White Mulberry

Morus Alba (of the family Moraceae), sometimes referred to as Mori Albae or White Mulberry, is a medicinal fruit (with roots and bark also having some medicial usage) with Traditional Chinese Medicine using White Mulberry for the purposes of antiphlogistic, diuretic, antitussive, expectorant, antiheadache, and antipyretic.^[1] Other names given to Morus Alba include Karayamaguwa (Japanese) when referring to the plant in general and Sohakuhi if referring to the medicinal root bark; Chinese terminology for the root bark is Sang-Bai-Pi^[2] and in english it is referred to as Ramulus Mori (branch of Mori).^[3]

When tea is made from Mulberry, it is referred to as a Sang-Yup tea when made from the leaves and a Sang-Ji tea when made from the stems.^[4]

White Mulberry (Morus Alba) is a Traditional Chinese Medicine where, although all parts have been used, the stems seem to be most focused on; teas have been made from the stems

The term 'Mulberry' refers to the genera of Morus, with 'White Mulberry' specifically referring to the species of Alba in the Morus genera (Morus Alba). Although the term Mulberry is sometimes used to refer to Morus Alba in particular due to its popularity, it may also refer to other species such as Morus nigra (Black) or Morus Rubra (Red).^[5][6] There are approximately 10-16 species of Mulberry in cultivation in subtropical, warm and temperate regions of Asia, Africa and North America^[7] and up to 24 in total^[6] with one varient known as Morus laevigata (Shahtoot) being used as a common hybrid species in Pakistan.^[6]

Mulberry is a general term for the genera of Morus, White Mulberry being specific for Morus Alba

The fruit itself tends to contain 81.72+/-2.25% Moisture, 0.57+/-0.11% Ash (minerals and other noncombustible compounds) 0.48+/-0.11% Lipid, 1.55+/-0.30% Protein, and 1.47+/-0.15% Fiber; giving the total carbohydrate content of the fresh fruit 14.21+/-1.01% (76% dry weight) and the fresh fruit having 67kcal per 100g.^[8] This is similar to both Morus Nigra and Morus laevigata except that Morus Nigra has a much higher fiber content (11% wet weight).^[8]

A variety of non-caloric bioactives that, for the most part, are unique to Morus Alba include:

• Morin (0.5771mg/g in 95% ethanolic extract of branches^[3]) or 4.7mcg/g (leaf), 5.8mcg/g (stem), 12.3mcg/g (bark), and 9.4mcg/g (root) with none in fruits^[9]
• The Arylbenzofuran compounds Moracin C and M,^[10] the latter of which can be synthesized from resorcinol.^[11] Also Moracin R, O, P, and D^[12] as well as V-Y^[13]
• Albanol A (root bark)^[1] and Alabafuran A^[12]
• Albanol F and G, which differ from the other 'Albanol' molecules as they also possess alternate names; Albanol F can also be referred to as either Kuwanone G or Moracenin B, while Albanol G can be referred to as Kuwanone F or Moracenin A^[2][14]
• Mulberrofurane E-G,^[15][16] L and Y;^[12] Isomulberrofuran G has also been reported^[17]
• Cyclomulberrin and cyclocommunol^[16]
• Kuwanone E,^[18] J, Q, R,^[19] S,^[20] and Y^[2] as well as 4′-methoxykuwanon E^[18]
• Sanggenon B-F, J-K,^[20] G,^[20] and O^[12][21][22] and Sanggenol A, L, P, N^[16]
• Pyrrole Alkaloids such as Morrole A^[23]
• Loliolide (high concentrations in the hot water extraction of the leaves)^[24]
• Moruslupenoic acid A and B^[25] and Monogolin B^[26]
• Morusinol (prenylated flavonoid),^[27] Morusin^[26][12] and Cyclomorusin^[16]
• Chalcomoracin, Morachalcone A-C (leaves)^[28], Moracin C, and Isobavachalcone^[29]
• Albosteroid^[30]
• 3′-Geranyl-3-prenyl-2′,4′,5,7-tetrahydroxyflavone and 3′,8-Diprenyl-4′,5,7-trihydroxyflavone^[20]
• Cudraflavone B, a prenylated flavone named after Cudrania tricuspidata^[31] (same family as Morus Alba) and also found in Morus Alba;^[32] it is basically Morusin with a cyclic prenyl side chain

In regards to the above molecules that are relatively unique to Morus Alba (they tend to be named after Morus or Alba) many of them have not yet been shown to be the causative active ingredients. It is definitely possible a unique bioactive here underlies some benefits of Morus Alba, but for the most part the main bioactives of concern are in the next sections

With various flavonoid molecules (that may be common to many plants) being:

