8.1.4 Bewegungsapparat und Gelenke



Acetyl-11-keto-beta-boswellic acid modulates macrophage polarization and Schwann cell migration to accelerate spinal cord injury repair in rats.
Wang Y, Xiong Z, Qiao Y, Zhang Q, Zhou G, Zhou C, Ma X, Jiang X, Yu W

BACKGROUND: Inhibiting secondary inflammatory damage caused by glial cells and creating a stable microenvironment is one of the main strategies to investigate drugs for the treatment of spinal cord injury. Acetyl-11-keto-beta-boswellic acid (AKBA) is the active component of the natural drug boswellia, which has anti-inflammatory and antioxidant effects and offers a possible therapeutic option for spinal cord injury.

METHODS: In this study, a spinal cord injury model was established by crushing spinal cord, respectively, to detect the M1 macrophage inflammatory markers: iNOS, TNF-α, IL-1β, and the M2 macrophage markers CD206, ARG-1, IL-10, and the detection of antioxidant enzymes and MDA. In vitro, macrophages were cultured to verify the main mechanism of the macrophage switch from Nrf2/HO-1 to M2 type by flow cytometry, immunofluorescence, and other techniques. Macrophage and Schwann cell co-culture validated the migration mechanism of Schwann cells promoted by AKBA.

RESULTS: AKBA significantly enhanced the antioxidant enzyme activities of CAT, GSH-Px, T-AOC, and SOD, reduced MDA content, and reduced oxidative damage caused by spinal cord injury via the Nrf2/HO-1 signaling pathway; AKBA mediates Nrf2/HO-1/IL-10, converts macrophages from M1 to M2 type, reduces inflammation, and promotes Schwann cell migration, thereby accelerating the repair of spinal cord injury in rats.

CONCLUSIONS: Our work demonstrates that AKBA can attenuate oxidative stress as well as the secondary inflammatory injury caused by macrophages after SCI, promote Schwann cell migration to the injury site, and thus accelerate the repair of the injured spinal cord.

CNS Neurosci Ther. 2024 Mar;30(3):e14642.
PMID: 38430464 [PubMed - indexed for MEDLINE]


Efficacy evaluation of standardized Boswellia serrata extract (Aflapin) in osteoarthritis: A systematic review and sub-group meta-analysis study.
Dubey V, Kheni D, Sureja V

BACKGROUND AND PURPOSE: Osteoarthritis (OA) is a joint disease characterized by pain, inflammation, and physical disability. Boswellia serrata (BS) is widely studied for its effectiveness in OA condition. Our systematic review and meta-analysis study was aimed to evaluate BS extract efficacy in OA. A sub-group analysis was performed to compare the efficacy of a standardized BS extract (Aflapin) with other BS extracts.

METHODS: Randomized controlled trials, identified from three online databases, evaluating the effect of BS extracts in OA were included. Quality of studies was assessed using PEDro scale and risk of bias was assessed using Cochrane Risk of Bias tool. Pooled effect was reported as mean difference (MD) and 95% confidence interval. Study was conducted as per the Cochrane guidelines (PROSPERO registration ID: CRD42023411356).

RESULTS: Nine RCTs with 712 participants were included. All studies (except one) were good quality studies. BS supplementation significantly reduced VAS (MD: -10.71; p<0.00001), LFI (MD: -2.99; p<0.00001), WOMAC-pain (MD: -10.69; p<0.0001), WOMAC-stiffness (MD: -5.49; p<0.00001), and WOMAC-function (MD: -10.69; p<0.00001) scores compared to control therapy. By sub-group analysis, Aflapin supplementation showed greater reduction in VAS (MD: -16.09 vs -4.68), LFI (MD: -3.81 vs -2.01), WOMAC-pain (MD: -18.68 vs -7.07), WOMAC-stiffness (MD: -14.25 vs -3.78), and WOMAC-function (MD: -14.99 vs -8.41) scores as compared to other BS therapies.

CONCLUSIONS: BS supplementation is effective OA symptomatic management. Sub-group analysis revealed that Aflapin supplementation may be better in improving the symptoms of OA which needs to be confirmed by more comparative clinical studies.

Explore (NY). 2024 Feb;():.
PMID: 38365549 [PubMed - as supplied by publisher]


A Systemic Review on Nutraceutical Supplements used in the Management of Osteoarthritis.
Nooreen Z, Wal P, Summaiyya F

Osteoarthritis (OA) is a progressive degenerative joint disease. It basically impairs the structural integrity of articulate cartilage and imbalances the catabolic and anabolic signals in the joint. A degenerative disease is characterized by swelling, pain, and joint stiffness. The treatment and management of osteoarthritis are based on analgesic and anti-inflammatory agents, whereas the exact cause of OA is not known yet. The negative effects of synthetic medications have led to a daily rise in the usage of nutraceuticals and dietary supplements. Clinicians are aware of these treatments, and they also recommend nutraceuticals in addition to the currently preferred therapy. Many in-vitro and in-vivo experiments have been performed in past years to evaluate the function of these on osteoarthritis. The collection of articles was published on search engines like PubMed, Scopus, Google Scholar, ResearchGate, and ScienceDirect. The evaluation covers every potential nutraceutical utilized in osteoarthritis, together with its supporting data and mode of action. The present review discusses nutraceuticals, including devil's claw, vitamin D, boswellic acid, capsaicin, ginger, curcumin, krill oil, ginger, and avocado/soybean unsaponifiable.

Recent Adv Food Nutr Agric. 2024 Jan;():.
PMID: 38258782 [PubMed - as supplied by publisher]


Anti-inflammatory and anti-arthritic potential of methotrexate in combination with BA-25, an amino analogue of β-boswellic acid in the treatment of rheumatoid arthritis.
Choudhary R, Saroch D, Kumar D, Anjum S, Andrabi NI, Akram T, Shah BA, Shukla SK, Bhagat A, Kour G, Ahmed Z

β- boswellic acid, a pentacyclic triterpene derived from Boswellia serrata is extensively known for its anti-inflammatory potential. BA-25 (3-α-o-acetoxy-4β-amino-11-oxo-24-norurs-12-ene) is an amino analogue of β-boswellic acid that has shown anti-inflammatory potential in LPS-induced macrophages and animal models. The present study aims at investigation of the combination of BA-25 with the conventional gold standard DMARD methotrexate (MTX) for its anti-inflammatory and anti-arthritic potential using in vitro and in vivo experimental models. The anti-inflammatory potential of MTX versus the combination (BA-25 + MTX) was investigated for inhibition of NO, ROS and pro-inflammatory cytokines including TNF-α and IL-6 using ELISA in LPS-stimulated RAW-264.7 cells. The results demonstrated significant reduction in NO, ROS, TNF- α and IL-6 production with the combination treatment in comparison to MTX alone. The cytokine inhibition potential of the combination was further validated in-vivo using balb/c wherein the combination restored LPS-induced increase in pro-inflammatory cytokines. The toxicological aspect of the in vivo doses of the combination was also investigated in mice after dosing for 28 days wherein the results suggested no significant change in the hematological parameters and serum biochemical parameters in the combination versus the vehicle group. The effect of BA-25 was also investigated on MTX-induced increase in liver function tests and the expression of Bax and blc2. The results demonstrated decrease in the production of liver enzymes with BA-25 administration along with downregulating the expression of apoptotic protein Bax while increasing the expression of anti-apoptotic protein Bcl2. Furthermore, pharmacokinetic studies of BA-25 were conducted in Balb/c mice wherein the compound showed rapid absorption, high volume of distribution and a t of 13.08. Finally the anti-arthritic effect of the combination of MTX + BA-25 vs MTX alone was investigated using CIA model in DBA/1 mice wherein the treatment with the combination resulted in significant reduction in paw inflammation, IL-6 and IL-1β levels. Furthermore, the western blot analysis demonstrated considerable decrease in the expression of p-NF-κB p and p-IκB in the ankle-joint tissue of the CIA mice treated with the combination therapy. The results insinuated increased anti-inflammatory and anti-arthritic potential of the combination of MTX with BA-25 as evident from in to vitro and in-vivo studies.

Cytokine. 2023 Dec;172():156398.
PMID: 37820446 [PubMed - indexed for MEDLINE]


Insights into the anti-inflammatory and anti-arthritic potential of 3-Acetyl-11-keto-β-Boswellic Acid as a therapeutic approach in Rheumatoid Arthritis.
Priya S, Singhvi G

Expert Opin Investig Drugs. 2023;32(10):867-871.
PMID: 37817458 [PubMed - indexed for MEDLINE]


Investigation of VEGF (rs 699947) polymorphism in the progression of Rheumatoid Arthritis (RA) and in-silico nanoparticle drug delivery of potential phytochemicals to cure RA.
Hussain N, Mumtaz M, Adil M, Ali Nadeem A, Sarwar A, Aziz T, Alharbi M, Alshammari A, Alasmari AF, Alharbi ME

Mutation in the VEGF gene disturbs the production of chondrocytes and angiogenesis which are essential for cartilage health. Cytokines and chemokines produced by auto-activation of B-cells degrade cartilage. Bruton's Tyrosine Kinase (BTK) plays a crucial role in the activation of these B-cells. VEGF has a central part in angiogenesis, in the recruitment of endothelial cells, and is involved in mechanisms that result in tumour formation. The objective of this research is to investigate the potential role of VEGF polymorphism in the development of Rheumatoid Arthritis (RA) and the screening of potential natural, synthetic BTK inhibitor compounds as possible in-silico chemotherapeutic agents to control auto-activation of B-cells and cartilage degrading cytokines. In this study, it had been shown that allele A frequency was significantly higher than that of allele C in RA-positive patients as compared to controls. Hence it depicts that allele A of VEGF (rs699947) can increase the risk of RA while allele C has a protective role. The phytochemicals which showed maximum binding affinity at the inhibitory site of BTK include beta boswellic acid, tanshinone, and baicalin. These phytochemicals as BTK inhibitor give insights to use them as anti-arthritic compounds by nanoparticle drug delivery mechanism.

Acta Biochim Pol. 2023 Sep;70(3):591-598.
PMID: 37669474 [PubMed - indexed for MEDLINE]


Nutritional Supplements in the Clinical Management of Tendinopathy: A Scoping Review.
Burton I, McCormack A

INTRODUCTION: Tendinopathy has a high prevalence and incidence in the general population and among athletes, with a lack of consensus among medical practitioners on optimal management strategies. The objective of this scoping review was to evaluate current research on the use of nutritional supplements for treating tendinopathies, including what supplements have been used and what outcomes, outcome measures, and intervention parameters have been reported.

METHODS: Databases searched included Embase, SPORTDiscus, the Cochrane Library, MEDLINE, CINAHL, and AMED. This scoping review considered primary studies investigating nutritional supplements for tendinopathies and was reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Extension for Scoping Reviews.

RESULTS: A total of 1527 articles were identified with 16 included in the review. Studies investigated a range of nutritional supplements in the clinical management of various tendinopathies, including several commercially available proprietary blends of several ingredients. TendoActive (mucopolysaccharides, type I collagen, and vitamin C) was used in 2 studies, TENDISULFUR (methylsulfonylmethane, hydrolyzed collagen, L-arginine, L-lysine, vitamin C, bromelain, chondroitin, glucosamine, Boswellia, and myrrh) was used in 3 studies, and Tenosan (arginine-L-alpha ketoglutarate, hydrolyzed collagen type I, methylsulfonylmethane, vitamin C, bromelain, and vinitrox) was used in 2 studies. Collagen peptides were used in 2 studies, with omega-3 fatty acids, combined fatty acids and antioxidants, turmeric rhizome combined with Boswellia, β-hydroxy β-methylbutyric, vitamin C in isolation and combined with gelatin, and creatine investigated in one study each.

CONCLUSION: Despite a paucity of studies to date, findings from this review suggest that several nutritional compounds may be beneficial in the clinical management of tendinopathies, by exerting anti-inflammatory effects and improving tendon healing. Nutritional supplements may have potential as an adjunctive method to standard treatment methods such as exercise, where their pain-relieving, anti-inflammatory, and structural tendon effects may augment the positive functional outcomes gained from progressive exercise rehabilitation.

