Astragalus

Astragalus membranaceus (of the family Fabaceae), or more commonly known as Astragalus, is a medicinal herb used in Traditional Chinese Medicine. According to Zhang et al. it "is the dry root of Astragalus membranaceus (Fisch.) Bge. or Astragalus membranaceus var. Mongholicus (Bge.) Hsiao of the Fabaceae family (and)...grows mainly in northern China, Mongolia and Siberia".^[1] Also known as Huang-Qi (Chinese), membranous milk-vetch root (English), ogi (Japanese) and Hwanggi (Korean), the roots are also sometimes referred to as Astragalus Radix; a mostly synonymous term.^[2] It tends to have a slightly warm and sweet taste when administered as a beverage made from root powder.^[2]

Using traditional terminology (Traditional Chinese Medicine), Astragalus Membranaceus has traditionally been used for disorders of the qi of the spleen; diarrhea, fatigue, and lack of appetite mostly.^[2] Its also implicated in 'yang qi' (stomach, uterine, and anal prolapse) and 'lung qi' (frequent colds, spontaneous sweating, loss of breath).^[2]

It is a central ingredient in several chinese herbal concoctions, one of which can be read up on in the Nutrient-Nutrient Interactions section under the entry of 'Angelicae Chinesis'.

It contains over 126 different components^[3], primarily flavonoids, saponins, and polysaccharides as the main bioactive components but also contains sucrose, amino acids, and phenolic acids.^[1]

As a herb, Astragalus Membranaceus contains:

The bolded ones are probably the ones that are most relevant to know

• Steroidal Saponins, Astragalosides I through VII, based on the cylcoastragenol backbone.^[4][5][6] Astrgaloside IV is at around 1083.14mcg/g dry weight of the root; or 1% of weight, without standardization^[7] although higher values have been recorded at 0.8-1.7% and 1.58%; root extracts tend to have a higher percentage than whole plant extracts.^[8][9][7]
• Related compounds known as isoastragalosides, I-III^[10][11][12]
• Astragalus Polysaccharides, two of them known as APS-I and APS-II. APS-I is a carbohydrate chain of arabinose and glucose in a 1:3.45 ratio, and APS-II is a chain of rhamnose, arabinose and glucose in a 1:6.25:17.86 ratio^[13]
• Astragalin, which is actually Kaempferol-3-O-b-Glucoside.^[14][4][14] This molecule may be the only bioactive polysaccharide, or at least the most prominent one, in Astragalus Membranaceus^[15] and at around 72.46mcg/g (0.073mg/g) dry root extract, and equally dispersed throughout the root and head of the plant.^[7]
• HDTIC isomers^[16]
• Formononectin and related glycosides.^[4][17] The glycoside of Formononectin-7-O-b-D-glycoside is also known as Ononin, and 6-acetylononin has also been seen in Astragalus.^[4][17][18]
• Dimethylhomoptercarpin and a glucoside^[4][17]
• Calycosin and related glycosides^[4][17] at 33.1mg per kg dried root extract^[10]
• {3R}-7,2'-dihydroxy-3',4'-dimethoxyisoflavan-7-O-beta-D-glucoside; a flavonoid^[4][17]
• Methylinissolin glycosides at 106mg per 1kg dried root, mostly methylinissolin-3-O-b-glucoside^[10]
• Licoagroside D, similar to methylinissolin structurally^[10]
• Isomucronulatol^[10][19]
• Other various, more common, flavonoids like kaempferol, quercetin, isorhamnetin, and rhamnocitrin^[20]
• Vesticarpan^[10]
• Pendulone, a benzoquinone^[10]
• Cyclocephaloside II^[21][10]
• GABA^[22]
• L-canavanine^[23]
• Astrapterocarpan^[24]
• Gluconic Acid^[2]
• An anti-proliferative lectin at 7.8mg per 5g root extract, glycoprotein in structure and relatively heat stable but not acid resistant^[25]
• The lignanoids bifenidate, (+)-Lariciresinol, and (–)-Syringaresinol ^[20]
• Choline and Betaine (trace amounts)
• Nicotinic Acid^[20]

The main ingredient of Astragalus Membranaceus is one of the Astragalosides, specifically Astragaloside IV. It is a steroidal saponin, but more specifically a cycloartane type triterpenoid glycoside.^[26] Its content in Astragalus plants is seen as a standard of quality. Other active ingredients that are noteworthy are the HDTIC isomers, the polysaccharides, and the flavonoids (half of the above list, anything deemed as having a 'glycoside').

The sum of all flavonoid compounds is probably at around 0.215+/-0.022mg Rutin equivalents/mL (measured by anti-oxidative capacity); a relatively low anti-oxidant capacity for a herb.^[27]

Astragalosides appear to be slightly unstable in methanolic solution; one study using a 20% methanolic solution noted that, over the course of 35 days at 5°C, Astragaloside I declined to 30% of originial content, astragalosides II and III between 50-75% of original content, while astragaloside IV and the polysaccharide Astragalin were near 100% after 35 days.^[7]

TA-65 is a brand name Astragalus Membranaceus extract orally dosed at 10-50mg daily, created and patented by TA Sciences and Geron Corporation; who wrote about it in this scholarly article.^[28] Looking at the patents^[29] it appears to be Astragaloside IV. TA-65 was shown to increase telomerase activity 2-3 fold in isolated human keratinocytes.^[28] It's highest activation in keratinocytes was at 0.1uM, and was able to induce activity at concentrations of 1nM in MRC5 cells.^[28] After oral ingestion in female mice, TA-65 at 25mg/kg bodyweight daily appears to preserve telomere length (note: Study also performed by a creator of TA-65).^[30] Additionally, standard health issues associated with aging (osteoporosis, insulin resistance, liver fat buildup) were apparently attenuated.^[30] These effects have been replicated in vitro with a 'related molecule' of TAT2, patented by Geron Corporation, albeit at a higher concentration.^[31] TAT2 appears to be the cycloastrogenol backbone.^[32] Said activation of telomerase could be vicariously through increasing TERT signalling, which was found to be 10-fold higher in the livers of treated rats;^[30] a mechanism which is shared by growth hormone^[33] and Akt.^[34] TA-65 does not directly influence Akt.^[30][31]