• Resveratrol and Oxyresveratrol^[33] (0.2358mg/g and 4.8398mg/g in 95% ethanolic extract of branches^[3]) and the diglucoside of oxyresveratrol, Mulberroside A at 0.8-1.5%.^[34][3] Mulberrosides B and _cis_Mulberroside A have also been reported^[35][12] with two glycosides of oxyresveratrol (4'-O-β-Glucopyranoside and 3-O-β-Glucopyranoside) and a diglycoside of resveratrol known as resveratrol 3,4'-di-O-β-D-glucopyranoside.^[35]
• Steppogenin-4'-O-beta-D-glucoside^[36]
• Luteolin (2.1mcg/g leaf, bark and branch, 4.3mcg/g root and none in fruits), Apigenin (3mcg/g roots, 4.2mcg/g bark, 43.8mcg/g stem, 3.5mcg/g fruits, and 42.7mcg/g leaf),^[9] and 6-geronylapigenin^[20][37]
• Phenophorbide A methyl ester 13²(S)-hydroxypheophorbide A methyl ester; breakdown products of chlorophyll found in the leaves^[38]
• Uvaol^[12] and Atalantoflavone^[20]
• 4-hydroxycinnamic acid (1.0839mg/g in 95% ethanolic branch extract^[3]), 7-hydroxycoumarin (Umbelliferon, 0.2382mg/g in 95% ethanolic branch extract^[39][3]) caffeic acid (7.3mcg/g leaf and 17.2mcg/g fruit; none in root, bark, or stem)^[9] and dicaffeic acid^[39]
• Iminosugars such as 1-deoxynojirimicin (a pipiridine alkaloid)^[40] at 2.24-3.08mg/g (stems), 0.62-1.61mg/g (young/fresh leaves), or 0.47-0.96mg/g (older leaves)^[41] and D-fagomine (25-103mg/kg in the leaves^[42] with 185mg/kg also being reported;^[43] both in the reported range of 50-660mg/kg^[44])
• Polyprenyl compounds (linear hydrophobic isoprenoid alcohols)^[45]
• Rutin (Quercetin-3-O-Rutinoside)^[40] at 0.0766mg/g in a 95% ethanolic branch extract^[3] and most content being centralized to leaves and fruits (179.1-293.5mcg/g);^[9] similar levels of free Quercetin, Hyperin, and Isoquercetin, with up to two-fold (0.1270-0.1402mg/g) of Kaempferol and Butein
• Chlorogenic Acid (19.1mcg/g stem, 28.6mcg/g bark, 47.3mcg/g branch, 226.9mcg/g fruit, 92.2mcg/g leaf)^[9][40] and Umbelliferone (15.7mcg/g in stem, 289.6-538.7mcg/g in bark and root; none in leaves or fruit)^[9]
• Anthocyanins such as Cyanidin-3-Glucoside and Cyanidin-3-Rutinoside from the Pomace of white mulberry,^[46] with higher content in Morus Nigra (Black Mulberry; due to the coloration)
• Astragalin (a glycoside of Kaempferol)^[47] and Kaempferol-3-O-β-d-glucoside^[26]
• Ursolic Acid^[16] and betulinic acid^[12]
• Taxifolin (6.53-21.42mcg/g) and Taxifolin Hexoside (undetectable to 9.06mcg/g)^[48]
• Maclurin (chalcone)^[49]
• Lectin^[50]
• Deguelin^[20]
• Volatiles (aromatic and flavorants) at 0.36+/-0.03% (leaves) and 0.25+/-0.03% (stems);^[4] of which major ones include n-hexanoic acid (19.83mcg/g stems) and (E)-β-ionone (9.32mcg/g), dihydroctinidiolide (9.65mcg/g) and 3-methylbutyl hexadecanoate (7.7mcg/g) in the leaves.^[4]
• β-sitosterol^[12]
• Chromium (up 1.48–6.43mg/kg of the fruits,^[51] but appears to be variable as 1.81mcg/g^[52] and 0.45-0.65mcg/g^[53] have been reported)
• Strontium (1.87-2.13mcg/g), Copper (1.23-1.31mcg/g), Cobalt (0.36-0.51mcg/g), Manganese (4.16-4.36mcg/g), Nickel (1.98-2.34mcg/g), Zinc (3.78-3.47mcg/g), and Iron (36.17-40.80mcg/g)^[53]
• Riboflavin (0.088+/-0.001 fresh weight), Niacin (3.10+/-0.60mg/100g fresh weight), and Vitamin C (15.20+/-1.25mg/100g fresh weight)^[8]

The Quercetin class of molecules, with notice to the 3-(6-malonylglucoside) conjugate, appear to play a role as do the stilbene class of molecules (resveratrol and oxyresveratrol, where the glycosides known as 'Mulberrosides' are unique to this plant). Beyond that, the iminosugars appear to play a large role in anti-diabetic effects. Ursolic acid and chlorogenic acid cannot be ruled out for anti-diabetic effects, while the anthocyanins probably can be ruled out since they are blue-red pigmentations and their content is low enough for this to still be called 'white mulberry' (they are at higher levels in Morus Nigra; Black Mulberry)

With the caloric bioactives being:

• Morin 20K, a 20kDa glycoprotein^[54]
• Moran A^[55]

A variety of larger molecules with the designation of Kuwanone or Albanol appear to be, structurally, a combination of an isoprenylated flavonoid with a chalcone structure; both of the latter also occurring in Morus Alba.^[2] These meta structures are referred to as Diels-Alder Adduct formation products, named after the specific chemical reaction that occurs in the plant to create them.

Total flavonoids in the leaves of Morus Alba are approximately 26.41+/-1.14mg/g Rutin equivalents dry weight^[5] or 58.09+/-2.32mg/g GAE.^[56] Total polyphenolics are around 260.00+/-20.00mg/g GAE.^[56]

Total Phenolics are highest in the leaf and lowest in the stem (fruit intermediate) where flavonoids are lowest in the fruit, with the leaves still the highest concentration.^[57] Comparatively, both Morus Alba and Morus Nigra seem to have similar levels of phenolics, with some studies noting a higher level in Nigra^[58] and others in Alba.^[8]

In general, the leaves of Morus Alba tend to have fairly potent anti-oxidant effects (IC₅₀ of 20.10+/-0.78mcg/mL in the DPPH assay ex vivo)^[59] which extends to teas.^[60][4] Ethanolic extracts (of any part of Morus Alba) are more potent than aqueous hot water extracts, however,^[57] with acetone extracts slightly better than ethanolic.^[58]

Phenolics (and the subset of phenolics known as 'flavonoids') are high in all parts of Morus Alba, with higher content in the stems and leaves; although they can be leeched into teas (hot water extractions) their levels are concentrated to higher levels in ethanolic and acetone extractions

Mulberroside A (oxyresveratrol diglucoside) appears to have a less than 1% oral bioavailability in the rat due to extensive metabolism to oxyresveratrol;^[61] oxyresveratrol appears to have comparatively better absorption in Caco-2 cells, and is subject to P-glycoprotein efflux proteins.^[62]