J Sport Rehabil. 2023 Jul;32(5):493-504.
PMID: 37146985 [PubMed - indexed for MEDLINE]


β Boswellic Acid Blocks Articular Innate Immune Responses: An In Silico and In Vitro Approach to Traditional Medicine.
Franco-Trepat E, Alonso-Pérez A, Guillán-Fresco M, López-Fagúndez M, Pazos-Pérez A, Crespo-Golmar A, Belén Bravo S, López-López V, Jorge-Mora A, Cerón-Carrasco JP, Lois Iglesias A, Gómez R

Osteoarthritis (OA) is hallmarked as a silent progressive rheumatic disease of the whole joint. The accumulation of inflammatory and catabolic factors such as IL6, TNFα, and COX2 drives the OA pathophysiology into cartilage degradation, synovia inflammation, and bone destruction. There is no clinical available OA treatment. Although traditional ayurvedic medicine has been using extracts (BSE) as an antirheumatic treatment for a millennium, none of the BSE components have been clinically approved. Recently, β boswellic acid (BBA) has been shown to reduce in vivo OA-cartilage loss through an unknown mechanism. We used computational pharmacology, proteomics, transcriptomics, and metabolomics to present solid evidence of BBA therapeutic properties in mouse and primary human OA joint cells. Specifically, BBA binds to the innate immune receptor Toll-like Receptor 4 (TLR4) complex and inhibits both TLR4 and Interleukin 1 Receptor (IL1R) signaling in OA chondrocytes, osteoblasts, and synoviocytes. Moreover, BBA inhibition of TLR4/IL1R downregulated reactive oxygen species (ROS) synthesis and MAPK p38/NFκB, NLRP3, IFNαβ, TNF, and ECM-related pathways. Altogether, we present a solid bulk of evidence that BBA blocks OA innate immune responses and could be transferred into the clinic as an alimentary supplement or as a therapeutic tool after clinical trial evaluations.

Antioxidants (Basel). 2023 Feb;12(2):.
PMID: 36829930 [PubMed - as supplied by publisher]


Extract, 5-Loxin®, Prevents Joint Pain and Cartilage Degeneration in a Rat Model of Osteoarthritis through Inhibition of Inflammatory Responses and Restoration of Matrix Homeostasis.
Shin MR, Kim HY, Choi HY, Park KS, Choi HJ, Roh SS

Osteoarthritis (OA) is a chronic, progressive joint disease associated with pain, functional impairment, and diminished quality of life in affected individuals. At a societal level, it also has a high economic burden. has been reported to have potent anti-inflammatory, antiarthritic, and analgesic effects. The aim of this study was to explore the therapeutic potential and possible underlying mechanism of 5-Loxin®, a standardized extract, in a rat model of OA. The OA model was established by the intra-articular injection of 50 L of monosodium iodoacetate (MIA) (60 mg/mL). 5-Loxin® was administered orally, and efficacy was evaluated through serum analysis, real-time polymerase chain reaction (PCR), histologic staining, and micro-computed tomography (micro-CT). Results indicated that administration of 5-Loxin® can relieve OA joint pain through inhibition of both inflammatory processes and cartilage degeneration. In the group of rats treated with 5-Loxin®, the suppression of inflammatory enzymes such as cyclooxygenase (COX)-2 and 5-lipoxygenase (LOX) resulted in a significant reduction in the prostaglandin (PG) E and leukotriene (LT) B levels. Moreover, 5-Loxin® ameliorated the deterioration of the main components of the articular extracellular matrix (ECM), such as glycosaminoglycans (GAGs) and aggrecan, through the downregulation of matrix metalloproteinases (MMPs). These findings suggest that 5-Loxin® may be a potential therapeutic agent for the treatment of OA.

Evid Based Complement Alternat Med. 2022;2022():3067526.
PMID: 36310623 [PubMed - as supplied by publisher]


Analysis of the Anti-Inflammatory and Anti-Osteoarthritic Potential of Flonat Fast, a Combination of DC. ex Meisn., Roxb., L., Bromelain and Escin (), Evaluated in In Vitro Models of Inflammation Relevant to Osteoarthritis.
Quarta S, Santarpino G, Carluccio MA, Calabriso N, Scoditti E, Siculella L, Damiano F, Maffia M, Verri T, De Caterina R, Massaro M

Osteoarthritis (OA) is a joint disease characterized by inflammation of the synovium, angiogenesis, cartilage degradation, and osteophyte formation. DC. ex Meisn., Roxb., L., Bromelain and Escin () are plants which extracts, together to Bromelain and Escin () are traditionally used in OA. However, their mechanistic role remains unclear. We aimed to investigate whether these bioactives alone or in combination (as in Flonat Fast) can suppress TNF-α-induced inflammation, angiogenesis, and osteophyte formation using two cell models involved in OA: endothelial cells and monocytes. Each plant extract was evaluated for its polyphenol content, antioxidant activity, and toxicity. In endothelial cells and monocytes, expression of genes involved in OA was assessed, functional assays for inflammation and angiogenesis were performed, and impairment of reactive oxygen species production (ROS) was evaluated. Exposure of cells to the bioactives alone and in combination before cytokine stimulation resulted in differential counterregulation of several gene and protein expressions, including those for cyclooxygenases-2, metalloproteinase-9, transforming growth factor β1, and bone morphogenic protein-2. We demonstrated that these bioactives modulated monocyte adhesion to endothelial cells as well as cell migration and endothelial angiogenesis. Consistent with radical scavenging activity in the cell-free system, the bioactives curbed TNF-α-stimulated intracellular ROS production. We confirmed the potential anti-inflammatory and antiangiogenic effects of the combination of , , Curcuma, Bromelain, and Escin and provided new mechanistic evidence for their use in OA. However, further clinical studies are needed to evaluate the true clinical utility of these bioactives as supportive, preventive, and therapeutic agents.

Pharmaceuticals (Basel). 2022 Oct;15(10):.
PMID: 36297375 [PubMed - as supplied by publisher]


Potential complementary and/or synergistic effects of curcumin and boswellic acids for management of osteoarthritis.
Sethi V, Garg M, Herve M, Mobasheri A

For several thousand years (~4000) and have been used in Aryuvedic medicine for treatment of various illnesses, including asthma, peptic ulcers, and rheumatoid arthritis, all of which are mediated through pathways associated with inflammation and pain. Although the pharmacology of both these natural ingredients is difficult to study because of poor bioavailability, data suggest that both influence gene expression mediated through nuclear factor kappa B (NF-κB). Therefore, the activity of pathways associated with inflammation (including NF-κB and lipoxygenase- and cyclooxygenase-mediated reduction in leukotrienes/prostaglandins) and those involved in matrix degradation and apoptosis are reduced, resulting in a reduction in pain. Additive activity of boswellic acids and curcumin was observed in preclinical models and synergism was suggested in clinical trials for the management of osteoarthritis (OA) pain. Overall, studies of these natural ingredients, alone or in combination, revealed that these extracts relieved pain from OA and other inflammatory conditions. This may present an opportunity to improve patient care by offering alternatives for patients and physicians, and potentially reducing nonsteroidal anti-inflammatory or other pharmacologic agent use. Additional research is needed on the effects of curcumin on the microbiome and the influence of intestinal metabolism on the activity of curcuminoids to further enhance formulations to ensure sufficient anti-inflammatory and antinociceptive activity. This narrative review includes evidence from and preclinical studies, and clinical trials that have evaluated the mechanism of action, pharmacokinetics, efficacy, and safety of curcumin and boswellic acids individually and in combination for the management of OA pain.

Ther Adv Musculoskelet Dis. 2022;14():1759720X221124545.
PMID: 36171802 [PubMed - as supplied by publisher]


and Extracts Modulate Different and Complementary Pathways on Human Chondrocytes : Deciphering of a Transcriptomic Study.
Sanchez C, Zappia J, Lambert C, Foguenne J, Dierckxsens Y, Dubuc JE, Delcour JP, Gothot A, Henrotin Y

(CL) and (BS) extracts are used to relieve osteoarthritis symptoms. The aim of this study was to investigate their mechanisms of action at therapeutic plasmatic concentrations on primary human osteoarthritic (OA) chondrocytes. BS (10-50 μg/ml) and CL (0.4-2 μg/ml corresponding to 1-5 µM of curcumin) were evaluated separately or in combination on primary chondrocytes isolated from 17 OA patients and cultured in alginate beads. Ten patients were used for RNA-sequencing analysis. Proteomic confirmation was performed either by immunoassays in the culture supernatant or by flow cytometry for cell surface markers after 72 h of treatment. Significant gene expression modifications were already observed after 6 h of treatment at the highest dose of CL (2 μg/ml) while BS was significantly effective only after 24 h of treatment irrespective of the concentration tested. The most over-expressed genes by CL were anti-oxidative, detoxifying, and cytoprotective genes involved in the pathway. Down-regulated genes were principally pro-inflammatory cytokines and chemokines. Inversely, BS anti-oxidant/detoxifying activities were related to the activation of and PPARα pathways. BS anti-inflammatory effects were associated with the increase in GDF15, decrease in cholesterol cell intake and fatty acid metabolism-involved genes, and down-regulation of Toll-like receptors (TLRs) activation. Similar to CL, BS down-regulated ADAMTS1, 5, and MMP3, 13 genes expression. The combination of both CL and BS was significantly more effective than CL or BS alone on many genes such as IL-6, CCL2, ADAMTS1, and 5. BS and CL have anti-oxidative, anti-inflammatory, and anti-catabolic activities, suggesting a protective effect of these extracts on cartilage. Even if they share some mechanism of action, the two extracts act mainly on distinct pathways, and with different time courses, justifying their association to treat osteoarthritis.

Front Pharmacol. 2022;13():931914.
PMID: 36034822 [PubMed - as supplied by publisher]


The Nutraceuticals as Modern Key to Achieve Erythrocyte Oxidative Stress Fighting in Osteoarthritis.
Mariano A, Bigioni I, Misiti F, Fattorini L, Scotto D'Abusco A, Rodio A

Osteoarthritis (OA), the most common joint disease, shows an increasing prevalence in the aging population in industrialized countries. OA is characterized by low-grade chronic inflammation, which causes degeneration of all joint tissues, such as articular cartilage, subchondral bone, and synovial membrane, leading to pain and loss of functionality. Erythrocytes, the most abundant blood cells, have as their primary function oxygen transport, which induces reactive oxygen species (ROS) production. For this reason, the erythrocytes have several mechanisms to counteract ROS injuries, which cause damage to lipids and proteins of the cell membrane. Oxidative stress and inflammation are highly correlated and are both causes of joint disorders. In the synovial fluid and blood of osteoarthritis patients, erythrocyte antioxidant enzyme expression is decreased. To date, OA is a non-curable disease, treated mainly with non-steroidal anti-inflammatory drugs and corticosteroids for a prolonged period of time, which cause several side effects; thus, the search for natural remedies with anti-inflammatory and antioxidant activities is always ongoing. In this review, we analyze several manuscripts describing the effect of traditional remedies, such as , and extracts, in the treatments of OA for their anti-inflammatory, analgesic, and antioxidant activity. The effects of such remedies have been studied both in in vitro and in vivo models, considering both joint cells and erythrocytes.