Application of 25mg/kg TA-65 was not able to significantly extend lifespan in said female mouse model, nor did it increase cancer incidence.^[30]

Unpublished data by TA Sciences suggest that circulating levels of TA-65 reach 1-20nM after 4-8 hours after ingestion of 5-100mg oral TA-65.^[28]

It seems to be effective in enhancing telomerase and reversing the aging phenotype, but the studies at this moment in time are somewhat confounded (all from sources which could profit) and an empirical enhancement of lifespan has not been shown. No mention whatsoever about the oral bioavailability of TA-65, whereas Astragaloside IV normally has poor (2.2%) bioavailability

Astragalus IV appears to have an apparent oral bioavailability of 2.2% in rats when serum was measured by HPLC with mass spectrometric detection after solid phase extraction^[26] and the one human study to attempt to measure Astragalosides in serum could not find any.^[20] In a model of Caco-2 cells, intestinal uptake of Astragaloside IV was maxed out at a concentration of 50ug/mL, and was not affected by co-incubation of P-glycoprotein inhibitors.^[26] Apical to Basolateral transport was linear between 15 and 120 minutes, with P_app values at 10, 20, and 30ug of 7.82, 6.19 and 5.95^10-8, respectively.^[26]

Unpublished data by TA Sciences (a producer of TA-65, patented Astragaloside IV) suggest that circulating levels of Astragaloside IV reach 1-20nM after 4-8 hours after ingestion of 5-100mg oral TA-65.^[28] Assuming linear absorption kinetics (5mg spiking serum levels by 1nM) and using a molecular weight of 784.97 ^[35] this equates to 0.00078g (0.078mg) circulating Astragaloside IV after 5mg oral ingestion, and thus a bioavailability of 1.5%; similar results to the rat study cited above.

The actual intestinal absorption of Astragaloside IV appears to be passively via a paracellular route, as evidenced by interactions with calcium ions in the intestinal lumen.^[36] The high molecular weight paired with paracellular transport may be a reason for it's low bioavailability, and it may be enhanced by compounds that reduce paracellular competition such as chitosan and sodium deoxycholate^[36] or perhaps compounds in whole Astragalus, as the whole plant appears to have greater uptake rate than unmodified and isolated Astrgaloside IV.^[26] As TA Sciences report a similar bioavailability, it is assumed their proprietary blend contains some modifications for bioavailability.^[28]

Astragaloside IV appears to have poor bioavailability, around 1.5-2.2%. Effects of Astragaloside IV in vitro would need to be near 1-5nM to be practical after oral administration

In regards to the flavonoid content of Astragalus Membranaceus; the compounds that have been found in human urine after consumption are calycosin and formononectin as well as their metabolites (both glucuronide, and calycosin sulfate).^[20] Dimethoxypterocarpan-3-O-b-D-glucuronide was also detected in urine, indicating that the parent dimethoxypterocarpan molecule was absorbed; Dihydroxy-2′,4′-dimethoxyisoflavan glucuronides are also detected.^[20] This information was derived from a study on a single person whose diet was highly controlled, but the sample size is a major limitation.

This study also noted that there was no detectable serum levels of saponins in the research subject, which they suggested is due to either low levels in the oral ingestion or poor bioavailability.^[20] Other compounds that were not flavonoids but exist in Astragalus (GABA, ferulic acid, HDTIC isomers, etc.) may not have been detectable due to either bioavailability or dosage.^[20]

Coingestion of the plant Angelicae Sinensis Radix may increase the bioavailability of the flavonoids Calycosin and Formononectin.^[37]

The flavonoid content, as well as glycosides of the flavonoids (this possibly being the polysaccharide content) appears to be absorbed; no evidence on the absolute bioavailability of this absorption though

At this moment in time, only preliminary studies on the pharmacology of Astragalus (the primary ingredient, astragalus IV) have been undertaken in dogs and rats; validating the LC/MS/MS using a triple quadrupole mass spectrometer method of analysis.^[38][39] There have been some more studies done on the isolated ingredient, Astragaloside IV.^[26]

When an oral dose of 20mg/kg bodyweight (isolated Astragalus IV) is given to rats, various measured parameters are a C_max of 0.38ug/mL, a T_max of 0.43 hours, a half-life of 4.65 hours, and an AUC to infinity of 1.06ug/mL/h.^[26]

Parameters in the blood look fairly normal, with a moderately long half-life; only real limitation with Astragaloside IV is the bioavailability

When looking at the volume of distribution at the central compartment, relative to total body water at 0.61kg rats had 0.201/kg and dogs 0.14+/-0.07 l/kg which suggests limited but present availability of Astragalus IV to peripheral tissues.^[39] When measuring Astragaloside IV levels in organs after injection, it appears that a limited amount can reach all measured organs (skin, stomach, heart, adipose, skeletal muscle, duodenum, spleen, ovary) with slightly higher levels reaching the lungs and kidneys and very high levels relative to other organs in the liver; minimal amounts of Astragaloside IV reached the brain, suggesting problems in crossing the blood brain barrier.^[39] Levels in these organs are high at 60 minutes after intravenous injection, and deplete rapidly to near baseline at 240 minutes after injection.^[39]

Appears to reach all organs, with more reaching areas that the herb is traditionally used for (lung and spleen) with a predictably high amount in the liver and relatively low amount in the brain

After IV injection, about 50% of Astragalus IV appears to undergo metabolism.^[39]

The flavonoid components of calycosin and formononectin appear to be subject to glucuronidation, and calycosin to sulphation, as evidenced by urinary glucoronides that did not exist in the parent plant.^[20]

Astragalus appears to have the ability to inhibit the CYP3A4 enzyme, and may increase the AUC of some pharmaceuticals when coingested.^[40][40]

