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Prevention and/or management of the dysregulated immune response in patients with COVID-19 is expected to help in the treatment of COVID-19. Boswellic acids (BAs) have great therapeutic potential because they have anti-inflammatory and immunomodulatory effects. Here, we aimed to investigate the mechanism of action of a BA formulation, Inflawell syrup, which was previously shown to be effective in reducing disease symptoms in patients who suffer from mild to moderate COVID-19. Patients with mild to moderate COVID-19 were treated with either Inflawell containing boswellic acids or a placebo for 14 days. The serum levels of inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α), interleukin (IL)-8, IL-1α, IL-17, IL-1Ra, and Monocyte Chemoattractant Protein-1 (MCP-1), were measured both at study onset and on day 14 after treatment started. In addition, to further investigate the signaling pathway(s) underlying the changes in cytokine levels, we evaluated the expression of tumor necrosis factor receptor 1 (TNFR1), tumor necrosis factor receptor 2 (TNFR2), and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) p65 mRNAs and phospho-inhibitor of nuclear factor kappa B (IκB) and IκB proteins. In our study, a significant decrease in the serum levels of IL-1α ( p < .009), IL-8 ( p < .04), TNF-α ( p < .0001), and MCP-1 ( p < .007) was detected in patients treated with Inflawell. Additionally, our data revealed a decrease in phospho-IκB protein levels ( p < .02) and NF-κB p65 mRNA levels ( p < .002), whereas the amount of IκB protein ( p < .01) in the Inflawell group was significantly greater than that in the placebo group. Furthermore, despite the decreasing trend in the expression of TNFR1 and TNFR2 in the Inflawell group, there was no statistically significant difference compared with that in the placebo group. In general, treatment with Inflawell syrup led to a lower level of proinflammatory cytokines and a decrease in the activity of the TNF-α/NF-κB signaling pathway.

Hepatic encephalopathy (HE) is a syndrome that arises from acute or chronic liver failure. This study was devised to assess the impact of a combination of boswellic acid (BA) and low doses of gamma radiation (LDR) on thioacetamide (TAA)-induced HE in an animal model. The effect of daily BA treatment (175 mg/kg body weight, for four weeks) and/or fractionated low-dose γ-radiation (LDR; 0.25 Gy, twice the total dose of 0.5 Gy) was evaluated against TAA (200 mg/kg, intraperitoneal) twice-weekly for four weeks to induce liver damage and HE in rats. TAA-exposed rats exhibited a significant elevation in serum activities of liver enzymes (GGT, ALP) and plasma ammonia levels at P < 0.05 (Duncan's test) compared to the control group. Moreover, there was an increase in the levels of proinflammatory cytokines (IL6, IL12, IL18) in the TAA-exposed animals accompanied by a depletion in the activities of paraoxonase-1 and neurotransmitter contents compared with normal control rats (P < 0.05). However, the administration of BA alone or in combination with LDR led to improvements in liver and brain parameter indices. Furthermore, the histopathological assessments of liver and brain tissues supported the findings of the biochemical investigations. From the statistical analysis, it can be concluded that the combined administration of BA and exposure to LDR may possess potential hepatoprotective effects against hepatic encephalopathy-associated hyperammonemia and the consequent damage to the liver and brain. This study proposes that a combination of therapeutic approaches, LDR and BA could be a new therapeutic candidate for the management of hepatic encephalopathy., Competing Interests: Declarations. Ethics approval and consent to participate: The present study was approved by the Institutional Animal Care and Use Committee Research Ethic Board of the National Center for Radiation Research and Technology (REC-NCRRT) (48A/22). Notably, all animal experimentation was conducted in accordance with applicable laws, regulations, and guidelines, prioritizing animal welfare and minimizing any potential harm. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Otitis media (OM) is a prevalent childhood ear disease characterized by inflammation of the middle ear cavity, which can lead to ear pain, fever, and hearing loss. The pathogenesis of OM is multifaceted, encompassing a variety of factors including bacterial or viral infections, host immune responses, and the function of middle ear epithelial cells. Boswellic acid (BA), a natural triterpene compound extracted from frankincense resin, has been proven to possess significant anti-inflammatory and immunomodulatory effects. This study aims to investigate the effects of BA on lipopolysaccharide (LPS)-stimulated inflammatory responses and apoptosis in human middle ear epithelial cells (HMEECs) and its potential mechanisms. Our findings demonstrated that BA enhances the proliferation of LPS-stimulated HMEECs and concurrently inhibits their apoptosis. In addition, BA blocked LPS-stimulated HMEEC inflammation. Mechanistically, BA suppressed the NF-κB/IκBα axis in LPS-stimulated HMEECs. In conclusion, BA effectively inhibits LPS-stimulated inflammation and apoptosis by mediating the NF-κB/IκBα axis, highlighting its potential as a therapeutic agent for OM., Competing Interests: Conflict of interest: Authors state no conflict of interest., (© 2024 the author(s), published by De Gruyter.)

Background: 3- O -acetyl-11-keto- β -boswellic acid ( β -AKBA), a triterpene natural product, is one of the main natural products of Boswellia sacra resin (BSR) and has reported biological and immunomodulatory effects. 1 H -1,2,3-triazole derivatives of β -AKBA (named 6a - 6d ) were synthesized from β -AKBA. The 1 H -1,2,3-triazole compounds are also known to have a wide range of biological and pharmacological properties as demonstrated by in vitro and in vivo studies. This study aimed to investigate the effects of these 1 H -1,2,3-triazole derivatives of β -AKBA on human T-cell proliferation and activation. Methods: PBMCs isolated from healthy donors were activated by anti-CD3/CD28 monoclonal antibodies in the presence of β -AKBA ( 1 ) or 1 H -1,2,3-triazole derivatives of β -AKBA or DMSO controls. Results: We found that similar to the parent compound β -AKBA ( 1 ), derivatives 6a , 6b , and 6d significantly inhibited T-cell expansion/proliferation and reduced the levels of CD25 activation marker on CD4 + and CD8 + T cells without exerting significant cytotoxic effects on T-cell viability at a concentration of 25 µM. However, compound 6c further inhibited T-cell expansion/proliferation and CD25 expression, but had a significant cytotoxic effect on cell viability at similar concentrations of 25 µM. Conclusions: These findings demonstrate the immunoinhibitory effects of β -AKBA ( 1 ) and its corresponding triazole derivatives on T-cell proliferation and activation, highlighting the promising therapeutic potential of these compounds in T-cell-mediated diseases.

Osteoarthritis is one of the most common locomotor diseases, with a steadily increasing prevalence and incidence. Loxacon ® is a food supplement capsule containing vitamins, minerals, and herbal extracts with Boswellia serrata extract and Harpagophytum procumbens extract as its two main active components. The study involved 88 patients at 4 sites. The 88 patients were divided into 3 groups. The first group received physical therapy and Loxacon ® capsules for 5 weeks, while the second group (30 patients) received physical therapy only for 5 weeks, and the third group (30 patients) received physical therapy and placebo capsules for 5 weeks. After 5 weeks, physical therapy was discontinued in all three groups and all groups continued Loxacon ® capsules exclusively for an additional 60 days. Physical therapy had been carried out by a standard protocol over 5 weeks. Investigated parameters included Western Ontario and McMaster Universities Arthritis Index (WOMAC) testing, European Quality of Life (EQ-5D-5L) quality of life test and the Range of Motion (ROM). Among the 4 visual analogue scale (VAS) values investigated from WOMAC, significant change was seen for functionality in all three groups; however, the extent of change was twice as large in the physical therapy + Loxacon ® group at Visit 2 in comparison with the other two groups. In the physical therapy + placebo group, improvement was seen only at the 3rd visit when they were also receiving Loxacon ® capsules. The most pronounced difference was seen in the minimum clinically important difference index, calculated from the quality of life-VAS, where those taking Loxacon ® capsules had a chance 3 times as high to obtain clinical improvement versus the other two groups. Our study confirmed that a combination of boswellic acid and harpagosides is beneficial as an additional therapy in knee OA.