Curr Issues Mol Biol. 2022 Aug;44(8):3481-3495.
PMID: 36005136 [PubMed - as supplied by publisher]


Protective effect of a novel polyherbal formulation on experimentally induced osteoarthritis in a rat model.
Orhan C, Tuzcu M, Durmus AS, Sahin N, Ozercan IH, Deeh PBD, Morde A, Bhanuse P, Acharya M, Padigaru M, Sahin K

Osteoarthritis (OA) is a musculoskeletal disorder mainly found in elderly individuals. Modern treatment of OA, like nonsteroidal anti-inflammatory drugs, corticosteroids, hyaluronic acid injections, etc., is linked to long-term side effects. We evaluated the anti-osteoarthritic properties of a novel joint health formula (JHF) containing Bisdemethoxycurcumin enriched curcumin, 3-O-Acetyl-11-keto-beta-Boswellic acid-enriched Boswellia, and Ashwagandha in monosodium iodoacetate (MIA)-induced knee OA in rats. Twenty-eight female rats were distributed into four groups: Control, OA, OA + JHF (100 mg/kg), and OA + JHF (200 mg/kg). JHF decreased the right joint diameters but increased the paw area and stride length compared to the OA group with no treatment. JHF significantly reduced the arthritic conditions after four weeks of supplementation (p < 0.05). JHF significantly decreased TNF-α, IL-1β, IL-10, COMP, and CRP in the serum of osteoarthritic rats (p < 0.0001). We observed reduced lipid peroxidation but increased SOD, GSH-Px, and CAT activities in response to JHF treatment in OA animals. JHF down-regulated MMP-3, COX-2, and LOX-5 and improved the histological structure of the knee joint of osteoarthritic rats. JHF demonstrated a protective effect against osteoarthritis, possibly due to anti-inflammatory and antioxidant activity in experimentally induced osteoarthritis in rats, and could be an effective option in the management of OA.

Biomed Pharmacother. 2022 Jul;151():113052.
PMID: 35588576 [PubMed - indexed for MEDLINE]


Bioavailability, anti-inflammatory and anti-arthritic effect of Acetyl Keto Boswellic acid and its combination with methotrexate in an arthritic animal model.
Banji D, Banji OJF, Rashida S, Alshahrani S, Alqahtani SS

ETHNOPHARMACOLOGICAL RELEVANCE: Rheumatoid arthritis is one of the most common disabling chronic progressive autoimmune diseases affecting the adult world population. Boswellia serrata has been a known anti-inflammatory agent since ancient times. Therefore, research on Boswellia extract based on Acetyl Keto Boswellic Acid (AKBA) content evaluating its efficacy and safety is necessary. The study aimed to find a suitable Boswellia extract rich in AKBA to evaluate its bioavailability, anti-inflammatory, and anti-arthritic effect. In addition, the synergistic action of AKBA extract with methotrexate (MTX) was also assessed on an animal model.

MATERIALS AND METHODS: Oral bioavailability of AKBA and the anti-inflammatory activity of 10% AKBA (5, 10, 20, 40 mg/kg b.w) was assessed and compared with 2% AKBA (40 mg/kg) and diclofenac (10 mg/kg). The effect of 10% AKBA at 20 mg/kg and 40 mg/kg was evaluated in the FCA induced arthritis animal model alone and combined with methotrexate (MTX) at 2 mg/kg b.w. Subplantar injection of FCA produced edema within a few hours with progressive arthritis by the 9th day after injection. All the treatments were initiated from the 10th day until the 45th day. Oral administration of 10% AKBA was done daily and MTX by intraperitoneal route once a week from day 10 to day 45. Paw volume, erythrocyte sedimentation rate (ESR), serum glutamic oxaloacetic transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT), alkaline phosphatase (ALP), total bilirubin, oxidative markers (superoxide dismutase (SOD) levels, malondialdehyde (MDA), total proteins and liver histopathology were examined.

RESULTS: 10% AKBA provided 8.48-fold, 24.22-fold, 47.36-fold, and 110.53-fold higher AUC (0-α) of AKBA at 5 mg/kg, 10 mg/kg, 20 mg/kg and 40 mg/kg, respectively compared to 2% AKBA at 40 mg/kg. Percentage paw edema inhibition of 10% AKBA at 20 mg/kg and 40 mg/kg were significantly higher than 2% regular AKBA (40 mg/kg) and diclofenac (10 mg/kg). 10% AKBA at a dose of 20 and 40 mg/kg significantly reduced ESR compared with FCA treated group. A combination of methotrexate with 10% AKBA showed the highest reduction in ESR. 10% AKBA at both dose levels significantly reduced hepatic marker enzymes and total bilirubin levels. Treatment with 10% AKBA showed a significant increase in total proteins, antioxidant enzymes and a decrease in malondialdehyde levels. Similarly, 10% AKBA protected the hepatocytes compared with the FCA and FCA + MTX treated group. 10% AKBA was capable of significantly minimizing FCA and FCA + MTX induced changes.

CONCLUSION: Anti-inflammatory activity of AKBA due to inhibition of lipoxygenase (LOX) enzymes supports the use of AKBA in inflammatory disorders. Combination therapy of 10% AKBA with MTX is effective in inhibiting arthritis and circumventing hepatotoxicity produced by MTX in arthritic animals.

J Ethnopharmacol. 2022 Jun;292():115200.
PMID: 35306043 [PubMed - indexed for MEDLINE]


Clinical efficacy of Curcuvet and Boswellic acid combined with conventional nutraceutical product: An aid to canine osteoarthritis.
Caterino C, Aragosa F, Della Valle G, Costanza D, Lamagna F, Piscitelli A, Nieddu A, Fatone G

INTRODUCTION: Osteoarthritis is a progressive degenerative joint disease which is high prevalent in dogs. In the late stage of the disease, it determines chronic neuropathic pain which leads to reduced quality-of-life in affected patients. To date it has not yet been identified a specific treatment, but it has been proved that nutraceutical and dietary supplements may play an important role in controlling inflammation and pain. The aim of this study was to evaluate, by the use of force plate gait analysis, the clinical efficacy of Boswellia and Curcuvet® combined with conventional nutraceutical therapy compared with conventional nutraceutical alone in dogs affected by osteoarthritis.

MATERIALS AND METHODS: Twenty client-owned dogs, over 12 months old and 20 kg of body-weight, with a confirmed diagnosis of Osteoarthritis, were included in this randomized, double-blinded study. The dogs were randomly divided into two groups: the first group (A) received a conventional nutraceutical (consisted in a preparation of glucosamine, chondroitin sulfate, fish-oil containing 80% of omega 3-fatty acid, vitamin C and E, saccharomyces Cerevisiae) with a combination of acid boswellic and Curcuvet®, while the second group (B) received a conventional nutraceutical. All the enrolled dogs underwent a washout period before starting the treatment with nutraceuticals products which were the only admitted treatment over the study period. A full orthopaedic and neurologic examination, and force plate gait analysis were performed before starting the treatment, at 45, 90, and 60 days post-treatment. Ground reaction forces were recorded and analyzed.

RESULTS: Twenty dogs were enrolled in the study. In both groups there was an increasing values of ground reaction forces. These results might indicate that both nutraceutical products determined a better condition in terms of pain feeling but that effect is much more visible after 60 days from the end of the administration in treated group.

DISCUSSION: In conclusion Curcuvet in combination with Boswellic acid could be considered a valid aid in a multimodal treatment for canine osteoarthritis.

PLoS One. 2021;16(5):e0252279.
PMID: 34048452 [PubMed - indexed for MEDLINE]


Systems pharmacology-based dissection of mechanisms of Tibetan medicinal compound Ruteng as an effective treatment for collagen-induced arthritis rats.
Huang XJ, Wang J, Muhammad A, Tong HY, Wang DG, Li J, Ihsan A, Yang GZ

ETHNOPHARMACOLOGICAL RELEVANCE: Compound Ruteng (CRT) is a prescribed formulation based on the theory of Tibetan medicine for the treatment of yellow-water-disease. It is consisted with 7 medicinal material include Boswellia carterii Birdw (named "Ruxiang" in Chinese); Tinospora sinensis (Lour.) Merr. (named "Kuan-Jin-Teng" in Chinese), Cassia obtusifolia L (named "Jue-Ming-Zi" in Chinese); Abelmoschus manihot (L.) Medic (named "Huang-Kui-Zi" in Chinese); Terminalia chebula Retz. (named "He-Zi" in Chinese); Lamiophlomis rotata (Benth.) Kudo (named "Du-Yi-Wei" in Chinese) and Pyrethrum tatsienense (Bur. et Franch.) Ling (named "Da-Jian-Ju" in Chinese). They are widely distributed in Tibet area of China and have been used to treat rheumatism, jaundice, and skin diseases for centuries.

AIM OF THE STUDY: The present study was conducted to investigate the anti-arthritis effect of CRT and to disclose the systems pharmacology-based dissection of mechanisms.

MATERIALS AND METHODS: The chemical constituents in CRT were identified using HPLC method, and CRT candidate targets against RA were screened by network pharmacology-based analysis and further experimentally validated based on collagen-induced arthritis (CIA) rat model. Furthermore, therapeutic mechanisms and pathways of CRT were investigated.

RESULTS: 391 potential targets (protein) were predicted against 92 active ingredients of 7 medicinal materials in CRT. Enrichment analysis and molecular docking studies also enforced the practiced results. X-ray based physiological imaging showed the attenuated effect of CRT on paw swelling, synovial joints and cartilage with improved inflammation in CIA rats. Moreover, the expression of biomarkers associated with RA such as MMP1, MMP3 and MMP13 and TNF-a, COX2 and iNOS are down-regulated in ankle joints, serum, or liver.

CONCLUSION: In conclusion, CRT compound could attenuate RA symptoms and active ingredients of this compound could be considered for drug designing to treat RA.

J Ethnopharmacol. 2021 May;272():113953.
PMID: 33610711 [PubMed - indexed for MEDLINE]


Herbal Composition LI73014F2 Alleviates Articular Cartilage Damage and Inflammatory Response in Monosodium Iodoacetate-Induced Osteoarthritis in Rats.
Kim HL, Lee HJ, Lee DR, Choi BK, Yang SH

The aim of this study was to determine the anti-osteoarthritic effects of LI73014F2, which consists of fruit, rhizome, and gum resin in a 2:1:2 ratio, in the monosodium iodoacetate (MIA)-induced osteoarthritis (OA) rat model. LI73014F2 was orally administered once per day for three weeks. Weight-bearing distribution and arthritis index (AI) were measured once per week to confirm the OA symptoms. Synovial membrane, proteoglycan layer, and cartilage damage were investigated by histological examination, while synovial fluid interleukin-1β level was analyzed using a commercial kit. Levels of pro-inflammatory mediators/cytokines and matrix metalloproteinases (MMPs) in the cartilage tissues were investigated to confirm the anti-osteoarthritic effects of LI73014F2. LI73014F2 significantly inhibited the MIA-induced increase in OA symptoms, synovial fluid cytokine, cartilage damage, and expression levels of pro-inflammatory mediators/cytokines and MMPs in the articular cartilage. These results suggest that LI73014F2 exerts anti-osteoarthritic effects by regulating inflammatory cytokines and MMPs in MIA-induced OA rats.

Molecules. 2020 Nov;25(22):.
PMID: 33238379 [PubMed - indexed for MEDLINE]


Huoxuezhitong capsule ameliorates MIA-induced osteoarthritis of rats through suppressing PI3K/ Akt/ NF-κB pathway.
Ju L, Hu P, Chen P, Xue X, Li Z, He F, Qiu Z, Cheng J, Huang F

Huoxuezhitong capsule (HXZT, activating blood circulation and relieving pain capsule), has been applied for osteoarthritis since 1974. It consists of Angelica sinensis (Oliv.) Diels, Panax notoginseng (Burkill) F. H. Chen ex C. H., Boswellia sacra, Borneol, Eupolyphaga sinensis Walker, Pyritum. However, the direct effects of HXZT on osteoarthritis and the underlying mechanisms were poorly understood. In this study, we aimed to explore the analgesia effect of HXZT on MIA-induced osteoarthritis rat and the underlying mechanisms. The analgesia and anti-inflammatory effect of HXZT on osteoarthritis in vivo were tested by the arthritis model rats induced by monosodium iodoacetate (MIA).. Mechanistic studies confirmed that HXZT could inhibit the activation of NF-κB and down-regulate the mRNA expression of related inflammatory factors in LPS-induced RAW264.7 and ATDC5 cells. Furtherly, in LPS-induced RAW264.7 cells, HXZT could suppress NF-κB via inhibiting PI3K/Akt pathway. Taken together, HXZT capsule could ameliorate MIA-induced osteoarthritis of rats through suppressing PI3K/ Akt/ NF-κB pathway.