Preliminary pharmacokinetic studies suggest that injection of 0.75mg/kg in rats (0.5mg/kg in dogs) showed that Astragalus had an elimination rate of 3ml/kg/min in rats and 4+/-1 ml/kg/min in dogs, which is about 5.43 and 12.9% of hepatic blood flow (respectively) and suggests low systemic clearance.^[41][39] Elimination half-lives for rats (at 0.75mg/kg) were 98.1 minutes and 60.02+/-8.39 in dogs, and these results are similar after oral administration of Astragalus in rats.^[26] The rate of elimination increases with dosages, as bolus injections of 0.75, 1.5 and 3 mg/kg Astragalus IV lead to elimination half-lives of 98.1, 67.2 and 71.8 minutes; respectively.^[39] Interestingly, this trend is reversed in females, with the same ascending dosages leading to elimination half-lives of 34.0, 66.9 and 131.6 minutes.^[39]

Does not appear to build up in the body, and is excreted both by the urine and by ejection through the liver into the intestines

The flavonoid components of calycosin and formononectin appear to be excreted in the urine, although this particular study did not measure fecal excretion.^[20]

This protective effect on mitochondria has been seen when evaluating the cristae in diabetic mice, where Astragalus at 700mg/kg daily was able to preserve mitochondrial structure.^[42] Mitochondrial membranes may be damaged via lipid peroxidation^[43] which is known to increase with age,^[44] Astragalus polysaccharides exert a dose-dependent inhibition of lipid peroxidation starting at a concentration of 2mg/L, and can inhibit upwards of 90% of lipid peroxidation in liver mitochondria and 78% in neurons at a concentration of 32mg/L.^[45] Astragalus also has been shown to prevent calcium-induced and oxidant-induced permeation of the mitochondrial membrane.^[45]

The mitochondria may also be a factor in some cardioprotective effects of astragalus,^[46] and is more effective when paired with Angelicae Sinensis in the chinese formulation of Dang-Gui Buxue Tang.^[47]

The HDTIC isomers from Astragalus have been shown to shorten the rate of telomere shortening in vitro;^[48] where control cells had a shortening rate of 71.1+/-4.9, 0.1uM of HDTIC-1 led to a reduced rate of 31.5+/-2.4 and 1uM of HDTIC-2 to 41.1+/-3.5 (note: numbers are based on length of telomeres (bd)/doubling of cell population(PD)) and protected the DNA from oxidative insult from hydrogen peroxide in a dose-dependent manner, and doses 10-fold higher than the above (1uM HDTIC-1, 10uM HDTIC-2) led to enhanced DNA repair (and reversal of phenotypic senescence) after H₂O₂ insult.^[49][48] The cell type was human fetal lung diploid fibroblast cells.^[48] This exact same dose and cell model has twice demonstrated slowed aging due to HDTIC isomers, with HDTIC-1 being more potent.^[48][16]

When investigating the mechanisms of action of HDTIC isomers, it appears they (in the same 2BS cell line) are able to prevent an age-associated upregulation of p16 mRNA and subsequent protein content, without affecting p26 mRNA expression.^[49] p16 is a CDKI of the INK4 family and is correlated with aging, and high expression may promote the aging phenotype.^[50][51]

Astragaloside IV has also been implicated in increasing telomerase activity and telomere length after oral ingestion of 5-10mg, so there may be more than one bioactive in Astragalus Membranceus contributing to telomere length.^[28] More information on this topic can be read under the heading of TA-65.

Whole Astragalus might be better than isolated Astragaloside IV due to bioactivity of HDTIC isomers towards telomere preservation; however, pharmacokinetic or in vivo data on oral HDTIC isomers is lacking

When looking at injections of Astragaloside IV and its body distribution, it appears that Astragaloside IV may have problems crossing the blood brain barrier as evidenced by lesser amounts accumulating in neural tissue than other organs.^[39]

An extract of Astragalus (63% Astragalosides) taken orally at 10-40mg/kg bodyweight was able to attenuate the pro-Alzheimer's effects of the drug Dexamethasone, a synthetic glucocorticoid with actions similar to cortisol in a dose-dependent manner.^[52] This extract was also able to preserve hippocampus neuronal structure and reduce adverse changes in caspase-3 and caspase-9, and suggests that Astragalus might protect from neurodegeneration from stress.^[52] These effects of preservation against stress have been noted previously with higher doses of regular Astragalus extract, and suggest the herb is adaptogenic.^[53]

It has been noted that the anti-inflammatory effects of Astragalus at doses of 40-80mg/kg bodyweight in rats are able to suppress the increase in TNF-α and IL-1β associated with cerebral Ischemia/reperfusion injury.^[54] This may lead to less neuronal death and nerve damage.^[55]

It is not known which ingredients contribute towards these effects, but despite limited absorption of Astragaloside IV it may be an active component. By itself, it can reduce damages associated with Ischemia/Reperfusion^[56][57] and general neuroprotection.^[58] When looking at the anti-stress effects of Astragalus, on a gram per gram basis the extract with more Astragalosides^[52] appears to be more potent than standard (1-2%) Astrgalus.^[53] The contribution of the flavonoid and polysaccharide fragments are not known.

Appears to be neuroprotective and adaptogenic. Probably due to the Astragaloside IV, but it hasn't been shown how the other bioactives contribute to these effects

Astragaloside IV, seems to partially protect the heart during myocardial ischemia and improved coronary heart flow vicariously through the Nitric Oxide Synthase enzyme.^[59] Sodium-Potassium channels have also been implicated in Ischemia-Reperfusion protection form Astragaloside IV.^[60]

Heart mitochondria are also protected by toxic insult (from Danourubicin) at 250mg/L bulk extract or greater with best results at 500mg/L, increasing the amount of Danourubicin needed to induce cell death.^[46] This was hypothesized to be secondary to alleviating oxidation and nuclear fragmentation of the mitochondria.^[46]

Astragaloside IV possesses an aortic relaxant effect, dilating and widening arteries.^[61] It seems to do this via the NO-cGMP pathway in the endothelium, and does so in a dose-dependent manner.^[62] Beyond direct relaxation, Astragalus can attenuate pro-contractile stimuli to the endothelium such as phenylephrine and angiotension-II, which gives Astragaloside IV two mechanisms of action.^[61]

Additionally, Astragaloside IV preserve relaxing stimuli (acetylcholine) during excessive exposure to homocysteine (inhibitor of acetylcholine actions)^[22] through its anti-oxidant actions, which is more general.^[63]

Endothelial benefit has been seen in a rat model of metabolic syndrome with injections of 0.5-2mg/kg Astragaloside IV,^[64] but has yet to be shown through oral ingestion.

