Boswellia

Last Updated: September 28 2022

An Ayurvedic herb also classified as a phytopharmaceutical (H15; Europe) which appears to be quite anti-inflammatory, helpful against osteoarthritis, and may help cerebral edema. Boswellia serrata appears to have preliminary evidence for anti-inflammatory joint disorders.

Boswellia is most often used for.

1.

Sources and Composition

1.1

Sources

Boswellia serrata (of the family Burseraceae) is a herb which has the gum resin extract used for medicinal purposes related to systemic and topical inflammation. In Ayurveda, this herb is known as Salai guggal and patented in India under Sallaki while being patented in Europe under the name of H15.[1] This is one of a few plants in the species of Boswellia (some important ones being Sacra, carterii,[2] papyrifera, neglecta, rivae,[3] frereana,[4] as well as ovalifoliolata[5]) and 25 species in the Boswellia genus in total.[6]

Boswellia serrata also sometimes referred to as Indian frankincense,[7] and in accordance with this name it has sometimes been traditionally burnt at ceremonies (believed to contribute so spiritual exaltation).[8]

The active component of Boswellia serrata is the oleo-gum resin, a plant exudate that is acquired after an incision into the tree. Traditional preparation of Boswellia gum includes a month-long waiting period where the water leaves this gum as it hardens; which results in a final product of 30-60% resin, 5-10% essential (and aromatic) oils (mostly monoterpenes such as E-beta-ocimene and limonene[9]), with the final 30-55% consisting of polysaccharides.[6]

Historical usage of Boswellia seems to be related to inflammatory conditions, with some religious association as well (which may inflate the renown of the herb; see Ganoderma Lucidum as an example of overpromising historical usage related to royalty)

Various other historical uses of Boswellia is its addition to wine to 'benumb the senses' of prisoners sentenced to death (from the Jewish Talmud, although the original source rather than English translation makes mention that it is used to 'confuse or lose the mind'), and to possess tranquilizing effects (Ethiopia).[8]

Historical case studies of Boswellia, as scientifically invalid as they are, suggest that this gum and its incense are tranquilizing anxiolytics

1.2

Composition

  • The two 'primary' Boswellic acids 11-keto-β-boswellic acid (KBA; 4.48-5.81mg/g) and 3-O-acetyl-11-keto-β-boswellic acid (AKBA; 32.7-44.2mg/g)[10][7]
  • α-Boswellic acid (αBA; 8.68-16.1mg/g) and its isomer β-Boswellic acid (β-BA; 53.5-246.9mg/g), and the acetylated forms of Acetyl-α-Boswellic and Acetyl-β-Boswellic acid (38.4-192.9mg/g) respectively,[10][7] the other four most research Boswellic acids (which round out the 'main six')
  • 9,11-dehydro-α-Boswellic acid and its isomer (9,11-dehydro-β-Boswellic acid) and their respective acetylated forms (Acetyl-9,11-dehydro-α-Boswellic and Acetyl-9,11-dehydro-β-Boswellic acids)[11]
  • Lupeolic acid and Acetyl-Lupeolic Acid[11]
  • Incensole Acetate,[12] known as a diterpenic cembrenoid.[13] Incensole oxide and Isoincensole oxide may also be found
  • A pentacyclic triterpenediol mixture of 3α,24-dihydroxyurs-12-ene and 3α,24-dihydroxyolean-12-ene[14][15]
  • Serratol[16]
  • α-Thujene[6]
  • α and β-Amyrin[17]
  • Tirucall-8,24-dien-21-oic acids[18]
  • Alpha-pinene and octyl acetate[19]

Beyond those non-caloric bioactives, the actual Boswellia gum does contain a polysaccharide content; these may be bioactive, and are most likely not in concentrated extracts (as concentrated extracts such as 5-Loxin and Aflapin are concentrated for the Boswellic acids):

  • BOS 2000, a polysaccharide involved in immunity[20]

Main three bioactives are considered the 11-keto Boswellic acids (KBA and AKBA) with comparably less research into other boswellic acids but one (β-Boswellic acid) possibly playing an importat role. Beyond that the aromatic compound Incensole appears to be important; amounts listed may not be accurate for patents or extracts with modified total Boswellic acid content

1.3

Structure and Properties

The structures for the primary six Boswellic Acids are pictured below. The molecular weights are 456.71 (α and β-Boswellic Acids), 498.75 (Acetylated forms), 470.70 for 11-keto-β-boswellic acid (KBA) and 512.74 for 3-O-acetyl-11-keto-β-boswellic acid (AKBA).[7] Many of these Boswellic Acids, especially AKBA, are hydrophobic (fat-soluble) in nature, as is the other non-Boswellic acid compound known as Incensole Acetate.[21]

image

1.4

5-Loxin and Aflapin

In comparison to a standard Boswellia Serrata extract standardized to 3% 3-O-acetyl-11-keto-β-boswellic acid (AKBA), 5-Loxin appears to induce more cumulative anti-inflammatory effects at the same overall weight due to having a higher concentration of AKBA (30%).[22]

Aflapin is a bioavailability enhanced formulation where the AKBA content is reduced to 20%, but it appears to have better overall antiinflammatory effects (relative to both standard Boswellia Serrata and 5-Loxin) due to having more AKBA reach systemic circulation.[23]

Both formulations are created by and owned by Laila Nutraceuticals of India.

2.

Molecular Targets

2.1

NF-kB

Boswellia serrata (via AKBA) appears to inhibit NF-kB activation from TNF-α, IL-1β, doxorubicin, LPS, PMA, H2O2, okadaic acid, and cigarette smoke;[24] all of which actiate NF-kB but from different mechanisms.[25] AKBA also appears to inhibit NF-kB activity in all tested cells demonstrating a ubiquitous effect on NF-kB[24] and is the most potent boswellic acid variant at inhibiting NF-kB and is able to fully abolish activity at 50µM.[24]

It appears that the mechanism by which AKBA acts is, at least in regards to TNF-α, interfering with the phosphorylation of IκBα and Akt (both required for TNF-α induced NF-kB activation[26][27]) and appears to act at a stage upstream of p65.[24]

While the exact mechanism of action is not known, the boswellic acids (most potent is AKBA) appear to inhibit NF-kB in response to pretty much all tested activators of NF-kB and in all tested cell lines

2.2

Microtubules

Microtulube proteins (seen as a cytoskeleton of a cell) is important for the structural integrity of a cell, and some toxins that induce amnesia (Colchicine) have been shown to interfere with microtubule formation[28] and stabilizing microtubules may be seen as therapeutic in instances of Alzheimer's Disease[29][30] related to Tau proteins, which may be a biomarker of impaired cellular integrity (as they maintain Microtubule protein constitution inhernetly, and become dissociated when structurally modified leading to neurofibrillary tangles).[31]

Tubulin assembly rate appears to be enhanced when β-boswellic acid is incubated at 150-300uM, with the higher concentration being associated with a near doubling of tubule length thought to be secondary to less disassembly (decrease in β-tubulin GTPase activity with concurrent GTP-cap stabilization).[32] The length of microtubule proteins was enhanced 21.4% and 38.5% at those two concentrations,[32] which are relatively high compared to those found in serum after oral ingestion of Boswellia Serrata.

One other study has noted positive influence on microtubule formation (polymerization) in fetal hippocampal cells at 0.15mM and 0.30mM by 25% and 41.6%.[33]

May enhance microtubule formation and strengthen the constitution of cells, but aside from being preliminary (and not demonstrated in vivo yet) a very high concentration is required for this. Practical relevance unknown

3.