Limited evidence all around, but the glycoside of oxyresveratrol appears to need to be metabolized into the aglycone oxyresveratrol before most absorption takes place

Most components of Mulberry, if they don't have their own respective page (like Quercetin or Chlorogenic Acid do) lack pharmacokinetic data

Mulberroside A can be metabolized to either Oxyresveratrol or one of two conjugates of oxyresveratrol (Oxyresveratrol-2-O-β-d-glucuronosyl via glucuronidation and oxyresveratrol sulfate), as detected in rat feces following oral administration;^[63] these fecal doses of conjugates account for up to half of the ingested oral dose of Mulberroside A.^[63][61]

Mulberroside A is surprisingly stable under varying pH conditions (surviving gastric juices for up to an hour ex vivo) and appears to be metabolized when incubated with colonic microflora.^[62]

Moracin M is a PDE4 inhibitor, inhibiting the D2 and B4 subsets with IC₅₀ values of 2.9μM and 4.5μM respectively with weak inhibitory potential on PDE5 (13-fold less inhibition than PDE4s) and PDE9 (30-fold less).^[10] Moracin C also inhibited PDE4D2 with lesser (26μM) potency, underperformed to the active control (roflumilast at 0.46nM)^[10] and compared to luteolin (a nonspecific PDE inhibitor from artichoke extract^[64]), Moracin M outperforms Luteolin's IC₅₀ of 19.1uM^[65] and the inhibition by resveratrol (14μM).^[66] PDE4 is a camp-specific phosphodiesterase enzyme, and its inhibition is thought to enhance synaptic function via elevating hippocampal cAMP concentrations^[67] (evidence by studies on Rolipram, a potent PDE4 seletive inhibitor).^[68][69]

Moracin M is a PDE4 inhibitor, more potent than other molecules derived from nutraceuticals (but still not as effective as the prototypical reference drug of Rolipram). Although PDE4 inhibition has been shown to enhance cognition (studies using Rolipram), and Morus Alba has been shown to increase cognition this has not yet shown to be due to PDE4 inhibition

An ethyl acetate fraction of Morus Alba appears to positively modulate GABA(A) receptors, which is thought to be due to the sanggenon compounds;^[21] with concentrations between 1-100µM exerting EC₅₀ values in the 13-17µM range and maximal potency around 30µM or more (curve of dose-response being attenuated at higher concentrations) being in the range of 718-750% increased activation of GABA(A) receptors and 30µM activating the receptors inherently, although much less potent than GABA itself.^[21] This study noted the potency of positive modulation was similar to 8-lavandulyl flavanoids from Sophora Flavescens^[70] and Wogonin from Scutellaria baicalensis.^[71] Anti-dopaminergic effects of the ethyl acetate fraction (unknown bioactive) have also been shown to augment phenobartitol induced sleep.^[72]

Two independent mechanisms suggest possible relaxation, anxiolytic, or sedative properties of unknown potency

Oral doses of 50, 100, or 200mg/kg of an extract from the fruits of Morus Alba over a period of a week can dose-dependently induce Nerve Growth Factor (NGF) release in the rat hippocampus, with downstream molecular targets (neurite outgrowth, synaptic formation, and cAMP induction) as well as enhanced learning being noted.^[73] Another study assessing the anti-stress effects and using an ethyl acetate fraction noted that 25-100mg/kg over 21 days was actually associated with a trend to outperform non-stressed control on step-down latency, indicative of memory improvements (no unstressed group given Morus Alba).^[74]

Appears to be able to enhance memory formation and cognition in otherwise normal rats. Limited studies and no bioactive currently found to be causative, but these occur with reasonable oral doses (50-100mg/kg in rats correlates to 8-16mg/kg in humans; this may simply be a few fruits)

A mulberry extract with a high Cyanidin-3-Glucoside content, at 1-50mcg/mL was able to reduce the 95.1+/-1.6% cell death induced by oxygen/glucose deprivation to 37.6+/-5.3% at the highest concentration and to 61.4-61.5% viability at lower concentrations of 5-10mcg/mL, and was seemingly ineffective against glutamate-induced neurotoxicity.^[75]

The methanolic extract of Morus Alba may possess anti-dopaminergic effects, as it has been shown to augment haloperidol and metoclopramide induced catalepsy in mice when Morus Alba is ingested at 50-200mg/kg and has also prolonged phenobartitol induced sleep time while reducing amphetamine-induced fights in mice.^[72] Alkaloids and saponins were determined to be in this extract, and an attenuation of the dopamine-induced vas deferens contractions was also noted.^[72]

Excessive usage of haloperidol (dopamine D2 antagonist) is associated with excitotoxicity, which Morus Alba appears to attenuate in vivo.^[76]

Possible anti-dopaminergic effects which may be tied into neuroprotection; practical relevance unknown

In a chronic restraint stress model, the ethyl acetate fraction of Morus Alba (25-100mg/kg) given 60 minutes prior to the stress test (done daily for 10 days) was able to prevent the cognitive deficits induced by stress, with the active control of 1mg/kg Diazepam outperforming all doses but 100mg/kg on day 1 (equal potency to 100mg/kg) and over 10 days all doses of Morus Alba becoming more effective than 1mg/kg Diazepam (passive shock avoidance and elevated plus maze tests).^[77] This study noted preservation of oxidant enzyme changes (altered with stress, somewhat normalized with both Morus Alba and Diazepam) and the serum corticosterone levels were normalized in all treated stress groups.^[77] Another study using chronic stress testing (21 days) with the same dose of the same extraction was able to preserve memory losses associated with chronic stress (Diazepam inactive) with the two lower doses (25-50mg/kg) trending to outperform non-stressed control.^[74] Both studies note normalization of serum glucose and organ weight alterations, biomarkers of stress.^[77][74]

Elsewhere, Morus Alba without stress at the same doses appears to have an anxiolytic effect (reductions in anxiety), with 100-200mg/kg having similar potency to Diazepam at 1mg/kg.^[78]

