kg in humans [33]. [But a rat study showed increased hair loss they used doses up to 1250mg/kg ~10g human]


Orange juice is mainly Naringenin instead of naringin - barely any naringin average 0.019mg/100ml Table 1 | Determination of Flavanones in Orange Juices Obtained from Different Sources by HPLC/DAD


https://www.tandfonline.com/doi/full/10.1080/13880209.2016.1216131 Naringin ~2g human dose in rats showed increased Bone mineral density. also shown to prevent calcium wasting. and helps increase BMD when too much Vitamin A caused bone loss.
also good for mitochondrial function
"naringin has been shown to significantly ameliorate mitochondrial dysfunction by restoring the mitochondrial matrix metalloproteinase activity and reactive oxygen species (ROS) and ATP levels in mitochondria"
"Our results showed that oral administration of naringin significantly improved the learning and memory abilities as evidenced by increasing recognition index by 52.5% in the novel object recognition test and inducing a 1.05-fold increase in the crossing-target number in the probe test, and ameliorated mitochondrial dysfunction in mice caused by HFD consumption. Moreover, naringin significantly enhanced insulin signaling pathway. Furthermore, the AMPK activity significantly increased in the naringin-treated (100 mg kg(-1) d(-1)) group. These findings suggest that an enhancement in insulin signaling and a decrease in mitochondrial dysfunction through the activation of AMPK may be one of the mechanisms that naringin improves cognitive functions in HFD-induced obese mice."


https://pubmed.ncbi.nlm.nih.gov/17994577/
^Protects mitochondrial enzymes at 10mg - 40mg / kg in rats / ~1g - 4g human
-Wistar rats. Rats subcutaneously injected with ISO (85 mg/kg) at an interval of 24 h for 2 days, resulting in significant (p < 0.05) increase in the levels of mitochondrial lipid peroxides. ISO-induction also showed significant (p < 0.05) decrease in the activities of mitochondrial tricarboxylic acid cycle enzymes (....malate dehydrogenase) and respiratory chain enzymes (NADH dehydrogenase and cytochrome c oxidase).
-Oral pretreatment with naringin (10, 20, and 40 mg/kg) to ISO-induced rats daily for a period of 56 days significantly (p < 0.05) minimized the alterations in all the biochemical parameters and restored the normal mitochondrial function.


In a rat model of Parkinson’s disease, intraperitoneal injection of naringin protects the nigrostriatal dopaminergic (DA) projection by increasing glial cell line-derived neurotrophic factor expression and decreasing TNF-α expression in DA neurons and microglia


https://journals.sagepub.com/doi/full/10.1177/15353702221117128 Reduces lactic acid & increases glycogen , increases exercise capacity
The aim of this study was to explore effects of naringin (Nar) on antifatigue ability; the weight-loaded and non-loading swimming tests were performed. Compared with the control group, dietary supplementation of Nar significantly prolonged the weight-loaded swimming time to exhaustion of mice (P < 0.01). Nar significantly reduced the serum lactic acid (LD) level and lactate dehydrogenase (LDH) activity, while increased the serum non-esterified free fatty acids (NEFA) level (P < 0.001).
-In addition, Nar significantly increased the liver glycogen and muscle glycogen contents (P < 0.05) and the phosphoenolpyruvate carboxykinase (PEPCK) (P < 0.01) and glucokinase (GCK) mRNA levels (P < 0.001) in liver and gastrocnemius (GAS) muscle. Furthermore, Nar significantly improved the antioxidant capacity, mitochondrial function, and muscle mitochondrial fatty acid β-oxidation (P < 0.05), and decreased inflammation and muscle damage–related gene expression (P < 0.05). These findings suggested that Nar can improve antifatigue effect by enhancing antioxidant capacity and mitochondrial function and preventing muscle damage.