Pharmacology

3.1

Absorption

In Caco-2 intestinal cells (in vitro assessment of bioavailability) KBA and AKBA appear to have relatively poor absorption but high retention in intestinal cells,[34] a phenomena associated with highly lipophilic drugs.[35] A later study revisiting the Caco-2 cell model but adding Bovine Serum Albumin to the recieving side noted moderate permeability (hypothesizing an absorption rate between 20-70%) and both KBA and AKBA showing better permeability.[36] Incubation with Vermapril (inhibitor of P-Glycoprotein) showed no influence on kinetics.[36]

Absorption, at the level of the intestinal cell, appears to be quite good for Boswellic acids (for the two 11-keto Boswellic acids, this doesn't seem to reflect serum levels)

The serum levels and subsequent tissue deposition of Boswellic acids can be markedly enhanced via by a lecithin delivery form (Phytosome) of Boswellia extract (known as Casperome™,[37] study duplicated in Medline[38]) a technology used with MERIVA® (a bioavailability enhanced form of curcumin) due to formulation of curcumin with phosphatidylcholine (PC).[39] Serum levels of KBA are increased 7-fold and serum levels of β-Boswellic Acid can be increased 3-fold when compared to standard Boswellia Serrata gum capsules with the same amount of Boswellic Acids (more mass overall due to the use of Phytosome technology) and an equal weight supplement with 39% of the initial content of Boswellic acids still outperforms standard Boswellia Serrata.[37]

Interestingly, this study noted that the high degree of variability in serum concentrations was attenuated with the use of this phospholipid-based delivery system; KBA had ranges exceed the actual serum value at most time points following oral administration of standard Boswellia Serrata (ie. 164.39+/-197.40ng/mL) while the use of the Boswellia serrata extract formulated with phospholipids both enhanced absorption while reducing variability (corresponding time point of equal weight supplement was 165.86+/-87.37ng/mL, equal boswellic acid content was 506.33+/-233.98ng/mL).[37]

Lecithin delivery form (Phytosome) of Boswellia extract enhance delivery of Boswellic acids to serum, thought to be mediated at the levels of the intestines. Enhanced intestinal absorption reduces the variability in serum

3.2

Serum

In response to 1400mg taken thrice daily (4800mg; free living conditions) Boswella Serrata gum resin, 11-keto-β-boswellic acid (KBA) was detected in a very variable range of 6.4-247ng/mL (0.01–0.5μM) between 14 participants, with one nonresponder (no detectable levels) and two respondents between 100-247ng/mL, all others (n=11) in the range of 6.4-64.2ng/mL, and the total oral intake of KBA was 423.6mg (all values steady state serum levels).[7] A case study of oral KBA intake (1800mg Boswellia Extract) noted a Cmax after one hour with detectable serum levels for 8 hours,[1] whereas rat studies that measuring the time-course of serum levels note that while all six boswellic acids are detected within 30 minutes of oral ingestion that peak levels appear to be around 4-5 hours, with fairly steady concentrations between 3 and 6 hours (study terminated at 6 hours)[40] Other standard pharmacokinetic parameters measured in rats following ingestion of 240mg/kg Boswellic Acid are a Tmax of 2.83+/-2.91(KBA), 3.17+/-1.17(AKBA), 5.50+/-2.17(αBA), 6.00+/-1.79(AαBA), 4.50+/-2.35(βBA), 6.33+/-1.51(AβBA) and a half-life of 0.74(KBA), 6.73+/-5.25(AKBA), 5.49+/-0.79(αBA), 5.38+/-3.23(AαBA), 10.12+/-8.29(βBA), 6.05+/-0.37(AβBA).[37]

3-O-acetyl-11-keto-β-boswellic acid (AKBA) was detected at 15.5ng/mL (0.03uM) in one out of 14 tested patients, and not detectable in the others at 1400mg thrice daily oral intake (4800mg) in free living conditions with a total oral intake of 80.4mg AKBA (all values steady state serum levels),[7] the level of detectable AKBA in this study (15.5ng/mL) being comparable to that found in a previous study using 2400mg Boswellia extract in three subjects over 4 weeks.[41] However, another study that paired Boswellia with fatty foods noted that serum levels reached 28.8ng/mL with food and recorded serum levels of 6ng/mL without,[42] and another study noting the average AUC of AKBA being increased by 55% (72.2+/-44.6ng/mL to 112.1+/-57.4ng/mL).[43] Increased absorption of KBA has been noted as well as AKBA when paired with a fatty meal, where the 75% response rate (if KBA was at all detected in serum) was increased to 92% and increased the Cmax and AUC by 31.2% and 37.2% without affecting Tmax or half-life.[43]

The other four Boswellic acids at 1400mg thrice daily oral intake in free living conditions (The basic α and β isomers and their acetylated versions) also highly variable in the range of 0.5ng/mL to 12ug/mL (12,000ng/mL).[7] The overall ranges for these four Boswellic acids were 36.7-4830.1ng/mL (967.2mg; α-Boswellic Acid), 87.0-11948.5ng/mL (2236.8mg; β-Boswellic Acid), 73.4-2985.8ng/mL (73.2mg; Acetyl-α-Boswellic Acid) and 131.4-6131.3ng/mL (228mg; Acetyl-β-Boswellic Acid). All values are steady state serum levels.[7]

All six primary boswellic acids are found in plasma, with the 'main' boswellic acid of 3-O-Acetyl-11-keto-β-boswellic acid sometimes not being detectable; all boswellic acids also exert very high variability in plasma following oral administration in humans (unreliable)

AKBA can be enhanced with fatty food intake, and liposomes can enhance absorption of all Boswellic aids; the high variability of serum concentrations still exists to a degree, however

One study measured serum levels of lesser studied triterpenoids in a case study of a single patient, and noted serum levels of 0.06umol/L (35mg; 9,11-dehydro-α-BA), 0.1umol/L (12mg; 9,11-dehydro-β-BA), 0.47umol/L (162mg; Acetyl-9,11-dehydro-α-BA), 0.29umol/L (101mg; Acetyl-9,11-dehydro-β-BA) with no detectable serum levels of Lupeolic and Acetyl-lupeolic acid (510mg and 226mg) after 10 days of supplementation.[11]

Other boswellic acids may be absorbed; as it was a case study variability cannot be assessed. Lupeolic acids not detected in serum

3.3

Distribution

The 6 primary Boswellic acids have been detected in tissues of rats following oral administration of 240mg/kg Boswellia (86.97mg/kg total Boswellic acids) in the eyes, liver, kidney, and skeletal muscle (brain also recorded, but discussed in the Neurology section).[37]

In the eyes, median values recorded over 6 hours reach concentrations of 5.67(KBA), 25.59(AKBA), 41.82(αBA), 8.04(AαBA), 123.4(βBA), 24.65(AβBA). In skeletal muscle, median values are 47.05(KBA), 79.81(AKBA), 105.67(αBA), 6.72(AαBA), 260.24(βBA), 35.02(AβBA).[37]

In the liver these median values are 868.49(KBA), 687.00(AKBA), 1188.48(αBA), 252.56(AαBA), 1012.29(βBA), 743.65(AβBA) and in kidney tissues they reached 226.7(KBA), 885.2(AKBA), 1486.6(αBA), 151.24(AαBA), 3208.8(βBA), 494.46(AβBA).[37]

All the above values are ng/g concentrations and are subject to high variability; variability is reduced and overall concentrations increased in response to Phytosome delivery.[37]

All six boswellic acids have been found in liver, kidney, retinal, and skeletal muscle tissues as well as the brain and serum

3.4

Serum

AKBA and KBA (the 11-keto Boswellic acids) appear to have high affinity for serum albumin.[44]

3.5

Metabolism

KBA, β-Boswellic Acid, and α-Boswellic Acid appear to be subject to Phase I metabolism in the liver, without being significantly affected by Phase II in vitro.[36] Mono or polyhydroxylated derivates (di- and tri-) appear to be the predominant metabolites of these unacetylated boswellic acids.[36]

Acetylated Boswellic acids (AKBA, Acetyl-β-Boswellic acid, and Acetyl-α-Boswellic Acid) appear to be rather resistant to metabolism in vitro in liver microsomes,[36] implicating the acetyl moiety at position 3 in attenuating metabolism rates of Boswellic Acids.[45]

Hydroxylation occurs to non-acetylated Boswellic acids, whereas Acetylated Boswellic acids appear to be resistant to metabolism

3.6

Enzymatic Interactions

Although inhibiting P-Glycoprotein (with Vermapril) does not appear to inhibit the uptake of Boswellic Acids,[36] the two 11-keto Boswellic acids themselves appear to inhibit the P-Glycoprotein inhibitor.[46]

4.

Neurology

4.1

Pharmacokinetics

All six primary Boswellic acids appear to be able to reach the brain after oral administration, with levels in the brain of rats given 240mg/kg (aqueous extract) Boswellia Serrata reaching (at 8 hours after ingestion) for 11-keto-β-boswellic acid (2.38mg/kg; 11.6+/-12.6ng/g), 3-O-Acetyl-11-keto-β-boswellic acid (1.91mg/kg; 37.5+/-56.8ng/g), β-boswellic acid (7.03mg/kg; 1066.6+/-781.6ng/g), Acetyl-β-boswellic acid (5.4mg/kg; 163.7+/-248.9ng/g), α-boswellic acid (3.36mg/kg; 485.1+/-363.8ng/g), and Acetyl-α-boswellic acid (1.68mg/kg; 43.0+/-55.7ng/g).[36] This study noted that the average brain levels of β-boswellic acid of 2.33umol/g wet weight fall within the pharmacological range and suspect that this is the active component for neural issues.[36]

Another study has assessed neural tissue concentrations of KBA and AKBA to levels of 99ng/g and 95ng/g (respectively) following oral intake of 240mg/kg Boswellia extract.[40] These higher concentrations were achieved with crushed H15 capsules, which are in the range of 10.6% KBA and 2% AKBA, higher oral doses relative to the previous study.