Biomed Pharmacother. 2020 Sep;129():110471.
PMID: 32768958 [PubMed - indexed for MEDLINE]


An Anti-Inflammatory Composition of Resin Extracts Alleviates Pain and Protects Cartilage in Monoiodoacetate-Induced Osteoarthritis in Rats.
Alluri VK, Kundimi S, Sengupta K, Golakoti T, Kilari EK

The boswellic acids, the active compounds in gum resin extract, are potent anti-inflammatory agents and are specific nonredox inhibitors of 5-Lipoxygenase (5-LOX). Here, we present the anti-osteoarthritis (OA) efficacy of LI13019F1 (also known as Serratrin®), a unique composition containing the acidic and nonacidic fractions of gum resin. This composition strongly inhibited 5-LOX activity with the half-maximal inhibitory concentration (IC) of 43.35 ± 4.90 g/mL. Also, LI13019F1 strongly inhibited the leukotriene B (IC, 7.80 ± 2.40 g/mL) and prostaglandin E (IC, 6.19 ± 0.52 g/mL) productions in human blood-derived cells. Besides, LI13019F1 reduced TNF- production with the IC of 12.38 ± 0.423 g/mL. On average, 1, 2.5, and 5 g/mL doses of LI13019F1 protected 34.62, 47.66, and 62.29% SW1353 human chondrosarcoma cells from IL-1 induced SOX-9 depletion, respectively. Further, a 28-day preclinical proof-of-concept study evaluated the pain relief efficacy of LI13019F1 in monoiodoacetate- (MIA-) induced rats. At the end of the study, 150 and 300 mg/kg doses of LI13019F1 supplemented rats showed significant improvements (55.17 ± 5.81 g ( < 0.05), and 66.22 ± 6.30 g ( < 0.05), respectively, vs. MIA: 31.22 ± 7.15 g) in body-weight-bearing capacities. Concurrently, LI13019F1-150 and LI13019F1-300 rats substantially ( < 0.05) increased the threshold of pain sensitivity to pressure (26.98 ± 2.36 and 28.06 ± 2.72-gram force, respectively; vs. 18.63 ± 5.82 in MIA) and increased ( < 0.05) the latent time to withdraw the paw after a thermal stimulus (23.61 ± 2.73 and 28.18 ± 1.90 sec, respectively; vs. 16.56 ± 1.22 sec. in MIA). Besides, the histological observations on Safranin-O green stained articular cartilage revealed that LI13019F1 also prevented the MIA-induced structural damage of the cartilage and reduced the loss of the extracellular matrix (ECM) components in the experimental rats. In conclusion, the present observations suggest that LI13019F1, a new composition of gum resin extracts, reduces pain and protects articular cartilage from the damaging action of MIA in a rodent model.

Evid Based Complement Alternat Med. 2020;2020():7381625.
PMID: 32565872 [PubMed - as supplied by publisher]


Anti-osteoarthritic Effects of an Herbal Composition LI73014F2 on Interleukin-1β-induced Primary Human Articular Chondrocytes.
Kim HL, Lee HJ, Lee DR, Choi BK, Yang SH

Osteoarthritis (OA) is one of the most well-characterized joint diseases and is associated with chondrocyte inflammation, metalloproteinase upregulation and apoptosis. LI73014F2 is a novel composition prepared from aqueous extract of fruit, alcohol extract of rhizome, and extract at 2:1:2 ratio. Earlier studies have shown that LI73014F2 inhibits cyclooxygenase-2 (COX-2), 5-lipoxygenase (5-LOX) activities, and attenuates clinical symptoms in OA subjects. In the present study, we evaluated the protective anti-inflammatory and anti-apoptotic effects, as well as the underlying mechanisms, of LI73014F2 in interleukin (IL)-1β-induced inflammation in human primary chondrocytes. Human chondrocytes were treated with LI73014F2 (0, 12.5, 25 and 50 μg/mL) in IL-1β (10 ng/mL)-containing chondrocyte growth medium for 24 h. Cell viability was assessed using an MTT assay. The pro-inflammatory mediator, inflammatory cytokines, MMPs, apoptosis-related proteins, mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) signaling pathways protein expression levels were detected by western blot analysis. The results demonstrated that LI73014F2 normalized the expressions of COX-2, mPGES-1, PGE, 5-LOX, LTB, IL-1β, TNFα, IL-6, MMP-2, MMP-3, MMP-9, MMP-13, Bax/Bcl-2, cleaved caspase-9 and -3, cleaved PARP, phospho-NF-κB p65 and phospho-p38 MAPK proteins in IL-1β-induced primary human chondrocytes. Moreover, the data suggested that LI73014F2 reduced IL-1β-induced inflammation and apoptosis, at least partially via the inhibition of the NF-κB/MAPK signaling pathway. In conclusion, the present findings provide the molecular basis of the anti-OA efficacy of LI73014F2.

Molecules. 2020 Apr;25(9):.
PMID: 32349389 [PubMed - indexed for MEDLINE]


Effect of Boswellia Serrata Extract on Acute Inflammatory Parameters and Tumor Necrosis Factor-α in Complete Freund's Adjuvant-Induced Animal Model of Rheumatoid Arthritis.
Kumar R, Singh S, Saksena AK, Pal R, Jaiswal R, Kumar R

CONTEXT: The worldwide prevalence of rheumatoid arthritis (RA) is about 1%, whereas in India, it is approximately 0.75%. The current therapy for RA includes nonsteroidal anti-inflammatory drugs corticosteroids, disease-modifying anti-rheumatic drugs and some recently developed biologic agents, but all of these are associated with adverse effects. Some herbal drugs, such as Boswellia serrata, have been reported to possess anti-inflammatory activity.

AIMS: The aim of this study is to evaluate the anti-arthritic activity of Boswellia serrata extract (BSE) in complete Freund's adjuvant (CFA)-induced arthritis in rats.

MATERIALS AND METHODS: Thirty-six Wistar rats were divided into six equal groups. RA was induced by intradermal injection of 0.1 ml CFA in hind paw. Body weight, ankle diameter, paw volume, arthritic index, tumor necrosis factor-α (TNF-α), and histopathological examination were assessed. The experimental data were statistically assessed by one-way analysis of variance (ANOVA).

STATISTICAL ANALYSIS USED: The recorded data were analyzed using paired -test and ANOVA test using SPSS. The data were analyzed and represented as mean difference. Value of < 0.05 was considered statistically significant.

RESULTS: BSE at dose 180 mg/kg showed statistically significant improvement in body weight and decrease in ankle diameter and arthritic index ( < 0.05); however, there was insignificant change in paw volume ( = 0.056). This improvement was comparable with Indomethacin. The level of TNF-α did not show any statistically significant change ( = 0.076). Histopathological results also exhibited a reduction in inflammatory parameters.

CONCLUSIONS: BSE might have usefulness as an adjunct to conventional therapy of RA.

Int J Appl Basic Med Res. 2019;9(2):100-106.
PMID: 31041173 [PubMed - as supplied by publisher]


Current status of top 10 nutraceuticals used for Knee Osteoarthritis in India.
Vaishya R, Agarwal AK, Shah A, Vijay V, Vaish A

Knee Osteoarthritis (OA) is a progressive degenerative joint disease affecting the quality of life of the elderly population. There is considerable evidence that nutraceuticals from natural herbs may play a significant role in inflammation and joint destruction in OA. We review the current status of some of the commonly used nutraceuticals in Indian market - Boswellia, Aflapin, Chondroitin sulphate, Glucosamine sulphate, Collagen peptide, Curcumin, Fish Oil, Ginger, Green tea, and Rosehip extract. We have summarized their mechanism of action, biological effects, toxicities and efficacy in the management of Knee OA. These supplements have been found to be effective in knee OA in various studies. No serious side effects have been reported for any of these supplements. Overall, our study identifies and support the use of these nutraceuticals to provide symptomatic relief to patients with knee OA and justify their use as an adjunct therapy for the management. More good quality trials are needed to provide definitive answers to questions related to their efficacy and safety for OA prevention and treatment.

J Clin Orthop Trauma. 2018;9(4):338-348.
PMID: 30449982 [PubMed - as supplied by publisher]


Natural Products for Promoting Joint Health and Managing Osteoarthritis.
Henrotin Y, Mobasheri A

PURPOSE OF REVIEW: Osteoarthritis, the most common joint disease, is associated with substantial medical costs, lost productivity, and reduced quality of life. However, available pharmaceutical treatments have limitations in terms of efficacy and long-term safety.

RECENT FINDINGS: In vitro evidence suggests that some natural products may possess anti-inflammatory and anti-oxidative properties and may inhibit the release of key osteoarthritis-related cytokines. There is, therefore, ongoing interest in identifying natural products that safely promote joint health and treat osteoarthritis. Numerous plant extracts, including curcumin, Boswellia extract, and pycnogenol, have shown effect sizes (ES) for reducing pain and functional disability larger than those observed with analgesics and products such as glucosamine and chondroitin. The ES for methylsulfonylmethane and avocado/soybean unsaponifiables are also considered to be clinically relevant. Data from a small number of studies using natural products for treating osteoarthritis are promising but require confirmation in further well-designed clinical trials.

Curr Rheumatol Rep. 2018 Sep;20(11):72.
PMID: 30232562 [PubMed - indexed for MEDLINE]


Micellar solubilisation enhances the antiinflammatory activities of curcumin and boswellic acids in rats with adjuvant-induced arthritis.
Khayyal MT, El-Hazek RM, El-Sabbagh WA, Frank J, Behnam D, Abdel-Tawab M

OBJECTIVE: Native extracts of curcumin and boswellia are known to exert antiinflammatory properties but have poor bioavailability when given orally. Using advanced micellation technology, it has been possible to produce stable solubilisates of these extracts with markedly enhanced bioavailability. In the present study, we compared the chronic antiinflammatory activities of native and micellar curcumin in the rat adjuvant arthritis model, using diclofenac as a reference drug.

METHODS AND PROCEDURES: Adjuvant arthritis was induced by injecting Freund's complete adjuvant (FCA) into the right hind paw of rats and monitoring paw volume over 3 wk. The drugs were given daily for 3 wk, starting from the day of adjuvant inoculation. The serum was collected at end of the experiment for the assay of inflammatory and oxidative stress parameters. Statistical comparisons between different groups were carried out by one-way analysis of variance followed by Tukey-Kramer multiple comparison test.

RESULTS: Solubilized curcumin showed better antiinflammatory activity than its native form. The reduction in paw volume was reflected in corresponding changes in relevant mediators of inflammation like tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), C-reactive protein (CRP), myeloperoxidase (MPO), and lipid peroxidation markers. The combination of curcumin and boswellia solubilisates synergistically produced an even more potent therapeutic effect.

CONCLUSION: The findings confirm that micellar solubilisation of curcumin and boswellia not only increases their bioavailability, but also enhances their biological activity. Micellar curcumin, in particular in combination with micellar boswellia, may thus represent a promising concomitant tool for antiinflammatory treatment and a potential antiinflammatory alternative to synthetic drugs.

Nutrition. 2018 Oct;54():189-196.
PMID: 30048884 [PubMed - indexed for MEDLINE]


Anti-inflammatory and anti-arthritic effects of methanol extract of the stem bark of Boswellia dalzielii Hutch (Burseraceae) in rats.
Mbiantcha M, Almas J, Atsamo AD, Ateufack G, Shabana SU, Bomba Tatsinkou DF, Yousseu Nana W, Nida D

Boswellia dalzielii is a tall tree (more than 13 m high) that produces aromatic white flowers. This plant is commonly used in indigenous medicine across Africa against diarrhea, malaria, vomiting, inflammation and arthritis. The present study focuses on the anti-inflammatory and anti-arthritis potential of methanol extract of Boswellia dalzielii (BDME). Anti-inflammatory activity was evaluated in inflammatory models induced by carrageenan, arachidonic acid, histamine, serotonin, prostaglandin and bradykinin. Anti-arthritis activity was measured using complete Freund's adjuvant model. Intracellular and extracellular ROS production and proliferation of T-cells were evaluated using chemiluminescence and liquid scintillation counter techniques, respectively. TNF-α and IL-1β production were assessed using ELISA and MTT assay performed for cytotoxicity. BDME revealed a significant anti-inflammatory effect by preventing the development of edema caused by carrageenan, arachidonic acid, histamine, serotonin, prostaglandin and bradykinin. For anti-arthritic properties of BDME, the results showed a significant reduction of the joint diameter and a decrease in pain in the treated animals. The extract also showed a noticeable systemic effect, maintaining the values of the evaluated parameters close to normal in treated rats with an inhibition of joint destruction as shown in histopathological analysis. Furthermore, BDME exhibited significant inhibition of extracellular and intracellular ROS production. Still, the extract displayed significant inhibitory activity on T-cell proliferation as well as a reduced production of TNF-α and IL-1β. Boswellia dalzielii could be considered as a promising tract in the prevention and/or management of inflammatory diseases.

