Assessing the Israeli Public Adoption of Nutritional Supplements, Including Frankincense, in COVID-19 Management: Patterns, Perceptions, and Efficacy

Endothelial cells are critical elements in the pathophysiology of inflammation. Tumor necrosis factor (TNF) alpha potently induces inflammatory responses in endothelial cells. Recently we have examined the genetic basis of the antiinflammatory effects of Boswellia extract (BE) in a system of TNFalpha-induced gene expression in human microvascular endothelial cells (HMECs). Of the 522 genes induced by TNFalpha in HMECs, 113 genes were sensitive to BE. BE prevented the TNFalpha-induced expression of matrix metalloproteinases (MMPs). In the current work, we sought to test the effects of BE on TNFalpha-inducible MMP expression in HMECs. Acetyl-11-ketobeta- boswellic acid (AKBA) is known to be an active principle in BE. To evaluate the significance of AKBA in the antiinflammatory properties of BE, effects of BE containing either 3% (BE3%) or 30% (BE30%, 5- Loxin) were compared. Pretreatment of HMECs for 2 days with BE potently prevented TNFalpha-induced expression and activity of MMP-3, MMP-10, and MMP-12. In vivo, BE protected against experimental arthritis. In all experiments, both in vitro and in vivo, BE30% was more effective than BE3%. In sum, this work lends support to our previous report that BE has potent antiinflammatory properties both in vitro as well as in vivo.

Inflammatory disorders represent a substantial health problem. Medicinal plants belonging to the Burseraceae family, including Boswellia, are especially known for their anti-inflammatory properties. The gum resin of Boswellia serrata contains boswellic acids, which inhibit leukotriene biosynthesis. A series of chronic inflammatory diseases are perpetuated by leukotrienes. Although Boswellia extract has proven to be anti-inflammatory in clinical trials, the underlying mechanisms remain to be characterized. TNF alpha represents one of the most widely recognized mediators of inflammation. One mechanism by which TNFalpha causes inflammation is by potently inducing the expression of adhesion molecules such as VCAM-1. We sought to test the genetic basis of the antiinflammatory effects of BE (standardized Boswellia extract, 5-Loxin) in a system of TNF alpha-induced gene expression in human microvascular endothelial cells. We conducted the first whole genome screen for TNF alpha- inducible genes in human microvascular cells (HMEC). Acutely, TNF alpha induced 522 genes and downregulated 141 genes in nine out of nine pairwise comparisons. Of the 522 genes induced by TNF alpha in HMEC, 113 genes were clearly sensitive to BE treatment. Such genes directly related to inflammation, cell adhesion, and proteolysis. The robust BE-sensitive candidate genes were then subjected to further processing for the identification of BE-sensitive signaling pathways. The use of resources such as GenMAPP, KEGG, and gene ontology led to the recognition of the primary BE-sensitive TNF alpha-inducible pathways. BE prevented the TNF alpha-induced expression of matrix metalloproteinases. BE also prevented the inducible expression of mediators of apoptosis. Most strikingly, however, TNF alpha-inducible expression of VCAM-1 and ICAM-1 were observed to be sensitive to BE. Realtime PCR studies showed that while TNF alpha potently induced VCAM-1 gene expression, BE completely prevented it. This result confirmed our microarray findings and built a compelling case for the anti-inflammatory property of BE. In an in vivo model of carrageenan-induced rat paw inflammation, we observed a significant antiinflammatory property of BE consistent with our in vitro findings. These findings warrant further research aimed at identifying the signaling mechanisms by which BE exerts its anti-inflammatory effects.

Plasma Concentrations of Boswellic Acids in Fasting Healthy Humans Supplemented with a Water-Soluble Boswellia Extract (78% AKBA) vs. Reference Boswellia Extract (30% AKBA) (P06-005-19)

Boswellic acid formulations are not suitable for treatment of pediatric high-grade glioma due to tumor promoting potential

The antimicrobial activity of essential oils of Boswellia and thyme (Boswellia sp., and Thyme sp.) was evaluated against 20 clinical isolates of Streptococcus pneumoniae and 5 isolates of Klebsiella pneumoniae. Essential oils were prepared using methanol and water (1:1) with HPLC technique. Antimicrobial activity and minimum inhibitory concentration (MIC) were measured using disk diffusion method against 20 isolates of S. pneumoniae and 5 isolates of K. pneumoniae isolated from different patients. Flavonoids and phenolic compounds are the main constituents of Boswellia and thyme which may have the antimicrobial activity. Boswellia extract was more efficient than thyme extracts; 60% of S. pneumoniae isolates and one K. pneumoniae isolate were sensitive to Boswellia extract, 30% of S. pneumoniae isolates were sensitive to thyme extract, and no effect on K. pneumoniae clinical isolates was observed. Inhibition zones ranged from 1-12 mm with thyme extract, while Boswellia extracts showed 2 to 30 mm diameters of inhibition zone. This study is significant due to the widespread problem of microbial drug resistance and the need for natural antibiotic to fight diseases.   Key words: Thymus sp., Boswellia sp., antibacterial effect, Pneumonia.

