Hesperidin enhances angiogenesis via modulating expression of growth and inflammatory factor in diabetic foot ulcer in rats
Rats with induced diabetes & ulcers were given Hesperidin orally, at does 10mg/kg - 80mg/kg .
Group I = non-diabetic non-wounded controls
Group II = non-diabetic wounded
Group III = diabetic wounded
Group IV =10mg/kg - Group VIII = 80mg/kg Hesperidin treatment
Group IX = Insulin treatment
The right CT50 = days to see wounds close
^ Shows us Hesperidin gives a linear response at correcting blood sugar back to normal levels & accelerates wound healing
significant starting at 20mg/kg and max effect at 80mg/kg rat weight. which is ~200mg/300mg - 800mg/1000mg human dose.
and i think this shows us Hesperidin accelerates wound healing in general (not just by correcting diabetes) -
if you look at groups VII & VIII , compared to the non-diabetic wounded group II , it shows wounds heal much faster than healthy control rats. amazingly it gave 3x faster healing at 800mg dose. 10 days vs 31 days
Hesperidin increases growth factors, increases hydroxyproline for collagen increase, & reduces oxidative damage
~500mg human dose also shown to protect brain tissue in diabetes
Hesperidin is found in orange juice. the amount varies but maybe 50mg/100ml. or readily available as a supplement.
At first I was apprehensive about taking it , as Hesperidin is a MAO-A inhibitor (mao-a inhibitors raise serotonin).
and it inhibits MAO-A in the brain along with reducing the decrease in tryptophan hydroxylase 1 shown in PTSD model Antidepressant-Like Effects of Hesperidin in Animal Model of Post-Traumatic Stress Disorder - PubMed.
showing it raised serotonin in the hippocampus. and the dose was ~200mg - 1g human
but
1. not sure how significant the rise is, can't see the results. i wonder if it just restored levels to normal controls (i.e wouldn't see much change without ptsd)
2. Hesperidin is also a MAO-B inhibitor and COMT inhibitor -> so (if the neurotransmitter rise is significant) , it should have a balanced elevation across neurotransmitters including dopamine and norepinephrine http://impactfactor.org/PDF/IJPCR/7/IJPCR,Vol7,Issue3,Article11.pdf
and 3.
*Hesperidin antagonizes a bunch of serotonin receptors. its used to increase appetite in cancer because of this.
and it probably activates the 5ht1a autoreceptor (as blocking the 5ht1a receptor gets rid of its antidepressant effect) (meaning it creates lower serotonin transmission in the brain) , so any rise in serotonin might be simply due to the lower serotonin receptor activeness / autoreceptor activation
It inhibits the 5-HT2B , 5-HT2C, and 5-HT6 receptors.
but it agonises the 5-HT4 receptor
(there's some controversy whether agonising 5-ht4 is actually good for bowel function. but considering Hesperidin works in vivo to improve constipation , and its oxidation damage protection and anti cancer effect , should be good here)
hesperidin improves constipation Hesperidin Improves Colonic Motility in Loeramide-Induced Constipation Rat Model via 5-Hydroxytryptamine 4R/cAMP Signaling Pathway
The analysis of our data suggested that hesperidin could obviously improve the gastrointestinal transmission function in loperamide-induced STC rat model
also:
*Hesperidin is an estrogen inhibitor. reduces estrogen in plasma in rats. in vivo - 120mg - 500mg / kg of food reduced estrogen in serum
(It reduces estrogen in cancer which is one of the mechanisms for it inhibiting cancer progression)
*does not lower iron , is protective against overload toxicity
*Something to know is it inhibits the CYP3A4 enzyme at 5-15mg/kg in rats but not at 1mg/kg, human dose ~60mg -200mg+ but not at 12mg
so if you're taking certain medications this could stop the break down of them & lead to harmful levels potentially. if its a problem the 10mg dose can still have some benefits.