Inflammopharmacology. 2018 Dec;26(6):1383-1398.
PMID: 29948494 [PubMed - indexed for MEDLINE]


Acetyl-11-Keto-β-Boswellic Acid Promotes Osteoblast Differentiation by Inhibiting Tumor Necrosis Factor-α and Nuclear Factor-κB Activity.
Bai F, Chen X, Yang H, Xu HG

Tumor necrosis factor (TNF) -α plays a crucial role in rheumatoid arthritis (RA)-related bone loss disease. The main mechanism of action of RA induced bone loss is the significant inhibitory effect of TNF-α on osteoblast differentiation. TNF-α inhibits osteoblast differentiation mainly by activating nuclear factor (NF) -κB signaling pathway. Owing to the crucial role of TNF-α and NF-κB in the inhibition of osteoblast differentiation, they are considered as targets for the development of therapeutic drugs. In the present study, we evaluated the NF-κB inhibitor Boswellic acid (BA) and its derivatives in the regulation of osteoblast differentiation and the molecular mechanism. Based on the cell model of TNF-α induced inhibition of osteoblast differentiation of MC3T3-E1, the regulatory role of BAs was studied. The result of MTT assay indicated that bone morphogenetic protein (BMP) -2, TNF-α, or acetyl-11-keto-β-BA (AKBA) impact no significant effect for cell viability of MC3T3-E1. The results of alkaline phosphatase (ALP activity assay and real-time polymerase chain reaction indicated that AKBA blocked TNF-α-induced inhibition of the expression of osteoblast markers, suggesting that AKBA rescued osteoblast differentiation from TNF-α-induced inhibition. Additionally, AKBA stimulated the BMP-2-induced expression of osteoblast markers, suggesting that AKBA promotes osteoblast differentiation directly. The results of western blotting and luciferase assay indicated that N-κB signaling was activated by TNF-α. The overexpression of NF-κB component p65 in MC3T3-E1 was found to attenuate the positive effect of AKBA in osteoblast differentiation, suggesting that AKBA potentiates osteoblast differentiation by inhibiting NF-κB signaling. Collectively, AKBA promotes osteoblast differentiation by inhibiting TNF-α and NF-κB. Our study revealed a new discovery of AKBA in regulating osteoblast differentiation, and demonstrated that AKBA may be a potential anabolic agent in the treatment of RA-derived bone loss disease.

J Craniofac Surg. 2018 Oct;29(7):1996-2002.
PMID: 29927820 [PubMed - indexed for MEDLINE]


A Placebo-Controlled Double-Blind Study Demonstrates the Clinical Efficacy of a Novel Herbal Formulation for Relieving Joint Discomfort in Human Subjects with Osteoarthritis of Knee.
Karlapudi V, Prasad Mungara AVV, Sengupta K, Davis BA, Raychaudhuri SP

LI73014F2 is a novel composition prepared from extracts of Terminalia chebula fruit, Curcuma longa rhizome, and Boswellia serrata gum resin with synergistic benefit in 5-Lipoxygenase (5-LOX) inhibition. This herbal composition with strong anti-5-LOX activity exhibited significant pain relief as indicated through improvements in weight-bearing capacity in a monosodium iodoacetate-induced osteoarthritis (OA) model of Sprague-Dawley rats. A 90-day randomized, placebo-controlled double-blind study evaluates the clinical efficacy and tolerability of LI73014F2 in the management of symptoms of OA of the knee (Clinical Trial Registration No. CTRI/2014/01/004338). Subjects, (n = 105), were randomized into three groups: placebo (n = 35), 200 mg/day of LI73014F2 (n = 35), and 400 mg/day of LI73014F2 (n = 35). All study participants were evaluated for pain and physical function by using standard tools, that is, Visual Analog Scale, Lequesne's Functional Index, and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) at the baseline (day 0) and on day 14 ± 3, 30 ± 3, 60 ± 3, and at the end of the study (day 90 ± 3). In addition, routine examinations on biochemical parameters in serum, urine, and hematological parameters were conducted on each visit to assess the safety of the study material. At the end of the trial period, LI73014F2 conferred significant pain relief, improved physical function, and quality of life in OA patients. In conclusion, preclinical and clinical data together strongly suggest that the herbal formulation LI73014F2 is a safe and effective intervention for management of joint discomfort, demonstrating efficacy as early as 14 days.

J Med Food. 2018 May;21(5):511-520.
PMID: 29708818 [PubMed - indexed for MEDLINE]


Which supplements can I recommend to my osteoarthritis patients?
Liu X, Eyles J, McLachlan AJ, Mobasheri A

OA is a chronic and disabling joint disease with limited evidence-based pharmacological treatment options available that improve outcomes for patients safely. Faced with few effective pharmacological treatments, the use has grown of dietary supplements and complementary medicines for symptomatic relief among people living with OA. The aim of this review is to provide a summary of existing evidence and recommendations supporting the use of supplements for OA. Systematic reviews and randomized controlled trials investigating oral supplements for treating OA were identified. Limited research evidence supports recommendations for the oral use of Boswellia serrata extract and Pycnogenol, curcumin and methylsulfonylmethane in people with OA despite the poor quality of the available studies. Few studies adequately reported possible adverse effects related to supplementation, although the products were generally recognized as safe. Further high quality trials are needed to improve the strength of evidence to support this recommendation and better guide optimal treatment of people living with OA.

Rheumatology (Oxford). 2018 May;57(suppl_4):iv75-iv87.
PMID: 29506080 [PubMed - indexed for MEDLINE]


Erratum: Terpenoids from the Oleo-Gum-Resin of Boswellia serrata and Their Antiplasmodial Effects In Vitro.
Greve HL, Kaiser M, Brun R, Schmidt TJ

Planta Med. 2017 Oct;83(14-15):E4.
PMID: 28847018 [PubMed - as supplied by publisher]


Assessment of toxicity and biochemical mechanisms underlying the insecticidal activity of chemically characterized Boswellia carterii essential oil against insect pest of legume seeds.
S K, Kujur A, Patel L, K R, Prakash B

The present study was undertaken to investigate the insecticidal activity of chemically characterized Boswellia carterii essential oil (EO) and its mode of action against the pulse beetle Callosobruchus chinensis and C. maculatus. GC-MS analysis depicted α-thujene (69.16%), α-Pinene (7.20) and α-Phellandrene (6.78%) as the major components of test EO. EO exhibited absolute toxicity at 0.10μl/ml air against both C. chinensis and C. maculatus following 24h exposure. EO caused a significant reduction in oviposition and further reproductive development at LC doses (0.050μl/ml to 0.066μl/ml in air). Compared to control, a significant elevation in ROS level accompanied with impairment in enzymatic (SOD and CAT) and non-enzymatic (GSH/GSSH) antioxidant defense system has been observed in EO exposed insect pest. However, EO has no significant effect on in vivo AChE activity. An absolute protection of Vigna radiata seeds samples exposed to EO at LC doses was observed without affecting seed germination. The findings revealed that the B. carterii EO has strong insecticidal potential, hence, it could be recommended as a biorational alternative to synthetic insecticides.

Pestic Biochem Physiol. 2017 Jun;139():17-23.
PMID: 28595917 [PubMed - indexed for MEDLINE]


Brazilian oral herbal medication for osteoarthritis: a systematic review protocol.
Moura Mdel G, Lopes LC, Biavatti MW, Busse JW, Wang L, Kennedy SA, Bhatnaga N, Bergamaschi Cde C

BACKGROUND: Osteoarthritis affects 1 % of the world's population and is the most common cause of musculoskeletal impairment in the elderly. Herbal medications are commonly used in Brazil to manage symptoms associated with osteoarthritis, and some of them are financed by the Brazilian government; however, the effectiveness of most of these agents is uncertain. The aim was to systematically review the efficacy and safety of 13 oral herbal medications used in Brazil for the treatment of osteoarthritis.

METHODS: Randomized clinical trials eligible for our systematic review will enroll adults with osteoarthritis treated by a Brazilian herbal medication or a control group (placebo or active control). Using terms to include all forms of osteoarthritis combined with herbal medications, we will search the following electronic databases: Cochrane Central Register of Controlled Trials (CENTRAL); MEDLINE; EMBASE; CINAHL; Web of Science; Health Star; AMED, the database of the Cochrane Complementary Medicine Field, LILACS; CAB abstracts, Clinical trial.gov, WHO trials registry, and Bank of Brazil Thesis (CAPES), to 31 January 2016, without restrictions concerning language or status of publication. Outcomes of interest include the following: symptom relief (e.g., pain), adverse events (gastrointestinal bleeding, epigastric pain, nausea, and allergic reactions), discontinuation due to adverse events, quality of life, and the satisfaction with the treatment. Dichotomous data will be summarized as risk ratios; continuous data will be given as standard average differences with 95 % confidence intervals. A team of reviewers will assess each citation independently for eligibility and in duplicate it. For eligible studies, the same reviewers will perform data extraction, bias risk assessment, and determination of the overall quality of evidence for each of the outcomes using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) classification system.

DISCUSSION: This is the first study that will evaluate the use of herbal medications used in Brazil for the treatment of pain caused by osteoarthritis. The results could guide prescribers in decision-making in clinical practice, to inform the patients with pain caused by osteoarthritis in relation to effective and safe treatment options and to inform the managers of the public health system which of the plants could actually be financed by the Brazilian government.


Syst Rev. 2016 May;5():86.
PMID: 27209428 [PubMed - indexed for MEDLINE]


Synthesis and biological evaluation of boswellic acid-NSAID hybrid molecules as anti-inflammatory and anti-arthritic agents.
Shenvi S, Kiran KR, Kumar K, Diwakar L, Reddy GC

Methyl esters of the β-boswellic acid (BA) and 11-keto-β-boswellic acid (KBA) obtained from Boswellia serrata resin were subjected to Steglich esterification with the different non-steroidal anti-inflammatory drugs (NSAID) viz., ibuprofen, naproxen, diclophenac and indomethacin. The novel hybrids of methyl boswellate (5-8) and that of methyl 11-keto boswellate (9-12) were evaluated for anti-inflammatory activity by carrageenan-induced rat hind paw edema model and anti-arthritic activity by Complete Freund's Adjuvant (CFA) induced arthritis in Wister albino rat. Significant inhibition on carrageenan-induced paw edema has been observed with 5, 6 and 10 where as in CFA induced rats, hybrids 5, 8, 9 and 12 exhibited pronounced antiarthritic activity. Hybrid molecules 5 and 9 have been found to be more effective in inhibiting in-vivo COX-2 than ibuprofen by itself, thus showing the synergistic effect. Hybrid 5 and 9 tested for in-vitro lipoxygenase and cyclooxygenase-2 (LOX/COX-2) inhibitory activity. The studies revealed that both 5 and 9 inhibited COX-2 relatively better than LOX enzyme.

Eur J Med Chem. 2015 Jun;98():170-8.
PMID: 26010018 [PubMed - indexed for MEDLINE]


Co-analgesic therapy for arthroscopic supraspinatus tendon repair pain using a dietary supplement containing Boswellia serrata and Curcuma longa: a prospective randomized placebo-controlled study.
Merolla G, Dellabiancia F, Ingardia A, Paladini P, Porcellini G

BACKGROUND: The cuff tendon that is most prone to full-thickness rotator cuff tears is the supraspinatus (SSP). Arthroscopic SSP repair ensures good to satisfactory mid- to long-term clinical outcomes. However, the intense postoperative pain reduces rehabilitation compliance and is cause of patient dissatisfaction. Many natural compounds act by inhibiting inflammatory pathways in a similar way to anti-inflammatory drugs

MATERIALS AND METHODS: This was a prospective randomized trial designed to assess the analgesic effect of a dietary supplement (DS) containing Boswellia serrata and Curcuma longa in a population of subjects with full-thickness SSP tendon tear treated by arthroscopy. Three weeks before surgery, patients were randomized to receive Tendisulfur(®) (group T) or a placebo (group P) for 2 months. The primary outcome measure was subjective VAS pain. Secondary outcomes measures were Constant-Murley score simple shoulder test, and patient global assessment (PGA) scores. Patients were assessed immediately at baseline and subsequently at 1, 2, 4, 6, 8, 12, and 24 weeks.