Background: Masticatory myofascial pain syndrome (MMPS) is a soft tissue inflammatory disorder that leads to acute or chronic localized pain and stiffness in the muscles. Catechol-O-methyltransferase (COMT) plays a crucial role in mediating pain perceptions in humans by transferring methyl groups to catecholamines. This process requires adequate S-adenosyl methionine (SAMe). A reduction in SAMe leads to COMT inhibition. Boswellia serrata possesses multiple therapeutic benefits and is used for treating chronic pain., Aim: The study aimed to evaluate the therapeutic potential of acetyl-11-keto-beta-boswellic acid (AKBA) by targeting COMT . Methodology: Molecular docking and dynamic simulations were conducted using Desmond software from Schrödinger LLC, USA, to evaluate the interaction between COMT protein and AKBA ligands. The COMT protein structure was sourced from the Protein Data Bank and preprocessed using optimized potentials for liquid simulations. Molecular docking identified potential binding sites between COMT and AKBA through hydrogen bonding, resulting in a docking score of -6.0 kcal/mol., Results: The molecular docking revealed a docking score of -6.0 kcal/mol for the interaction between COMT and AKBA. The dynamic simulation demonstrated that the COMT-AKBA complex remained stable within a 3.0 Angstrom range over 60 nanoseconds. These findings indicate stable natural small molecular interactions between COMT and AKBA., Conclusion: AKBA exhibits potential as a therapeutic agent for MMPS, demonstrating stable interactions with COMT. These findings warrant further in vitro and in vivo analyses to confirm efficacy., Competing Interests: Human subjects: All authors have confirmed that this study did not involve human participants or tissue. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Suresh et al.)

Cyclophosphamide (CYP) is a chemotherapeutic drug used to treat various cancers. However, its clinical use is limited due to severe organ damage, particularly to the kidneys. While several phytochemicals have been identified as potential therapeutic targets for CYP nephrotoxicity, the nephroprotective effects of boswellic acid (BOSW) and betulinic acid (BET) have not yet been investigated. Our study used 42 rats divided into six equal groups. The study included six groups: control, CYP (200 mg/kg), CYP+BOSW20 (20 mg/kg), CYP+BOSW40 (40 mg/kg), CYP+BET20 (20 mg/kg), and CYP+BET40 (40 mg/kg). The pre-treatments with BOSW and BET lasted for 14 days, while the application of cyclophosphamide was performed intraperitoneally only on the 4th day of the study. After the experimental protocol, the animals were sacrificed, and their kidney tissues were isolated. Renal function parameters, histological examination, oxidative stress, and inflammation parameters were assessed both biochemically and at the molecular level in kidney tissue. The results showed that oxidative stress and inflammatory response were increased in the kidney tissue of rats treated with CYP, leading to impaired renal histology and function parameters (p < 0.05). Oral administration of both doses of BET and especially high doses of BOSW improved biochemical, oxidative, and inflammatory parameters significantly (p < 0.05). Histological studies also showed the restoration of normal kidney tissue architecture. BOSW and BET have promising biological activity against CYP-induced nephrotoxicity by attenuating inflammation and oxidative stress and enhancing antioxidant status., (© 2024. Pleiades Publishing, Ltd.)

This study aims to explore the protective machinery of pegylated polymeric micelles of boswellic acid-selenium (PMBS) against secondary neuronal damage triggered by mild repetitive traumatic brain injury (RTBI). After PMBS characterization in terms of particle size, size distribution, zeta potential, and transmission electronic microscopy, the selected formula was used to investigate its potency against experimental RTBI. Five groups of rats were used; group 1 (control) and the other four groups were subjected to RTBI. Groups 2 was RTBI positive control, while 3, 4, and 5 received boswellic acid (BSA), selenium (SEL), and PMBS, respectively. The open-field behavioral test was used for behavioral assessment. Subsequently, brain tissues were utilized for hematoxylin and eosin staining, Nissl staining, Western blotting, and ELISA in addition to evaluating microRNA expression (miR-155 and miR-146a). The behavioral changes, oxidative stress, and neuroinflammation triggered by RTBI were all improved by PMBS. Moreover, PMBS mitigated excessive glutamate-induced excitotoxicity and the dysregulation in miR-155 and miR-146a expression. Besides, connexin43 (Cx43) expression as well as klotho and brain-derived neurotrophic factor (BDNF) were upregulated with diminished neuronal cell death and apoptosis because of reduced Forkhead Box class O3a(Foxo3a) expression in the PMBS-treated group. The current study has provided evidence of the benefits produced by incorporating BSA and SEL in PEGylated polymeric micelles formula. PMBS is a promising therapy for RTBI. Its beneficial effects are attributed to the manipulation of many pathways, including the regulation of miR-155 and miR-146a expression, as well as the BDNF /Klotho/Foxo3a signaling pathway., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The present study aimed to develop food packaging films by using a combination of pectin (PE) and sodium alginate (SA) enriched with Acetyl-11-keto-beta-boswellic acid (AKBA) as a functional or active ingredient. The fabricated films underwent comprehensive evaluation of their morphological, chemical, mechanical, barrier, optical, thermal, antioxidant, and antimicrobial properties. SEM and FTIR analysis showed that AKBA had good compatibility with film-forming components. The AKBA-loaded film samples exhibited a decrease in their barrier properties and tensile strength, but enhancements in both elongation at break and thickness values was observed. With the addition of AKBA, a significant increase (p < 0.05) in the ultraviolet barrier properties of the films and total colour variation (ΔE) was observed. TGA analysis of the films unveiled an improvement in thermal resistance with the incorporation of AKBA. Moreover, the films loaded with AKBA exhibited potent antioxidant activity in the ABTS and DPPH assay methods. Disk diffusion analysis showed the antimicrobial activity of AKBA-loaded films against P. aeruginosa, highlighting the potential of AKBA as a natural antimicrobial agent for the safety of food products. The results demonstrate the practical application of PE and SA active films loaded with AKBA, particularly within the food packaging industry., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

COVID-19 appeared as a highly contagious disease after its outbreak in December 2019 by the virus, named SARS-CoV-2. The threat, which originated in Wuhan, China, swiftly became an international emergency. Among different genomic products, spike protein of virus plays a crucial role in the initiation of the infection by binding to the human lung cells, therefore, SARS-CoV-2's spike protein is a promising therapeutic target. Using a combination of a structure-based virtual screening and biochemical assay, this study seeks possible therapeutic candidates that specifically target the viral spike protein. A database of ~ 850 naturally derived compounds was screened against SARS-CoV-2 spike protein to find natural inhibitors. Using virtual screening and inhibitory experiments, we identified acetyl 11-keto-boswellic acid (AKBA) as a promising molecule for spike protein, which encouraged us to scan the rest of AKBA derivatives in our in-house database via 2D-similarity searching. Later 19 compounds with > 85% similarity with AKBA were selected and docked with receptor binding domain (RBD) of spike protein. Those hits declared significant interactions at the RBD interface, best possess and excellent drug-likeness and pharmacokinetics properties with high gastrointestinal absorption (GIA) without toxicity and allergenicity. Our in-silico observations were eventually validated by in vitro bioassay, interestingly, 10 compounds (A3, A4, C3, C6A, C6B, C6C, C6E, C6H, C6I, and C6J) displayed significant inhibitory ability with good percent inhibition (range: > 72-90). The compounds C3 (90.00%), C6E (91.00%), C6C (87.20%), and C6D (86.23%) demonstrated excellent anti-SARS CoV-2 spike protein activities. The docking interaction of high percent inhibition of inhibitor compounds C3 and C6E was confirmed by MD Simulation. In the molecular dynamics simulation, we observed the stable dynamics of spike protein inhibitor complexes and the influence of inhibitor binding on the protein's conformational arrangements. The binding free energy ΔG TOTAL of C3 (-38.0 ± 0.08 kcal/mol) and C6E (-41.98 ± 0.08 kcal/mol) respectively indicate a strong binding affinity to Spike protein active pocket. These findings demonstrate that these molecules particularly inhibit the function of spike protein and, therefore have the potential to be evaluated as drug candidates against SARS-CoV-2., (© 2024. The Author(s).)

Introduction: Frankincense preparations are frequently used as traditional anti-inflammatory remedies in folk medicine with increasing popularity. Boswellic acids (BAs), especially 3-O-acetyl-11-keto-βBA (AKBA), are unique anti-inflammatory principles of frankincense, with multiple pharmacological actions and target proteins. We recently showed that AKBA favorably impacts lipid mediator (LM) networks in innate immune cells, by modulation of lipoxygenase (LOX) activities. Thus, AKBA binds to allosteric sites in 5-LOX, shifting the regiospecificity to a 12/15-lipoxygnating enzyme, and to an analogous site in 15-LOX-1, leading to enzyme activation, which favors specialized pro-resolving mediator (SPM) formation at the expense of leukotriene production. Methods: Here, we investigated Boswellin super® (BSR), a commercially available frankincense extract with ≥30% AKBA, used as remedy that approved efficacy in osteoarthritis trials, for its ability to modulate LM pathways in human monocyte-derived macrophage (MDM) phenotypes, neutrophils, and neutrophil/platelet co-incubations. LM profiling was performed by using targeted ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS-MS). Results: BSR concentration-dependently (10-100 μg/ml) suppressed formation of pro-inflammatory 5-LOX products including LTB4 in exotoxin-stimulated M1-MDM and neutrophils, and strongly elevated 12/15-LOX products and SPM in activated M2-MDM and neutrophil/platelet cocultures, starting at 10 μg/mL. Also, BSR (≥10 μg/mL) induced robust 12/15-LOX product and SPM generation in resting M2-MDM, which was further markedly elevated when exogenous docosahexaenoic acid (DHA) and eicosahexaenoic acid (EPA) were supplied, and induced translocation of 15-LOX from a soluble to a particulate locale in M2 MDM. Discussion: We conclude that BSR especially when co-added with DHA and EPA, promotes the LM class switch in innate immune cells from pro-inflammatory to pro-resolving mediators, which might be a plausible mechanism underlying the anti-inflammatory actions of BSR., Competing Interests: Author MG was employed by company Evonik Operations GmbH. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Nischang, Witt, Börner, Gomez, Jordan and Werz.)