*may agonise Gaba A, dopamine d2 receptors, opioid receptors for a couple hours post dosing
(not sure how significantly, but i wouldn't dose too high as gaba A agonists can come with rebound anxiety)
*protects against harm of toxic heavy metals
Protective in heart & brain against arsenic at 1g
Also works at a lower dose, 400mg-500mg against cadmium https://journals.sagepub.com/doi/10.1177/0748233716665301
*protection of red blood cells (erythrocytes) in lead toxicity (Dafflon is diosmin + hesperidin, they're similar compounds - when used together they are good for vascular function against venous insufficiency). Group II red is lead Group IV green is supplement
*500mg hesperidin is protective against radiation Hesperidin attenuates brain biochemical changes of irradiated rats - PubMed
*in low doses its also good in cancer as it restores appetite through ghrelin. proven at 50mg-70mg human dose for majority of the effect (59% appetite restoration)
*inhibits prostate cancer Hesperidin Suppresses the Proliferation of Prostate Cancer Cells by Inducing Oxidative Stress and Disrupting Ca2+ Homeostasis
*lower doses work too, ~150mg human dose prevents chemically induced lung cancer Antioxidant and anticancer efficacy of hesperidin in benzo(a)pyrene induced lung carcinogenesis in mice - PubMed , protects mitochondrial function and ATP generation Hesperidin attenuates mitochondrial dysfunction during benzo(a)pyrene-induced lung carcinogenesis in mice - PubMed
*its active even at very low doses for some things. shows an anti-depressant effect in rats at 3mg - 5mg human dose.
supplementation with water-dispersible hesperetin was able to positively impact blood flow in women with cold sensitivity within 70 min after intake [80]. Both concentrations of 17 mg and 170 mg significantly suppressed the drop in blood flow in the air-conditioned room at 22 °C
Interesting one-> *Reverses aging when taken later in life
https://jbiomedsci.biomedcentral.com/articles/10.1186/s12929-022-00838-7
(hesperidin breaks down to hesperitin in the body)
changing their genetic expression to match that seen in youth. it wasnt profound enough to move them back completely to youth of course. but shifted them more towards that across many measures its actually a great effect. some measures were actually profound enough to match youthful measures.
e.g glycogen synthesis restored completely, reversal of glyclolysis.
it improved muscle function, lymphocyte count,
their metabolism completely restored and even EXCEEDED youthful levels in oxygen consumption and basal energy expenditure during light period, & all measures went up significantly higher than non treated aged rats. their mitochondria is thriving again
their lean body mass % went way up and their muscle performance went up a lot. their heart function improved.
lifespan increase:
amazing study
amazing effects for 1 thing with a great safety profile (as long as you watch out for the CYP450 enzyme inhibition when taking at the same time as some medications)
2 things that stood out on baseline measures after , there's a slight drop in magnesium. and a big increase in fasting insulin.
"The dose used in this study is an achievable dose in humans and is a human equivalent dose of 491 mg/60 kg/day" , over 3 to 6 months.
Hesperi tin is harder to find as a supplement than hesperidin. but the body breaks hesperidin down into hesperetin
"Bioavailability Is Improved by Enzymatic Modification of the Citrus Flavonoid Hesperidin in Humans: A Randomized, Double-Blind, Crossover Trial"
~180mg 2.92mg/kg body weight of hesperidin cMax in blood of hesperetin = 1.07
~80mg 1.21mg/kg body weight of hesperetin cMax in blood of hesperetin = 2.66
takes 7 hours to get there taking hesperidin vs hesperetin 30 mins
so assuming thats linear , 80mg hesperetin = 450mg hesperidin for same dose of hesperetin in blood. need 5.5x hesperidin to get same amount of hesperetin.
491mg hesperetin = 2.5g hesperidin
but maybe hesperidin works similar at a regular dose
For toxic metals protection I think a combo of:
500mg vit C (too much may be serotonergic in gram amounts. but 500mg is proven protection against toxic metals) , (plus you get the added bonus of Vit C inhibiting conversion of nitrates into nitrites - which is high in drinking water , and nitrites are cancerous when combined with amines in certain foods in stomach at the same time)
+ 125mg taurine (if 500mg isn't tolerated this dose still has a significant effect which takes 7 days to hit fully),
+ hesperidin at 400mg - 500mg , if not then 150mg should have a good effect still
^These should give good sufficient protection against the majority of toxic metal effects.
and adding +10mg zinc picollinate, replenishing copper that's probably being lost,
ray peat:
Assuming damaged red blood cells & white blood cells need to renew to gain the benefits of the new protection, should take up to 120 days to see full renewal for full effect of the protection.