RESULTS: Stratification of pain scores and subscores demonstrated significantly lower overall pain scores in group T versus group P at 1 week (p = 0.0477), and lower but not significantly different scores on week 2 (p = 0.0988); at subsequent time points, differences were not significant (p > 0.05). PGA scores were good in all subjects.

CONCLUSIONS: In conclusion, this study provides objective data on the effect of a DS containing natural substances, added to standard analgesics, on postoperative RC pain. DS alleviated short and partially mid-term pain, while long-term pain was unchanged. This limitation can probably be addressed by a dosage increase over the first 4 weeks and by extending treatment by 1 or 2 months.

Musculoskelet Surg. 2015 Sep;99 Suppl 1():S43-52.
PMID: 25957549 [PubMed - indexed for MEDLINE]


Development and optimisation of 3-Acetyl-11-keto-β-boswellic acid loaded poly-lactic-co-glycolic acid-nanoparticles with enhanced oral bioavailability and in-vivo anti-inflammatory activity in rats.
Bairwa K, Jachak SM

OBJECTIVES: 3-Acetyl-11-keto-β-boswellic acid (AKBA) is a potent anti-inflammatory compound of Boswellia serrata. However, anti-inflammatory activity of AKBA is impeded by poor oral bioavailability due to its poor aqueous solubility. In this context, we aimed to develop poly lactic-co-glycolic acid (PLGA)-based nanoparticle formulation of AKBA (AKBA-NPs) in order to improve its oral bioavailability and in-vivo anti-inflammatory activity in rats.

METHODS: AKBA-NPs were prepared and characterised by analysing particle size and zeta potential using zeta sizer, surface morphology by scanning electron microscopy and transmission electron microscopy, and physical property using differential scanning calorimetry and X-ray diffraction techniques. The optimised nanoparticles were evaluated for in-vitro drug release and oral bioavailability studies, and in-vivo anti-inflammatory activity by carrageenan-induced rat paw oedema method.

KEY FINDINGS: The optimised AKBA-NPs showed the particle size of 179.6 nm with 0.276 polydispersity index and entrapment efficiency of 82.5%. AKBA-NPs showed increased in-vivo anti-inflammatory activity as compared with AKBA. Bioavailability study revealed about six times higher peak plasma concentration of AKBA in AKBA-NPs. Moreover, t1/2 and total area under the curve of AKBA were also enhanced by two and ninefold, respectively, in AKBA-NPs as compared with corresponding AKBA.

CONCLUSIONS: The promising results of improved oral bioavailability and in-vivo anti-inflammatory activity of AKBA suggested the successful nanoparticle formulation of AKBA.

J Pharm Pharmacol. 2015 Sep;67(9):1188-97.
PMID: 25851251 [PubMed - indexed for MEDLINE]


Inhibition of LPS-induced TNF-α and NO production in mouse macrophage and inflammatory response in rat animal models by a novel Ayurvedic formulation, BV-9238.
Dey D, Chaskar S, Athavale N, Chitre D

Rheumatoid arthritis is a chronic crippling disease, where protein-based tumor necrosis factor-alpha (TNF-α) inhibitors show significant relief, but with potentially fatal side effects. A need for a safe, oral, cost-effective small molecule or phyto-pharmaceutical is warranted. BV-9238 is an Ayurvedic poly-herbal formulation containing specialized standardized extracts of Withania somnifera, Boswellia serrata, Zingiber officinale and Curcuma longa. The anti-inflammatory and anti-arthritic effects of BV-9238 were evaluated for inhibition of TNF-α and nitric oxide (NO) production, in lipopolysaccharide-stimulated, RAW 264.7, mouse macrophage cell line. BV-9238 reduced TNF-α and NO production, without any cytotoxic effects. Subsequently, the formulation was tested in adjuvant-induced arthritis (AIA) and carrageenan-induced paw edema (CPE) rat animal models. AIA was induced in rats by injecting Freund's complete adjuvant intra-dermally in the paw, and BV-9238 and controls were administered orally for 21 days. Arthritic scores in AIA study and inflamed paw volume in CPE study were significantly reduced upon treatment with BV-9238. These results suggest that the anti-inflammatory and anti-arthritic effects of BV-9238 are due to its inhibition of TNF-α, and NO, and this formulation shows promise as an alternate therapy for inflammatory disorders where TNF-α and NO play important roles.

Phytother Res. 2014 Oct;28(10):1479-85.
PMID: 24706581 [PubMed - indexed for MEDLINE]


Boswellia serrata extract attenuates inflammatory mediators and oxidative stress in collagen induced arthritis.
Umar S, Umar K, Sarwar AH, Khan A, Ahmad N, Ahmad S, Katiyar CK, Husain SA, Khan HA

Rheumatoid arthritis (RA) is a chronic inflammatory disease which leads to destruction of joints. Current treatment modalities for RA either produce symptomatic relief (NSAIDs) or modify the disease process (DMARDs). Though effective, their use is also limited by their side effects. As a result, the interest in alternative, well tolerated anti-inflammatory remedies has re-emerged. Our aim was to evaluate the antioxidant and antiarthritic activity of Boswellia serrata gum resin extract (BSE) in collagen induced arthritis. Arthritis was induced in male Wistar rats by collagen induced arthritis (CIA) method. BSE was administered at doses of 100 and 200mg/kg body weight once daily for 21 days. The effects of treatment in the rats were assessed by biochemical (articular elastase, MPO, LPO, GSH, catalase, SOD and NO), inflammatory mediators (IL-1β, IL-6, TNF-α, IL-10, IFN-γ and PGE2), and histological studies in joints. BSE was effective in bringing significant changes on all the parameters (articular elastase, MPO, LPO, GSH, catalase, SOD and NO) studied. Oral administration of BSE resulted in significantly reduced levels of inflammatory mediators (IL-1β, IL-6, TNF-α, IFN-γ and PGE2), and increased level of IL-10. The protective effects of BSE against RA were also evident from the decrease in arthritis scoring and bone histology. The abilities to inhibit proinflammatory cytokines and modulation of antioxidant status suggest that the protective effect of Boswellia serrata extract on arthritis in rats might be mediated via the modulation of immune system.

Phytomedicine. 2014 May;21(6):847-56.
PMID: 24667331 [PubMed - indexed for MEDLINE]


Oral and topical boswellic acid attenuates mouse osteoarthritis.
Wang Q, Pan X, Wong HH, Wagner CA, Lahey LJ, Robinson WH, Sokolove J

OBJECTIVE: Boswellic acid is a plant-derived molecule with putative anti-inflammatory effects. This study was performed to determine whether oral or topical administration of boswellic acid can attenuate joint damage in a mouse model of osteoarthritis (OA).

METHODS: Levels of boswellic acid were measured in the blood and synovium of mice treated with oral or topical boswellic acid. OA was generated by surgical destabilization of the medial meniscus (DMM). Therapy with oral or topical boswellic acid was initiated one day after surgery and continued for 12 weeks, when knees were harvested and scored histologically for degree of cartilage loss, osteophyte formation, and synovitis. Microdissected OA synovium was stimulated with IL-1β or lipopolysaccharide (LPS) in the presence or absence of boswellic acid and cytokine production by quantitative polymerase chain reaction (PCR) or multiplex enzyme linked immunoabsorbant assay (ELISA).

RESULTS: Topical treatment resulted in synovial concentrations of boswellic acid 2-6-fold higher than that measured in plasma. Cartilage loss was significantly reduced in mice treated with oral or topical boswellic acid compared with vehicle control (P < 0.01 for both oral and topical therapies). Likewise, treatment with either oral boswellic acid or boswellic acid ointment reduced of synovitis (P = 0.006 and 0.025, respectively) and osteophyte formation (P = 0.009 and 0.030, respectively). In vitro, boswellic acid was able to inhibit IL-1β and TLR4 mediated induction of several inflammatory mediators from OA synovial explant tissue.

CONCLUSIONS: Significant synovial concentration and therapeutic efficacy can be achieved with topical boswellic acid treatment. These findings suggest that boswellic acid has potential as a disease-modifying agent in OA.

Osteoarthritis Cartilage. 2014 Jan;22(1):128-32.
PMID: 24185109 [PubMed - indexed for MEDLINE]


Disease-modifying effect of anthraquinone prodrug with boswellic acid on collagenase-induced osteoarthritis in Wistar rats.
Dhaneshwar S, Dipmala P, Abhay H, Prashant B

Diacerein and its active metabolite rhein are promising disease modifying agents for osteoarthritis (OA). Boswellic acid is an active ingredient of Gugglu; a herbal medicine commonly administered in osteoarthritis. Both of them possess excellent anti-inflammatory and anti-arthritic activities. It was thought interesting to conjugate rhein and boswellic acid into a mutual prodrug (DSRB) and evaluate its efficacy on collagenase-induced osteoarthritis in rats wherein the conjugate, rhein, boswellic acid and their physical mixture, were tested based on various parameters. Oral administration of 3.85 mg of rhein, 12.36 mg of boswellic acid and 15.73 mg of DSRB which would release equimolar amounts of rhein and boswellic acid, exhibited significant restoration in rat body weight as compared to the untreated arthritic control group. Increase in knee diameter (mm), due to edema was observed in group injected with collagenase, which reduced significantly with the treatment of conjugate. The hematological parameters (Hb, RBC, WBC and ESR) and biochemical parameters (CRP, SALP, SGOT and SGPT) in the osteoarthritic rats were significantly brought back to normal values on treatment with conjugate. It also showed better anti-ulcer activity than rhein. Further the histopathological studies revealed significant anti-arthritic activity of conjugate when compared with the arthritic control group. In conclusion, the conjugate at the specified dose level of 15.73 mg/kg, p. o. (BID) showed reduction in knee diameter and it could significantly normalize the hematological and biochemical abnormalities in collagenase-induced osteoarthritis in rats. Further the histopathological studies confirmed the additive anti-arthritic effect of DSRB as compared to plain rhein.

Inflamm Allergy Drug Targets. 2013 Aug;12(4):288-95.
PMID: 23701173 [PubMed - indexed for MEDLINE]


Efficacy of boswellic acid on lysosomal acid hydrolases, lipid peroxidation and anti-oxidant status in gouty arthritic mice.
Sabina EP, Indu H, Rasool M

OBJECTIVE: To evaluate the efficacy of boswellic acid against monosodium urate crystal-induced inflammation in mice.

METHODS: The mice were divided into four experimental groups. Group I served as control; mice in group II were injected with monosodium urate crystal; group III consisted of monosodium urate crystal-induced mice who were treated with boswellic acid (30 mg/kg/b.w.); group IV comprised monosodium urate crystal-induced mice who were treated with indomethacin (3 mg/kg/b.w.). Paw volume and levels/activities of lysosomal enzymes, lipid peroxidation, anti-oxidant status and inflammatory mediator TNF-α were determined in control and monosodium urate crystal-induced mice. In addition, the levels of β-glucuronidase and lactate dehydrogenase were also measured in monosodium urate crystal-incubated polymorphonuclear leucocytes (PMNL) in vitro.

RESULTS: The activities of lysosomal enzymes, lipid peroxidation, and tumour necrosis factor-α levels and paw volume were increased significantly in monosodium urate crystal-induced mice, whereas the activities of antioxidant status were in turn decreased. However, these changes were modulated to near normal levels upon boswellic acid administration. In vitro, boswellic acid reduced the level of β-glucuronidase and lactate dehydrogenase in monosodium urate crystal-incubated PMNL in concentration dependent manner when compared with control cells.