Herbal drug related warfarin intoxication

Boswellic acids, the main active ingredients of Boswellia serrata, are gaining more and more importance in the treatment of peritumoural oedema and chronic inflammatory diseases. They may be even considered as alternative drugs to corticosteroids in reducing cerebral peritumoural oedema. An important focus for drugs acting in the central nervous system is achieving a high extent of brain penetration. Today there is increasing evidence for the importance of transporters, especially P-glycoprotein (Pgp), for drug disposition and resulting clinical response. Pharmacokinetic studies revealed that the concentrations of the potent keto derivatives, the 11-keto-beta-boswellic acid (KBA) and the acetyl-11-keto-beta-boswellic acid (AKBA), in proportion to boswellic acids lacking a keto group, like the beta-boswellic acid, are much lower in plasma than in the orally administered extract. Moreover the brain/plasma ratio for KBA and AKBA determined in preliminary experiments on rats was only about 0.51 and 0.81, respectively, in spite of their lipophilicity. Until now little is known about the cerebral pharmacokinetics of boswellic acids and how it may be influenced. Since many drugs are known to interact with Pgp at the level of the intestine and the blood-brain barrier the modulatory potencies of the Boswellia serrata extract of H15(R) and the major boswellic acids on the transport activity of Pgp have been determined in two in vitro assays. A human lymphocytic leukaemia cell line (VLB cells) expressing Pgp was chosen as model for human Pgp, and porcine brain capillary endothelial cells (PBCEC cells) were taken as model for the blood-brain barrier using calcein acetoxymethyl ester (calcein-AM) as Pgp substrate. It was found that the Boswellia extract, as well as the keto-boswellic acids inhibit the transport activity of Pgp in the micromolecular range in both cell types. No modulation was observed using those boswellic acids which have no keto group in their structure. The inhibition of Pgp at the blood-brain barrier by Boswellia extract is probably not relevant for the brain availability of other Pgp substrates, because of the low plasma levels determined for KBA and AKBA. However the presented data could not exclude the possibility of drug interactions caused by modulation of Pgp by extracts of Boswellia serrata on the gastrointestinal level.

Tocilizumab versus the Covid19 tempest: All’s well that ends well or much ado about nothing?

Frankincense is obtained from the trees of the genus Boswellia and has been used historically for many reasons, including medicinal purposes. Previous research indicates that mice treated with a purified component from frankincense, incensole acetate (IA), had a decrease in anxious behavior during anxiety tests. Boswellia extract can be purchased from General Nutrition Centers (GNC). Since IA has been found to be have antidepressant properties in mice, this study investigated whether the Boswellia extract from GNC, e.g. unpurified IA, would also have anti-depressant/anti-anxiety affect. Sixty CD1 mice, 30 male and 30 female, were treated for approximately 25 days and were tested for the anti-depressant and anti-anxiety effects of Boswellia extract and sertraline (Zoloft®) compared to the control group. Each group of mice was analyzed by three behavioral tests: an open-field test, tail suspension test, and marble-burying test to determine the effects of these drugs. It was found that female mice treated with sertraline demonstrated significant reduction of anxiety behaviors as measured in the open field test, indicating reduced anxiety. Treatment with Boswellia, on the other hand, did not show a significant reduction in anxiety behaviors in either gender of mice. The tail suspension results showed that both Boswellia and sertraline significantly increased immobility time. These results suggest the Boswellia and sertraline reduce anxiety, but not depression in CD1 mice.

The oleo-resinous gum of Boswellia trees has been used for religious rituals, but also for medical purposes in different civilizations for ages. The active principles of the gum resin are boswellic acids. The ethnopharmacology of frankincense indicate activity towards inflammatory diseases and cancer. There is compelling evidence from experimental investigations that boswellic acids reveal anti-inflammatory activity, and the results of clinical trials confirm that Boswellia extracts are also clinically effective. No serious side effects were recorded. Occasional side effects included fatigue, vomiting, diarrhea, unspecific skin rash, azoospermia, and neutropenia. Several investigations using Boswellia extracts or isolated boswellic acids demonstrated growth inhibition of tumors in mice and rats, and increased survival time of animals. The treatment effects were associated with inhibition of AKT, reduced NF-κB activation, and down-regulation of anti-apoptotic proteins. Clinical application in glioblastoma patients showed an improvement of clinical symptoms in terms of edema reduction, but no reduction of tumor size.