For diabetes / wound healing
800mg should work well if tolerated. with effects hitting at 200mg
Rats with induced diabetes & ulcers were given Hesperidin orally, at does 10mg/kg - 80mg/kg .
Group I = non-diabetic non-wounded controls
Group II = non-diabetic wounded
Group III = diabetic wounded
Group IV =10mg/kg - Group VIII = 80mg/kg Hesperidin treatment
Group IX = Insulin treatment
The right CT50 = days to see wounds close
^ Shows us Hesperidin gives a linear response at correcting blood sugar back to normal levels & accelerates wound healing
significant starting at 20mg/kg and max effect at 80mg/kg rat weight. which is ~200mg/300mg - 800mg/1000mg human dose.
and i think this shows us Hesperidin accelerates wound healing in general (not just by correcting diabetes) -
if you look at groups VII & VIII , compared to the non-diabetic wounded group II , it shows wounds heal much faster than healthy control rats. amazingly it gave 3x faster healing at 800mg dose. 10 days vs 31 days
Hesperidin increases growth factors, increases hydroxyproline for collagen increase, & reduces oxidative damage
The results advocate angiogenesis activity of HSP was enhanced owing to reduction in hyperglycemia and oxidative stress–induced damage, reduced expression of inflammatory mediators, and enhanced expression of growth-related factors, thereby promoting healing of diabetic foot ulcer.
Results in the investigation envisaged advocate angiogenesis effect in diabetic wound induced in rats after treatment with HSP. Supporting aspects include reduced HbA1C and increase in HOMA-IR values. Wound healing was also measured using CT50 value and wound dimensions, thereby revealing efficacy of wound-healing potential of HSP.
Reduction of inflammatory mediators such as TNF-α and IL-6 also marks acceleration in wound healing. Increase in level of hydroxyproline after HSP administration, marks tissue repair by increase in collagen in tissues. Increase in the expression of VEGF was identified by mRNA quantification, revealing angiogenesis with administration with HSP
~500mg human dose also shown to protect brain tissue in diabetes
Hesperidin is found in orange juice. the amount varies but maybe 50mg/100ml. or readily available as a supplement.
At first I was apprehensive about taking it , as Hesperidin is a MAO-A inhibitor (mao-a inhibitors raise serotonin).
and it inhibits MAO-A in the brain along with reducing the decrease in tryptophan hydroxylase 1 shown in PTSD model Antidepressant-Like Effects of Hesperidin in Animal Model of Post-Traumatic Stress Disorder - PubMed.
showing it raised serotonin in the hippocampus. and the dose was ~200mg - 1g human
but
1. not sure how significant the rise is, can't see the results. i wonder if it just restored levels to normal controls (i.e wouldn't see much change without ptsd)
2. Hesperidin is also a MAO-B inhibitor and COMT inhibitor -> so (if the neurotransmitter rise is significant) , it should have a balanced elevation across neurotransmitters including dopamine and norepinephrine http://impactfactor.org/PDF/IJPCR/7/IJPCR,Vol7,Issue3,Article11.pdf
and 3.