Astragaloside IV appears to have potent endothelial protective effects, but it's practical relevance when orally ingested is not known

At least one human study using oral administration has noted decreased blood pressure associated with Astragalus ingestion (1,050mg daily) but was confounded with Coptis Chinensis (630mg daily) and Lonicera Japonic (2,520mg daily).^[65] A study in rats using a Shichimotsukokato (SKT) formula of Astragalus Membranaceus and 6 other herbs found blood pressure reductions in rats subject to nephrectomy by preventing downregulation of a key anti-hypertensive enzyme,^[66] and another study using 100-200mg/kg of a related Astragalus plant (Complanatus) found that the flavonoid content (similar in profile to Membranaceus) was able to reduce blood pressure by 17% after oral administration.^[67]

Although the flavonoid component of Astragalus seems suspect,^[67] Astragaloside IV injections have also been shown to reduce blood pressure in hypertensive rats at 0.5-2mg/kg bodyweight.^[64]

At least one in vitro study using a water extract of Astragalus Root in HEK293T cells noted dose-dependent increases in erythropoetin (EPO) expression and mRNA, measured at a 60% increase over baseline at 1mg/mL concentration.^[68] This was shown to be due to flavonoids rather than astragalosides or polysaccharides, and Calycosin-7-O-β-d-glucoside was shown to be most potent in more than doubling EPO mRNA (120%) with an EC₅₀ value of 1.47μM; these effects were secondary to an accumulation of Hypoxia-Inducible factor 1 (HIF-1) due to less degradation of HIF-1.^[68]

This section has interactions with both 'Lipid Metabolism' (in regards to lipoproteins) as well as 'Immunity and Inflammation' (in regards to cohesion factors and anti-inflammation); perusing all three sections would be prudent.

Astragalus (as polysaccharide) seems to be able to protect the receptor (ABCA1) responsible for reverse cholesterol transport from pro-inflammatory insult.^[69] Via inhibiting the effects of NF-kB in macrophages turned into foam cells, it may reduce plaque build-up in arteries from foam cells (one component of arterial plaque).^[70]

In a test as to whether Astragalus could prevent foam cell formation from macrophages, it was found ineffective in vitro.^[71]

One study with 90 patients of Chronic Heart Failure noted improved cardiac contractions with Astragalus (as Astralagus Granule), with 4.5g and 7.5g showing similar but better benefits than 2.25g daily. A dose-dependent response was seen in Quality of Life.^[72]

Astralagus is a highly studied herb in china, and is available as injections for the treatment of cardiac heart failure. There are numerous texts (in Chinese) available involving intervention studies via IV injection.^{[73][74][75][76][77]} (Articles given as example, vast majority not available through Medline Database)

That being said, a 2011 PLoS review (terminated prior to being a meta-analysis) noted that Astralagus as injections has a moderate to large body of literature (62 interventions) but of low methodological quality.^[78] This review calls for more controlled evidence in regards to Chronic Heart Failure.

Astragalus polysaccharide has been shown to reduce triglycerides by 30% after oral administration of 0.25g/kg bodyweight in hypercholesterolemic hamsters.^[79]

After oral administration of Astragalus Polysaccharides at 0.25g/kg in hypercholesterolemic rats, LDL-C and total cholesterol were both reduced by 45.8% and HDL-C by approximately 2.5% (value derived from graph).^[79] The mechanism of lipoprotein lowering appears to be mostly through bile salts and enhancing cholesterol efflux from the liver into the intestines; a process which may indiscriminately reduce all circulating lipoproteins.^[80][81] Other mechanisms that were identified were upregulation of the LDL receptor, inhibiting cholesterol absorption, and inducing cyp7α-1 gene expression.^[79] These results should be taken with a grain of salt, as inter-species differences between hamsters and humans have been noted in regards to HDL efflux.^[82]

Astragalus polysaccharide (APS) appears to be able to bind to bile acids, and has five times greater affinity for cholic acid when compared to a reference standard of psyllium husk on a gram per gram basis.^[15] As binding to bile acids in the intestines and causing their loss in the feces (indirectly stimulating cholesterol conversion to replace bile acids, and depleting systemic cholesterol) is a mechanism behind psyllium husk's cholesterol lowering abilities^[83][84] it is thought Astragalus Polysaccharide can reduce cholesterol by this same mechansim. This hypothesis is validated by a study done in hamsters, showing that 0.25g/kg bodyweight polysaccharides was able to reduce plasma cholesterol by 45.8% and LDL-C by 47.4%, with an additional benefit on reducing triglycerides by 30%.^[79]

Astragalus appears to be effective in preventing palmitate-induced insulin resistance as excess phosphorylation of IRS-1 by palmitate was inhibiting PTP1B (a negative regulator of insulin signalling) and NF-kB in muscle cells, improving glucose uptake by 25% of a concentration of 0.2mg/mL.^[85] This suppression of PTP1B, which indirectly potentiates insulin signalling, seems to be localized to skeletal muscle rather than liver tissue^[86] and may be important in improving peripheral insulin sensitivity.^[42] In vivo studies on diabetic rats suggest that increasing peripheral glucose metabolism via Astragalus can alleviate the state of type II diabetes induced by diet with oral doses of 400-700mg/kg bodyweight in diabetic rats.^[87][88][89] These effects are due to Astragalus Polysaccharides rather than the steroidal saponin content.^[85]

When looking at AMPK's role in skeletal muscle glucose uptake, the reduction of phosphorylation of AMPK seen with palmitate-induced insulin sensitivity is not reversed with Astragalus.^[85] Over time, however, AMPK can be restored to its baseline activity via Astragalus indirectly and eventually contribute to glucose homeostasis in skeletal muscle.^[88][87]

In myotubes that are not insulin resistant, however, Astragalus can prevent glucose toxicity via activation of AMPK.^[87]