The oleo-gum-resin of Boswellia serrata, an Ayurvedic herb for the treatment of chronic inflammatory diseases, contains both volatile (terpenes) and nonvolatile (boswellic acids) molecules as responsible for its bioactivity. The present randomized, double-blinded, placebo-controlled, crossover study evaluated the human pharmacokinetics of a 'natural' hybrid-hydrogel formulation of a unique full-spectrum boswellia extract (BFQ-20) (standardized for both volatile and nonvolatile bioactives) in comparison with unformulated extract (U-BE), for the first time. Mass spectrometry coupled with LC (UPLC-MS/MS) and gas chromatography (GC-MS/MS) measurements of the plasma concentration of boswellic acids and α-thujene at different post-administration time points followed by a single dose (400 mg) of U-BE and BFQ-20, to healthy volunteers (n = 16), offered 4-fold enhancement in the overall bioavailability of boswellic acids from BFQ-20, [area under the curve (AUC) (BFQ-20) = 9484.17 ± 767.82 ng * h/mL vs. AUC (U-BE) = 2365.87 ± 346.89 ng * h/mL], with the absorption maximum (T max ) at 6.3 h post-administration and elimination half-life (T 1/2 ) of 15.5 h (p < 0.001). While plasma α-thujene was not detectable upon U-BE administration, BFQ-20 provided significant absorption, [AUC (BFQ-20): 298.60 ± 35.48 ng * h/mL; C max : 68.80 ± 18.60 ng/mL; T max : 4.12 ± 0.38 h; T 1/2 : 16.24 ± 1.12 h]. Further investigation of the anti-inflammatory effect revealed 70.5% inhibition of paw edema in rats compared to 38.0% for U-BE. In summary, the natural self-emulsifying reversible hybrid-hydrogel (N'SERH) formulation of boswellia extract using fenugreek mucilage (FenuMat ® ) significantly increased the solubility (58-fold), stability, and bioavailability of both the volatile and non-volatile bioactives which in turn improved the anti-inflammatory efficacy of Boswellia extract.

This study aimed to develop a local 3 D-printed bioactive graft using poly-caprolacton (PCL) as a drug carrier and 3- O -acetyl-β-boswellic acid (β-ABA) as an anticancer compound. β-ABA-loaded 3 D-printed scaffold was fabricated and physically characterized. The results indicated more desirable mechanical and physical properties of the β-ABA-loaded PCL mat in comparison with the PCL scaffold. Following sustained release of β-ABA, the β-ABA-loaded PCL scaffold revealed selective cytotoxic activity against melanoma cells, while the PCL + ABA with the bolus delivery of β-ABA was toxic against fibroblast cells. Followed by the induction of apoptosis in melanoma cells at the gene level, the result of the western blot showed that the β-ABA-loaded scaffold significantly up-regulated P53 and down-regulated BCL2, with an increment in the ratio of Bax/BCL2. The selective anti-cancer properties of β-ABA-loaded 3 D printed scaffold against melanoma cells indicated that this scaffold could be potentially used as a bioactive graft to improve the melanoma treatment.

Objective: Pharmacological treatments of osteoarthritis (OA) have several side effects. Boswellia serrata resin (frankincense) is rich in boswellic acids that have antioxidant and anti-inflammatory effects; though, their oral bioavailability is low. The aim of this study was evaluation of the clinical effectiveness of frankincense extract in the treatment of knee OA. In a randomized double-blind placebo-controlled clinical trial, eligible patients with knee OA were randomly divided into two groups of drug (33 patients) and control (37 patients), to use oily solution of frankincense extract or placebo, respectively, on the involved knee three times daily for four weeks. WOMAC (Western Ontario and McMaster Universities Osteoarthritis Index), VAS (visual analogue scale; for pain severity), and PGA (patient global assessment) scores were determined before and after intervention., Results: For all evaluated outcome variables, there was a significant decrease from baseline in both groups (P < 0.001 for all). Furthermore, the end-of-intervention values for all parameters were significantly lower in drug group than placebo group (P < 0.001 for all), showing more effectiveness of drug compared to placebo., Conclusion: Topical oily solution containing enriched extract of boswellic acids could decrease pain severity and improve the function in patients with knee OA. Trial Registration Trial registration number: IRCT20150721023282N14. Trial registration date: September 20, 2020. The study was retrospectively registered in Iranian Registry of Clinical Trials (IRCT)., (© 2023. The Author(s).)