*Hesperidin antagonizes a bunch of serotonin receptors. its used to increase appetite in cancer because of this.
and it probably activates the 5ht1a autoreceptor (as blocking the 5ht1a receptor gets rid of its antidepressant effect) (meaning it creates lower serotonin transmission in the brain) , so any rise in serotonin might be simply due to the lower serotonin receptor activeness / autoreceptor activation
Ki - inhibition potential Hesperidin itself has a Ki towards the 5-HT2B receptor (5.3µM), the 5-HT2C receptor (20.9µM), and the 5-HT6 receptor (21.9µM), and while the affinity on 5-HT2B is significantly less than related flavonoids nobelitin (310nM), tangeretin (590nM), and 3,3',4',5,6,7,8-heptamethoxyflavone (210nM) it was the only tested flavonoid with inhibitory actions on 5-HT6 while only isoliquirtigenin (licorice) also inhibited 5-HT2C.[
It inhibits the 5-HT2B , 5-HT2C, and 5-HT6 receptors.
but it agonises the 5-HT4 receptor
(there's some controversy whether agonising 5-ht4 is actually good for bowel function. but considering Hesperidin works in vivo to improve constipation , and its oxidation damage protection and anti cancer effect , should be good here)
hesperidin improves constipation Hesperidin Improves Colonic Motility in Loeramide-Induced Constipation Rat Model via 5-Hydroxytryptamine 4R/cAMP Signaling Pathway
The analysis of our data suggested that hesperidin could obviously improve the gastrointestinal transmission function in loperamide-induced STC rat model
also:
*Hesperidin is an estrogen inhibitor. reduces estrogen in plasma in rats. in vivo - 120mg - 500mg / kg of food reduced estrogen in serum
(It reduces estrogen in cancer which is one of the mechanisms for it inhibiting cancer progression)
*does not lower iron , is protective against overload toxicity
*Something to know is it inhibits the CYP3A4 enzyme at 5-15mg/kg in rats but not at 1mg/kg, human dose ~60mg -200mg+ but not at 12mg
so if you're taking certain medications this could stop the break down of them & lead to harmful levels potentially. if its a problem the 10mg dose can still have some benefits.
Compared with the control group (given diltiazem alone), hesperidin (5 or 15 mg/kg) significantly altered the pharmacokinetic parameters of diltiazem, except for 1 mg/kg hesperidin. The area under the plasma concentration-time curve from time 0 h to infinity (AUC0-∞) was significantly (5 mg/kg, P < 0.05; 15 mg/kg, P < 0.01) increased by 48.9–65.3% and the peak plasma concentration (Cmax) was significantly (P < 0.05) increased by 46.7–62.4% in the presence of hesperidin (5 or 15 mg/kg).
*may agonise Gaba A, dopamine d2 receptors, opioid receptors for a couple hours post dosing
(not sure how significantly, but i wouldn't dose too high as gaba A agonists can come with rebound anxiety)
*protects against harm of toxic heavy metals
Protective in heart & brain against arsenic at 1g
HES co-treatment has an antioxidant, anti-inflammatory, antiapoptotic effect on SA-induced toxicity and aids to protect tissue architecture by showing a regulatory effect on all values. Consequently, it was determined that HES co-treatment had a protective effect on SA-induced heart and brain toxicity in rats.
Also works at a lower dose, 400mg-500mg against cadmium https://journals.sagepub.com/doi/10.1177/0748233716665301
Cd administration significantly decreased the mitochondrial electron transport chain complexes (I, II, III and IV) in the brain of rats. Preadministration of Hp (40 mg/kg b.w., oral) significantly attenuated the Cd-induced oxidative stress and mitochondrial dysfunction, restored the antioxidant and membrane-bound enzyme activities and decreased apoptosis in the brain of rats.
*protection of red blood cells (erythrocytes) in lead toxicity (Dafflon is diosmin + hesperidin, they're similar compounds - when used together they are good for vascular function against venous insufficiency). Group II red is lead Group IV green is supplement
*500mg hesperidin is protective against radiation Hesperidin attenuates brain biochemical changes of irradiated rats - PubMed
Hesperidin treatment has significantly attenuated oxidative stress, monoamines alterations and mitochondrial damage in the cerebral hemispheres of irradiated rats.