<p><em>Boswellia serrata</em> Roxb. is a tree that is mainly found in the dry regions of India. Its oleoresin, known internationally as Indian frankincense, is used in Ayurvedic, traditional Arabic and Chinese medicine. This gum resin contains 15-20% of boswellic, lupeolic and other pentacyclic triterpenic acids, of which the boswellic acids (beta-boswellic acid, keto-beta-boswellic acid and acetil-11-keto-beta-boswellic acid) have been shown to have anti-inflammatory, anticancer and antidiabetic properties and are used in the modern pharmaceutical industry. Besides its ability to prevent and treat various diseases (rheumatoid arthritis, osteoarthritis, Chron’s disease, ulcerative colitis and asthma), other biological functions of B. serrata resin should not be neglected.<br />The aim of this study was to analyze, for the first time, extracts of <em>B. serrata</em> resin obtained with subcritical water at different temperatures (110–190 °C) for their phenolic and flavonoid content. The total phenolic content (TPC) was determined by UV-spectrophotometry using the Folin-Ciocalteu method. The total flavonoid content (TFC) was also determined by UV-spectrophotometry using a simple method with AlCl<sub>3</sub>. <br />With increasing extraction temperature, the TPC increased from 3.76 mg GAE/g DW at 110 °C to 13.78 mg GAE/g DW at 190 °C. The highest TFC was observed in the extract obtained at 170 °C (8.56 mg RE/g DW). <br />The results of this study suggest that extracts of B. serrata resin obtained with subcritical water are a rich source of bioactive compounds that can be used in pharmaceuticals, dietary supplements and functional foods.  </p>

Mechanistic role of boswellic acids in Alzheimer’s disease: Emphasis on anti-inflammatory properties

In consideration of the increasing popularity of frankincense and the widely published quality problems associated with botanical dietary supplements, a survey was conducted for the first time on the quality of frankincense containing botanical dietary supplements. Six US products representing 78 % of the units sold and 70 % of the market value, and 11 European products representing 30 % of the units sold and 40 % of the market value were tested for their boswellic acid composition profile, label compliance, and claimed health benefits. Special focus was also set on the statements made with regard to the frankincense applied.Only five products out of seventeen disclosed all relevant information for the Boswellia extract, mentioning the species, the part of plant used, and the boswellic acid content. Whereas all products but one claimed to use Boswellia serrata, three products did not mention the resin as the part applied and 10 products did not declare the boswellic acid content. Apart from the different boswellic acid composition determined with a sensitive LC/MS method, 41 % of the products did not comply with the label declaration. Hence, one product from Italy did not contain any of the six characteristic boswellic acids (KBA, AKBA, αBA, βBA, AαBA, AβBA) at all and another US product contained only traces, suggesting the absence of frankincense or the use of Boswellia frereana instead of B. serrata. In another product, the ratios of the individual boswellic acids were different from B. serrata gum resin, indicating the use of another species such as Boswellia sacra or Boswellia carterii. Furthermore, two products revealed different boswellic acid contents from those declared on the label. Further, two products did not declare the use of manipulated Boswellia gum resin extract being enriched in acetyl-11-keto-boswellic acid content reaching up to 66 %. In addition, consumers could be misled by outdated literature or references to in vitro studies performed at dosages that can never be achieved in humans following oral administration.In summary, this survey reveals that in spite of increased regulations on botanical dietary supplements, the problem of mislabeling still exists and needs to be addressed by the manufacturers, so that consumers get greater confidence in the botanical dietary supplements they use.

Incensole acetate prevents beta-amyloid-induced neurotoxicity in human olfactory bulb neural stem cells

Frankincense, the gum resin derived from Boswellia species, showed anti-inflammatory efficacy in animal models and in pilot clinical studies. Boswellic acids (BAs) are assumed to be responsible for these effects but their anti-inflammatory efficacy in vivo and their molecular modes of action are incompletely understood. A protein fishing approach using immobilized BA and surface plasmon resonance (SPR) spectroscopy were used to reveal microsomal prostaglandin E(2) synthase-1 (mPGES1) as a BA-interacting protein. Cell-free and cell-based assays were applied to confirm the functional interference of BAs with mPGES1. Carrageenan-induced mouse paw oedema and rat pleurisy models were utilized to demonstrate the efficacy of defined BAs in vivo. Human mPGES1 from A549 cells or in vitro-translated human enzyme selectively bound to BA affinity matrices and SPR spectroscopy confirmed these interactions. BAs reversibly suppressed the transformation of prostaglandin (PG)H(2) to PGE(2) mediated by mPGES1 (IC(50) = 3-10 µM). Also, in intact A549 cells, BAs selectively inhibited PGE(2) generation and, in human whole blood, β-BA reduced lipopolysaccharide-induced PGE(2) biosynthesis without affecting formation of the COX-derived metabolites 6-keto PGF(1α) and thromboxane B(2) . Intraperitoneal or oral administration of β-BA (1 mg·kg(-1) ) suppressed rat pleurisy, accompanied by impaired levels of PGE(2) and β-BA (1 mg·kg(-1) , given i.p.) also reduced mouse paw oedema, both induced by carrageenan. Suppression of PGE(2) formation by BAs via interference with mPGES1 contribute to the anti-inflammatory effectiveness of BAs and of frankincense, and may constitute a biochemical basis for their anti-inflammatory properties.