Possible adaptogenic and anxiety reducing effects of similar potency to 1mg/kg Diazepam, repeated studies but all by the same research group

Morus Alba appears to inhibit pancreatic lipase with an IC₅₀ of 3.41+/-0.67mg/L,^[79] although none appear to be present in the leaves.^[80] Another study noted an IC₅₀ of 244.94+/-83.96ug/mL, which was effectively the weakest herb tested.^[81]

Technically can inhibit fatty acid absorption, is comparatively very weak at doing so

Intravenous administration of the methanolic extract of the root bark leads to dose-dependent reductions in blood pressure in rabbits, which is due to the bioactives kuwanon G and H (0.2% and 0.13% of the methanolic extract).^[82] These results have been replicated in other studies, where Kuwanon G and H were temporarily designated alternate names (Albanins or Moracenins).^[83][84][2]

When the water extract is given to mice fed an atherogenic diet, an attenuation of the development of high blood pressure occurs with 100-250mg/kg over 14 weeks; this study noted that both doses outperformed the active control fluvastatin and reduced blood pressure to lower than the control group.^[85]

May preserve blood pressure in disease states (diabetes or atherosclerosis) where blood pressure is increased

A study in HUVEC cells (endothelial) with the leaves of Morus Alba at 400mcg/mL (deemed a physiologically relevant dose citing this study^[86]) is able to inhibit the expression of P‐selectin and fractalkine induced by resistin, with similar potency to 20uM Curcumin (both fully abolishing the effects of resistin) thought to be related to attenuating NADPH oxidase activity (abolished with Morus Alba, reduced to 30% of control with Curcumin).^[87] Resistin induces P-Selection and fractalkine expression in endothelial cells, which increases monocyte adhesion and may be pro-atherosclerotic^[88] and in HUVEC cells Morus Alba was shown to inhibit monocyte binding to a potency correlating greatly with NADPH oxidase activity.^[87]

In LDLR^-/- mice prone to atherosclerotic lesions fed 3% of the diet as Mulberry leaf powder for 8 weeks, atherosclerotic lesions were greatly reduced and partly attributed to the Quercetin content of the leaves (with 0.5% Quercetin also reducing lesions, and 0.5% Quercetin-3,6-malonylglucoside being intermediate in potency to the high dose Mulberry and equal dose Quercetin).^[86] As the mulberry group had 0.4% Quercetin content overall yet outperformed the other groups, it appears other bioactives are at play.^[86] The entire leaf extract itself appears to reduce the atherogenic index to the same level as Fluvastatin (3mg/kg), thought to be related to mixed anti-oxidant and anti-inflammatory effects but with a concomitant increase in HDL-C.^[85]

Appears to protect against atheroscelrosis, with the bioactive of Quercetin-3,6-Malonylglucose playing a major role (more potent than the Quercetin aglycone). Relative to other plants, this is a respectable potency in animal models but lacks human studies

In vitro, Morusinol can inhibit clotting with IC₅₀ values of 13.4+/-5.4ug/mL for Collagen-induced clotting 19.8+/-3.5ug/mL for Arachidonic Acid-induced clotting with no significant effect on thrombin-induced clotting.^[27] This was thought to be due to inhibition of thromboxane 2 (TBX2) production, which reached 99% inhibition at 30mcg/mL (a potency requiring 200mcg/mL Aspirin).^[27]

Morusinol, a prenylated flavonoid given at 20mg/kg bodyweight, occlusion time was prolonged 90% over control.^[27] Compared to the active control of Aspirin at 20mg/kg, Morusinol significantly outperformed the ability of 30mg/kg Aspirin to increase occlusion time by 30%.^[27]

Limited evidence with little practical application thereof, but Morusinol seems more potent than an equal dose of Aspirin at inhibiting blood clotting

Mechanistically, a study noting lipase inhibition (preventing absorption of fatty acids) noted that Morus Alba fruits had an IC₅₀ against pancreatic lipase of 244.94+/-83.96ug/mL (weakest tested plant)^[81] and a slight inhibition of cholesterol uptake was noted in Caco-2 cells (76.10+/-3.98 of control) but was much less than black pepper and green tea catechins and no compound outperformed Ezetimbe.^[81] A weak inhibition of HMG-CoA activity was noted (64.57+/-5.97 inhibition at 100ug/mL) which underperformed relative to 0.4mcg/mL Pravastatin (103.96+/-4.08) and 100mcg/mL Horseradish tree (106.46+/-3.70).^[81]

Morus Alba can activate both α1 and α2 isoforms of AMPK in skeletal muscle (a possible anti-diabetic and anti-lipidemic mechanism), which noted rapid activation to 1.6-fold higher than baseline after incubation with 4.28mg/mL Morus Alba and up to 1.9-fold at 14.3mg/mL.^[89]

Seems to have weak effects on preventing lipid and cholesterol uptake and weak effects in attenuating cholesterol synthesis; may reduce lipids via AMPK activation

A study in LDLR^-/- mice noted that total cholesterol was reduced (and LDL trended to be reduced) with 3% Mulberry leaf extract or 0.5% of the diet as Quercetin-3,6-Malonylglucoside, but not with 0.5% Quercetin, over 8 weeks of supplementation.^[86]

In otherwise normal rats given an atherogenic diet, the inclusion of 100-250mg/kg Morus Alba water extract can slightly attenuate the increases in total cholesterol, LDL-C, and Triglycerides while promoting HDL-C levels to above that of control and atherogenic control.^[85] This increase in HDL-C was the reason Morus Alba rivalled the active control Fluvastatin on the atherogenic index, since Fluvastatin had greater reductions in the other three parameters.^[85] Other studies using high-fat fed rats (which then get hyperlipidemia) note reductions in serum triglycerides and LDL-C, with no seeming effect on rats with normal lipid profiles.^[90]