*in low doses its also good in cancer as it restores appetite through ghrelin. proven at 50mg-70mg human dose for majority of the effect (59% appetite restoration)
Hesperidin by itself at 5mg/kg orally to rats (where anorexia was induced by cisplatin) appears to attenuate the reduction in food intake seen with cisplatin by 59% while as a potency comparable to 1,000mg/kg Rikkunshito but lesser than the synthetic 5-HT2C receptor antagonist SB242084HCl (full negation),[33] and the attenuation of anorexia seen with all of the three aforementioned was prevented with a GHS-R1a (Growth hormone secretagogue receptor) antagonist,[33] which is the receptor that Ghrelin acts upon
hesperidin has been reported to ameliorate the delay in gastric emptying induced by 5-HT. Previous studies have shown that hesperidin has an an-tagonistic effect for 5-HT2B and 2C receptors and restores the plasma level of ghrelin after administration of cisplatin
*inhibits prostate cancer Hesperidin Suppresses the Proliferation of Prostate Cancer Cells by Inducing Oxidative Stress and Disrupting Ca2+ Homeostasis
*lower doses work too, ~150mg human dose prevents chemically induced lung cancer Antioxidant and anticancer efficacy of hesperidin in benzo(a)pyrene induced lung carcinogenesis in mice - PubMed , protects mitochondrial function and ATP generation Hesperidin attenuates mitochondrial dysfunction during benzo(a)pyrene-induced lung carcinogenesis in mice - PubMed
*its active even at very low doses for some things. shows an anti-depressant effect in rats at 3mg - 5mg human dose.
supplementation with water-dispersible hesperetin was able to positively impact blood flow in women with cold sensitivity within 70 min after intake [80]. Both concentrations of 17 mg and 170 mg significantly suppressed the drop in blood flow in the air-conditioned room at 22 °C
Interesting one-> *Reverses aging when taken later in life
https://jbiomedsci.biomedcentral.com/articles/10.1186/s12929-022-00838-7
(hesperidin breaks down to hesperitin in the body)
that makes it sound like a superpower compound lol.Hesperetin, a promising Cisd2 activator, when orally administered late in life, enhances Cisd2 expression and prolongs healthspan in old mice.
Secondly, hesperetin functions mainly in a Cisd2-dependent manner to ameliorate age-related metabolic decline, body composition changes, glucose dysregulation, and organ senescence.
Finally, a youthful transcriptome pattern is regained after hesperetin treatment during old age.
changing their genetic expression to match that seen in youth. it wasnt profound enough to move them back completely to youth of course. but shifted them more towards that across many measures its actually a great effect. some measures were actually profound enough to match youthful measures.
e.g glycogen synthesis restored completely, reversal of glyclolysis.
it improved muscle function, lymphocyte count,
their metabolism completely restored and even EXCEEDED youthful levels in oxygen consumption and basal energy expenditure during light period, & all measures went up significantly higher than non treated aged rats. their mitochondria is thriving again
To study the anti-aging and beneficial effects of hesperetin on age-related metabolic decline, we examined the whole-body energy metabolism and body composition of the old mice treated with hesperetin. Our results reveal that the VO2, CO2 and EE of Veh-treated old (28-month old) WT mice were significantly decreased compared to young (3-month old) WT mice. Importantly and intriguingly, hesperetin treatment for 6 months attenuates these age-related reductions that affect the whole-body metabolism of the old mice during their dark period
their lean body mass % went way up and their muscle performance went up a lot. their heart function improved.
^ holy ***tInterestingly, after 3 months of hesperetin treatment (Fig. 5K), the ultrastructural damage to the aged heart had largely disappeared and seem to have been reversed resulting in the ICD features and mitochondria
now resembling the situation observed in the hearts of 3-month WT mice
lifespan increase:
8.7% , up to 13.9% lifespan increase (and thats starting supplementation at old age, probably more lifespan increase starting middle age).The median lifespan of the hesperetin-treated WT mice was increased by 2.25 months (8.7%; from 25.95- to 28.2-month old) relative to Veh-treated WT mice (p = 0.04), with the maximum lifespan increase being 4.1 months (13.9%; from 29.5- to 33.6-month old)
amazing study
amazing effects for 1 thing with a great safety profile (as long as you watch out for the CYP450 enzyme inhibition when taking at the same time as some medications)
2 things that stood out on baseline measures after , there's a slight drop in magnesium. and a big increase in fasting insulin.