-On average, the loaded swimming time in 0.04% (naringin) group increased by 30.51%. (800mg human dose?)
-Compared with the control group, 0.04% Nar treatment significantly increased GSH-Px activities, and reduced the content of MDA
-Compared with the control group, 0.04% Nar treatment significantly increased the ATP (P < 0.01) and COX activity (P < 0.05) in liver and GAS muscle of mice
^ *liver ATP actually doubled


accelerates wound healing in diabetic mice
https://dergipark.org.tr/tr/download/article-file/1118200
naringin wound healing.png
^ used in cream but also works orally "Similarly, in a previous study which was conducted by Kandhare et al., it was shown that daily Naringin (20, 40 and 80 mg/kg, p.o.) treatment was able to shorten foot ulcer healing time in diabetic rats"


General Anti-ulcer effect ^
Naringin (200 mg/kg) has significantly reduced the ulcer index and improved gastric mucosal morphology in acetylsalicylic acid-induced ulceration in rats [203]. Moreover, naringin (400 mg/ kg) has also been shown to prevent the development of gastric ulcers following ethanol ingestion in rats, presumably by mechanisms not involving prostaglandins [204]. In another model of gastrointestinal motility dysfunction, naringin (50 mg/kg, orally and 5 mg/kg, i. v.) has been shown to exhibit in vivo prokinetic activity via activation of ghrelin receptors [2


https://pdfs.semanticscholar.org/b65c/fa36293301cbc085b7309e32aa776d435185.pdf ~500mg - 1g human dose protects against aspirin induced ulcers. protects against aldehydes.


Naringin also has the highest binding affinity to covid out of the flavanoids, tho i aint sure regular doses would reach the concentration needed still maybe would be a help https://www.iasj.net/iasj/download/c44a052f61838442


Naringin half life / time to max https://www.frontiersin.org/files/A...11-00364-HTML/image_m/fphar-11-00364-t001.jpg
~2.5-3 hours half life (lasts 5-6 hours directly)
~2 hours time to peak
-300mg-500mg gives Cmax of 5-10 ng/ml

So i might test this for sleep quality. 500mg - 1g
But obviously in everyday life increasing adenosine and decreasing inosine doesnt look desirable.
 
Last edited:

Hans

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This enzyme breaks down adenosine to inosine, Naringin was shown to moderately inhibit this enzyme, but would high intakes of OJ lead to increased adenosine levels / decreased inosine levels?

(they used cordycepin as it mimicks adenosine. in a rat study it increases NREM stage of sleep, but at doses practically too high to get from cordyceps)

"As cordycepin exhibits a wide range of biological functions including anticancer effects, derivatives of adenosine could be a promising candidate for a new drug. However, to protect the molecules from the rapid degradation by ADA, noncytotoxic but effective ADA inhibitors need to be coadministered"

"Inhibition assays revealed that naringin exhibited an inhibitory effect against the deamination of cordycepin. Strong inhibition of ADA activities by potent ADA inhibitors such as pentostatin or deficiency of ADA1 gene can cause immune deficiency (Kraut et al. 1990; Ozsahin et al. 1997).
[inosine increases immune cell function so too much inhibition giving too little inosine conversion probably plays a part] Meanwhile, the inhibitory effect of naringin was moderate, suggesting that severe adverse reactions such as immune deficiency would not occur with naringin."
As a side note, adenosine deaminase is upregulated in people with ED, so naringin and naringenin will also help with erections. OJ is a good source, but orange peel powder is a better source. You can also buy naringin and naringenin on Amazon, which is rather the route I would go for an experiment.
 
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without knowing this for sure..wouldn’t the bitter gross flavour of an orange peel give hints that you shouldn’t eat it. I would imagine along with any benefits there would be some negatives as well.
 

Hans

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without knowing this for sure..wouldn’t the bitter gross flavour of an orange peel give hints that you shouldn’t eat it. I would imagine along with any benefits there would be some negatives as well.
A lot of people eat orange marmalade, but that's because it's a good blend of bitter/tangy and sweet. It has many health benefits.
 
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You’re right. I’ve enjoyed it from time to time. Same with cinnamon and garlic even but I guess it’s just not meant to be a food but maybe more of a flavouring perhaps with some benefits just like other herbs.
 

Hans

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You’re right. I’ve enjoyed it from time to time. Same with cinnamon and garlic even but I guess it’s just not meant to be a food but maybe more of a flavouring perhaps with some benefits just like other herbs.
Most likely yes.
 
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cs3000

cs3000

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So i might test this for sleep quality. 500mg - 1g
But obviously in everyday life increasing adenosine and decreasing inosine doesnt look desirable.

Looked promising so i've been giving it a try. doses from 150mg - 1000mg.