Decent efficacy in reducing blood lipids, although the increase in HDL-C ('good' cholesterol) appears to be larger than other herbs despite the reductions seen in LDL-C and Total Cholesterol being less potent

In assessing compounds that may have anti-obese effects, 20uM of various prenylated flavonoids (kuwanon A, C and T; Morusin and sanggenon F) and two triterpenoids (Uvaol and betulinic acid) showed inhibitory effects on triglyceride accumulation into preadipocytes (3T3-L1) with potency greater than 34%, which was the active control of Quercetin at 20uM, with the most potent being Sanggenon F at 56.0% inhibition at 20uM.^[12] A mixture of Morus Alba with two other herbs (Lemon Balm and Artemisia Capillaris) appears to inhibit adipogenesis in preadipocytes, associated with a downregulation of PPARγ and aP2 mRNA by 34% and 37%.^[91] In rats given the leaf extract (250-100mg/kg) for 9 weeks, it is noted that the expression of Cyp4a2 and Cyp4a3 (genes encoding the rate limit of omega-oxidation of long chain fatty acids), Phyh (encodes the rate limit for alpha-oxidation of 3-methyl branched fatty acids) and the expression of CPT1A (rate limiting step of beta-oxidation) were both upregulated; some products associated with short-chain fatty acids were downregulated (Hsd17b10, Acaa2, and Echs1).^[92] In vivo, the enhancement of oxidative metabolism was met with a decrease in oxidative stress due to antioxidant properties of Mulberry.^[92]

Morus Alba in general can increase glucose uptake into fat cells in a concentration-dependent manner, with 5-45mcg/mL increasing glucose uptake (via GLUT4 translocation) by 31-54%, which are mediated via PI3K activation (possibly insulin-dependent) and may be due to gallic acid.^[93]

Appears to beneficially influence gene expression in the liver and may increase glucose uptake into fat cells (without enhancing their proliferation, which normally occurs after glucose uptake)

Melanin-concentrating hormone (MCH) mostly in the lateral hypothalamus and zona incerta (of the CNS) appears to act on its receptor subtype 1 (MCH1)^[94] to activate hunger, and antagonism of this receptor is seen as a therapeutic target to reduce food intake.^[95]

The ethanolic extract of Morus Alba has been shown to inhibit MCH-induced calcium influx into cells in a concentration dependent manner (10-100mcg/mL) and oral ingestion of this extract (100-500mg/kg in two divided doses) over 2 weeks (much weaker than sulbutiamine as active control) and prolonged over 22-32 weeks (whereas the benefits of sulbutiamine attenuated to the same degree as Morus Alba, which was constant).^[96] The overall weight loss in this study attributed to reduced food intake was 3.1% (250mg/kg) and 4.9% (500mg/kg).^[96]

Another study in rats measuring food intake replicated a suppression of food intake when the 50% ethanolic leaf extract was used at either 3% or 6% of the diet, but it was not to a degree where body weight after 60 days was significantly different (despite being lower in the first few weeks).^[97]

Limited evidence, but there appears to be a bioactive in Morus Alba that acts as an MCH antagonist and reduces food intake. This has been noted to occur with high dose ethanolic extracts of Morus Alba in studies intentionally looking for how it affects food intake and by studies who merely noted it as a side-effect of treatment

One study using 3% or 6% ethanolic leaf extract over 60 days noted that treated rats had a reduction in perirenal, but not epididymal, adipose tissue without any noted dose-dependence.^[97] 250, 500, or 1000mg/kg Mulberry leaf powder for 7 weeks in normal rats given a high fat diet failed to significantly modify body weight despite decreasing serum levels of NEFAs and Triglycerides.^[92]

One study using genetically obese mice given a mixture of Morus Alba, Artemisia capillaris, and Melissa officinalis (found to have anti-angiogenic properties by the same researchers^[98]) noted reduced rate of weight gain associated with the mixture of herbs over 5 weeks and thought to be due to inhibiting angiogenesis; dosage of active ingredients not disclosed.^[99]

Some beneficial trends noted in body fat disposition, but they are unreliable and limited; there are numerous studies noting no significant influence on body weight when food intake is not affected. It is possible weight loss only occurs with Morus Alba secondary to reduced food intake

Morus Alba is one of the most studied herbal options for carbohydrate digestion inhibition, alongside Salacia reticulata.^[100]

Morus Alba leaves appear to inhibit carbohydrate digestive enzymes with an IC₅₀ value of 0.59+/-0.06mg/mL (maltase) and 0.94+/-0.11mg/mL (sucrase) with this study noting the IC₅₀₅₀Morus Alba leaf extract on α-amylase being more than 5mg/mL^[56] but other studies with a confirmed (0.11%) 1-deoxynojirimycin content noting an IC₅₀ of 324.5 μg/mL on amylase (and noted a similarly potent IC₅₀ on alpha-glucoside enzymes at 41.0 μg/mL)^[101] and 1440μg/mL with an isopropanolic extract.^[102] This inhibition has been noted with hot water extracts (teas made from the leaves) with good inhibition at a 3-5 minute steep time.^[103]

The former study notes that Morus Alba outperformed other herbs such as Clitoria Ternatea (minimal efficacy on all enzymes) and chrysanthemum, with both Mulberry and Chrysanthemum being synergistic with Roselle extract (Hibiscus sabdariffa).^[56] Inhibition of carbohydrate digestive enzymes have been replicated on sucrase and maltase, and extends to palatinase; a lack of efficacy has been noted on trehalase and lactase,^[104] and competition on disaccharidase enzymes appears to be competitive.^[105]

When looking at bioactives that may underlie the effects above, it is thought that isoquercitrin and astragalin may play roles on the α-glucosidase enzymes.^[47] D-Fagomine (found in water extracts of the leaves) is also known to be able to attenuate the rate of glucose absorption due to its structural similarity.^[106] This also applies to the structurally related iminosugar 1-deoxynojirimycin, which is an α-glucoside inhibitor^[107] of comparable potency (IC₅₀ values) to Arcabose (with 1-deoxynojirimycin also inhibiting α-amylase, but much weaker than Arcabose).^[101]