The flavonoids from Astragalus, Formononectin and Calycosin, appear to interact with PPAR receptors. Formononectin is an agonist of PPARγ and PPARα with activation ratios between 3:1 and 1:1 depending on in vitro assay;^[90] it's EC₅₀ value was 2.6-4.3μmol/L on PPARγ and >1.0-3.7μmol/L on PPARα.^[90] These effects induced adipocyte differentiation, which is an anti-diabetic mechanism that is done by the pharmaceutical glass of thiazolidinedione (glitazone) compounds. The polysaccharide content of Astragalus may also share this mechanism^[91][92] as well as Astragaloside IV.^[93]

Finally, two other astragalosides (Astragaloside II and Isoastragaloside I) have been shown to increase adiponectin secretion from adipocytes (without affecting adipogenic genes) and, vicariously through this mechanism, improves the glucose parameters of rats who were suffered from metabolic syndrome both by diet and genetically induced models.^[94] Adiponectin mRNA increase to 1.2-fold control levels and enhanced the rate of secretion into medium from 80% to 100% at 5ug/mL concentration,^[94] and the in vivo experiment was done with a high dose of 50mg/kg bodyweight Astragaloside II + Isoastragaloside I for 6 weeks.^[94]

Astragalus appears to have the ability to, via adipocytes, improve glucose metabolism and possibly the diabetic state by a variety of mechanisms and compounds. Not much research on how it influences body fat, but it is possible it possesses a pro-obesogenic effect via increasing adipocyte differentiation

The flavonoids from Astragalus, Formononectin and Calycosin, appear to interact with PPAR receptors. Formononectin is an agonist of PPARγ and PPARα with activation ratios between 3:1 and 1:1 depending on in vitro assay;^[90] it's EC₅₀ value was 2.6-4.3μmol/L on PPARγ and >1.0-3.7μmol/L on PPARα.^[90] These effects induced adipocyte differentiation, which is an anti-diabetic mechanism that is done by the pharmaceutical glass of thiazolidinedione (glitazone) compounds. The polysaccharide content of Astragalus may also share this mechanism^[91][92] as well as Astragaloside IV.^[93]

Finally, two other astragalosides (Astragaloside II and Isoastragaloside I) have been shown to increase adiponectin secretion from adipocytes (without affecting adipogenic genes) and, vicariously through this mechanism, improves the glucose parameters of rats who were suffered from metabolic syndrome both by diet and genetically induced models.^[94] Adiponectin mRNA increase to 1.2-fold control levels and enhanced the rate of secretion into medium from 80% to 100% at 5ug/mL concentration,^[94] and the in vivo experiment was done with a high dose of 50mg/kg bodyweight Astragaloside II + Isoastragaloside I for 6 weeks.^[94]

Astragalus appears to have the ability to, via adipocytes, improve glucose metabolism and possibly the diabetic state by a variety of mechanisms and compounds. Not much research on how it influences body fat, but it is possible it possesses a pro-obesogenic effect via increasing adipocyte differentiation

One study using Boi-ogi-to, a herbal blend consisting of Astragalus (27%) and 5 other herbs in which Astragalus exerts a synergizing effect on the interaction between Boi-ogi-to and blood glucose/insulin betterment, significantly reduced weight gain assocaited with menopause in rats fed 1% Boi-ogi-to in their diet.^[95] Mechanism of Boi-ogi-to is unknown.

Beyond this one highly confounded study, Astragalus has not been highly studies in regards to weight loss.

Astragalus appears to be effective in preventing palmitate-induced insulin resistance as excess phosphorylation of IRS-1 by palmitate was inhibiting PTP1B (a negative regulator of insulin signalling) and NF-kB in muscle cells, improving glucose uptake by 25% of a concentration of 0.2mg/mL.^[85] This suppression of PTP1B, which indirectly potentiates insulin signalling, seems to be localized to skeletal muscle rather than liver tissue^[86] and may be important in improving peripheral insulin sensitivity.^[42] In vivo studies on diabetic rats suggest that increasing peripheral glucose metabolism via Astragalus can alleviate the state of type II diabetes induced by diet with oral doses of 400-700mg/kg bodyweight in diabetic rats.^[87][88][89] These effects are due to Astragalus Polysaccharides rather than the steroidal saponin content.^[85]

When looking at AMPK's role in skeletal muscle glucose uptake, the reduction of phosphorylation of AMPK seen with palmitate-induced insulin sensitivity is not reversed with Astragalus.^[85] Over time, however, AMPK can be restored to its baseline activity via Astragalus indirectly and eventually contribute to glucose homeostasis in skeletal muscle.^[88][87]

In myotubes that are not insulin resistant, Astragalus can prevent glucose toxicity via activation of AMPK, however.^[87]

The polysaccharide content of Astragalus (APS) has been investigated as a macrophage stimulator^[97][98] that appears to act via heparinase, an enzyme that potentiates the macrophage response, by increasing its activity.^[99] When Astragalus Polysaccharide is incubated with macrophages, APS appears to increase the production of cytokines from the macrophage (TNF-a, GM-CSF, and Nitric Oxide).^{[99][100][101]} This stimulation has been seen in vivo, by potentiating macrophage infiltration and phagocytosis (eating) of cells when injected into mice.^[96]

This is in contrast to the flavonoid content, as formononectin appears to be able to suppress NO release from LPS-stimulated macrophages.^[102] Studies investigating how Astragalus affects macrophages when coincubated with pro-inflammatory agents (Lipopolysaccharide is common) find that Astragalus is able to prevent LPS induced activation of iNOS in macrophages, and pro-inflammatory signalling from macrophages from excess Nitric Oxide production of iNOS^{[103][10][102]} and downstream pro-inflammatory factors such as TNF-a and IL-8.^[104] These effects on pro-inflammatory factors do not appear to be existent at lower doses without LPS, but can be forced with high concentrations of Astragalus.^[105][106]

Although the steroidal saponin (Astragaloside) content of Astragalus can influence immunity,^[107][108] most beneficial effects are secondary to the Astragalus polysaccharide content.