AKBA may cross the blood brain barrier easier than KBA in vivo when assessing the ratios of serum to neural concentrations, but does not tend to reach overall higher amounts due to the lesser amount in Boswellia extracts.[40]

All main Boswellic Acids show neural permeability, with the same degree of variance seen in serum

When using a phytosome delivery system (enhanced bioavailability), concentrations of Boswellic acids in the brain can be enhanced, relative to the same oral dose of Boswellic acids without enhanced delivery, from undetectable to 62.1ng/g (KBA), 9.63ng/g to 314.91ng/g (AKBA; ), undetectable to 886.64ng/g (βBA), 7.34ng/g to 120.34 (AαBA), 9.63ng/g to 381.86ng/g (αBA), and undetectable to 402.96ng/g (AβBA).[37]

Phytosome delivery results in significantly higher concentrations in brain tissue following oral administration

4.2

Mechanisms

Incensole Acetate has been found to activate neural TRPV3 receptors (different than Evodia Rutaecarpa; which acts on TRPV1). TRPV3 is a thermoreceptor with a threshold temperature 31–39°C expressed in epithelial cells of the skin and oropharynx[47][48][49] and elicits a warming sensation upon activation. Incensole Acetate activates calcium influx through TRPV3 with an EC50 of 16uM (with 500uM being as effective as 10mM Camphor, another known TRPV3 agonist), with minimal efficacy on TRPV1 and 4 and no influence on TRPV2.[8] Incensole has been investigated whether it possesss affinity for (and subsequently failed to show any appreciable affinity) for Adrenoreceptors (Alpha 1 and 2; Beta 1 and 2), adenosine A3, Dopamine D1 and D2, Histamine H1 and H2, Tachykinin NK1 or NK2, Muscarinic acetylcholine, 5-HT, Benzodiazepine nor Opioid while not interacting with acetylcholinesterase nor the Norephinephrine transporter.[8]

In the hippocampus, mRNA levels of CRF (regulator of corticosteroids) is dose-dependently reduced following injections of Incensole Acetate, and significantly reduced corticosterone levels in a breed of mice (submissive) with higher resting corticosterone levels; no significant effect in wild type mice.[12] The mRNA levels of CRFR1 and both receptors (mineralocorticoid and glucocorticoid receptors) were unaffected.[12] Many modulatory effects on c-Fos activity have been noted in areas pertaining to stress as well.[8]

Incensole Acetate, a bioactive not belonging to the Boswellic acid family, appears to act as a TRPV3 agonist and may have adaptogenic effects by this novel mechanism

β-Boswellic Acid was able to, in vitro with fetal hippocampal neurons at 10, 20, and 30nM over a period of 8 days, was able to enhance length of neurons (58%, 109%, and 158%) and the mean number of neuronal branches (87%, 139%, and 251%).[33]

Some potential enhancement of neuronal branching and growth, unknown relevance in vivo

A methanolic extract of Boswellia socotrana has been found to have potent anti-cholinesterase properties with 22.32% inhibition at 0.05mg/mL and 71.21% inhibition at 0.2mg/mL, whereas another tested species (elongata) inhibited 11.23% and 46.34% respectively.[50] Anti-cholinesterase properties have been detected with boswellic acids previous (in particular, 11-hydroxy-β-Boswellic Acid from Boswellia Carterii[50]) so it is possible that Boswellia Serrata possesses these properties. It is currently unexplored

Theoretically possible for Boswellia Serrata to have acetylcholinesterase inhibiting properties, as it has been noted with the species before; unexplored

4.3

Neuroinflammation

A controlled study in mice where 1 hour of Ischmia (deprivation of oxygen) was followed by 24 hours of Reperfusion (resupply of oxygen coupled with oxidative damage) had intravenous Incensole Acetate administered at 1, 10, or 50mg/kg during Reperfusion found that the lesions in control were reduced by 22.3%, 57.8%, and 69.6% respectively.[51] Protection from neurological deficit induced by I/R injury followed a similar dose-dependent trend, and the mechanisms were thought to be secondary to anti-inflammation (with 50mg/kg reducing proinflammatory cytokines by 88% (TNF-α), 77% (IL-1β) and 80% (TGF-β) while suppressing NF-kB activity up to 84% at the highest dose and in a dose-dependent manner).[51] This protective effect was acute in nature, as starting intravenous application of Incensole Acetate 6 hours after reperfusion (rather than immediately) attenuated the reduction in infarct size form 77% to 37%.[51]

4.4

Edema

Boswellia Serrata gum was assigned the orphan drug status for the reduction of peritumoral edema by the European Medicines Agency (EMA) in 2002, where it goes by (in Europe) the name of H15.[52] A series of case studies in 12 persons with cerebral edema (7 glioblastoma, 2 anaplastic astrocytoma, two low-grade astrocytoma, and one with cerebral metastases from malignant melanoma) either off or on a stable dose of corticosteroids were given 1200mg H15 thrice a day (3600mg total) for 12 weeks was associated with reduced edema in 2/7 tumor bearers but benefitted all patients with edema due to radiotherapy.[52] Out of the 7 patients with tumors, no tumor responded to Boswellia and overall Boswellia was well tolerated.[52] Similar results have supposedly been found in a clinical trial mentioned in some studies,[53] where 30 patients with glioblastoma recieving 1200mg thrice daily Boswellia extract had less peritumoral edema accompanied with a general improvement of well being. The trial (Winking M et al; Boswellic acid as an inhibitor of the perifocal edema in malignant glioma in man. Neurooncology 1996) is not located online.

Appears to have limited but promising clinical effectiveness in reducing neural edema associated with radiotherapy

In a small unblinded study of 4 persons with chronic cluster headaches who also reported disturbed sleep (due to the headaches) given 350-700mg Boswellia Serrata thrice daily (1050-2100mg total) for up to 3 months noted resoluations in nocturnal headaches in all four subjects and an attenuation of overall headache severity and frequency.[54] It should be noted that cluster headaches have edema as a possible sign.[55]

Basically case studies (so not the most statistically sound), but shows promise for cluster headaches

4.5

Depression

A constituent of Boswellia known as Incensole (Acetate) appears to have anti-depressant effects in the Forced Swim Test in mice when injected with 50mg/kg acutely[8] and is effective at 10mg/kg in submissive mice.[12] Lower doses appear effective over time, with 1-5mg/kg in the submissive mice (10-50% acute dose) having similar effects after 1 week of ingestion.[12]

When 10mg/kg in submissive mice was compared to Paroxetine at 10mg/kg, it was technically not statistically different although underperformed,[12] while in normal mice given 50mg/kg it was less effective than 5mg/kg Diazepam in a Forced Swim Test.[8] Anti-depressant effects of Incensole Acetate may be mediated by TRPV3 receptors, as mice lacking these receptors do not have anti-depressant effects in response to injected Incensole.[8]

4.6

Anxiety

A constitient of Boswellia known as Incensole Acetate has failed to significantly influence anxiety at the same dose required to exert anti-depressive effects, 10mg/kg in submissive mice.[12] A reduction in anxiety has been seen at 50mg/kg in otherwise healthy mice as assessed by an elevated plus maze (with comparable effects to Diazepam).[8]

Anxiolytic effects of Incensole Acetate may be mediated by TRPV3 receptors, as mice lacking these receptors do not have anxiolytic effects in response to injected Incensole.[8]

4.7

Locomotion

A constitient of Boswellia known as Incensole Acetate has failed to significantly influence locotmotion at the same dose required to exert anti-depressive effects.[12] A reduction in locomotion has been noted in otherwise healthy mice given 50mg/kg Incensole.[8]

4.8

Cognition

One study using Boswellia papyrifera (similar assortment of bioactives, but may not apply to Serrata) as a 300mg/kg ethanolic extract orally thrice a day (900mg/kg total dose) for 4 weeks showed significant reductions in escape latency and travel distance in a water platform finding test; suggesting improved spatial memory formation.[56] These effects were also seen with isolated Boswellic Acids, and 300mg/kg Boswellic acids thrice a day (900mg/kg) was as effective at enhancing spatial memory formation as the active control of Nicotine (as tartrate salt; 1mcg infusion into the brain daily) although 100mg/kg thrice a day (300mg/kg) was also effective.[56]

5.