May reduce or slow some carbohydrate absorption from disaccharides (sucrose and maltose) and shows some synergism with Hibiscus sabdariffa in doing so. A few ingredients may be causative here, but most of the inhibition appears to be related to 1-deoxynojirimycin (an iminosugar)

Relative to other herbal options, Morus Alba (particularly teas made from the stems and leaves, as they have a higher 1-deoxynojirimycin content than the fruits) seems to be a respectable option for reducing the absorption of carbohydrates (although its effects on starches and lactose are subpar relative to its efficacy in inhibiting other disaccharides)

A hot water extraction of Morus Alba leaves (high Loliolide content) appears to enhance glucose uptake into isolated adipocytes (fat cells) via insulin dependent and independent means.^[24] These effects have been noted in vitro with the 20kDa glycoprotein Morin 20K.^[54]

Quercetin-3,6-Malonylglucoside (Q3MG) appears to enhance the activity of glucokinase (2.81-fold) and ATP Citrate Lyase (2.27-fold) after oral ingestion at 0.7mg/kg in rats fed a high fat diet, relative to high fat control, over 8 weeks.^[108] This study noted, however, that PGC-1a gene activity was reduced 2.19-fold, Heat shock protein 1B down 9.53-fold, and that Cdkn1A activity was reduced 10.19 fold (high magnitude changes that should be noted, with practical relevance unknown).^[108]

May have some anti-diabetic effects indpendent of inhibiting absorption of carbohydrates, but these do not appear to be too notable

A 70% ethanolic extract from the roots of Morus Alba to streptozotocin-induced diabtic rats at 600mg/kg bodyweight (200-400mg/kg not being significant) for 10 days effectively normalized serum glucose, insulin and lipid peroxides while normalizing body weight; suggesting protective effects on the pancreas (target of streptozotocin toxicity).^[109] A larger dose in this same rat model (1,000mg/kg) was able to reduce blood glucose by 22% over 6 weeks of oral ingestion paired with a reduction in HbA1c to 75% of the untreated group.^[110]

In KK-Ay diabetic mice (spontaneously diabetic and fed a high sucrose diet), a 50% ethanolic extract of the leaves standardized to 0.77% 1-deoxynojirimycin (DNJ) noted a slight reduction in food intake at 3% and 6% of feed intake as mulberry extract but not enough to significantly alter body weight over 60 days; a significant reduction in blood glucose occured in a dose-dependent manner in this study.^[97]

In Alloxan-induced diabetic mice, Morus Alba with Silkworm powder (4,000mg/kg, or 0.4% of the diet) was able to reduce serum glucose by 50% relative to untreated control.^[111] This research model has experienced a 61% reduction of serum glucose in response to the water extract of Morus Alba leaves with an enhanced content of 1-deoxynojirimycin (5% of extract; link to Korean full text)^[112] and alloxan-induced diabetic mice also see reductions in blood glucose in a dose-dependent manner with the isolated compounds Moracin M, Steppogenin-4'-O-beta-D-glucoside (a flavonoid), and Mullberroside A (stilbene glycoside) at the oral dose of 50-100mg/kg each over 3 days, although none of these outperformed 50mg/kg gliclazide.^[36]

These effects extend to normal male Wistar rats given Morus Alba, where the ethanolic extract of Morus Alba was shown to reduce carbohydrate absorption with IC₅₀ values of 0.11 g/kg (sucrose), 0.44 g/kg (maltose), and 0.38 g/kg (starch).^[113] In otherwise healthy Sprague-Dawley rats given 500-1,000mg/kg of Morus Alba ethanolic extract (0.11% 1-deoxynojirimycin) using 5mg/kg Arcabose as an active control, Morus Alba was comparable to Arcabose in reducing the spikes in blood glucose in response to a sucrose or maltose load but underperformed in a starch load.^[101] Fecal analysis confirmed undigested carboydrates in response to sucrose and maltose, but failed to find significant evidence for undigested starches in response to Morus Alba ingestion over 3 weeks,^[101] although this was noted as a positive in this study as excessive starch malabsorption from Arcabose resulted in reduced intestinal transporting capacity and this reduction was not noted with Morus Alba;^[101] starch malabsorption is thought to underlie the only side-effects with Arcabose, namely abdominal distention, flatulence, meteorism, and possibly diarrhea.^[114]

Studies that use normal rats but fed a high fat diet note that 1% Mulberries (0.02% 1-deoxynojirimycin) or an equivalent amount of Quercetin-3,6-Malonylglucoside (0.01%; 0.7mg/kg) for 8 weeks reduce plasma glucose (20.4% Mulberry; 31% Q3MG), free fatty acids (Q3MG only; 44%) and LDL-C (Q3MG only; 70%) relative to high fat control; no influence on body weight was noted in either group, and no influence on food intake in the Q3MG group (Mulberry ate 21% more, but did not appear to gain weight).^[108]

A large amount of repeated studies in rats showing reductions in blood glucose in all apparent states (food or toxin-induced diabetes as well as normal healthy rats) where Morus Alba and primarily its 1-deoxynojirimycin content reduce fasting blood glucose (diabetic rats) or post-prandial spikes in glucose from ingested food (diabetic and normal rats)

Some compounds derived from the methanolic (and ethyl acetate^[115]) fractions of Morus Alba root barks show NF-kB inhibitory potential, with IC₅₀ values of 4.65uM (Kuwanon J 2,4,10″-trimethyl ether) and 7.38uM (Kuwanon R), both of which were able to inhibit NF-kB by 87% and 75% (respectively) at 5ug/mL;^[19] both underperformed relative to the reference compound Celastrol (from Thunder God Vine) with an IC₅₀ of 4.1+/-1.05uM.^[19] Sanggenon C and O also appear to inhibit NF-kB, and their respective IC₅₀ values of 3.38 and 1.29uM appear to be comparable to Celastrol, and in this study was noted to be comparable to deguelin.^[116]