- did not notice any beneficial effect on sleep quality
(naringin also inhibits acetylcholine esterase , so that likely works against the other mechanisms)

will probably try straight up ATP instead as it gets converted to adenosine
- maybe helped sleep onset in some of the doses
- mild increase in overall appetite i'd say
- no benefit on increasing bowel movements
- maybe mild increase in irritability
- My hemoglobin hovers around the low end, and i noticed some body weakness / being a bit more tired in general. likely coming from the iron chelation , as it's the same feeling as when i've tried other polyphenols that have this chelating (or virus binding) effect at 150mg+.
i also noticed some short term memory impairment / drop in verbal fluenc. maybe also down to the iron chelation effect. so good for people with iron overload but not for me.

- has benefits in low dose too <50mg. e.g anti-depressant and anxiety lowering effect in mice , anti-asthma effect
, bone loss protection & strengthening [bone enzymes like ALP were maximally increased at 5mg/kg mice dose] [also i wonder if that's beneficial for stopping calcification of soft tissue too], radiation protection , tumor growth supression , protection from oxidative stress , where too high doses in the 100s of mgs might impair cholesterol.

so will stick to 25mg for the future and try something else for sleep quality.
 
Last edited:

facesavant

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Messages
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This enzyme breaks down adenosine to inosine, Naringin was shown to moderately inhibit this enzyme, but would high intakes of OJ lead to increased adenosine levels / decreased inosine levels?

(they used cordycepin as it mimicks adenosine. in a rat study it increases NREM stage of sleep, but at doses practically too high to get from cordyceps)

"As cordycepin exhibits a wide range of biological functions including anticancer effects, derivatives of adenosine could be a promising candidate for a new drug. However, to protect the molecules from the rapid degradation by ADA, noncytotoxic but effective ADA inhibitors need to be coadministered"

"Inhibition assays revealed that naringin exhibited an inhibitory effect against the deamination of cordycepin. Strong inhibition of ADA activities by potent ADA inhibitors such as pentostatin or deficiency of ADA1 gene can cause immune deficiency (Kraut et al. 1990; Ozsahin et al. 1997).
[inosine increases immune cell function so too much inhibition giving too little inosine conversion probably plays a part] Meanwhile, the inhibitory effect of naringin was moderate, suggesting that severe adverse reactions such as immune deficiency would not occur with naringin."


also https://www.pnas.org/doi/abs/10.1073/pnas.0505414102
"Here we show in humans that a genetic variant of adenosine deaminase, which is associated with the reduced metabolism of adenosine to inosine, specifically enhances deep sleep and SWA during sleep"


another interesting thing Naringin exhibits in vivo prokinetic activity via activation of ghrelin receptor in gastrointestinal motility dysfunction rats - PubMed is that naringin activates the Ghrelin receptor in vitro & in vivo. oral bioavailability 11%.
[another study below mentions this was from 50mg/kg orally]
^ it helped increase gut motility, better orally than IV
"it turned out that intravenous administration of naringin led to a lower prokinetic effect than when administrated orally to rats, indicating that naringin prefers to act on the intestinal wall rather than getting absorbed into the systemic circuit"

and ghrelin has increased slow wave sleep in humans Ghrelin promotes slow-wave sleep in humans - PubMed (prolactin also plays a role)



Active orally in mice at 50mg/kg ~ 250mg human dose & stimulated hippocampal neurogenesis Naringin Mediates Adult Hippocampal Neurogenesis for Antidepression via Activating CREB Signaling

Ng-treated mice were orally administrated with Ng at the dosage of 50 mg/kg/d
Overall, those results indicate that naringin is an ideal drug candidate for antidepression treatment. A previous study suggests the safety profile of naringin even used at the dosage up to 500 mg/kg body weight per day and continuously used for 3 and 6 consecutive months

Naringin treatment (50 mg/kg/d) increased BrdU+/NeuN+ cells in the hippocampus of the CORT-induced depressant mice. Naringin treatment remarkably increased the density of DCX+ fibers and the DCX+ dendritic fibers expanding to molecular layer. Thus, we remark that naringin could induce neuronal differentiation and the maturation of NSPCs for hippocampal neurogenesis.

[but may be act as estrogenic only in high doses]
?