CONCLUSIONS: The results obtained in this study further strengthen the anti-inflammatory/antiarthritic effect of boswellic acid, which was already well established by several investigators.

Asian Pac J Trop Biomed. 2012 Feb;2(2):128-33.
PMID: 23569882 [PubMed - indexed for MEDLINE]


Antiarthritic activity of a standardized, multiherbal, Ayurvedic formulation containing Boswellia serrata: in vitro studies on knee cartilage from osteoarthritis patients.
Sumantran VN, Joshi AK, Boddul S, Koppikar SJ, Warude D, Patwardhan B, Chopra A, Chandwaskar R, Wagh UV

A validated in vitro model of cartilage damage and published data were used showing that this model measures the chondroprotective and antiinflammatory effects of different antiarthritic drugs. In this report, this model was used to evaluate the effects of a new antiarthritic Ayurvedic formulation containing Zingiber officinale root, Tinospora cordifolia stem, Phyllanthus emblica fruit and oleoresin of Boswellia serrata. Glucosamine sulphate was used as a positive control in the study. Aqueous extracts of each drug were tested on explant cultures of knee cartilage obtained from osteoarthritis patients undergoing knee replacement surgery. The new formulation caused a sustained and statistically significant inhibition in the release of glycosaminoglycans and aggrecan by cartilage explants from these patients. This formulation also induced a transient antiinflammatory effect as measured by a reduction in the levels of nitric oxide released by explants. Furthermore, the data strongly suggest that oleoresin of B. serrata plays a crucial role in the chondroprotective and antiinflammatory activity of this formulation. In summary, this report provides the first, direct, in vitro biochemical evidence of anti-arthritic activity a new Ayurvedic formulation. This formulation significantly reduced damage of articular knee cartilage from chronic osteoarthritis patients.

Phytother Res. 2011 Sep;25(9):1375-80.
PMID: 25363757 [PubMed - indexed for MEDLINE]


3-Acetyl-11-keto-beta-boswellic acid loaded-polymeric nanomicelles for topical anti-inflammatory and anti-arthritic activity.
Goel A, Ahmad FJ, Singh RM, Singh GN

OBJECTIVES: The aim of this study was to develop 3-acetyl-11-keto-beta-boswellic acid (AKBA)-loaded polymeric nanomicelles for topical anti-inflammatory and anti-arthritic activity.

METHODS: Polymeric nanomicelles of AKBA were developed by a radical polymerization method using N-isopropylacrylamide, vinylpyrrolidone and acrylic acid. The polymeric nanomicelles obtained were characterized by Fourier transform infrared (FTIR), transmission electron microscopy (TEM) and dynamic light scattering (DLS). In-vitro and in-vivo evaluations of AKBA polymeric nanomicelles gel were carried out for enhanced skin permeability and anti-inflammatory and anti-arthritic activity.

KEY FINDINGS: TEM and DLS results demonstrated that polymeric nanomicelles were spherical with a mean diameter approximately 45 nm. FTIR data indicated a weak interaction between polymer and AKBA in the encapsulated system. The release of drug in aqueous buffer (pH 7.4) from the polymeric nanomicelles was 23 and 55% after 2 and 8 h, respectively, indicating sustained release. In-vitro skin permeation studies through excised abdominal skin indicated a threefold increase in skin permeability compared with AKBA gel containing the same amount of AKBA as the AKBA polymeric nanomicelles gel. The AKBA polymeric nanomicelle gel showed significantly enhanced anti-inflammatory and anti-arthritic activity compared with the AKBA gel.

CONCLUSIONS: This study suggested that AKBA polymeric nanomicelle gel significantly enhanced skin permeability, and anti-inflammatory and anti-arthritic activity.

J Pharm Pharmacol. 2010 Feb;62(2):273-8.
PMID: 20487208 [PubMed - indexed for MEDLINE]


Boswellia frereana (frankincense) suppresses cytokine-induced matrix metalloproteinase expression and production of pro-inflammatory molecules in articular cartilage.
Blain EJ, Ali AY, Duance VC

The aim of this study was to assess the anti-inflammatory efficacy of Boswellia frereana extracts in an in vitro model of cartilage degeneration and determine its potential as a therapy for treating osteoarthritis. Cartilage degradation was induced in vitro by treating explants with 5 ng/ml interleukin1alpha (IL-1alpha) and 10 ng/ml oncostatin M (OSM) over a 28-day period, in the presence or absence of 100 microg/ml B. frereana. Treatment of IL-1alpha/OSM stimulated cartilage explants with B. frereana inhibited the breakdown of the collagenous matrix. B. frereana reduced MMP9 and MMP13 mRNA levels, inhibited MMP9 expression and activation, and significantly reduced the production of nitrite (stable end product of nitric oxide), prostaglandin E2 and cycloxygenase-2. Epi-lupeol was identified as the principal constituent of B. frereana. This is the first report on the novel anti-inflammatory properties of Boswellia frereana in an in vitro model of cartilage degradation. We have demonstrated that B. frereana prevents collagen degradation, and inhibits the production of pro-inflammatory mediators and MMPs. Due to its efficacy we propose that B. frereana should be examined further as a potential therapeutic agent for treating inflammatory symptoms associated with arthritis.

Phytother Res. 2010 Jun;24(6):905-12.
PMID: 19943332 [PubMed - indexed for MEDLINE]


Role of Sandhika: a polyherbal formulation on MC3T3-E1 osteoblast-like cells.
Tripathi YB, Tripathi P, Korlagunta K, Chai SC, Smith BJ, Arjmandi BH

Sandhika is a polyherbal formulation, (water soluble fraction of Commiphora mukul, Boswellia serrata, Semecarpus anacardium and Strychnos nux vomica), which has been in clinical use in India for last 20 years. Its modified formulation BHUx has shown specific inhibition of cyclooxygenase (COX)-2 and lipoxygenase (LOX)-15 and has prevented diet-induced atherosclerosis in rabbits. In order to explore the possibility of the use of Sandhika for the management of osteoporosis, we have examined its influence on MC3T3-E1 osteoblast-like cells in presence of lipopolysaccharide (1 microg/ml) in terms of calcium nodule formation and alkaline phosphatase activity. MC3T3-E1 osteoblast-like cells (80% confluence in 6-well plates) were treated with water extract of Sandhika, for 10 days, in the concentration range of 0.5 to 16 mg/ml final concentration, in presence of LPS. Media was changed on every third day and culture supernatant was collected after every change to assess the alkaline phosphatase activity and on the tenth day, cells were washed and stained with "Alizarin S" for visualization of calcium nodules by using Meta Morph software (Universal Imaging, Downingtown, PA). The results showed significant enhancement in calcium nodule formation in the dose dependent manner up to 2 mg/ml, followed by gradual decrease at higher concentrations. This change was accompanied with the increase in the alkaline phosphatase activity in these plates, indicating a potential anabolic effect of this polyherbal formulation on osteoblast-like cells under inflammatory conditions induced by LPS.

Inflammation. 2008 Feb;31(1):1-8.
PMID: 17687634 [PubMed - indexed for MEDLINE]


Boswellic acids and glucosamine show synergistic effect in preclinical anti-inflammatory study in rats.
Singh S, Khajuria A, Taneja SC, Khajuria RK, Singh J, Qazi GN

The present study revealed the synergistic effect of boswellic acid mixture (BA) and glucosamine for anti-inflammatory and anti-arthritic activities in rats. Two studies were conducted, that is, acute anti-inflammatory by carrageenan edema and chronic anti-arthritic by Mycobacterium-induced developing arthritis. Five groups of animals were included in each of the study: the vehicle control, positive control (ibuprofen 100mg/kg), boswellic acids (250 mg/kg), glucosamine (250 mg/kg) and a combination of boswellic acids (125 mg/kg) and glucosamine (125 mg/kg). BA when administered at 250 mg/kg in rats, carrageenan-induced paw edema and Mycobacterium-induced developing arthritis were significantly inhibited. In comparison to boswellic acids, glucosamine when administered at 250 mg/kg showed a mild effect in carrageenan-induced edema and moderate inhibition of paw swelling against developing arthritis. Although the combination of boswellic acids and glucosamine did not affect the acute inflammation to a greater extent yet a significant anti-arthritic activity was observed in rats. In conclusion, a synergistic effect was observed in chronic inflammatory conditions when two chemical entities were administered in combination in preclinical study.

Bioorg Med Chem Lett. 2007 Jul;17(13):3706-11.
PMID: 17481895 [PubMed - indexed for MEDLINE]


Natural products as a gold mine for arthritis treatment.
Khanna D, Sethi G, Ahn KS, Pandey MK, Kunnumakkara AB, Sung B, Aggarwal A, Aggarwal BB

Arthritis, an inflammation of the joints, is usually a chronic disease that results from dysregulation of pro-inflammatory cytokines (e.g. tumour necrosis factor and interleukin-1beta) and pro-inflammatory enzymes that mediate the production of prostaglandins (e.g. cyclooxygenase-2) and leukotrienes (e.g. lipooxygenase), together with the expression of adhesion molecules and matrix metalloproteinases, and hyperproliferation of synovial fibroblasts. All of these factors are regulated by the activation of the transcription factor nuclear factor-kappaB. Thus, agents that suppress the expression of tumour necrosis factor-alpha, interleukin-1beta, cyclooxygenase-2, lipooxygenase, matrix metalloproteinases or adhesion molecules, or suppress the activation of NF-kappaB, all have potential for the treatment of arthritis. Numerous agents derived from plants can suppress these cell signaling intermediates, including curcumin (from turmeric), resveratrol (red grapes, cranberries and peanuts), tea polyphenols, genistein (soy), quercetin (onions), silymarin (artichoke), guggulsterone (guggul), boswellic acid (salai guggul) and withanolides (ashwagandha). Indeed, several preclinical and clinical studies suggest that these agents have potential for arthritis treatment. Although gold compounds are no longer employed for the treatment of arthritis, the large number of inexpensive natural products that can modulate inflammatory responses, but lack side effects, constitute 'goldmines' for the treatment of arthritis.

Curr Opin Pharmacol. 2007 Jun;7(3):344-51.
PMID: 17475558 [PubMed - indexed for MEDLINE]


Effects of an acetone extract of Boswellia carterii Birdw. (Burseraceae) gum resin on adjuvant-induced arthritis in lewis rats.
Fan AY, Lao L, Zhang RX, Zhou AN, Wang LB, Moudgil KD, Lee DY, Ma ZZ, Zhang WY, Berman BM

Ruxiang (Gummi olibanum), the dried gum resin of Boswellia carterii (BC), has been used in traditional Chinese medicine to alleviate pain and inflammation for thousands of years. In this random, blinded study, the anti-arthritic effects of a BC extract were observed and compared to vehicle control in a Lewis rat adjuvant arthritis model (n=8/group). Arthritis was induced by injecting CFA subcutaneously into the base of the tail, and the extract was administered orally (i.g.) for 10 consecutive days beginning on day 16 after the injection. Arthritic scores, paw edema, and the local tissue pro-inflammatory cytokines tumor necrosis factor alpha (TNF-alpha) and interleukin-1 beta (IL-1beta) were assessed. Toxicity and adverse effects of the extract were evaluated. At 0.90 g/kg per day, BC significantly decreased arthritic scores between days 20 and 25 (p<0.05) and reduced paw edema on days 18, 20 and 22 compared to control (p<0.05). It also significantly suppressed local tissue TNF-alpha and IL-1beta (p<0.05). No major adverse effects were observed in animals during the repeated-dose treatment profile although mild fur discoloration was noted. The data show that BC extract has significant anti-arthritic and anti-inflammation effects and suggest that these effects may be mediated via the suppression of pro-inflammatory cytokines.

J Ethnopharmacol. 2005 Oct;101(1-3):104-9.
PMID: 15970410 [PubMed - indexed for MEDLINE]


Effects of an acetone extract of Boswellia carterii Birdw. (Burseraceae) gum resin on rats with persistent inflammation.
Fan AY, Lao L, Zhang RX, Wang LB, Lee DY, Ma ZZ, Zhang WY, Berman B

OBJECTIVE: Ruxiang, or Gummi olibanum, an herbal medicine derived from the gum resin of Boswellia carterii Birdw. (BC) of the family Burseraceae, has been used traditionally in China to alleviate pain and reduce inflammation. The present study is an investigation of the effects of a BC extract on persistent hyperalgesia and edema in rats with peripheral inflammation.