Cardiovascular Health

5.1

Platelets

8 hours after consumption of 800mg Boswellia Serrata, there appears to be reduced collagen and arachidonic acid-induced blood clotting in otherwise healthy persons with no effect on Thrombin formation;[43] this was attributed to inhibition of cathepsin G,[41] but was deemed to be weak when compared to Naproxen.[43]

5.2

Immunology

Endothelial cells respond to TNF-α (a pro-inflammatory cytokine), and 22% of the genes influenced by TNF-α (n=552) are influenced by Boswellic Acids,[22] particularly those related to proteolysis, cell adhesion, and inflammation.[57] Three metalloproteins (MMP-3, 10, and 11) are potently suppressed in HMECs (endothelial cells) with incubation of Boswellic acids, with more potency being derived from a mixture with a higher concentration of 3-O-Acetyl-11-keto-β-Boswellic Acid (AKBA) where TNF-α induced MMP release was almost abolished.[22] These effects may underlie the protection seen with AKBA in ApoE-/- mice, where 100umol/kg injections of AKBA halved the size of lesions induced by LPS, a proinflammatory molecule[58] and to explain a reduction in TNF-α induced ICAM-1 secretion in vitro (ICAM-1 being an adhesion factor).[59] It should be noted that the direct sequestering of LPS applies to β-Boswellic Acid and not AKBA, and cannot explain these observed results.[58]

The anti-inflammatory effects of AKBA may be cardioprotective by reducing inflammation and atherosclerosis; this has been seen in vivo after injections, but practical significant of oral ingestion is not known (AKBA tends to have low oral absorption)

6.

Fat Mass and Obesity

6.1

Warmth

A component of Boswellia known as Incensole (Acetate) appears to actiate TRPV3, a receptor upon which activation induces the sensation of warmth;[8] this is a mechanism similar to Evodia Rutaecarpa, and the sensation of warmth may create a false positive for fat loss (despite no energy being expended to produce heat, but merely a sensory change).

Warmth from Boswellia Serrata (currently not demonstrated to be an effect) may be a false positive for fat loss due to having the ability to act on a receptor class that induces the sensation of warmth independent of fat burning

7.

Skeleton and Bone Health

7.1

Osteoclasts

A protein known as RANKL is able to induce osteoclastogenesis via activating NF-kB[60][61] and boswellia serrata (via AKBA) can suppress RANKL-induced osteclastogenesis secondary to NF-kB inhibition at a concentration as low as 300nM (75% inhibition in vitro); AKBA also prevented TNF-α from activating NF-kB (3μM).[24] It does not appear to directly interfere with the TNF-α induced NF-kB complexation, but interferes with the genomic transcription of NF-kB.[24]

Boswellia serrata (via NF-kB inhibition from AKBA) appears to hinder the proliferation of osteoclasts

7.2

Mechanisms

In human chondrocytes (joint cells), Boswellia with 30% AKBA is able to suppress the TNF-α induced release of MMP-3 with an IC50 of 31.71ug/mL;[59] thought to be relevant to osteoarthritis pathology.

7.3

Osteoarthritis

Boswellia Serrata is thought to aid the pathology of Osteoarthritis due to being involved in a herbal combination therapy alongside Ashwagandha and Curcuma Longa (source of Curcumin);[62] the same mixture of herbs which has failed to show any benefit to Rheumatoid arthritis.[63]

In a study comparing two treatments against placebo, the first treatment under the brand name of 5-Loxin (100mg of Boswellia Serrata standardized to 30mg AKBA) was compared to another formulation of Boswellia (Aflapin at 100mg) in 60 persons with confirmed osteoarthritis;[59] the results over 90 days suggested that 5-Loxin reduced symptoms of osteroarthritis on several rating scales by 31.6% (Visual Analogue Scale), 30.3% (WOMAC; pain subset), 42.2% (WOMAC; stiffness subset), 21.25% (WOMAC; functionality subset), and 18.35% (Lequesne's Functional Index) although the Aflapin group outperformed on all parameters. Both groups reported statistically significant improvements within a week of treatment (around 8% reduction with 5-Loxin)[59] with another study noting improvements by day 5 on VAS and LFI rating scales but not WOMAC[64] and a third study suggesting that the improvements within a week occur with higher (250mg) dose of 5-Loxin and take longer with lower (100mg) doses.[65] Overall magnitude of benefits in other studies are improved symptoms of osteoarthritis as assessed by VAS (37.6%), LFI (32%), and WOMAC subsets of pain (40.1%) stiffness (41.3%) and function (38.8%) after 30 days of 100mg Aflapin[64] and reductions in VAS (48.83-65.94%), LFI (23.79-31.34%), WOMAC pain ( 39.61-52.05%) function (49.34%) and stiffness (62.22%) over 90 days of either 100mg or 250mg of 5-Loxin; with the more significant improvements associated with the higher oral dose and both the function ( 28.62%) and stiffness (42.5%) with the low dose failing to be statistically significant.[65]

Currently a multitude of well controlled studies with either 5-Loxin or Aflapin (nutraceutical patents of Boswellia Serrata with concentrated AKBA to 30% and 20%, respectively), but all the studies using these formulations procured external funding from the producer of the supplements. It did not appear to have any influence on the results and seem to have been conducted indpendently.

Another study of persons with osteoarthritis noted that 6g of basic plant extract in three doses of 2g alongside meals was able to reduce knee pain 70.96-73.68%, shoulder pain by 83.33%, and absolved spinal pain from baseline; improvements occurred in swelling and joint mobility to similar degrees and improvements were noted in happiness and activity levels secondary to reduced pain.[66] Conclusions from this study are limited due to being unblinded and without control group,[66] and despite the promise of the above studies in potency there may not be sufficient independent evidence for Boswellia Serrata for attenuating general joint pain.[67][68]

Definitely shows a large degree of promise in treating joint pain without adverse effects, but the amount of interventions on the matter are enough to show this promise but not enough to draw conclusive statements on its efficacy for treating joint pain; a highly promising but not fully established nutraceutical

8.

Inflammation and Immunology

8.1

Mechanisms (Enzymatic)

5-Lipoxygenase (5-LOX) is an enzyme that used Arachidonic Acid (omega-6 fatty acid) as a substrate to create pro-inflammatory cytokines such as 5-hydroxyeicosatetraenoic acid (5-HETE) and Leukotriene B4; this 5-LOX/Leukotriene pathway being a pro-inflammatory signalling pathway in the body.[69] 11-keto-β-boswellic acid and 3-O-Acetyl-11-keto-β-boswellic acid are inhibitors of 5-LOX with IC50 values of 2.8uM and 1.5uM respectively,[70][71] and although other Boswellic acids (such as β-boswellic acid) can inhibit the enzyme partially the 11-keto group appears to enhance potency.[71] The inhibitory potential of Boswellic Acids on 5-LOX is nonredox in nature.[72] Due to the inhibitory potential of these two Boswellic acids in particular on 5-LOX, the 11-keto Boswellic acids are thought to be the most important.

However, serum binding of AKBA to albumin is very high (greater than 95%), and 800mg of Boswellia given to participants failed to influence plasma Leukotriene B4 levels (which should be reduced with oral intake of 5-LOX inhibitors);[44] whether this can be overcome with higher doses traditionally used in interventions is not known.

Boswellic Acids do not appear to greatly inhibit 12-LOX nor Cyclooxygenase (COX) enzymes in vitro, nor do they prevent peroxidation of Arachidonic acid induced by iron or ascorbate.[73][74] One study using platelets, however, did note inhibition on COX1 and 12LOX by 3-O-acetyl-11-keto-β-Boswellic Acid (AKBA) with an IC50 of 6uM in platelets and 32uM in a cell-free assay;[75] with another author suggesting that their unpublished data is in accordance.[76]

The most well known mechanism of action of Boswellia appears to he 5-Lipoxygenase inhibition, and the two most potent bioactives in this regard appear to be the 11-keto Boswellic acids. The 5-LOX inhibition is direct and specific, rather than a general inhibition that can be induced by anti-oxidant compounds; however, whether this mechanism is active in vivo is currently under investigation (with one report suggesting it is unlikely)

No significant interactions with the two Cyclooxygenase enzymes (COX1 and COX2), the targets of NSAID drugs, although some inhibition of COX1 may be possible

Other antiinflammatory mechanisms of Boswellic acid include NF-kB inhibition,[77] which has been noted in vivo in mice given the boswellic acid AKBA in 100umol/kg injections[58][78] and appears to be mediated by multiple mechanisms. In response to Tumor-Necrosis Factor alpha (TNF-α), AKBA appears to bind directly to IKKs and prevent activation of IκBα and p65 (which then prevents induction of NF-kB)[79] and may also directly bind to Lipopolysaccharide (LPS; a bacterial toxin that induces NF-kB).[80] β-Boswellic acid was able to sequester LPS with an IC50 of 1.8uM, which underperformed the active control of polymyxin B which wholly sequestered LPS at 100nM.[80][81] This appears to be a main mechanism of anti-inflammation, as the reduction of iNOS induction seen in macrophages is wholly due to binding to LPS (with Boswellic acids that do not bind to LPS, such as AKBA, being ineffective).[80] Both studies noted that NF-kB translocation induced by interferons (IFN-γ) was unaffected by Boswellic acids.[79][80]