Arylbenzofuran compounds (usually named 'Moracin' in this plant) and prenylated flavonoids also show anti-inflammatory potential by inhibiting nitric oxide release from macrophages, with the former class having IC₅₀ values ranging from 7.1-19.3uM (n=10) and the latter class ranging from 10.5-19.0uM (n=5).^[12] Many compounds in these two classes outperformed aminoguanidine (17.5uM) and the saponin structures were fairly inactive (greater than 100uM).^[12] The prenylated flavone known as Cudraflavone B (THP-1 cytotoxicity at 47.6uM^[31]) can inhibit TNF-α gene trancription after LPS stimulation^[18] to a potency greater than indomethacin at 10uM,^[31] inhibited COX-2 induction with an IC₅₀ of 2.5+/-0.89uM (slightly weaker than indomethacin, but with greater selectivity at 1.70-fold more for COX1 than COX2) and inhibited nuclear translocation of NF-kB by 2.3-fold (relative to control).^[31]

Sanggenons C, E, and O appear to inhibit COX-1 and COX-2 with potencies ranging from 10-14μM and 40-50μM, respectively, with Moracin-structured compounds being ineffective.^[22] which may be downstream of NF-kB inhibition (seen with C and O).^[116]

Bioactives have, in vitro, fairly potent anti-inflammatory properties; more potent than many nutraceuticals but they do not appear to be among the most potent (Thunder God Vine and Feverfew appear to still be more effective on these parameters)

In macrophages, two pyrrole compounds (2-formyl-5-(hydroxymethyl)-1H-pyrrole-1-butanoic acid and 2-formyl-5-(methoxymethyl)-1H-pyrrole-1-butanoic acid) were able to activate macrophages in the concentration range of 10-100uM as assessed by nitric oxide release, phagocytic activity, and release of cytokines (IL-12 and TNF-α); the potency was lesser than that of LPS-induced activity and no group altered cell viability.^[23]

Some compounds may have immunostimulatory properties, with practical potency of these unknown

In a database search for ADAMTS1 inhibitors, Kuwanon P and X as well as both albafuran C and mulberrofuran J from Morus Alba where able to inhibit the enzyme in bacterial-expressed cultures and human cell cultures with IC₅₀ values of 5.5-7.6uM, 15.5-16.2uM, 10.7-11.9uM, and 18.4-25.4uM respectively.^[117] ADAMTS1 is a protein complex that has catalytic activities towards proteoglycans such as aggrecan, versican and brevican^[118] which are major components of articular cartilage;^[119][120] its inhibition is throught to be therapeutic for arthritis.^[117]

Therapeutic efficacy in arthritis not yet known, but components of White Mulberry appear to be theoretically therapeutic by a novel mechanism

One mouse study using the cortex (outer part of root) at 50-200mg/kg (with 10mg/kg Cyclosporin A as active control) for 6 weeks (5 days a week) noted that only the 200mg/kg group reduced airway hyperresponsiveness (a measurement of allergic asthma^[121]) to a similar degree as Cyclosporin A, although 50mg/kg was not at all different than control rats.^[122] These observations occurred with reduced airway inflammation and collagen deposition in the lungs, reduced eosinophil count (no influence on basophils or monocytes) and reduced IgE and Histamine secondary to reduced Th2 cell proliferation.^[122]

^[122]

The ethanolic extract of the branch of Morus Alba between 10-40mg/kg in mice with hyperuricemia (high blood uric acid) noted that this extract, with a high mulberroside A content (1.5%), was able to attenuate the increase in uric acid induced by potassium oxonate wholly at 20-40mg/kg and attenuate the increase at 10mg/kg.^[3] Mulberroside A is the bioactive causative of these effects.^[123]

Mori Alba showed comparable efficacy to the active control of 100mg/kg probenecid, and was associated with normalizing the upregulation of mURAT1 and mGLUT9 mRNA levels and the downregulation of mOAT1 (all of which are perturbed in hyperuricemia and involved in its regulation^[124][125]); along these lines, Morus Alba failed to reduce serum uric acid in normal mice, and preserved renal function in mice with high blood uric acid.^[3]

May attenuate increases in uric acid by promoting its urinary excretion

One study using HL-60 cells noted that Albinol A was able to inhibit cell proliferation with an IC₅₀ of 1.7uM, which was comparable to Cisplatin (IC₅₀ 1.9uM) with the other tested compound being subpar (Mulberrofurane Q; IC₅₀ of 37.6uM).^[1] Albinol A appears to be a topoisomerase type II inhibitor with an IC₅₀ of 22.8uM which was comparable to Etoposide, although the potency of Albinol A on Topoisomerase type I was much lesser (88.4uM) and underperformed relative to Camptothecin; this is thought to underlie apoptosis in this cell line.^[1]

A study using CRL1579 melanoma cells stated that Albinol A was comparable to Cisplatin in regards to IC₅₀ value in inhibiting cell proliferation in vitro, although the IC₅₀ for Albinol A (9.8uM) was seemingly less than Cisplatin (21.1uM).^[1]

A lectin (known as MLL) isolated from Morus Alba noted an IC₅₀ value of inhibiting cell proliferation of 8.5mcg/mL in MCF-7 cells, underperforming relative to Cisplatin (2mcg/mL);^[50][126] the morphology of cells undergoing growth inhibition is similar to that observed with apoptosis by Cisplatin and associated with Caspase-3 release.^[50]

In HCT-15 (colorectal cancer cells), a lectin known as MLL has an IC₅₀ value of inhibiting cell proliferation of 16mcg/mL, underperforming relative to Cisplatin (1mcg/mL).^[50][126] These anti-proliferative effects are mediated via apoptosis related to Caspase-3 release, and are morphologically similar to Cisplatin-induced apoptosis.^[50]