Specialized pro-resolving mediators (SPM), primarily produced in innate immune cells, exert crucial bioactions for resolving inflammation. Among various lipoxygenases (LOX), 15-LOX-1 is key for SPM biosynthesis, but cellular activation principles of 15-LOX-1 are unexplored. It was shown that 3-O-acetyl-11-keto-β-boswellic acid (AKBA) shifts 5-LOX regiospecificity from 5- to 12-lipoxygenation products. Here, it is demonstrated that AKBA additionally activates cellular 15-LOX-1 via an allosteric site accomplishing robust SPM formation in innate immune cells, particularly in M2 macrophages. Compared to ionophore, AKBA-induced LOX activation is Ca 2+ - and phosphorylation-independent, with modest induction of 5-LOX products. AKBA docks into a groove between the catalytic and regulatory domains of 15-LOX-1 interacting with R98; replacement of R98 by alanine abolishes AKBA-induced 15-LOX product formation in HEK293 cells. In zymosan-induced murine peritonitis, AKBA strikingly elevates SPM levels and promotes inflammation resolution. Together, targeted allosteric modulation of LOX activities governs SPM formation and offers new concepts for inflammation resolution pharmacotherapy., (© 2022 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Boswellic acid (BA)s are pentacyclic triterpenic acids present in gum resin of Boswellia species (such as B. serrata and B. carterii). They possess a variety of pharmacological effects such as anti-inflammatory, anti-oxidant, and anti-excitotoxic effects. These properties may have potential therapeutic implication in neurological disorders. Notably, the BAs-induced neuroprotection is proposed to be associated with the ability to reduce neurotoxic aggregates, decrease oxidative stress, and improve cognitive dysfunction. Recently, BAs have been suggested as potential agents for the treatment of brain tumors due to their potential to attenuate cell proliferation, migration, metastasis, angiogenesis, and promote apoptosis during both in vitro and in vivo studies. The present review aims to address these studies and highlights the possible underlying mechanisms of the observed effects. Besides, novel formulations and improving pharmacokinetic properties may enhance the therapeutic efficacy of BAs., Competing Interests: Declaration of interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Nature is the chief source of various remedies which are used to cure various diseases. Boswellic acid (BA) is a secondary metabolite from the pentacyclic terpenoid compound groups that are derived from the plant genus Boswellia. The oleo gum resins of these plants are primarily composed of polysaccharides, with the remaining amounts of resin (30-60%) and essential oils (5-10%) soluble in organic solvents. BA and its analogs are also reported to exhibit various in vivo and biological responses for example anti-inflammatory, anti-tumor, free radical scavenging activity, etc. Among all analogs, 11-keto-β-boswellic acid (KBA) and 3-O-acetyl-11-keto-β-boswellic acid (AKBA) has been demonstrated to be the most effective at reducing cytokine production and inhibiting the inflammatory responsecausing enzymes. In this review, we summarized the computational ADME prediction via the SwissADME computational tool and the structure-activity relationship of the Boswellic acid scaffold for the aspect of anticancer and antiinflammatory potency. In addition to these research findings which are associated with the therapy of acute inflammation and some cancers, the potential of boswellic acids against other disorders was also discussed., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Neurodegenerative procedures include a large spectrum of disorders with diverse pathological features and clinical manifestations, such as Alzheimer's Disease (AD), Parkinson's disease (PD), Multiple sclerosis, and Amyotrophic lateral sclerosis (ALS). Neurodegenerative diseases (NDs) are indicated by progressive loss of neurons and cognitive function, which is associated with free radical formation, extra and intercellular accumulation of misfolded proteins, oxidative stress, mitochondrial and neurotrophins dysfunction, bioenergetic impairment, inflammation, and apoptotic cell death. Boswellic acid is a pentacyclic triterpene molecule of plant origin that has been applied for treating several inflammatory disorders. Numerous studies have also investigated its' therapeutic potential against multiple NDs., Objective: In this article, we aim to review the neuroprotective effects of boswellic acid on NDs and the related mechanisms of action., Methods: The databases of PubMed, Google Scholar, Web of Sciences, and Scopus were searched to find studies that reported the effects of boswellic acid on NDs without time limits. Review articles, letters, editorials, unpublished data, and articles not published in the English language were not included in the study., Results: Overall, 17 studies were included in the present study (8 NDs in general, 5 AD, 3 PD, and 1 ALS). According to the reports, boswellic acid exerts anti-inflammatory, antioxidant, antiapoptotic, and neuromodulatory effects against NDs. Boswellic acid decreases Tau phosphorylation and amyloid-β (Aβ) generation in AD. This substance also protects nigrostriatal dopaminergic neurons and improves motor impairments in PD and modulates neurotransmitters, decreases the demyelination region, and improves behavioral functions in ALS., Conclusion: Due to the significant effects of boswellic acid in NDs, more clinical studies are necessary to evaluate the pharmacokinetics of this substance because it seems that boswellic acid can be used as a complementary or alternative treatment in patients with NDs., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: 3-acetyl-11-keto-beta-boswellic acid (AKBA) and 11-keto-boswellic acid (KBA) are the main active components of frankincense as pentacyclic triterpenoids, which are designated by the European Pharmacopoeia 8.0 as the quality standard for the evaluation of Indian frankincense, 2-methoxy-8,12-epoxygermacra- 1(10),7,11-trien-6-one (MCS134) is a non-volatile sesquiterpene compound in myrrh., Objective: In this paper, the absorption pharmacokinetics and metabolites of AKBA, KBA and MCS134 after frankincense, myrrh and their compatibility were analyzed, elaborated their absorption and metabolism mechanism and provided the ideas for the research on the bioactive components of frankincense and myrrh compatibility in vivo ., Methods: The area under the blood concentration time curve (AUC), half-life (t_1/2) and drug clearance (CL) of AKBA, KBA and MCS134 in rats were analyzed by LC-TQ / MS. The metabolites of AKBA, KBA and MCS134 in rats were analyzed by ultra-high pressure liquid chromatography with a linear ion trap-high resolution Orbitrap mass spectrometry system (UHPLC-LTQ-Orbitrap-MS)., Results: The results showed that AKBA, KBA and MCS134 reached the maximum plasma concentration at about 2 h, 2 h and 15 min, respectively. AUC_0-t and t_1/2 of the three components increased in varying degrees after compatibility, and the clearance/ bioavailability (CL/F) decreased. AKBA, KBA and MCS134 were metabolized in phase I and phase II in rats, and there represented differences before and after compatibility., Conclusion: After the compatibility of frankincense and myrrh, the absorption of effective components was improved to some extent, and there were some differences in the metabolites in rats. The results provide ideas for elucidating the in vivo effect mechanism of frankincense and myrrh., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Phytopathogenic Fusarium species are restricting factors causing diseases and yield loss in crop production. As part of exploration for pesticides from medicinal plants, this study aimed to isolate and characterize bioactive compounds from Lantana camara L. and evaluate their efficiency against Fusarium phytopathogens. Phytochemical investigation of ethyl acetate leaf extract led to separation of lantadene A (22-angeloyloxy-9-hydroxy-3-oxo-olean-12-en-28-oic acid) and boswellic acid (11-keto-β-boswellic acid). The chemical structures of the aforementioned compounds were confirmed using physical properties, spectroscopic analysis, and published data. Lantadene A exhibited significant antifungal activity against F. subglutinans , F. proliferatum , F. solani , F. graminearum , and F. semitectum with minimum inhibitory concentration (MIC) less than or equal to 0.63 mg/mL. Boswellic acid exhibited strong activity (MIC = 0.63 mg/mL) against F. subglutinans and F. semitectum . In terms of their toxicity towards Raw 264.7 cells, lantadene A and boswellic acid recorded half-maximal inhibitory concentration values of 84.2 μg/mL and 186.6 μg/mL, respectively. Both lantadene A and boswellic acid had no phytotoxic effect against seed germination and seedling root length. Lantadene A and boswellic acid have strong potential to be further investigated as lead natural fungicides (biopesticides) to control Fusarium crop diseases., Competing Interests: The authors declare no conflict of interest., (© 2022 The Author(s).)

Petroleum oil leakage and industrial oily waste on the water surface are sustainable pollutions. The removal process by eco-friendly adsorbents is a critical challenge. It also requires sustainable treatment. The natural hydrophobic material such as abietic acid, boswellic acid, and chitosan was added to magnetite nanoparticles with different concentrations of 10, 15, and 20% on its surface. The magnetite acquires partially hydrophobic properties. The prepared natural adsorbents were analyzed by employing wide-angle X-ray diffraction (WAXD), vibrating sample magnetometer (VSM), Fourier transform infrared spectroscopy (FTIR), scanning electron microscope (SEM), particle size and zeta potential, and contact angle measurements. Chitosan adsorbs at the outer surface of magnetite nanoparticles while boswellic and abietic absorb in bulk. All prepared adsorbents are effective in adsorbing waste oil from the water surface. The contact angle of MB20 (magnetite/20 percent boswellic) is greater than that of MA20 and MC20 (magnetite/20% abietic or chitosan, respectively), indicating that it has more hydrophobic characteristics. The oil removal efficiency and adsorption capacity of MB20 are the highest values 57.6%, and 24 g/g, respectively. All eco-friendly adsorbents are nontoxic with low-cost production and are used many times., (© 2022. The Author(s).)

Boswellic acids, triterpenoids derived from the genus Boswellia (Burseraceae), are known for their anti-inflammatory and anti-tumor efficacy. Atopic dermatitis is a chronic, non-infectious inflammatory skin disease. However, the effects of α-boswellic acid on atopic dermatitis have not been studied. Therefore, in this study we examined the expression level of pro-inflammatory cytokines, histopathological analysis, and physiological data from BALB/c mice with atopic-like dermatitis induced by 2,4-dinitrochlorobenzene and TNF-α/IFN-γ-stimulated HaCaT cells to better understand the agent's anti-atopic dermatitis efficacy. First, we found that α-boswellic reduced the epidermal thickening, mast cell numbers, and dermal infiltration of 2,4-dinitrochlorobenzene-induced atopic-like dermatitis in BALB/c mice. Furthermore, we also found that α-boswellic acid can restore transepidermal water loss and skin reddening in mice. In human keratinocytes inflamed by TNF-α/IFN-γ, α-boswellic acid inhibited MAP kinase activation and showed a reduction in NF-κB nuclear translocation. Finally, α-boswellic acid can reduce the expression level of cytokines (IL-1β, IL-6, and IL-8) following the stimulation of TNF-α/IFN-γ in HaCaT cells. Taken together, our study suggests that α-boswellic acids are a potential component for the development of anti-atopic dermatitis drugs., Competing Interests: The authors declare no conflict of interest.

Triterpenic acids are a widespread class of phytocompounds which have been found to possess valuable therapeutic properties such as anticancer, anti-inflammatory, hepatoprotective, cardioprotective, antidiabetic, neuroprotective, lipolytic, antiviral, and antiparasitic effects. They are a subclass of triterpenes bearing a characteristic lipophilic structure that imprints unfavorable in vivo properties which subsequently limit their applications. The early investigation of the mechanism of action (MOA) of a drug candidate can provide valuable information regarding the possible side effects and drug interactions that may occur after administration. The current paper aimed to summarize the most recent (last 5 years) studies regarding the MOA of betulinic acid, boswellic acid, glycyrrhetinic acid, madecassic acid, moronic acid, and pomolic acid in order to provide scientists with updated and accessible material on the topic that could contribute to the development of future studies; the paper stands as the sequel of our previously published paper regarding the MOA of triterpenic acids with therapeutic value. The recent literature published on the topic has highlighted the role of triterpenic acids in several signaling pathways including PI3/AKT/mTOR, TNF-alpha/NF-kappa B, JNK-p38, HIF-α/AMPK, and Grb2/Sos/Ras/MAPK, which trigger their various biological activities.