Incensole Acetate in Boswellia species may also inhibit NF-kB activation, as Incensole can inhibit IKK activation loop phosphorylation induced by TAK/TAB and has no inhibitory effect in T-Cells.[82]

General inhibitory effects on NF-kB, a locus for inflammation in response to antigens and dietary stressors; Incensole seems to have novel mechanisms of action, and β-Boswellic acid appears to bind directly to LPS

Cathepsin G (CatG) inhibition, with β-Boswellic acid having an IC50 of 0.8umol/L.[41] Cathepsin inhibition is a therapeutic target for antiinflammatory actions in neutrophils (immune cells).[83] AKBA may also be relevant for CatG inhibition as it has an IC50 of 1.2umol/L

Microsomal prostaglandin E2 synthase inhibition has been noted with Boswellic acids,[84] where the IC50 value for β-Boswellic acid is 5umol/L and the 11-keto Boswellic acids ('main' two) appear to be relatively inert following injections into rats.[84] MPE2S inhibition is an antiinflammatory therapeutic target.[85] Additionally, a lupeolic acid (a minor class of compounds in Boswellia Serrata) appears to inhibit Phospholipase A(2) with an IC50 range of 2.3-6.9uM in general and cytoplasmic PLA(2)α at 3.6uM; this inhibits formation of Arachidonic Acid prior to subsequent metabolism by 5-LOX, 12-LOX, or COX-1.[86]

Human Leukocyte Elastase (HLE) is also inhibited by Boswellic acids.[87] HLE is an enzyme released by immune cells (PMNs) and 3-O-Acetyl-11-keto-β-Boswellic acid inhibits HLE with an IC50 of 15μM (7.5ug/mL has also been reported[76]), and in this same study they noted some inhibition with both β-boswellic acid and ursolic acid, but an apparent lack of effect of the structurally related compound 18-β-glycyrrhetinic acid (from Licorice).[87] No other compound in this assay inhibited 5-Lipoxygenase.

Several other direct anti-inflammatory mechanisms exist that are within the physiological ranges observed in pharmacokinetic studies, suggesting that they may be relevant to the actions of Boswellia

8.2

Innate Immunity

α-boswellic acid and β-boswellic acid have been noted to inhibit the guinea pig complement system at 5-100uM (Wagner et al. 1987 in German; cited vicariously through[76]) and have been replicated elsewhere,[88] and this was thought to be secondary to inhibiting C3-convertase in vitro.[88]

8.3

Adaptive Immunity (B-Cells and Antibodies)

In a test in mice given sheep erythrocytes (to stimulate humoral immunity), a single dose of 50-200mg/kg Boswellic acids (mixed) induced a dose-dependent reduction of primary hemagglutinating antibody titres when measured 4 days after simultaneous administration of Boswellic acids and the antigen by 10.4–32.8%,[89] Azathioprine at 200mg/kg as an active control reduced hemagglutinating antibody titres by 10.4%.[76]

However, when oral dosing of Boswellic acids were given for 5 days preceding and following exposure to the antigen antibody production was increased by 15.38–26.92% at oral doses of 25-200mg/kg Boswellic acids (with most potency at the lowest dose).[89] This same dose range produced a 37.93–63.79% increase in the primary humoral response when preloaded for 7 days, while the active control of Levamisole (2.5mg/kg) increased the primary response by 25%.[89]

Increased antibody synthesis has also been noted with the polysaccharide fragment in both primary (83.8%) and secondary (79.3%) titres in response to oral ingestion of 10mg/kg polysaccharide, which was more potent than the active control of 2.5mg/kg Levamisole (which was comparable in potency to 1-3mg/kg polysaccharide) over 7-15 days of treatment.[20]

May enhance immunity (antibody response to antigens, or adaptive immunity in response to infection) but this may require constant loading rather than acute loading. A single dose may actually be immunosuppressive

One study conducted in mice given an antigen (hepatitis B surface antigen) using BOS2000 (polysaccharides) as an adjunvant alongside vaccination noted that BOS2000 was able to dose dependently increase the IgA response to the antigen, with 10mcg/mL outperforming 0.5mg/mL aluminum (active control) and doses up to 80mcg increasing the response further.[90]

May augment vaccine efficacy, but no oral studies have been conducted

8.4

Lymphocytes

It has previously been noted that in non-immunized mice with no antigen, Boswellic acids have no cumulative effect on Lymphocyte proliferation at 1.95-125ug/mL while acute incubation with Boswellic acids and mitogen stimulating factors (PHA, LPS, Alloantigen, and Concanavalin A) suppress proliferation of lymphocytes.[89] This is in contrast to a study conducted with Boswellia cartenii in heparanized venous blood from participants where acute incubation of different extracts with mitogens (PHA) suggested that T-cell transformation was enhanced with the ethanolic extract (containing Boswellic acids common to both species).[91] This study noted that that TC50 value (concentration of bioactive converting half of lymphocytes to active T-cells) β-boswellic acid, Acetyl-β-boswellic acid, and Acetyl-α-Boswellic acid were 0.0022uM, 0.005uM, and 0.0029uM respectively. Other compounds that appeared to be active were Lupeol (0.0029uM) and 3-oxo-tirucallic acid (0.011uM) while 1mg/mL of the alcoholic extract overall had a TC50 of 0.55mg/mL and induced 90% conversion at 1mg/mL.[91] These effects were reported to be comparable to Echinacea Purpurea.

Stimulation has been noted with the polysaccharide fragment in response to mitogens at 1, 3, and 10mg/kg with maximal effectiveness at 3mg/kg.[20] This same study noted a proliferation of both CD4 and CD8 positive lymphocytes.[20]

Mixed results in regards to lymphocyte proliferation, but appears to stimulate proliferation (pro-immunity result)

8.5

Macrophages

Activation of Macrophages by LPS (may only hold biological relevance when it comes to gut-immunity relations, as LPS is unique to bacteria) can be abolished with direct binding between β-Boswellic acid and LPS.[80]

Otherwise, phagocytosis of macrophages is enhanced when Boswellic acids are incubated with the macrophages at concentrations of 1.95–125μg/mL, with maximal efficacy at 62.25μg/mL.[89] Enhancement of phagocytosis is also noted in vivo after oral adminsitration of low doses of the polysaccharide component BOS 2000 where 1, 3, and 10mg/kg increased phagocytosis [20] Relative to the active control of 2.5mg/kg Levamisole, 1mg/kg was similarly effective while 3mg/kg was more effective and 10mg/kg outperforming all other groups.[20]

8.6

Pancreatic

In a rodent model of toxin-induced Type 1 diabetes (multiple low dose streptozotocin at 40mg/kg), injections of 150mg/kg Boswellia Serrata (5.48% and 4.66% KBA and AKBA) failed to influence blood glucose in otherwise normal mice yet outright abolished the increase of blood glucose in response to the toxin when both were administered fro 5-10 days and measured over 25 subsequent days.[92] Histology between control and the Boswellia group did not appear significantly different from each other, and the serum increase in granulocyte-colony stimulating factor was normalized (with a significant attenuation of GM-CSF) while the levels of IL-1A, IL-1β, and TNF-α were equal between control and Boswellia (attenuation of IL-2, IL-6, and IFN-γ that was not equal to control but lesser than disease control group).[92]

Anti-inflammatory effects have potent protective effects against streptozotocin-induced toxic effects to the pancreas, with this rat study literally negating most of the toxic effects of streptozotocin

9.

Interactions with Hormones

9.1

Testosterone

Although AKBA has been demonstrated to interfere with androgen signalling in prostatic cancer cells, no normal cells lines have been investigated for interactions between AKBA and the androgen receptor.[93]

Investigations into how boswellic acids interact with the normal androgen receptor are yet to be conducted, as studies in prostatic cancer cells do not necessarily apply to noncancerous states

9.2

Cortisol

In a structural test on how compounds can interact with the 11βHSD enzymes (Type 1, which converts cortisol to cortison and type 2 which acts in reverse) it was noted that at a concentration of 20uM that 11-keto-β-boswellic acid and AKBA inhibited the 11βHSD1 enzyme 52% and 63%, which was rivalled by Ganoderic Acid A (from Ganoderma Lucidum) with 46% inhibition; these same concentrations inhibited the 11βHSD type 2 by 68% and 52% (KBA and AKBA; Ganodermic Acid A at 76%), suggesting they are nonselective inhibitors.[94]

10.