Astragalus polysaccharide appears to induce secretion of pro-inflammatory cytokines and stimulate immune cell production when there is no pro-inflammatory insult, but actively prevent large pro-inflammatory signals from acting on macrophages that would induce large spikes of inflammation. There is biological plausibility for Astragalus' claim to be an 'immune system modulator'

Via inhibition of NF-kB, the downstream effects of TNF-a induced expression of VCAM-1 and ICAM-1 are reduced; with lesser expression of these cellular adhesion molecules, there is less leukocyte migration into tissues.^[109] This mechanism may also exert anti-atherogenic effects against plaque build-up from foam cells, which are basically dead macrophages.^[109]

Both Astragalus Polysaccharides as well as Astragaloside IV are implicated in the inhibition of NF-kB that result in less VCAM-1 and ICAM-1 recruitment; the anti-inflammatory effects.^{[110][111][100]}

It shows mitogenic (encourages cell proliferation) effect on T cells in vitro on mouse and human cells when the T cells were depleted, but had no effect on B cells. It was highly mitogenic on splenocytes, where it can increase receptor content of IL-6 receptors.^[96]

It has been shown to activate mouse B cells via expression of membranous immunoglobulins and Macrophages via TLR4; T cells were unaffected in this study^[112] but noted with coadministration of an antigen.^[113] Upregulation of TLR4 has been noted in other studies.^[114][113]

Suppression of Tregs cells has also been noted and subsequent suppression of Foxp3 and IL-10^[113][115], and appears to be mediated through TLR4 in vivo.^[115] However, at least one study in mice noted upregulation or Treg activities.^[116]

It may also be involved in maturation of dendritic cells.^[117]

After administration of HT042 (mixture of Astragalus Membranaceus root, Phlomis umbrosa root, and Eleuthercoccus Senticoccus stem at a 31.2:26.5:42.3 ratio) at 200mg/kg bodyweight daily in 2 divided doses for 3 weeks was found enhance bone length and thickness in adolescent rats, which may be related to higher circulating IGF-1 levels.^[118] Astragalus is one of a few herbs traditionally used (in Korea) to enhance growth in youth.^[118][119] Astragalus has been shown, in isolation, to increase IGF-1 levels in serum in rats with cerebral degeneration.^[120]|published=2007 Feb|authors=Wu HL, Zhou HJ|journal=Zhongguo Zhong Yao Za Zhi]

Might increase circulating IGF-1 levels, but needs more research on it

Astragalus Membranaceus at doses between 100-1000mg/kg bodyweight, in rats, can attenuate the negative effects on sperm from cyclophosphamide by 9-49% (in regards to motility, with a dose-dependent relationship); suggesting it may help preserve male fertility.^[121] Astragalus was able to preserve expression and protein content of cAMP response element modulator protein (CREM),^[121] which is normally reduced after cyclophophamide injections and suppressed in infertile men.^[122] Testosterone was not measured in this study, and no direct studies into Astragalus' effects on testosterone have been conducted.

When assessing the influence of astragalus on the androgen receptor, 20μg/mL does not appear to significantly influence signalling.^[123]

In a screening of medicinal herbs for estrogenic or antiestrogenic effects, the 95% ethanolic extract of Astragalus failed to exert any significant interactions with the estrogen receptor at concentrations below 1mg/mL.^[124]

In humans, Astragalus has been implicated in reducing the amount of damage done to the kidneys done by shock wave lithotripsy; a clinical treatment for urinary calculi. The results, however, were confounded with 10 other herbs.^[125] Astragalus in isolation has been implicated in kidney protection elsewhere, as an injection of astragalus prior to cardiopulmonary bypass surgery can reduce adverse effects on the kidneys,^[126][127] help with nephritis associated with lupus,^[128] diabetic nephropathy,^[129] and IgA-associated and general nephropathy.^[130][131] At least for clinical usage of Astragalus, it's protective effects on kidney function during disease states has been said to be significant according to one meta-analysis^[132] which agrees with prior consensus on animal studies.^[1][133] At least one case study has noted that 15g oral ingestion in a human was associated with recovery from renal pathology in a situation where said person was unresponsive to medication.^[134]

Despite the large body of evidence on Astragalus' effects on kidney tissue, many of the studies are conducted with Astragalus injections. Oral doses appear to be effective, but all recorded oral dosages are quite high relative to preventative health doses of 500-1,000mg.

The mechanism of protection seems to be in part anti-oxidative^[135] and anti-inflammatory effects, in which 1g/kg (oral rat dose) astragalus polysaccharide was shown to reduce NF-kB activation in kidney tissue^[136] and other studies using Astragalus note downregulation of TGF-b; a biomarker of inflammatory renal damage.^[137][113]

Astragalus has been associated with increasing diuresis (urination) at an oral dose of 0.3g/kg bodyweight in humans.^[138] The mechanism is through enhancing the effects of atrial natriuretic peptide (ANP) on kidney tissue within 4 hours after ingestion, and although the bioactive responsible is unknown it is not Astragaloside IV.^[138]

Although the effects of Astragalus on protecting the kidneys during disease states appears to be quite potent and reliable, its effects on the kidneys as a preventative medicine at basic oral doses is not known. It seems likely that Astragalus as a supplement would confer protection, but it has not been demonstrated

The above notice is prudent as the active ingrient of Astragalus has not been located and polysaccharides, flavonoids, and Astragaloside IV are all suspect; due to low oral bioavailability of Astragaloside IV, low doses of Astragalus may not confer renal protective effects if taken orally yet exert them with intravenous injections

In a mouse model, astragalus appears to restore depressed immune function of animals who possessed tumors^[96] and the depressed mitogenic response in these animals.^[139]

It shows cytostatic ability against myeloid-like and macrophage-like tumors,^[139]

After oral administration of Astragalus in a mouse model of Atopic Dermatitis at an oral dose of 100mg/kg bodyweight is able to suppress skin reactions in response to 2,4-dinitrofluorobenzne, a chemical used to induce dermatitis, and was more effective than 3mg/kg bodyweight Prednisone at this suppression of outbreak.^[140] When looking at the mechanisms, Astragalus was not able to inhibit the rise in IgE (raised levels of which are a hallmark of atopic dermatitis) nor the rise in IL-4 (aids in conversion of IgM to IgE), but still seemed to suppress inflammation.^[140] The mechanisms may be through IFN-y suppression, of which Astragalus and Prednisone were of equal potency.^[140]