Boswellic acids are biologically active pentacyclic terpenoid compounds derived from Boswellia sp. plants. Extracts containing these acids have a number of positive effects on human health, especially in the treatment of inflammation, arthritis, or asthma. With increasing resistance to common antibiotics, boswellic acid-containing extracts could serve as an alternative or work in synergy with commonly available preparations. This study aims to determine the effect of boswellic acids on suspension cells and biofilms of Staphylococcus epidermidis , Enterococcus faecalis , and Escherichia coli. The antimicrobial and antibiofilm effect found was compared with commonly available antibiotics to control these undesirable microorganisms. The synergistic effect of boswellic acids and common antibiotics on the growth of these microorganisms was also determined. All tested microorganisms showed a positive additive effect of antibiotics and boswellic acid extract. The most significant effect was found in Enterococcus faecalis ATCC 29212 in a combination of 0.2 × MIC80 erythromycin (0.2 mg/L) and 0.8 × MIC80 boswellic acid extract (16 mg/L).

Bisphenol-A (BPA) and gamma-radiation are two risky environmental pollutants that human beings are exposed to in everyday life and consequently they threaten human health via inducing oxidative stress, inflammation, and eventually tissue damage. This study aims at appraising the protective effect of Boswellic Acid (BA) (250 mg/kg/day, orally) administration on BPA (150 mg/kg/day, i.p) and γ-irradiation (IR) (3 Gy/week for 4 weeks up to cumulative dose of 12 Gy/experimental course) for 4 weeks-induced damage to liver and heart tissues of rats. The present results indicated a significant improvement against damage induced by BPA and IR revealed in biochemical investigations (hepatic PPAR-α/P38 and cardiac ET-1/Calcineurin-A/NFATc1/P38) and histopathological examination of liver and heart. It could be concluded that BA possesses a protective effect against these two deleterious environmental pollutants which attracted major global concerns due to their serious toxicological impact on human health.

In this study, chitosan-coated niosome (ChN) was utilised for bioavailability enhancement of curcumin (Cn) and boswellic acids (BAs). The bare niosome (BN) was prepared by the heating method and optimised by using the mixture design procedure. Physicochemical stability, as well as the in vitro release, and bioavailability of Cn and BAs in BN and ChN were studied. The optimised BN had a mean diameter of 70.00 ± 0.21 nm and surface charge of -31.00 ± 0.25 mv, which changed to 60.01 ± 0.20 nm and +40.00 ± 0, respectively, in ChN. In-vitro digestion study revealed chitosan layer augmented the bioavailability of Cn and BAs to 79.02 ± 0.13 and 81 ± 0.10, respectively. The chitosan layer obviously improved the physical stability of Cn and BA in the niosome vehicle, by means of vesicle size, zeta potential, and encapsulation efficiency. The ChN was considered to be promising delivery system for increasing the bioavailability of Cn and BAs.

Background: Boswellic acids in Olibanum (known as frankincense) are potent anti-inflammatory properties in treating ulcerative colitis (UC), but its low bioavailability limited drug development. Evidence accumulated that vinegar processing of frankincense exerts positive effects on improving absorption of compositions. The underlying mechanism is unknown. In recent decades, spectacular growth and multidisciplinary integration of metabolic application were witnessed. The relationship between drug absorption and curative effect has been more or less established. However, it remains a knowledge gap in the field between drug absorption and endocrine metabolism., Purpose: To investigate the enhancement mechanism of vinegar processing in the absorption of boswellic acids via the aspect of bile acid metabolism., Methods: The effects of raw frankincense (RF) and processed frankincense (PF) were compared by the UC model of rats. The plasma concentration of boswellic acids and the hepatic and colonic bile acids contents were quantified by UPLC-TQ-MS. The levels of mRNA and protein associated with bile acid metabolism were also compared., Results: The results showed that PF exhibited re-markable mitigating effects on UC with the elevated plasma level of boswellic acid and upregulated expression of the absorption-related protein multidrug resistance-associated protein 2 (MRP2) and organic anion transporting polypeptide 1B3 (OATP1B3) in the liver and colon. It improved colonic lithocholic acid (LCA), which promoted the expression of bile acid nuclear receptors constitutive androstane receptor (CAR) and pregnane X receptor (PXR), resulting in the upregulation of MRP2 and OATP1B3., Conclusion: This paper revealed the mechanisms behind the absorption promotion effects of processing. Bile acids metabolism exhibits potential status in pharmaceutical development. The results shed light on the interdisciplinary collaboration between the metabolism and drug absorption fields., (Copyright © 2022. Published by Elsevier GmbH.)

Chemical diversity of natural products with drug-like features has attracted much attention from medicine to develop more safe and effective drugs. Their anti-inflammatory, antitumor, analgesic, and other therapeutic properties are sometimes more successful than chemical drugs in controlling disease due to fewer drug resistance and side effects and being more tolerable in a long time. Frankincense, the oleo gum resin extracted from the Boswellia species, contains some of these chemicals. The anti-inflammatory effect of its main ingredient, boswellic acid, has been traditionally used to treat many diseases, mainly those target memory functions. In this review, we have accumulated research evidence from the beneficial effect of Frankincense consumption in memory improvement and the prevention of inflammation and cancer. Besides, we have discussed the molecular pathways mediating the therapeutic effects of this natural supplement., (© 2022 John Wiley & Sons Ltd.)

The use of antibiotics or antifungals to control infections caused by pathogenic microorganisms is currently insufficiently effective because of their emerging resistance. Thanks to the ability of microorganisms to form a biofilm and thus increase their resistance to administered drugs even more, modern medicine faces the task of finding novel substances to combat infections caused by them. In this regard, the effects of essential oils or plant extracts are often studied. Among the relatively neglected plants is Boswellia serrata , which has a high content of biologically active boswellic acids. In this study, we focused on one of the most common nosocomial infections, which are caused by Candida species. The most common representative is C. albicans , although the number of infections caused by non-albicans species has recently been increasing. We focused on the antifungal activity of Boswellia &nbsp; serrata extract Bioswellix against planktonic and adhering cells of Candida albicans , Candida parapsilosis and Candida krusei. The antifungal activity against adhering cells was further explored by determining the metabolic activity of cells (MTT) and determining the total amount of biofilm using crystal violet. Boswellic acid-containing plant extract was shown to suppress the growth of a suspension population of all tested Candida species. Boswellia serrata extract Bioswellix was most effective in inhibiting C. albicans biofilm formation.

Background: The development of anti-cancer drugs with the ability to inhibit brain metastasis through the blood-brain barrier (BBB) is substantially limited due to the lack of reliable in vitro models., Main Methods: In this study, the Geltrex-based Transwell and microfluidic BBB models were applied to screen the effect of β-boswellic acid (β-BA) on the metastasis of MDA-MB-231 cells through the BBB in static and dynamic conditions, respectively., Major Results: The toxicity assay revealed that β-BA deteriorates MDA-MB-231 cells, while β-BA had no detectable toxic effects on human umbilical vein endothelial cells (HUVECs) and astrocytes. Trans-endothelial electrical resistance evaluation showed sustainable barrier integrity upon treatment with β-BA. Vimentin expression in HUVECs, evaluated using western blot, confirmed superior barrier integrity in the presence of β-BA. The obtained results were confirmed using an invasion study with a cell tracker and a scanning electron microscope. β-BA significantly inhibited metastasis by 85%, while cisplatin (Cis), a positive control, inhibited cancer cell migration by 12% under static conditions. Upon applying a dynamic BBB model, it was revealed that β-BA-mediated metastasis inhibition was significantly higher than that mediated by Cis., Conclusions and Implications:  In summary, the current study proved the anti-metastatic potential of β-BA in both static and dynamic BBB models., (© 2021 Wiley-VCH GmbH.)

Introduction: Diffuse intrinsic pontine glioma (DIPG) is a rare and aggressive childhood brainstem malignancy with a 2-year survival rate of <10%. This international survey study aims to evaluate the use of complementary and alternative medicine (CAM) in this patient population., Methods: Parents and physicians of patients with DIPG were asked to participate in a retrospective online survey regarding CAM use during time of illness., Results: Between January and May 2020, 120 parents and 75 physicians contributed to the online survey. Most physicians estimated that <50% of their patients used CAM, whereas 69% of the parents reported using CAM to treat their child during time of illness. Cannabis was the most frequently used form of CAM, followed by vitamins and minerals, melatonin, curcumin, and boswellic acid. CAM was mainly used with the intention of direct antitumor effect. Other motivations were to treat side effects of chemotherapy or to increase comfort of the child. Children diagnosed from 2016 onwards were more likely to use CAM (χ 2  = 6.08, p = .014). No significant difference was found between CAM users and nonusers based on ethnicity (χ 2  = 4.18, p = .382) or country of residence (χ 2  = 9.37, p = .154). Almost 50% of the physicians do not frequently ask their patients about possible CAM use., Conclusion: This survey demonstrates that worldwide, a considerable number of patients with DIPG use CAM. Physicians should be more aware of potential CAM use and actively discuss the topic. In addition, more research is needed to gain knowledge about possible anticancer effects of CAM and (positive/negative) interactions with conventional therapies., (© 2021 The Authors. Pediatric Blood & Cancer published by Wiley Periodicals LLC.)