DESIGN: In this randomized, blinded study, the antihyperalgesic and antiedema effects of 3 dosages of BC were compared to a vehicle control. Inflammation was induced in rats by injecting complete Freund's adjuvant (CFA) into one hind paw. A single oral dose of the BC extract was administered daily for 7 days, beginning one day before CFA. Hyperalgesia was assessed using a paw withdrawal latency (PWL) test pre-CFA and 2 hours, 5 hours, 1 day, and 5 days post-CFA. Edema was determined by measuring paw thickness at the same time points. Spinal Fos protein expression was analyzed 2 hours post-CFA. Adverse effects of the extract were monitored by observing the animals closely for unusual behavioral changes.

RESULTS: Compared to control, a dosage of 0.45 g/kg BC significantly lengthened PWL and reduced paw edema on day 5 post-CFA. At 0.90 g/kg, BC significantly lengthened PWL at 5 hours, 1 day, and 5 days, and reduced paw edema at 2 hours, 5 hours, 1 day, and 5 days. This dosage also significantly suppressed spinal Fos expression in the medial half of laminae I-II. At 1.80 g/kg, BC significantly lengthened PWL and reduced paw edema at all time points. No noticeable adverse effects were observed in animals given the lower dosages of BC, but adverse effects in some animals were observed at 1.80 g/kg per day. In the acute toxicity study, the maximal single dose of 2.50 g/kg produced no adverse effects in the treated rats during the 14 days of observation.

CONCLUSIONS: The data suggest that BC produces significant antihyperalgesia and anti-inflammation effects and that the antihyperalgesia may be mediated by suppressed inflammation-induced Fos expression in the spinal dorsal horn neurons.

J Altern Complement Med. 2005 Apr;11(2):323-31.
PMID: 15865500 [PubMed - indexed for MEDLINE]


Dietary support with Boswellia resin in canine inflammatory joint and spinal disease.
Reichling J, Schmökel H, Fitzi J, Bucher S, Saller R

An open multi-centre veterinary clinical trial, comparing conditions before and after treatment with a herbal dietary supplement consisting of a natural resin extract of Boswellia serrata, was conducted by 10 practicing veterinarians in Switzerland. This traditional plant-based supplement is known for its anti-rheumatic and anti-inflammatory properties. 29 dogs with manifestations of chronic joint and spinal disease were enrolled. Osteoarthritis and degenerative conditions were confirmed radiologically in 25 of 29 cases. The resin extract (BSB108, product of Bogar AG) was administered with the regular food at a dose of 400 mg/10 kg body weight once daily for 6 weeks. Already after two weeks of treatment, an overall efficacy of the dietary supplement was evident in 71% of 24 eligible dogs. A statistically significant reduction of severity and resolution of typical clinical signs in individual animals, such as intermittent lameness, local pain and stiff gait, were reported after 6 weeks. Effects of external factors that aggravate lameness, such as "lameness when moving" and "lameness after a long rest" diminished gradually. In 5 dogs, reversible brief episodes of diarrhea and flatulence occurred, but only once was a relationship to the study preparation suspected. Because quality and stability of the resin extract were ensured, these data suggest that a standardized preparation can be recommended as a herbal dietary supplement providing symptomatic support in canine osteoarthritic disease.

Schweiz Arch Tierheilkd. 2004 Feb;146(2):71-9.
PMID: 14994484 [PubMed - indexed for MEDLINE]


Boswellic acids and protease activities.
Rall B, Ammon HP, Safayhi H

The involvement of human leukocyte elastase (HLE) in several inflammatory processes and the reported inhibitory effect of ursolic acid on HLE has prompted the authors to start investigation on the effects of acetyl-11-keto-β-boswellic acid (AKBA) on serine proteinases including HLE.

Phytomedicine. 1996 May;3(1):75-6.
PMID: 23194866 [PubMed - as supplied by publisher]


Anti-inflammatory activity of resins from some species of the plant family Burseraceae.
Duwiejua M, Zeitlin IJ, Waterman PG, Chapman J, Mhango GJ, Provan GJ

The anti-inflammatory activities of extracts from the resins of four species of the plant family Burseraceae, Boswellia dalzielli, Boswellia carteri (gum olibanum), Commiphora mukul, and Commiphora incisa, were studied. The aqueous extracts of the resins of B. dalzielli, C. incisa, and C. mukul significantly inhibited both the maximal edema response and the total edema response during 6 h of carrageenan-induced rat paw edema. The octanordammarane triterpenes, mansumbinone and mansumbinoic acid, isolated from the resin of C. incisa, were separated and tested. Administered prophylactically, mansumbinone proved to be more than 20 times less potent than indomethacin and prednisolone in inhibiting carrageenan-induced rat paw edema. However, the molar potency of mansumbinoic acid was within one order of magnitude of those of indomethacin and prednisolone. The anti-inflammatory action of the acid on the carrageenan-induced edema was dose-related between 1.3 x 10(-5) and 2.5 x 10(-4) mol kg-1 when given before the inflammatory stimulus. The acid was able to reverse an established carrageenan-induced inflammatory response when administered 2 h after induction. Daily administration of mansumbinoic acid at a single dose level (1.5 x 10(-4) mol kg-1) significantly reduced joint swelling in adjuvant arthritis in rats. The results indicated that this compound is worthy of further investigation as an anti-inflammatory drug.

Planta Med. 1993 Feb;59(1):12-6.
PMID: 8441773 [PubMed - indexed for MEDLINE]


A sensitive and relevant model for evaluating anti-inflammatory activity-papaya latex-induced rat paw inflammation.
Gupta OP, Sharma N, Chand D

A new model employing latex of papaya as an inflammagen has been developed for testing anti-inflammatory activity. The latex (exudate) was harvested from the unripe papaya fruit, which had been dried under vacuum. The latex was then suspended in 0.05 M sodium acetate buffer. This suspension when injected in rat hind paw produced concentration-dependent inflammation. Of the 0.25% of this suspension, 0.1 ml was found ideal for evaluating anti-inflammatory activity of test drugs. This concentration produced 70%-100% inflammation lasting for about 5 hr with a maximum effect at h 3. The test drugs employed were prednisolone, aspirin, indomethacin, phenylbutazone, ibuprofen, piroxicam, chloroquine, levamisole, and a mixture of boswellic acids. For comparison, these drugs were also tested against carrageenan-induced inflammation. All the test drugs--steroidal, aspirin, and non-aspirin-like--showed anti-inflammatory activity against latex-induced inflammation. The activity of chloroquine, levamisole, and boswellic acids was significantly more against latex as compared with that of the carrageenan model. The inflammation caused by latex may be attributed to both its hydrolytic enzymes--papain and chymopapain--and glutathione, the activator of these enzymes. These enzymes seem to act like lysosomal enzymes that are released in inflammatory disease processes which mediate inflammation by stimulating the synthesis of prostaglandins. The papaya latex-induced inflammation model appears to be a sensitive, broad-based, and relevant one likely to prove useful for discovering new and effective drugs against inflammation and rheumatoid arthritis.

J Pharmacol Toxicol Methods. 1992 Aug;28(1):15-9.
PMID: 1392054 [PubMed - indexed for MEDLINE]


Studies on the metabolism of glycosaminoglycans under the influence of new herbal anti-inflammatory agents.
Reddy GK, Chandrakasan G, Dhar SC

The in vivo effect of an herbal based, non-steroidal anti-inflammatory product, salai guggal, prepared from the gum resin exudate of Boswellia serrata and its active principle "boswellic acids" on glycosaminoglycan metabolism has been studied in male albino rats. The biosynthesis of sulfated glycosaminoglycans, as evaluated by the uptake of [35S]sulfate, and the content of glycosaminoglycans were measured in specimens of skin, liver, kidney and spleen. Statistical analysis of the data obtained with respect to the boswellic acids and salai guggal were compared with those of ketoprofen. A significant reduction in glycosaminoglycan biosynthesis was observed in rats treated with all of the drugs. Glycosaminoglycan content was found to be decreased in the ketoprofen-treated group, whereas that of the boswellic acids or salai guggal treated groups remained unaltered. The catabolism of glycosaminoglycans was followed by estimating the activities of lysosomal glycohydrolases, namely beta-glucuronidase, beta-N-acetylglucosaminidase, cathepsin B1, cathepsin B2 and cathepsin D, in tissues and by estimating the urinary excretion and hexosamine and uronic acid. The degradation of glycosaminoglycans was found to be reduced markedly in all drug-treated animals as compared to controls. The potential significance of boswellic acids and salai guggal was discussed in the light of changes in the metabolism of glycosaminoglycans.

Biochem Pharmacol. 1989 Oct;38(20):3527-34.
PMID: 2818645 [PubMed - indexed for MEDLINE]


Anti-arthritic activity of boswellic acids in bovine serum albumin (BSA)-induced arthritis.
Sharma ML, Bani S, Singh GB

The effect of boswellic acids on bovine serum albumin (BSA)-induced arthritis in rabbits was studied. Oral administration of boswellic acids (25, 50 and 100 mg/kg/day) significantly reduced the population of leucocytes in a BSA-injected knee and changed the electrophoretic pattern of the synovial fluid proteins. The local injection of boswellic acids (5, 10 and 20 mg) into the knee 15 min prior to BSA challenge also significantly reduced the infiltration of leucocytes into the knee joint, reduced the infiltration of leucocytes into the pleural cavity and inhibited the migration of PMN in vitro. The leucocyte-inhibitory activity of boswellic acids was not due to its cytotoxic effect. The boswellic acids did not show any detergent or surfactant properties.

Int J Immunopharmacol. 1989;11(6):647-52.
PMID: 2807636 [PubMed - indexed for MEDLINE]


Effect of a new non-steroidal anti-inflammatory agent on lysosomal stability in adjuvant induced arthritis.
Reddy GK, Dhar SC

The effect of new non-steroidal anti-inflammatory agents on lysosomal stability was studied by determining the activity of beta-glucuronidase, a typical lysosomal enzyme, in various sub-cellular fractions and its release from the lysosome-rich fraction. Adjuvant arthritic animals showed a significant increase in the beta-glucuronidase activity in sub-cellular fractions. The increased rate of the release of beta-glucuronidase from lysosome-rich fraction clearly suggested that arthritic syndrome caused decreased stability of the lysosomes. Administration of boswellic acids or salai-guggal to arthritic animals was found to increase the lysosomal stability by inhibiting the rate of release from lysosome-rich fraction and reducing beta-glucuronidase activity in various sub-cellular fractions. Of the two anti-inflammatory agents tested, salai-guggal was found to afford more therapeutic value than boswellic acids.

Ital J Biochem. 1987;36(4):205-17.
PMID: 3429205 [PubMed - indexed for MEDLINE]


Pharmacology of an extract of salai guggal ex-Boswellia serrata, a new non-steroidal anti-inflammatory agent.
Singh GB, Atal CK

Pharmacological evaluation of alcoholic extract of salai guggal (AESG) has been carried out in experimental animals. AESG displayed marked anti-inflammatory activity in carrageenan induced oedema in rats and mice and dextran oedema in rats. It was equally effective in adrenalectomised rats. In formaldehyde and adjuvant arthritis, AESG produced prominent anti-arthritic activity but no significant effect was observed in cotton pellet-induced granuloma test. It inhibited inflammation induced increase in serum transaminase levels and leucocyte counts but lacked any analgesic or anti-pyretic effects. The gestation period or parturition time in pregnant rats or onset time of castor oil-induced diarrhoea was unaffected by AESG and no significant effect was seen on cardiovascular, respiratory and central nervous system functions. No ulcerogenic effects were found in the rat stomach. The oral and intraperitoneal LD50 was greater than 2 g/Kg in mice and rats.

Agents Actions. 1986 Jun;18(3-4):407-12.
PMID: 3751752 [PubMed - indexed for MEDLINE]