Via it's ability to inhibit MMPs, specifically MMP1, astragalus may be able to protect the skin from photoaging induced by UV irradiation.^[141] It is able to reduce both mRNA transcription and subsequent protein content of MMP-1 in vitro, perhaps secondary to inhibition of fibroblast ERK phosphorylation or NF-kB translocation.^[141]

Additionally, the putative components HDTIC-1 and 2 seem to preserve human fibroblast quality and negate the visible effects of aging in vitro at concentrations of 0.1uM and 1uM, respectively.^[16] The potency was of HDTIC-2 at 1uM was similar to carnosine at 20mM, while HDTIC-1 at 0.1uM was more effective; protein glycosylation and oxidation was also lower in cells incubated with HDTIC isomers.^[16]

Via mechanisms that parallel anti-inflammatory mechanisms (MMP-1, NF-kB), Astragalus may protect protect the skin from harmful insults. The best estimate of a topical dose is 0.5% (from skin healing rate studies), and best delivered via a hydrogel with sodium alginate at 1% (with gelatin and 1:100 DimethylSulfoxide:Astragalus for solubility)

Interestingly, another component of Astragalus Membranaceus called calycosin (a flavonoid) seems to be able to inhibit melanin pigmentation formation in skin cells by inhibiting tyrosinase;^[142] suggesting that calycosin may reduce tan formation and lighten skin.

Astragaloside IV, the main ingredient of Astragalus, is effective in increase keratinocyte migration and subsequent wound healing at concentrations of 100umol/L, which in vitro models suggest doubles to triples the rate of wound healing (as keratinocytes are recruited to form a new layer of skin).^[143] Rat models showed that with daily topical administration of a 0.5% Astragaloside IV solution to the wound, that 21% of wound healing was complete at day 6 after the wound was inflicted, rather than 8% in the control group.^[143] At day 30, the Astragaloside IV group had full healing whereas control had notable scarification.^[143]

Skin Healing rates have been shown elsewhere with Astragalus (0.25g) combined in a hydrogel made from sodium alginate (1%) and gelatin, applied daily, which was significantly more effective at accelerating wound healing than basic Astragalus solution.^[144]

As mentioned in the Nutrient-Nutrient interactions section, pairing Astragalus with Rehmanniae Radix may synergistically enhance wound healing.

Application of 25-100umol/L Astragaloside IV to a wound can significantly suppress TGF-b secretion in vitro in fibroblasts,^[143] yet increase circulating levels of TGB-b.^[144] TGF-b is seen as crucial to the formation of scar tissue from wounds.^[145] A TGF-b inhibitor (Mannose-6-Phosphate, aka. Juvidex) has once before been shown to reduce scar formation and accelerate wound healing.^[146] After 30 days of treatment with Astragaloside IV, scars induced by wounds are not noticeable.^[143]

Astragalus Membranaceus may be more effective than isolated Astragaloside IV, as another component of AM extract (formononectin) is also able to accelerate wound healing.^[147]

One study using Astragalus for the purpose of reducing allergic rhinitus noted that the pairing of Astragalus Membranaceus with calcium-aluminum silicate as a mineral carrier was found to be synergistic in unpublished preclinical trials, but did not give indication as to the parameter(s) it was synergistic with.^[148] The blend of the two is patented with the Croatian Ministry of Health and sold as Lectranal.^[148]

Salvia miltiorrhiza, also known as Danshen, has been tested in conjunction with Astragalus Membranaceus at a 1:1 ratio for its effects on Fatigue. This concoction, known as Myelophil, was administered at either 3g or 6g daily for 4 weeks and was noted to decrease fatigue relative to control.^[149] However, the control did use a herbal concoction themself as an active placebo (Hyangsapyunweesan) and the group seeing the most benefit (3g) was significantly worse off at baseline.

Angelicae Sinensis Radix, also known as Dang Gui, is the other herb that is found in the chinese herbal blend known as Dang gui Bu xue Tang (DBT) alongside Astragalus in a 5:1 Astragalus:Angelicae ratio. Traditional preparation was to combine 30g Astragalus Membranaceus and 6g Angelicae Sinensis, and boil them in two bowls of water over moderate heat until the overall weight is reduced by half.^[150][151] This particular combination of herbs is recommended to menopausal women to 'reduce the effects' of menopause; an invigorator of sorts. It actually appears that this extraction process is best suited to the 5:1 ratio, as higher and lower ratios result in less flavonoids (calycosin, formononectin) and Astragaloside IV, as well as ferulic acid from Angelicae.^[151] Interestingly, this ratio had significantly lower levels of ligustilide.^[151] Adding wine (ethanolic extract) to the mixture exacerbate the effects, increasing astragaloside IV and ferulic acid extraction.^[151] The enhanced rate of recovery with traditionally prepared Dang-Gui Buxue Tang is associated with better protective effects on the heart than either herb alone.^[47]

The molecules of which are a concern in Angelicae Sinensis seem to be ferulic acid and ligustilide.^[152][153]

Angelicae Sinensis has been found to increase the intestinal absorption of two flavonoids from Astragalus; formononectin and calycosin in vitro.^[37] As well, the combination of the two herbs confers more anti-oxidative potential than either herb in isolation and then mathematically added together.^[27] This latter study was done in vitro, and is independent of increased bioavailability when coingested.

The combination is also being investigated for stimulating erythropoesis in vivo, as it can upregulate expression of the gene that encodes for erythropoetin.^[154][155] Combination therapy of both herbs at 0.5g/kg each (1g/kg total) is more effective than either herb in isolation at 1g/kg in rats at increasing serum iron (no significant difference on iron binding protein), with nonsignificant trends towards synergism for serum B12.^[154] Beyond stimulating erythropoetin, the combination has been implicated in hematopoesis^[156]

In regards to menopausal symptoms (traditional usage of this herb pairing), a 5:1 ratio appears to be synergistic at promoting osteoclast differentiation in vitro, stimulating estrogen signalling in vitro, and at anti-platelet functions.^[151] In vitro studies also suggest that the combination is synergistic in regards to promoting endothelial differentiation and DNA expression.^[157]

One of the more traditionally used combinations with Astragalus Membranaceus; seems to be a fairly prudent combination if it isn't too hard to get a hold of. The traditional preparation and extraction of 5:1 Astragalus:Angelicae with a bit of wine actually appears to be the best scientifically as well, according to one study.

