Inhibition of adenosine deaminase (ADA)-mediated metabolism of cordycepin by natural substances
Cordycepin, which is an analogue of a nucleoside adenosine, exhibits a wide variety of pharmacological activities including anticancer effects. In this study, ADA1- and ADA2-expressing HEK293 cells were established to determine the major ADA isoform responsible ...
www.ncbi.nlm.nih.gov
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
^ 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.
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