The oral no observed adverse effect level of naringin is approximately 200 mg/kg in humans [33]. [But a rat study showed increased hair loss they used doses up to 1250mg/kg ~10g human]


Orange juice is mainly Naringenin instead of naringin - barely any naringin average 0.019mg/100ml Table 1 | Determination of Flavanones in Orange Juices Obtained from Different Sources by HPLC/DAD


https://www.tandfonline.com/doi/full/10.1080/13880209.2016.1216131 Naringin ~2g human dose in rats showed increased Bone mineral density. also shown to prevent calcium wasting. and helps increase BMD when too much Vitamin A caused bone loss.
also good for mitochondrial function
"naringin has been shown to significantly ameliorate mitochondrial dysfunction by restoring the mitochondrial matrix metalloproteinase activity and reactive oxygen species (ROS) and ATP levels in mitochondria"
"Our results showed that oral administration of naringin significantly improved the learning and memory abilities as evidenced by increasing recognition index by 52.5% in the novel object recognition test and inducing a 1.05-fold increase in the crossing-target number in the probe test, and ameliorated mitochondrial dysfunction in mice caused by HFD consumption. Moreover, naringin significantly enhanced insulin signaling pathway. Furthermore, the AMPK activity significantly increased in the naringin-treated (100 mg kg(-1) d(-1)) group. These findings suggest that an enhancement in insulin signaling and a decrease in mitochondrial dysfunction through the activation of AMPK may be one of the mechanisms that naringin improves cognitive functions in HFD-induced obese mice."


https://pubmed.ncbi.nlm.nih.gov/17994577/
^Protects mitochondrial enzymes at 10mg - 40mg / kg in rats / ~1g - 4g human
-Wistar rats. Rats subcutaneously injected with ISO (85 mg/kg) at an interval of 24 h for 2 days, resulting in significant (p < 0.05) increase in the levels of mitochondrial lipid peroxides. ISO-induction also showed significant (p < 0.05) decrease in the activities of mitochondrial tricarboxylic acid cycle enzymes (....malate dehydrogenase) and respiratory chain enzymes (NADH dehydrogenase and cytochrome c oxidase).
-Oral pretreatment with naringin (10, 20, and 40 mg/kg) to ISO-induced rats daily for a period of 56 days significantly (p < 0.05) minimized the alterations in all the biochemical parameters and restored the normal mitochondrial function.


In a rat model of Parkinson’s disease, intraperitoneal injection of naringin protects the nigrostriatal dopaminergic (DA) projection by increasing glial cell line-derived neurotrophic factor expression and decreasing TNF-α expression in DA neurons and microglia


https://journals.sagepub.com/doi/full/10.1177/15353702221117128 Reduces lactic acid & increases glycogen , increases exercise capacity
The aim of this study was to explore effects of naringin (Nar) on antifatigue ability; the weight-loaded and non-loading swimming tests were performed. Compared with the control group, dietary supplementation of Nar significantly prolonged the weight-loaded swimming time to exhaustion of mice (P < 0.01). Nar significantly reduced the serum lactic acid (LD) level and lactate dehydrogenase (LDH) activity, while increased the serum non-esterified free fatty acids (NEFA) level (P < 0.001).
-In addition, Nar significantly increased the liver glycogen and muscle glycogen contents (P < 0.05) and the phosphoenolpyruvate carboxykinase (PEPCK) (P < 0.01) and glucokinase (GCK) mRNA levels (P < 0.001) in liver and gastrocnemius (GAS) muscle. Furthermore, Nar significantly improved the antioxidant capacity, mitochondrial function, and muscle mitochondrial fatty acid β-oxidation (P < 0.05), and decreased inflammation and muscle damage–related gene expression (P < 0.05). These findings suggested that Nar can improve antifatigue effect by enhancing antioxidant capacity and mitochondrial function and preventing muscle damage.

-On average, the loaded swimming time in 0.04% (naringin) group increased by 30.51%. (800mg human dose?)
-Compared with the control group, 0.04% Nar treatment significantly increased GSH-Px activities, and reduced the content of MDA
-Compared with the control group, 0.04% Nar treatment significantly increased the ATP (P < 0.01) and COX activity (P < 0.05) in liver and GAS muscle of mice
^ *liver ATP actually doubled


accelerates wound healing in diabetic mice
https://dergipark.org.tr/tr/download/article-file/1118200
View attachment 44338
^ used in cream but also works orally "Similarly, in a previous study which was conducted by Kandhare et al., it was shown that daily Naringin (20, 40 and 80 mg/kg, p.o.) treatment was able to shorten foot ulcer healing time in diabetic rats"