Rehmanniae Radix is a plant used traditionally in Chinese medicine to treat diabetes, a similar claim to that of Astragalus. The combination of the two in a 2:1 ratio of Astragalus to Rehmanniae has been deemed 'NF3' in the literature.^[158][159]

They combination is being looked at for wound healing in diabetics, and the combination of the two is synergistically beneficial.^[160] It appears to work via WnT^[161][158] and pathways of angiogenesis mostly related to VEGF.^[158] Due to its traditional use in diabetics, it has also been investigated for its usage in glucose uptake and insulin sensitivity in diabetic rats but to no significant effects.^[162]

The combination of the two, however, has been found to inhibit both CYP3A4 (IC₅₀ of 0.88mg/mL and K_i of 1.6mg/mL) and CYP2C9 (IC₅₀ of 0.86mg/mL, K_i of 0.57mg/mL).^[163] The high K_i values suggest lower potential for adverse herb-drug interactions.^[163]

The combination of these two herbs in a 2:1 ratio of Astagalus:Rehmanniae appears to be effective in producing angiogenesis in vivo and aids in wound healing

At least one study has noted synergistic interactions in vivo with Astragalus (110mg/kg) and Panax Notoginseng (115mg/kg) in regards to inhibition of MMP-9 and induction of TIMP-1, two effects which are seen as protective against cerebral ischemia-reperfusion injury;^[164] This may also be mediated in part by an anti-oxidative effect.^[165] When looking at a chinese mixture containing these two in rats (qizhu tang),^[166] it appears the mixture is effective while the individual ingredients at these dosages were not. This mixture also contains Rhizoma atractylodis and Poria, so four-way synergism may exist (has not been shown).^[166]

Also referred to as Radix Glycyrrhizae, it showed synergistic anti-oxidant potency when paired with Astragalus. However, due to Astragalus's weak anti-oxidant potential initially, the synergism was not significantly greater than Glycyrrhiza in isolation.^[27]

Sometimes known as Radix et Rhizoma Rhei, appears to be highly synergistic with Astragalus in regards to anti-oxidant abilities assessed by DPPH assays.^[27]

Also known as Rhizoma Atractylodis Macrocephalae, Atractylodes shows synergistic anti-oxidant potential when paired at a 1:1 ratio with Astragalus in DPPH assays; yet due to the weak anti-oxidant potential of Astragalus relative to Atractylodes, the synergistic reaction was not significantly greater than isolated Atractylodes.^[27]

Also known as Radix Paeoniae Alba by itself and Qi-Shao-Shuang-Gan when paired with Astragalus,^[167] Paeonia lactiflora appears to exert synergistic anti-oxidative effects when paired with Astragalus.^[27] 10g of each herbal extract showed more anti-oxidative potential than the sum of the parts, but despite this was not more potent than Paeonia lactiflora in isolation due to its large anti-oxidative potential relative to Astragalus.^[27]

Paeonia has also displayed synergism with Astragalus in regards to systemic anti-inflammatory effects in a mouse model of sepsis.^[167]

Schisandra Chinensis (of the family Magnoliaceae) is a herb that, alongside Astragalis, is widely used in China and also sometimes is formulated into 'healthy' foods.^[168] An ethanolic extract of schisandra chinensis fruits (23.1% lignan content) and water extract of Astragalis were found to be synergistic in suppressing elevations of liver enzymes seen with introduction of a hepatotoxin, CCl₄.^[168]

Whereas Astragalus (polysaccharides) at 450mg/kg oral ingestion were able to suppress elevations in ALT, AST, and ALP to 87%, 86.5%, and 92.6% of the toxin-only group the addition of 135mg/kg bodyweight Schisandrae ethanolic extract reduced the elevations to 43.8%, 53.4%, and 67.1%; respectively.^[168] Shisandrae at 45mg/kg and Astrgalus at 150mg/kg was significantly more hepatoprotective than 450mg/kg Astragalus on all parameters.^[168]

Although neither ingredient in isolation affected CCL₄ depleted glutathione levels, the combination was able to with a CDI (coefficient of drug interaction) of 0.84.^[168]

Stephania tetrandra is a plant also from traditional chinese medicine. The two compounds (Stephanie and Astragalus) are two herbs used in a Japanese medicine called Boi-ogi-to (Chinese name of Fang-ji-huang-qi-tang) alongside some other herbs (Atractylodes, licorice, ginger, and the fruits of Ziziphus Jujuba). It has traditionally been used for edema and arthritis, as well as treatment of diabetes such as diabetic retinopathy.^[169][170] Recently in rats, an active component of Stephania tetrandra known as fangchinoline was shown to possess anti-diabetic activity in rats in a dose-dependent manner.^[171]

The water extract of Astragali was shown to potentiate the effects of Fangchinoline,^[171] and later it was found that both formononectin and calycosin (flavonoids from Astragalus) synergistically potentiated the fangchinoline induced release of insulin, although only formononectin was statistically significant.^[172] While 3-100mg/kg astragalus had no effect, and 0.3g/kg fangchinoline had no effect, when coingested a dose-dependent effect of astragalus on blood sugar and insulin was seen vicariously through fangchinoline; all effects seen may be secondary to enhancing insulin release.^[172]

Astragalus may enhance Stephania's effects on blood glucose reduction and insulin secretion, and enhance the anti-diabetic effects of Stephania Tetrandra

Up to 100g/kg Astragalus Membranaceus have been given by gavage to rats with no serious side-effects according to the Chinese Herbal Medicine: Materia Medica (1993).^[2] When injected in mice, the LD₅₀ of Astragalus appears to be 40g/kg.^[2]

A combination with rhubarb, red sage, ginger, and turmeric (containing curcumin) was found to exert no toxicity in females rats of reproductive age up to doses of 430mg/kg bodyweight with astragalus at 13.3%, whereas the 860mg/kg dosage was associated with maternal weight loss.^[173] This particular blend is a patented^[174] aimed towards anti-obesity via rhubarb with lacklustre results thus far.^[175][176]