Interactions with the Intestines

10.1

Motility

Boswellia serrata appears to concentration-dependently reduce intestinal contractions in response to acetylcholine, barium chloride, or by EFS in a range of 1-1000mcg/mL with more efficacy in inhibiting the former two rather than EFS.[95] There was no significant effect on basal activity of the intestines despite the inhibition of contractions, and feeding of 100-400mg/kg of Boswellia Serrata to rats did not per se interact with motility although 200-400mg/kg significantly attenuated the increase in motility induced by croton oil and reduced the occurrence of diarhhea when rats were given castor oil.[95]

Limited evidence, but suggests Boswellia Serrata gum can prevent rapid intestinal motility without affecting motility that is not unnecessarily rapid

10.2

Fibrosis

An animal model of inflammation-induced fibrosis via the toxin 2,4,5-trinitrobenzene sulphonic acid noted that oral treatment of 50mg/kg daily Boswellia Serrata gum was able to attenuate the percent of damage to the intestines from 12.27+/-9.84% in toxin control to 5.00+/-5.90% (none present in true control) and attenuate a shortening of the colon but failed to significantly reduce many other parameters (Strictures, Adhesions, Dilation, etc.).[96] Combination therapy with 150mg/kg Scutellaria baicalensis, inactive on its own, synergistically reduce the effects of 2,4,5-trinitrobenzene sulphonic acid on all parameters.[96]

10.3

Inflammatory Conditions

One of the few instances where usage of Boswellia Serrata extends into Traditional Chinese Medicine (rather than being isolated in Ayurvedic medicine) is for the usage of treating inflammatory bowel conditions.[97]

In a rat model of colitis (colonic inflammation), 34.2mg/kg Boswellia extract (1% 3-O-acetyl-11-keto-β-boswellic acid; AKBA) given for 2 days prior to or 2 days after colitis induction with acetic acid (experimentally used to induce colitis when injected into the colon) noted that the reduction in anal sphincter pressure was partly normalized with either preloading or therapeutic intervention of Boswellia.[98] This study noted an almost normalization of lipid peroxidation in the colon (via TBARS) as well as normalization of anti-oxidant enzymes (glutathoine, superoxide dismutase, and glutathoine peroxidase).[98] Another study using indomethacin-induced colitis did note that AKBA reduced leukocyte recruitment to the colon, and this apparently immunosuppressive effect may underlie the protection observed[99] and chemotaxis (recruitment) of leukocytes plays a significant role in colitis pathology;[100] the degree of protection with AKBA is similar to corticosteroids.[99]

Only one study has been conducted in humans using Boswellia (as deduced by a systematic review[101]) found that adults with confirmed Collagenous colitis (an inflammatory bowel disorder subset) noted that thrice daily consumption of 400mg Boswellia Serrata for 6 weeks (totalling 1200mg daily) increase the amount of persons in remission from 26.7% to 43.8%, suggesting moderate efficacy.[102]

Some protective effects on colitis related to suppressing the inflammation induced by injury

A preliminary study conducted in youth with Crohn's disease using a nutraceutical combination therapy (Boswellia Serrata, Curcumin, and a standard multivitamin) with twice weekly administration of probiotics and daily injections of Growth Hormone appeared to significantly prolong remission time in a small sample.[103]

With isolated Boswellia in persons with Crohn's Disease (who were at risk for remission) using 1200mg (Thrice daily dosing of 400mg; 80% ethanolic extract known as Boswellan) for one year noted that Boswellia was not more effective than placebo at retaining persons in a state of Remission.[104] Boswellia did not improve quality of life more than placebo (both groups reporting a decline), and although there was a trend for Boswellia to reduce general reported side-effects this was not significant.[104] The only significant difference was the clinical ferritin reading, which decline in treatment with Boswellia (which was thought to be normalizing the excess ferritin levels induced by inflammation).[104]

Has once failed to show benefit to Crohn's Disease, and the promising studies are highly confounded

11.

Interactions with Organ Systems

11.1

Mouth

3-O-Acetyl-11-keto-β-boswellic acid (AKBA) appears to possess inhibitory activities on oral pathogens with a Minimum inhibitory concentration (MIC) in the 2-4ug/mL range against S. Mutans, E. Faecalis, E. Faecium, A. Viscosus, and S. Sanguinis (lesser activity against F. nucleatum), which rivals Triclosan on the first five strains.[105] β-boswellic acid and 11-keto-β-boswellic acid both showed some inhibitory potential while Acetylated-β-boswellic acid was seemingly inactive, and AKBA inhibited biofilm production by S. mutans and A. viscosus with an IC50 of 16ug/mL.[105] The essential oil of Boswellia in general carries this biofilm protective effect,[106]

Appears to have potent anti-bacterial properties, which may be useful as a chewing gum

11.2

Kidneys

One study has been conducted in rats to assess the prophylactic effects of Boswellia Serrata on renal failure over 8 weeks (adenine induced renal failure), and compared the efficacy of Boswellia (900mg/kg) against Ginger (500mg/kg) and Arabic gum (200mg/kg).[107] Ginger was able to reduce the increases in urea, creatinine, BUN, and serum LDH (50-57%) while Boswellia was protective on all parameters but to a lesser degree than Ginger.[107]

11.3

Lungs

300mg of Boswellia gum resin thrice a day (total of 900mg) for 6 weeks in persons aged 18-75 with acute bronchiol asthma associated with breathlessness and wheezing (smoking status not disclosed) noted significant improvements in asthmatic symptoms as assessed by FEV1, FVC, and PEFR; treatment improved the rate of significant improvements from baseline from 27% to 70%.[108] This study may be limited by the experimental group trending to have worsened symptoms at baseline, as noted in a systemic review on the topic.[109]

Boswellia is thought to benefit asthmatic symptoms secondary to its anti-inflammatory actions, but specifically its ability to inhibit leukotriene synthesis (via being a 5-LOX inhibitor),[110] and has shown efficacy in combination with Licorice and Turmeric root (source of Curcumin).[110]

Limited evidence, but shows promise for asthma related to inflammation

12.

Cancer Metabolism

12.1

Mechanisms

Beyond immunological mechanisms (outlined under 'Inflammation and Immunology'), 3-O-Acetyl-11-keto-β-Boswellic Acid (AKBA) appears to inhibit Hypoxia Inducible Factor 1 (HIF-1).[111] HIF-1 is a protein where its alpha section (HIF1α) has increased activity in response to low oxygenation[112] and has been designated a target for chemotherapy,[113] and while the Boswellia extract appears to inhibit HIF1α transcription absolutely at 25mcg/mL when hypoxia was induced by desferrioxamine, known to induce hypoxia. AKBA itself was effective at abolishing HIF-1 transcriptional activity (as were other Boswellic acids, and some unknown compounds), and these compounds acted on the same HIF-1 binding site as Quercetin despite structural differences.[111]

Appears to inhibit HIF-a induction and attenuate changes associated with hypoxia

AKBA appears to be a potent VEGFR2 kinase inhibitor, and via acting on endothelial cells in the 1-5umol/L range with an IC50 value of 1.68umol/L on VEGFR2k AKBA can inhibit angiogenesis potently and suppress the related downstream angiogenic pathways of Src/FAK, AKT, ERK, mTOR and p70S6.[114] HUVEC (endothelial cell) apoptosis may also occur, with 10umol/L AKBA reducing the VEGF-induced increase in cell viabiltiy to 40% of control.[114]

May directly inhibit angiogenss via direct enzymatic inhibition

3-O-Acetyl-11-keto-β-Boswellic acid (AKBA) appears appears to be a topoisomerase I inhibitor,[115] and appeared to work (as do many pentacyclic terpenoids) by competing with DNA for binding to the enzyme.[116] In cells that do not express 5-Lipoxygenase (HL-60 and CCRF-CEM[117]), AKBA is able to inhibit apoptosis via inhibiting Topoisomerase I at concentrations exceeding 10uM.[115] This inhibition of Topoisomerse I extends to Topoisomerase II, and does not per se influence DNA fragmentation.[115][118]

May inhibit Topoisomerase, practical relevance unknown

12.2

Glioma

A glioma is a subset of tumor in the brain or spinal cord, consisting of 45–55% of brain tumors (with a subset of 'glioblastoma' up to half of gliomas).[119]

Mechnistically, in glioma cells Boswellic acids appear to induce apoptosis via CD95L (with no alterationsin CD95) and although it does not inherently require tumor suppressor genes p21 is induced (thought to be reactive from the cell against apoptosis) and a wild-type p53 is more conducive to apoptosis than overexpressed; boswellic acids do not modify Bax/Bcl-2.[118]

Boswellic acids can induce apoptosis in multiple glioma cell lines (T98G, LN-18, LN-229 and LN-308) with Acetyl-β-Boswellic acid being more potent than AKBA (β-Boswellic acid less so) at 20-40uM, with all cell lines possessing less than 20% cell viability at 30uM or more.[118] EC50 values of apoptosis were averaged out to be 20uM, 27uM, and 40uM for ABA, AKBA, and BA respectively.[118]