Triterpenes (30-carbon isoprene compounds) represent a large and highly diverse class of natural products that play various physiological functions in plants. The triterpene biosynthetic enzymes, particularly those catalyzing the late-stage regio-selective modifications are not well characterized. The bark of select Boswellia trees, e.g., B. serrata exudes specialized oleo-gum resin in response to wounding, which is enriched with boswellic acids (BAs), a unique class of C3α-epimeric pentacyclic triterpenes with medicinal properties. The bark possesses a network of resin secretory structures comprised of vertical and horizontal resin canals, and amount of BAs in bark increases considerably in response to wounding. To investigate BA biosynthetic enzymes, we conducted tissue-specific transcriptome profiling and identified a wound-responsive BAHD acetyltransferase (BsAT1) of B. serrata catalyzing the late-stage C3α-O-acetylation reactions in the BA biosynthetic pathway. BsAT1 catalyzed C3α-O-acetylation of αBA, βBA, and 11-keto-βBA in vitro and in planta assays to produce all the major C3α-O-acetyl-BAs (3-acetyl-αBA, 3-acetyl-βBA, and 3-acetyl-11-keto-βBA) found in B. serrata bark and oleo-gum resin. BsAT1 showed strict specificity for BA scaffold, whereas it did not acetylate the more common C3β-epimeric pentacyclic triterpenes. The analysis of steady-state kinetics using various BAs revealed distinct substrate affinity and catalytic efficiency. BsAT1 transcript expression coincides with increased levels of C3α-O-acetyl-BAs in bark in response to wounding, suggesting a role of BsAT1 in wound-induced biosynthesis of C3α-O-acetyl-BAs. Overall, the results provide new insights into the biosynthesis of principal chemical constituents of Boswellia oleo-gum resin., (© 2021 Society for Experimental Biology and John Wiley & Sons Ltd.)

The metal-organic frameworks (MOF) have shown fascinating possibilities in biomedical applications, designing a multifunctional drug delivery system based on the MOF is important. In this study, 5-sulfosalicylic acid and boswellic acids (BAs) were loaded to the pH sensitive zeolitic imidazolate framework-8 (ZIF-8) nanocomposite containing bovine serum albumin (BSA) as the center. The ZIF layer acts as a capsule for the nontoxic storage of 5-sulfosalicylic acid and boswellic acids (BAs) under physiological conditions. The results of the characterization demonstrated the performance of the nanocarrier formation. The pH-sensitive drug release of 5-sulfosalicylic acid was detected due to the innate pH-dependent stability of ZIF-8. An effective pH-sensitive drug delivery system using a 5-sulfosalicylic acid/BSA@ZIF-8, and 5-sulfosalicylic acid/BSA/BAs@ZIF-8, in which the 5-sulfosalicylicacid is not free in physiological pH but it is released at acidic pH (5.0) has been fabricated. The best biocompatibility has been found in 5-sulfosalicylic acid/BSA/BAs@ZIF-8 comparing to the 5-sulfosalicylic acid/BSA, 5-sulfosalicylic acid /BSA/BAs, and 5-sulfosalicylic acid/BSA@ZIF-8. Additionally, 5-sulfosalicylic acid/BSA /BAs@ZIF-8 exhibited higher effectiveness than other compounds against the breast cancer cell line, MCF-7, with less toxicity. It is concluded from the results of the current study that the fabricated ZIF-8 based nanocarrier may potentially provide therapeutic effects on breast cancer cells., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The study investigated the ability of boswellic acid (BA) to alleviate the testicular and oxidative injury FPN insecticide intoxication in the male rat model. Rats were randomly assigned to six equivalent groups (six rats each) as the following: control rats orally administered with 2 mL physiological saline/kg of body weight (bwt); boswellic acid (BA1) rats orally administered 250 mg BA/kg bwt; boswellic acid (BA2) rats orally administered 500 mg BA/kg bwt; fipronil (FPN) rats orally administered 20 mg FPN/kg bwt; (FPN + BA1) rats orally administered 20 mg FPN/kg bwt plus 250 mg BA/kg bwt, and (FPN + BA2) rats orally administered 20 mg FPN/kg bwt plus 500 mg BA/kg bwt. After 60 days, semen viability percentage and live spermatozoa percentage were decreased, and a considerably increased abnormality of the sperm cells in FPN-administered rats improved substantially with the co-administration of BA. BA had refinement of the histological architecture of testes and sexual glands. Quantitative analysis recorded a noticeable decline in the nuclear cell-proliferating antigen (PCNA) percentage area. FPN triggered cell damage, which was suggested by elevated malondialdehyde and interleukin 6, tumor necrosis factors alpha, and decreased glutathione level. Proapoptotic factor overexpression is mediated by FPN administration, while it decreased the antiapoptotic protein expression. Similarly, BA has shown significant upregulation in steroidogenic and fertility-related gene expression concerning the FPN group. Pathophysiological damages induced by FPN could be alleviated by BA's antioxidant ability and antiapoptotic factor alongside the upregulation of steroidogenic and fertility-related genes and regimented the detrimental effects of FPN on antioxidant and pro-inflammatory biomarkers.

In several parts of the world, Boswellia sacra Fluck. is one of the most commonly used herbs for the treatment of arthritis. Its usage should be validated in light of recent findings of haematotoxicity. This study was aimed to determine the effect of chronic administration of standardized methanolic extract of frankincense on blood cell count in experimental animals. Using high-performance liquid chromatography, the active constituents of B. sacra extract; boswellic acids were analyzed. The effect of three different doses of the extract (250, 500, and 1000 mg/kg) on different blood cells and associated parameters was investigated. The behavior, food, and water consumption of the rats were recorded. Boswellic acids were present in varying amounts with α-boswellic acid and β-boswellic acid present in more amounts compared to other boswellic acids in the extract. All three doses tested had no effect on the animals' behavior, food consumption, or weight gain. The administration of a low (500 mg/kg) and high (1000 mg/kg) dose of the extract resulted in a non-dose dependent reduction in MCH ( p  < 0.01 and p  < 0.05, respectively), but no other blood parameters were significantly affected. The B. sacra extract produces hypochromic normocytic anemia in rats at higher doses of 500 and 1000 mg/kg and this effect was not dose-dependent.

Boswellic acids, and particularly 11-keto-boswellic acids, triterpenoids derived from the genus Boswellia ( Burseraceae ), are known for their anti-inflammatory and potential antitumor efficacy. Although boswellic acids generally occur as α-isomers (oleanane type) and β-isomers (ursane type), 11-keto-boswellic acid (KBA) was found only as the β-isomer, β-KBA. Here, the existence and natural occurrence of the respective α-isomer, 11-keto-α-boswellic acid (α-KBA), is demonstrated for the first time. Initially, α-KBA was synthesized and characterized by high-resolution mass spectrometry (HR-MS) and nuclear magnetic resonance (NMR) spectroscopy, and a highly selective, sensitive, and accurate high-performance liquid chromatography coupled with tandem mass spectrometry (HPLC-MS/MS) method was developed by Design of Experiments (DoE) using a pentafluorophenyl stationary phase. This method allowed the selective quantification of individual 11-keto-boswellic acids and provided evidence for α-KBA in Boswellia spp. oleogum resins. The contents of α-KBA as well as further boswellic acids and the composition of essential oils were used to chemotaxonomically classify 41 Boswellia oleogum resins from 9 different species. Moreover, α-KBA exhibited cytotoxicity against three treatment-resistant triple-negative breast cancer (TNBC) cell lines in vitro and also induced apoptosis in MDA-MB-231 xenografts in vivo. The respective β-isomer and the acetylated form demonstrate higher cytotoxic efficacies against TNBC cells. This provides further insights into the structure-activity relationship of boswellic acids and could support future developments of potential anti-inflammatory and antitumor drugs.