"The dose used in this study is an achievable dose in humans and is a human equivalent dose of 491 mg/60 kg/day" , over 3 to 6 months.
Hesperi tin is harder to find as a supplement than hesperidin. but the body breaks hesperidin down into hesperetin
"Bioavailability Is Improved by Enzymatic Modification of the Citrus Flavonoid Hesperidin in Humans: A Randomized, Double-Blind, Crossover Trial"
~180mg 2.92mg/kg body weight of hesperidin cMax in blood of hesperetin = 1.07
~80mg 1.21mg/kg body weight of hesperetin cMax in blood of hesperetin = 2.66
takes 7 hours to get there taking hesperidin vs hesperetin 30 mins
so assuming thats linear , 80mg hesperetin = 450mg hesperidin for same dose of hesperetin in blood. need 5.5x hesperidin to get same amount of hesperetin.
491mg hesperetin = 2.5g hesperidin
but maybe hesperidin works similar at a regular dose
For toxic metals protection I think a combo of:
500mg vit C (too much may be serotonergic in gram amounts. but 500mg is proven protection against toxic metals) , (plus you get the added bonus of Vit C inhibiting conversion of nitrates into nitrites - which is high in drinking water , and nitrites are cancerous when combined with amines in certain foods in stomach at the same time)
+ 125mg taurine (if 500mg isn't tolerated this dose still has a significant effect which takes 7 days to hit fully),
+ hesperidin at 400mg - 500mg , if not then 150mg should have a good effect still
^These should give good sufficient protection against the majority of toxic metal effects.
and adding +10mg zinc picollinate, replenishing copper that's probably being lost,
ray peat:
The protein, metallothionein, is rich in sulfhydryl groups, which bind heavy metals. It is assumed that this protein helps to detoxify and eliminate the toxic metals. This protein is induced by exposure to either a heavy metal or cortisol. A larger amount is produced in response to the combination of heavy metals and cortisol, than by either alone. Since copper, like the toxic metals cadmium, lead, mercury, and silver, reacts strongly with sulfhydryl groups, the body is likely to lose some copper when it is subjected to heavy metals or cortisol.
I think this chronic loss of copper accounts for the obvious features of aging, such as loss of elasticity of the skin, lungs, and blood vessels, the depigmentation (demelanization) of skin, hair, and (in Parkinson's disease) substantia nigra, and for the decrease in respiratory capacity. The replacement of the copper by iron (and the loss of the copper-enzymes which protect against iron-catalyzed free radicals) probably accounts for the increased formation of lipofuscin during aging. When copper-dependent mitochondrial respiration fails, lipofuscin has the ability to sustain energy production through glycolysis (by keeping the coenzyme NAD, nicotinamide adenine dinucleotide, relatively oxidized), so it is possible that lipofuscin is a primitive sort of defense against stress.
In animals, copper supplementation can restore natural color to white hair, and in one experiment, it increased longevity. At present, there isn't enough knowledge about the safety of different ways of administering supplemental copper. It can be toxic, and it oxidizes other nutrients.
Besides choosing foods high in copper and low in iron and other heavy metals, other dietary choices which support thyroid limction will tend to promote the retention of copper. Other dietary practices can minimize our production of cortisol
and adding iron as mostly heme iron if needed due to blood counts dropping (restoring red blood cells & saturating the metal transporter to prevent re-absorption of toxic metals).Besides the distortion of our food supply by the propaganda of the seed oil industry, there is increasing contamination of our food supply by heavy metals. Food additives are often contaminated with heavy metals from the sulfuric acid used in their manufacture. Many people are aware of the famous experiments in which food restriction increased the longevity of animals, as if eating were toxic. But removing toxic heavy metals from the food, without restricting the amount of food eaten, has had the same life-extending effect in experimental animals.
Assuming damaged red blood cells & white blood cells need to renew to gain the benefits of the new protection, should take up to 120 days to see full renewal for full effect of the protection.
For diabetes / wound healing
800mg should work well if tolerated. with effects hitting at 200mg
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