In an animal model of glioma (nonlethally injecting a tumor into the cerebrum) subsequently fed 60, 120, or 240mg/kg Boswellia Gum thrice a day (total daily doses being 180, 360, and 720mg/kg respectively) until death from brain tumor, it was noted that Boswellia diminished tumor size in a dose dependent manner after 14 days (13.5% with 60mg/kg, 65.7% with 120mg/kg; highest dose actually preventing solid tumor formation and only revealed tumor cell clusters).[53] Apoptotic cells increased in a dose-dependent manner (50%, 106%, and 147%), enhanced vitality on all measures, and doubled survival relative to control rats; the two lower doses were reported to be free of side-effects, with 720mg/kg (240mg/kg thrice daily) group suffering slight hair loss.[53] One case study in an adult female notes similar effects, where the metastasis of her breast cancer reached her brain and supplementation of Boswellia Serrata (given to reduce edema and suppress headaches) at 3 doses of 800mg eliminated the presence of the tumor in her brain as assessed by CT scans.[120]

Rat evidence that oral administration of Boswellia gum can significantly suppress brain tumor (glioma-type) formation; the potency associated with high (720mg/kg rodent dose) being fairly astounding

12.3

Intestinal and Colorectal

Mechanistically, 3-O-acetyl-keto-β-boswellic acid (AKBA) appears to have a moderate potency but highly generalized demethylation ability on the genome in cancer cells, suggesting that a mechanism of action may be demethylation of tumor suppressor genes (which can be suppressed when methylated).[121] This may precede upregulation of the let-7 and miR-200 microRNA families in colorectal tumor cells in response to AKBA,[122] both of which are tumor suppressor genes that influence further downstream targets of CDK6, vimentin and E-cadherin.[122] AKBA may activate the PI3K/Akt pathway (which encourages pro-survival), and as such inhibitors of this pathway synergistically augment the cytotoxic effects of AKBA in colon cancer cells.[123]

AKBA may have inhibitory potential on intestinal carcinomas in mice after oral consumption, where polyp size after 8 weeks of daily ingestion was reduced 48.9% (small intestine) and 60.4% (colon) in APC/Min+ mice; no overt toxicity was noted, and the mechanisms of action thought to be via anti-inflammatory and apoptotic means.[124]

Oral ingestion of Boswellia has shown efficacy in reducing polyp size in experimental animals, synergistic with PI3K/Akt inhibitors, and fairly potent following oral ingestion (as AKBA has low absorpton, much is sequestered in the colon; these results may be practically relevant)

12.4

Prostate

In LNCaP cells (androgen responsive), cell proliferation is reduce by 58.92% (20uM), 79.26% (30uM), and 94.33% (40uM) AKBA concentrations with an IC50 of 20.07uM despite being in the presence of androgens (10nM DHT).[125] This was associated with G0/G1 cell cycle arrest with a decrease percentage of cells in S phase without significant apoptosis but an induction of p21WAF1/CIP1.[125] These changes were thought to be due to 30uM AKBA potently suppressing androgen receptor activity, with 30uM AKBA reducing genomic activity of the androgen receptor below that of control cells despite being in the presence of 10nM DHT by interfering with the coregulator Sp1.[125] NF-kB inhibition (another anti-tumor mechanism of Boswellia related to anti-inflammation) may not be relevant to androgen responsive LNCaP cells due to low expressed NF-kB in this cell line.[126]

One study did note that both 11-keto boswellic acids induced apoptosis in PC-3 cells in vitro with EC50 values of 12.1uM (11-keto-α-boswellic acid) and 4.9uM (AKBA); the mechanism was not fully established but was related to caspase-3 release, suggestive of DNA fragmentation.[127] Proliferation is unaffected at 50uM in this cell line,[114] but can be suppressed by transfection with the androgen receptor to make them similar to LNCaP cells.[125] The aforementioned induction of apoptosis appears to occur in both PC-3 cells and LNCaP cells actually, and 10mcg/mL or higher concentriations of AKBA mediate apoptosis via the Death Receptor 5 (DR5) by upregulating its mRNA levels and activating the promoter, secondary to JNK activation and CHOP induction (with NF-kB not playing a significant role).[128]

AKBA appears to be anti-androgenic in prostate cancer cells and can normalize proliferation in vitro via suppressing the actions of DHT on the genome in prostate cells. It may induce apoptosis independent of the androgen receptor

3-O-Acetyl-11-keto-β-boswellic acid (AKBA) was able to potently prostatic tumor weight and normalized the tumor volume in mice injected with 10mg/kg AKBA after they had prostatic tumors implanted and then measured for 30 days (PC-3 cell line).[114] While in control mice implanted tumors increased 459% from 95.83+/-43.37mm3, in the AKBA group they actually decline from a similar level by 49%; thought to be secondary to suppressing angiogenesis (established in vivo and in vitro) with 60mcg AKBA in vitro abolishing VEGF-induced microvessel sprouting.[114] It was determined that AKBA is a potent VEGFR2 kinase inhibitor with an IC50 of 1.68 μMol/L, and secondary to this AKBA inhibited expression of a variety of proangiogenic pathways (Src/FAK, AKT, ERK, mTOR and p70S6K).[114]

Has shown in vivo efficacy in mice injected with PC-3 cell lines where tumor size was effectively normalized after injections of 10mg/kg AKBA

12.5

Cervical

A hot water extract of Boswellia Serrata can induce apoptosis in cervical cancer cells (HeLa), with 1mg/mL seeming to max out at 40% apoptosis; this was associated with increases in GRP78 and CHOP levels and though to be mediated via endoplasmic reticulum stress as calpain activity was induced to a degree that correlated with apoptosis (calcium could not inherently be measured as Boswellic acids conferred their own color to the system).[129] Additionally, one compound found in Boswellia Serrata that is not one of the Boswellic acids (an isomeric mixture of 3a,24-dihydroxyurs-12-ene and 3a,24-dihydroxyolean-12-ene) was able to induce cytotoxicity in HeLa and SiHa cells with equal potency and about 5-fold less than that required to damage healthy cells;[15] 70-100ug/mL induced DNA fragmentation and appeared to work via increasing nitric oxide and ROS production and induced mitochondrial instability and subsequent apoptosis.[15]

Beyond those two studies, other studies on cervical cancer cells are those done with synthetic analogiues of β-boswellic acid or AKBA as an attempt to synthesize new anti-cancer molecules; cyano-derivatives seem potent, but do not naturally exist in Boswellia Serrata.[130][131]

May induce apoptosis in cervical cancer cells, but there is less research on this type of cell than in other cancer cell lines and no current assessment of potency relative to other control drugs

12.6

Myeloma

STAT proteins are a family of transcription factors associated with angiogenesis, proliferation, and chemoresistance of cells;[132] the specific protein STAT3 is highly expressed in Myeloma cells (and some other cell lines), and its activation results in upregulation of VEGF, Bcl-2, Cyclin D1, Survivin,[132] and the metastatic TWIST.[133] AKBA appears to inhibit STAT3 as well as c-Src and JAK, resulting in suppression of the aforementioned STAT3-related gene products.[134] This inhibition was time and concentration dependent with 4 hours of exposure at 50mcg/mL wholly inhibited STAT3 in Human MM and U266 cells, is reversible upon washing the cell, abolishes IL-6 induced activity of JAK2 and STAT3, the inhibition itself is abolished by Protein tyrosine phosphatases activation, and is thought to be due to an upregulation of SHP-1 as the siRNA of SHP-1 abolishes the benefits;[134] SHP-1 being a transmembrane protein that regulates STAT3.[135] Beyond this, another study notes that in U266 Myeloma cells that CXCR4 (a chemokine receptor) is downregulated.[136]

When incubated in cells, Human MM and U266 cells have their proliferation almost abolished with 50uM AKBA associated with accumulation in the Sub-G1 phase.[134]

Apoptosis can be induced via caspase-3 cleavage in Human MM and U266 cells with subsequent PARP cleavage, mediated via an induction of SHP-1 suppressing STAT3 activation.[134]

May be anti-proliferative and induce apoptosis of Myeloma cells at moderate to high concentrations; seemingly potent in vitro, but currently does not have any active control or in vivo evidence to assess practical potency

12.7

Leukemia

In human myeloid KBM-5, AKBA appears to potentiate cytotoxicity induced by classical chemotherapeutic agents (doxorubicin, 5-flurouracil) secondart to NF-kB inhibition, and this applied to TNF-α induced apoptosis which was increased from 10% to 47.8% with 3μM AKBA.[24]

May potentiate chemotherapy secondary to inhibiting NF-kB, a mechanism which is common to many supplements and drugs (NF-kB inhibition per se tends to augment cytotoxicity from the reference drugs)