Objective: Olibanum (OLIB) and its component boswellic acid (BOSA) are suggested to have anti-inflammatory, anti-oxidant and neuroprotective effects. In the present work, we examined effect of OLIB, and BOSA on the synaptic plasticity impairment and oxidative stress indicators in a rat model of neuro-inflammation induced by lipopolysaccharide (LPS)., Materials and Methods: Forty rats were divided into the following four groups: (1) Control, (2) LPS, (3) OLIB (200 mg/kg), and (4) BOSA (10 mg/kg). The animals were pre-treated with OLIB extract, BOSA or the vehicle 30 min before LPS (1 mg/kg) administration, for 6 days. On the 6 th day, electrophysiological recording was done. Long-term potentiation (LTP) from CA1 area of hippocampus was assessed. The animals were then sacrificed and their brains were removed for evaluation of the levels of interleukin-6 (IL-6), nitric oxide (NO) metabolites, malondialdehyde (MDA), thiol, superoxide dismutase (SOD) and catalase (CAT) in the cortex., Results: Administration of LPS decreased amplitude (p<0.001) and slope (p<0.01) of field excitatory postsynaptic potential (fEPSP). Pre-treatment enhanced these parameters (p<0.05 to p<0.001). LPS also increased cortical levels of IL-6 (P<0.01), NO, and MDA (p<0.001) while decreased thiol, SOD (p<0.001), and CAT (p<0.05). OLIB and BOSA diminished IL-6 (p<0.05-p<0.001), NO (p<0.01-p<0.001) and MDA level (p<0.01 and p<0.001, respectively) while improved SOD (p<0.05 and p<0.001, respectively), CAT (p<0.05 and p<0.001, respectively) and thiol content (p<0.001)., Conclusion: The results showed that OLIB and BOSA could improve synaptic plasticity impairment induced by LPS as shown by a decrease in an inflammation indicator along with the anti-oxidant effects.

Chronic inflammation is a key culprit factor in the onset and progression of several diseases. Novel and pharmacologically effective therapeutic approaches are needed for new treatment remedy or improved pharmacokinetics and pharmacodynamics for existing synthetic drugs, in particular natural products. Boswellic acids are well-known natural products, with capacity to effectively retard inflammation without severe adverse effects. However, the therapeutic use of Boswellic acids are greatly hindered by its poor pharmacokinetic properties. Co-administration strategies that facilitate the oral absorption and distribution of Boswellic acids should lead to a safe and more effective use of this product prophylactically and therapeutically in inflammatory disorders. In this study, we examined the effect of Piper longum extract on the absorption and bioavailability of Boswellic acid in rabbits. In addition, we further explored computational pharmacodynamic interactions between Piper longum and Boswellic acid. Piper longum extract at 2.5 and 10 mg/kg, increased the bioavailability of Boswellic acid ( p < 0.05). Based on our drug-based computational modeling, cytochrome P450 (CYP450)-mediated mechanism was involved in increased bioavailability. These findings confirmed that Piper longum with Boswellic acid may be administered orally together for effective therapeutic efficacy. Thus, our studies support the application of Piper longum with Boswellic acid as a novel therapeutic avenue in diseases associated with inflammation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Vijayarani, Govindarajulu, Ramesh, Alturki, Majrashi, Fujihashi, Almaghrabi, Kirubakaran, Ren, Babu, Smith, Moore and Dhanasekaran.)

Natural products suited for prophylaxis and therapy of inflammatory diseases have gained increasing importance. These compounds could be beneficially integrated into bacterial cellulose (BC), which is a natural hydropolymer applicable as a wound dressing and drug delivery system alike. This study presents experimental outcomes for a natural anti-inflammatory product concept of boswellic acids from frankincense formulated in BC. Using esterification respectively (resp.) oxidation and subsequent coupling with phenylalanine and tryptophan, post -modification of BC was tested to facilitate lipophilic active pharmaceutical ingredient (API) incorporation. Diclofenac sodium and indomethacin were used as anti-inflammatory model drugs before the findings were transferred to boswellic acids. By acetylation of BC fibers, the loading efficiency for the more lipophilic API indomethacin and the release was increased by up to 65.6% and 25%, respectively, while no significant differences in loading could be found for the API diclofenac sodium. Post -modifications could be made while preserving biocompatibility, essential wound dressing properties and anti-inflammatory efficacy. Eventually, in vitro wound closure experiments and evaluations of the effect of secondary dressings completed the study.

Bisphenol A (BPA) is a low molecular weight chemical compound that has a deleterious effect on the endocrine system. It was used in plastics manufacturing with injurious effects on different body systems. Occupational exposure to low-level ionizing radiation (<1 Gy) is shown to attenuate an established inflammatory process and therefore enhance cell protection. Therefore, the objective of this study was to investigate the protective effect of boswellic acid (BA) accompanied by whole-body low-dose gamma radiation (γ-R) against BPA-induced lung toxicity in male albino rats. BPA intoxication induced with 500 mg/kg BW. Rats received 50 mg BA/kg BW by gastric gavage concomitant with 0.5 Gy γ-R over 4 weeks. The immunoblotting and biochemical results revealed that BA and/or γ-R inhibited BPA-induced lung toxicity by reducing oxidative damage biomolecules; (MDA and NADPH oxidase gene expression), inflammatory indices (MPO, TNF-α, IL-6, and gene expression of CXCR-4). Moreover, BA and or/γ-R ameliorated the lung inflammation via regulation of the JNK/ERK/c-Fos and Nrf2/ HO-1 signaling pathways. Interestingly, our data demonstrated that BA in synergistic interaction with γ-R is efficacious control against BPA-induced lung injury via anti-oxidant mediated anti-inflammatory activities., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2020.)

Ethnopharmacological Relevance: Frankincense (Boswellia sacra Fluck.,) is a widely used herbal drug and household medicine for treatment of several diseases. Earlier toxicological studies revealed its proulcerogenic effect and no significant hepatotoxic or nephrotoxic effects in rats. However, some other members of Boswellia species such as Boswellia papyrifera (Caill. ex Delile) Hochst and Boswellia carterii have been reported for testicular toxicity in rats., Aim of the Study: Testicular toxicity of standardized methanolic extract of B. sacra oleo gum resin was determined through repeated oral dose administration for 28 days. Biochemical, histological and genetic changes in rat testes were evaluated., Materials and Methods: B. sacra extract was analyzed for its boswellic acid content by high performance liquid chromatography (HPLC) method. The extract was administered at three different doses to rats. Effect on behavior, weight, food and water consumption along with changes in serum testosterone levels and cytoarchitecture of testis, epididymis and adrenal gland were determined. Gene expression of GSTPi, IGFBP3 and HSP70 in testis was also studied., Results: Boswellic acids (α and β) were present in highest concentration whereas acetyl-11-keto beta boswellic acid was present in relatively smaller amounts. The extract did not produce any significant change in the behavior of the animals, food/water consumption or weight gain. Serum testosterone levels were significantly decreased only by highest tested dose of Boswellia extract (1000 mg/kg, p.o). Histological examination did not reveal any variation in the structure of testis, adrenal gland and epididymis after administration of the extract while the expression of all three studied genes was significantly decreased., Conclusion: The results indicate that B. sacra extract does not possess any toxic effect on testis. On the contrary, decrease in gene expression of GSTPi, IGFBP3 and HSP70 revealed its antioxidant potential that may protect testes against effect of toxicants. However, a significant reduction in serum testosterone levels point to mechanisms other than direct testicular toxicity., (Copyright © 2020 Elsevier B.V. All rights reserved.)

In the current investigation, a series of heterocyclic derivatives of boswellic acids were prepared along with new monomers of 3- O -acetyl-11-keto-β-boswellic acid (AKBA, 1 ) 11-keto-β-boswellic acid (KBA, 2 ) and several new bis-AKBA and KBA homodimers and AKBA-KBA heterodimers. The effects of these compounds on the proliferation of different human cancer cell lines, viz., FaDu (pharynx carcinoma), A2780 (ovarian carcinoma), HT29 (colon adenocarcinoma), and A375 (malignant melanoma), have been evaluated. Thus, KBA homodimer 21 effectively inhibited the growth of FaDu, A2780, HT29, and A375 cells with EC 50 values below 9 μM. In addition, compounds 7 , 8 , 11 , 12 , 15 , 16, and 17 also exhibited cytotoxic effects for A2780, HT29, and A375 cancer cells. In particular, the pyrazine analog 8 was highly cytotoxic for A375 cancer cells with an EC 50 value of 2.1 μM.

Background: Osteoarthritis (OA) is a joint disease involving articular cartilage degeneration causing patients pain, joint stiffness, physical disability, and significantly reducing their quality of life (QoL). Purpose: The aim of this study was to assess whether the daily consumption of a gastroresistant food supplement formulation containing a combination of B oswellia serrata and bromelain could improve the QoL of patients suffering from various forms of OA. Materials and Methods: Forty-nine patients were enrolled in this pilot study conducted from June 2015 to October 2016. Patients took a Boswellia- and bromelain-based supplement for a period between 1 and 6 months. At baseline and at the end of the study, patients completed a self-assessment QoL questionnaire regarding their independence in performing daily activities. QoL scores were compared between baseline and follow-up by means of the Wilcoxon signed-rank test in all patients and in the subgroups of patients with knee, hip, or generalized OA. Results: Forty-nine patients, 6 men and 43 women, aged between 23 and 92 years, (mean age 63.24) participated in the study. At follow-up (3.0 ± 0.7 months), a significant improvement was observed for 7 of 10 QoL questions and, overall, for the total QoL score. The most significant improvements were observed in the joints that were more strongly affected at baseline. A similar trend was observed when separately considering patients with knee, hip, or generalized OA. No patients experienced adverse events and no drug interactions were reported. Conclusions: From this pilot study, it emerges that the use of the gastroresistant formulation containing the combination of Boswellia and bromelain supplements can represent a valuable nonpharmacological tool for improving the QoL of patients suffering from different forms of OA. Further studies should be conducted to confirm this first evidence.