General Anti-ulcer effect ^
Naringin (200 mg/kg) has significantly reduced the ulcer index and improved gastric mucosal morphology in acetylsalicylic acid-induced ulceration in rats [203]. Moreover, naringin (400 mg/ kg) has also been shown to prevent the development of gastric ulcers following ethanol ingestion in rats, presumably by mechanisms not involving prostaglandins [204]. In another model of gastrointestinal motility dysfunction, naringin (50 mg/kg, orally and 5 mg/kg, i. v.) has been shown to exhibit in vivo prokinetic activity via activation of ghrelin receptors [2


https://pdfs.semanticscholar.org/b65c/fa36293301cbc085b7309e32aa776d435185.pdf ~500mg - 1g human dose protects against aspirin induced ulcers. protects against aldehydes.


Naringin also has the highest binding affinity to covid out of the flavanoids, tho i aint sure regular doses would reach the concentration needed still maybe would be a help https://www.iasj.net/iasj/download/c44a052f61838442


Naringin half life / time to max https://www.frontiersin.org/files/A...11-00364-HTML/image_m/fphar-11-00364-t001.jpg
~2.5-3 hours half life (lasts 5-6 hours directly)
~2 hours time to peak
-300mg-500mg gives Cmax of 5-10 ng/ml

So i might test this for sleep quality. 500mg - 1g
But obviously in everyday life increasing adenosine and decreasing inosine doesnt look desirable.
Hi 3000,
I'm trying to understand adenosine deaminase better. If I took a blood test while using MelaNon topically twice a day on & before the blood test Potentially the MelaNon ( Naringenin and apigenine) could cause a lower adenosine deaminase test result. Is that correct?
if adenosine deaminase test is low does that mean high adenosine and low inosine? Thank you for your help.
 
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cs3000

cs3000

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Hi 3000,
I'm trying to understand adenosine deaminase better. If I took a blood test while using MelaNon topically twice a day on & before the blood test Potentially the MelaNon ( Naringenin and apigenine) could cause a lower adenosine deaminase test result. Is that correct?
if adenosine deaminase test is low does that mean high adenosine and low inosine? Thank you for your help.
hi , naringenin inhibited the enzyme less only up to -10% where naringin is -20%. i dont know about apigenin part but probably similar. and competitive / reversable inhibition so effect wears off when the flavonoid does (timeframe depends on dose taken / dose needed in vivo for effect idk what that is, amount that makes it in human blood might not even be enough for effect).

so if it does it shouldnt affect it much. going high with naringenin likely inhibits thyroid where hesperidin has less effect on thyroid https://raypeatforum.com/post-950023 but if using the small amounts in melanon probably isnt an issue

yeah low adenosine deaminase = less inosine and more adenosine as adenosine isnt converted to inosine as much


(thread update , for raising ghrelin & appetite instead i think small amounts of cayenne/capsaicin should work better by a week or so. my appetite increased ~300mg/400mg cayenne powder & at that dose likely to not be gut damaging. but can inhibit immunity while taking it increasing macrophages repair expression (effective in autoimmune conditions).
1697957626505.png
 
Last edited:

facesavant

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hi , naringenin inhibited the enzyme less only up to -10% where naringin is -20%. i dont know about apigenin part but probably similar. and competitive / reversable inhibition so effect wears off when the flavonoid does (timeframe depends on dose taken / dose needed in vivo for effect idk what that is, amount that makes it in human blood might not even be enough for effect).

so if it does it shouldnt affect it much. going high with naringenin likely inhibits thyroid where hesperidin has less effect on thyroid https://raypeatforum.com/post-950023 but if using the small amounts in melanon probably isnt an issue

yeah low adenosine deaminase = less inosine and more adenosine as adenosine isnt converted to inosine as much


(thread update , for raising ghrelin & appetite instead i think small amounts of cayenne/capsaicin should work better by a week or so. my appetite increased ~300mg/400mg cayenne powder & at that dose likely to not be gut damaging. but can inhibit immunity while taking it increasing macrophages repair expression (effective in autoimmune conditions).
View attachment 57131
So what else could affect and lower adenosine deaminase? What would someone do to raise it?
Does low inosine cause dry skin? Thank you for your help.
 

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