A downregulation of the chemokine receptor CXCR4, secondary to preventing NF-kB from acting on the CXCR4 promoter, has been noted in leukemia cancer (KBM-5) cells in vitro.[136] A triterpendiol mixture form Boswellia Serrata (not boswellic acids) on HL-60 cells has also been found to upregulate DR4 receptors and TNF-R1 and induce caspase-8 release and PARP cleavage (indicative of apoptosis).[14] This triterpendiol mixture additionally suppressed proliferation with an IC50 value of 15mcg/mL.[14]

12.8

Breast

A downregulation of the chemokine receptor CXCR4, secondary to preventing NF-kB from acting on the CXCR4 promoter, has been noted in breast cancer (MDA-MB-231) cells in vitro with 50uM abolishing proliferation in a Matrigel assay;[136] this may be biologically relevant as at least one case study has noted that breast cancer metastasis that reached the brain in an adult female was seemingly abolished after 10 weeks of 800mg thrice daily dosing of Boswellia Serrata.[120]

Usage of another species of Boswellia (Sacra) that also possesses the standard Boswellic acids (19.6-30.1mg/mL) has noted that in a variety of breast cancer cell lines (T47D, MCF7, MDA-MB-231, and MCF10-2A) noted that the oil was able to induce apoptosis and reduce cell count potently in all cell lines except MCF10-2A and exhibited anti-proliferative effects in vitro.[137] Boswellia species that do not have a large boswellic acid content (socotrana and dioscorides) do not have significant apoptotic effects on MCF-7 cells.[138]

Limited evidence and no animal studies, but Boswellia appears to generally be anti-proliferative on breast cancer cells; there is a single case study suggesting that oral Boswellia has eliminated a metastatic breast cancer tumor located in a female's brain

12.9

Pancreatic

The invasiveness of pancreatic (PANC-28) cells has been noted to be suppressed in vitro with AKBA (50umol/L resulting in an abolishment of pancreatic proliferation in Matrigel assay), thought to be related to a downregulation of CXCR4.[136] CXCR4 is a receptor responding to chemokines that, upon activation, appears to favorably influence metastasis and tumor progression in cancer cells.[139] 12 hours of 50umol/L AKBA in PANC-28 cells, the receptor was downregulated in a concentration and time dependent manner independent of cell viability (unaffected).[136] This downregulation is associated with downregulation of HER2 and NF-kB, and appears to reduce the genomic transcription of CXCR4 by preventing NF-kB from acting on the CXCR4 promoter.[136] This was later shown to occur in four pancreatic cancer cell lines; PANC-28, BxPC-3 (most sensitive with 25umol/L abolishing proliferation) AsPc-1 and Paca-2,[140] and was found to potentiate the activity of gemcitabine.[140]

After tumor implantation of PANC-28 cells in nude mice, expression of CXCR4 was shown to occur in vivo from 73% (control) to 15%, tumor size was reduced 50%, and metastasis significantly suppressed.[136] This experiment was expanded upon later by the same authors,[140] and while AKBA (100mg/kg daily oral ingestion) was nonsignificantly more effective than Gemcitabine (25mg/kg injections twice weekly) at reducing tumor volume the combination was highly effective (nearly abolishing the increase in tumor size) with the synergism also applying to suppression of metastatic potential of injected PANC-28 cells.[140] 454+/-23 ng/ml of AKBA was found in plasma in these experiments, which correlated to 273+/-13ng/mL concentration in excised pancreatic cells.[140] Suppression of tumor size in vivo has been demonstrated elsewhere with an extraction of mixed Boswellic Acids, and noted that extractions with lower molecular weight compounds (lower concentration of boswellic acids) were still effective in vitro.[141]

Appears to very potently reduce Pancreatic cell invasiveness and tumor size, which has been demonstrated at least once in nude mice implanted with tumors following oral administration of AKBA at 100mg/kg; due to the reasonable dosage and method of administration significantly suppressing tumorogenesis, this is a highly promising nutraceutical for Pancreatic Cancer

13.

Interactions with Aesthetics

13.1

Skin

Mechanistically, Boswellic acids may act to inhibit hyaluronidase (an enzyme that degrades hyaluronic acid),[142][143] Leukocyte elastase,[87] and via the anti-inflammatory effects can inhibit expression of a variety of Metalloproteinases (MMP1, 3, 10, and 12) in endothelial cells.[22] These pro-inflammatory enzymes are known to have roles in degradation of the extracellular matrix, collagen, and elastic fibers of skin cells.

A skin cream containing 0.5% Boswellic acids appeared to enhance skin elasticity, reduce sebum excretions, and confer photoprotective in female participants using the cream for a period of 30 days both at the end of treatment as well as during one month followup, in 15 women applying the cream to half their face (other half used as control for reference) with a mean age of 44.4;[143] this study is duplicated in Medline,[144] and other improvements that were noted to occur with 0.5% Boswellic acid cream are less roughness (26% reduction cream side, 11% control side), less 'fine smooth lines'(20% reduction on cream side, 3% control side) and nonsignificant trends to improve erythema and wrinkles, and all benefits were maximally effective within 30 days (with no added benefit at day 60).[143][144]

Has demonstrated efficacy in improving skin quality and elasticity when applied to human faces, possibly mediated by anti-inflammatory effects

14.

Nutrient-Nutrient Interactions

14.1

Aflapin

Aflapin® is a brand name for Boswellia Serrata that appears to have greater bioavailability than when compared to 5-Loxin, a patented version of Boswellia Serrata consisting of 30% 3-O-Acetyl-11-keto-β-boswellic acid (AKBA).[145]

A comparative study of 5-Loxin (100mg Boswellia; 30% AKBA) against Aflapin (100mg; 20% AKBA) noted that Aflapin was able to outperform 5-Loxin on all measured parameters while both were significantly better than placebo;[59] this study was funded by Laila Nutraceuticals, producers of both supplements.[59]

14.2

BHUx

BHUx is a 5-herb combination formula consisting of Boswellia Serrata, Termenalia arjuna, Strychnox nux vomica, Commiphora mukul, and Semecarpus anacardium though to be effective in treating atherosclerosis and hyperlipidemia.[146]

14.3

Commiphora myrrha

The combination of the Boswellia genus (Frankincense) and Commiphora myrrha (Myrrh) has a fair bit of historical usage, even being immortalized in the New Testament of the Bible (Christianity) as being two of the valued gifts given by the Three Wise Men upon the birth of Jesus (alongside Gold itself). Interestingly, both are used in Traditional Chinese Medicine in combination.

In an animal model of formalin-induced paw edema (to assess anti-inflammatory properties), the water extract of Myrrh (3.9g) appeared to outperform the water extract of Boswellia (6.8g) while the combination was in between with both groups underperforming to Indomethacin as active control.[147] In a careegnan-induced paw edema test, synergism existed where the combination therapy (5.2g) was equally effective to 10mg/kg Indomethacin.[147] PGE(2) and Nitrate production failed to show synergism.[147]

In regards to Oxytocin-induced dysmenorrhea, Myrrh was able to reduce writhing times (suggesting an analgesic effect) and while Boswellia had no significant influence on its own it enhanced the activity of Myrrh in reducing the writhing time and frequency.[147]

Frankincense is somewhat synergistic with Myrrh; gold uninvestigated (usually inedible)

14.4

Salvia miltiorrhiza

Salvia miltiorrhiza and Boswellia have been investigated for their combination on hepatic fibrosis in mice where Boswellia (50mg/kg) and Salvia (150mg/kg) were both tested in isolation and in combination against DMN-induced hepatic fibrosis.[148] Combination therapy was able to suppress the pathology of liver fibrosis in mice associated with reductions in TGF-β1, Smad3 and Smad7 signalling and mostly attributed to Salvia Miltiorrhiza.[148]

15.

Safety and Toxicology

15.1

General

It appears that Boswellia Serrata extracts have an LD50 in rats of over 5000mg/kg when using a bioavailability enhanced formula[145] with a similar safety threshold of over 5000mg/kg with a Boswellia extract standardized to 30% AKBA;[149] these correlate to 2,000-3,000 times the effective dose in humans and appear to be nontoxic.[149][59]

Boswellia Serrata bioactives appear to be nongenotoxic as assessed by AMES reverse mutation assay,[150] chromosomal aberration test (Hamster cells) and mouse peripheral blood micronucleus assay.[59] An oral dose of up to 1000mg/kg Boswellia Resin to rats (equivalent human dose of 160mg/kg, or 11g for a 150lb person) has also failed to show genotoxic effects.[151]

Standard oral doses have been subject to toxicology testing and appear safe and nongenotoxic

15.2

Case Studies

At least one case study has noted the possibility of an allergy to Boswellia Serrata when topically applied as a cream.[152]

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