The 5-lipoxygenase enzyme is a proinflammatory enzyme and produces leukotrienes. Evidence has shown that inflammation contributes to Alzheimer's disease. On the other hand, boswellic acid derivatives have also been shown to be involved in Alzheimer's disease. In this study, the interaction of four different derivatives of boswellic acid with 5-lipoxygenase enzyme was investigated using molecular dynamics simulation. The simulation of the enzyme was also carried out alone. Calculation of Cα-RMSD indicates that the enzyme stability is slightly affected by boswellic acid derivatives. Calculating the radius of gyration of the enzyme also shows that the overall shape of the protein is not affected by ligands. The RMSF values of the enzyme residues were calculated in the presence of boswellic acid derivatives and it was compared with that in the absence of ligands. The results show that the flexibility of the enzyme residues is influenced by ligands. The residues, whose flexibility is reduced, are scattered throughout the enzyme. However, their number is great in the N-terminal residue. The binding affinity between boswellic acid derivatives and the enzyme residues was calculated using the measure of conformation factor. The results show that the residues interacting with ligands are in the area of the first domain of enzyme. The results obtained from molecular dynamics simulation are well-consistent with the experimental evidence related to the inhibitory effect of the mentioned compounds with 5-lipoxygenase., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The oleo gum resin of Boswellia sacra Fleuck. (Burseraceae) is widely consumed for treatment of several diseases and disorders. To determine the effect of repeated administration of this resin on liver and kidney functions, three different doses of standardized methanolic extract were administered orally to rats for 28 days. Apart from histological studies and determination of biomarkers of hepatotoxicity and nephrotoxicity, other parameters of sub-chronic toxicity such as behavioral change, food consumption and change in body weight were assessed. The extract contained about 36.91% of total boswellic acids; of which 11-keto beta boswellic acid, acetyl-11-keto beta boswellic acid, boswellic acids (α and β) and acetyl boswellic acid (α and β) were found to be 5.81%, 1.91%, 21.92% and 7.27% respectively. Oral administration of the extract for 28 consecutive days did not show any sign of behavioral toxicity and did not affect food consumption or weight gain significantly. Determination of biomarkers of hepatic and nephrotoxicity revealed that extract was safe at the tested doses as it did not produce any significant change in the studied biomarkers except producing a dose dependent increase in serum total protein levels. The histological examination supported biochemical findings. To conclude, methanolic extract of Boswellia sacra doen not produce any significant toxicity to liver and kidney up to doses of 100 mg/kg body weight. The results contradict earlier reports that members of boswellia species produce organ toxicity in rats., (© 2019 King Saud University.)

Inflammation plays a major role in chronic airway diseases like asthma, COPD, and cystic fibrosis. Inflammation plays a crucial role in the worsening of the lung function resulting in worsening symptoms. The inflammatory process is very complexed, therefore the strategies for developing an effective treatment for inflammatory airway diseases would benefit from the use of natural substances. Plant products have demonstrated anti-inflammatory properties on various lung disease models and numerous natural plant agents have successfully been used to treat inflammation. Naturally occurring substances may exert some anti-inflammatory effects by modulating some of the inflammatory pathways. These agents have been used in different cultures for thousands of years and have proven to be relatively safe. Parthenolide, apocynin, proanthocyanidins, and boswellic acid present different mechanisms of actions - among others, through NF-kB or NADPH oxidase inhibition, therefore showing a wide range of applications in various inflammatory diseases. Moreover, some of them have also antioxidant properties. This review provides an overview of the anti-inflammatory effects of some of the natural agents and illustrates their great potential as sources of drugs to cover an extensive range of pharmacological effects., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Frankincense and myrrha (FM), commonly used as a classical herbal pair, have a wide range of clinical applications and definite anti-inflammatory activity. However, anti-neuroinflammation effects and mechanisms are not clear. In this study, we adopted a lipopolysaccharide (LPS)-induced microglial (BV2) cell model and a network pharmacology method to reveal the anti-neuroinflammatory effects and mechanisms of boswellic acid (BA) and myrrha sesquiterpenes (MS) with different proportions of compatibility. The data showed that the different ratios of BA and MS had different degrees of inhibition of interleukin-1β (IL-1β), IL-6, and inducible nitric oxide synthase (iNOS) mRNA expression, down-regulated the phosphor-nuclear factor kappa B/nuclear factor kappa B (p-NF-ҡB)/(NF-ҡB), phosphorylated protein kinase b/protein kinase b (p-AKT/AKT), and Toll-like receptor 4 (TLR4) protein expression levels, and increased phospho-PI3 kinase (p-PI3K) protein expression levels. When the ratios of BA and MS were 10:1, 5:1, and 20:1, better effective efficacy was exhibited. According to the correlation analysis between the effect index and bioactive substances, it was suggested that 2-methoxy-5-acetoxy -fruranogermacr-1(10)-en-6-one (Compound 1), 3 α -acetyloxylanosta-8,24-dien-21-oic acid (Compound 2), 11-keto-boswellic acid (Compound 3), and 3-acetyl-11-keto- β -boswellic acid (Compound 4) made important contributions to the treatment of neuroinflammation. Furthermore, based on the network pharmacological analysis, it was found that these four active compounds acted on 31 targets related to neuroinflammation and were involved in 32 signaling pathways which mainly related to the immune system, cardiovascular system, and nervous system, suggesting that BA and MS could be used to treat neuroinflammation.

For centuries, frankincense extracts have been commonly used in traditional medicine, and more recently, in complementary medicine. Therefore, frankincense constituents such as boswellic and lupeolic acids are of considerable therapeutic interest. Sixteen frankincense nutraceuticals were characterized by high-performance liquid chromatography with tandem mass spectrometry (HPLC-MS/MS), revealing major differences in boswellic and lupeolic acid compositions and total contents, which varied from 0.4% to 35.7%. Frankincense nutraceuticals significantly inhibited the release of proinflammatory cytokines, such as TNF-α, IL-6, and IL-8, by LPS-stimulated peripheral blood mononuclear cells (PBMC) and whole blood. Moreover, boswellic and lupeolic acid contents correlated with TNF-α, IL-1β, IL-6, IL-8, and IL-10 inhibition. The nutraceuticals also exhibited toxicity against the human triple-negative breast cancer cell lines MDA-MB-231, MDA-MB-453, and CAL-51 in vitro. Nutraceuticals with total contents of boswellic and lupeolic acids >30% were the most active ones against MDA-MB-231 with a half maximal inhibitory concentration (IC 50 ) ≤ 7.0 µg/mL. Moreover, a frankincense nutraceutical inhibited tumor growth and induced apoptosis in vivo in breast cancer xenografts grown on the chick chorioallantoic membrane (CAM). Among eight different boswellic and lupeolic acids tested, β-ABA exhibited the highest cytotoxicity against MDA-MB-231 with an IC 50 = 5.9 µM, inhibited growth of cancer xenografts in vivo, and released proinflammatory cytokines . Its content in nutraceuticals correlated strongly with TNF-, IL-6, and IL-8 release inhibition., Competing Interests: The authors declare no conflict of interest.

Natural compounds, in recent years, have attracted significant attention for their use in the prevention and treatment of diverse chronic diseases as they are devoid of major toxicities. Boswellic acid (BA), a series of pentacyclic triterpene molecules, is isolated from the gum resin of Boswellia serrata and Boswellia carteri . It proved to be one such agent that has exhibited efficacy against various chronic diseases like arthritis, diabetes, asthma, cancer, inflammatory bowel disease, Parkinson's disease, Alzheimer's, etc. The molecular targets attributed to its wide range of biological activities include transcription factors, kinases, enzymes, receptors, growth factors, etc. The present review is an attempt to demonstrate the diverse pharmacological uses of BA, along with its underlying molecular mechanism of action against different ailments. Further, this review also discusses the roadblocks associated with the pharmacokinetics and bioavailability of this promising compound and strategies to overcome those limitations for developing it as an effective drug for the clinical management of chronic diseases.