Mulberry extracts appears to have similar tyrosinase-inhibiting potential as hydroquinone and kojic acid, two reference compounds.^[127] The bioactive responsible may be Mulberroside A (Oxyresveratrol diglucoside), although Mulberroside A is weaker than its metabolite Oxyresveratrol, with both compounds being more effective than arbutin.^[128] Oxyresveratrol has been demonstrated to reduce tyrosinase activity to 62.6+/-1.4% of control (Mulberroside A to 78.6%, Arbutin to 82.4%) and reduced melanin concentrations in a dose-dependent manner,^[128] and biotransformation of Mulberroside A into its aglycones has been noted elsewhere to enhance anti-tyrosinase activity, where oxyresveratrol demonstrated mixed competitive inhibition of Tyrosinase in response to L-Tyrosine and noncompetitive to L-DOPA.^[129] These benefits may extend to Morus Nigra due to sharing bioactives.^[130]

In a trail on Melasma in persons with Fitzpatrick phototypes III-IV (dark white to light brown skin tone) advised to apply a 75% Mulberry oil (in coconut oil base) to their problematic skin twice daily for a period of 8 weeks noted significant improvements on symptoms of Melasma as assessed by both the Melasma Area and Severity Index (MASI) and Mexameter readings; quality of life improved with Mulberry oil but not placebo.^[131]

The only human study on Morus Alba at this time is one using the oils topically, where the anti-tyrosinase and skin whitening capabilities were demonstrated to be better than placebo

Administration of the water extract of Mori Albae at 858.2+/-29.5mg/kg bodyweight to rats was able to decrease serum levels of ethanol when given either 30 minutes before or simultaneously with ethanol and preserve serum levels of ethanol when given to rats 30 minutes after ethanol (3g/kg bodyweight) ingestion.^[132] Mori Albae was able to attenuate the decrease in Alcohol Dehydrogenase activity that occurs with alcohol ingestion (less potent than Dolichorus Semen and Alpiniae Katsumadai), despite other compounds like hovenia dulcis failing to do so.^[132]

A compound in Morus Alba known as albosteroid also appears to exert protective effects against ethanol-induced gastric ulcers in a dose-dependent manner.^[30]

May increase the metabolism rate of alcohol when ingested before alcohol or preserve the serum level of alcohol when coingested (due to being less effective at reducing serum ethanolic and merely attenuates a further increase). Note that serum levels correlate with the state of drunk, and preloading Morus Alba (if effective in reducing the perception of drunk; no human evidence on this) may require more alcohol to 'get the job done'

One study that used four Traditional Chinese Medicine herbs together noted that the combination of Morus Alba (0.48mg/mL) with Schisandra chinensis (3mg/mL), Coptis Chinensis (80mcg/mL), and Psidium guajava leaves (374.56mcg/mL) showed alpha-glucosidase inhibitory potential.^[133]

In a high fat and high sucrose fed group of rats that developed diabetes, 10.25, 20.50, or 51.25mL/kg of this ratio daily for 9 weeks (totalling 4.92-24.6mg/kg Morus Alba, 30.75-153.75mg/kg schisandra chinensis, 820-4100mcg/kg Coptis, and 3.8-19.2mg/kg Psidium) noted that acutely, only the highest dose was able to attenuate the spike in blood glucose seen with an oral glucose tolerance test to the levels seen in normal mice 30 minutes after ingestion; with all groups being equally effective between 60-120 minutes but not significantly more than control.^[133] All groups appeared to be simiarly effective in an insulin tolerance test, and fasting blood glucose decreased in a dose-dependent manner over the nine weeks with the high dose group normalizing 62% of the increase in seen in diabetic control versus lean control.^[133]

Roselle (Hibiscus sabdariffa) appears to be synergistic with Morus Alba in inhibiting carbohydrate digestive enzymes in vitro, where their individual inhibitory potential on pancreatic α-amylase at 2mg/mL was 18.99+/-1.39% and 1.17+/-0.74% (respectively) and the combination was 65.75+/-0.60% inhibition; this synergism with roselle extends to Chrysanthemum Indicus and Aegle marmelos.^[56]

Hibiscus Sabdariffa appears to be synergistic with a few herbs in inhibiting pancreatic amylase activity (starch digestive enzyme), of which Morus Alba is one of them

A study using the bioactive Morin noted that consumption og 10mg/kg Morin for 7 days prior to a Piracetam load of 50mg/kg was able to increase the subsequent Piracetam AUC by approximately 50% and the C_max of Piracetam by 45%, credited to inhibition of CYP3A4 and P-Gyp.^[134] A single dose of Morin was unable to mimic these effects, and this oral dose of Morin can be attained with 813mg/kg of the bark (highest Morin concentration) or more practically with ethanolic extracts, which have been noted to concentration Morin up to 0.5mg/g^[3] (and thus would require 20mg/kg).

Possible synergism with a diet rich in Morin-containing foods such as Morus Alba with Piracetam, but the oral dose required may denote supplementation of Morin is needed rather than food sources (which are comparatively low to the oral dose used)

Samjunghwan is a herbal mixture containing Morus Alba fruits, Lycii Radicis Cortex, and Atractylodis Rhizoma Alba; thought to promote neural longevity and attenuate neurodegeneration.^[135]

One study assessing the usage of Morus Alba at 100mg/kg in pregnant rats (either healthy, diabetic, hypercholesterolemic, or both diabetic and hypercholesterolemic mother rats) that noted increases in glucose and retinal pathology (increased risk for cataract formation) noted that Morus Alba exerted protective effects on the mother rats, and less adverse events extended to the pups once they were born (although this was said to be due to lessened pathological signs, and not an inherently beneficial effect of Morus Alba on pups).^[136]