Xylopic Acid Research Articles

Kaurane Diterpenoids from Xylopia aethiopica Inhibits Alpha-Amylase and Alpha-Glucosidase: A Combined in Silico and in Vitro Approach

Background/Objectives Diabetes mellitus is among the leading cause of death worldwide. This study evaluated the alpha amylase and alpha glucosidase inhibitory properties of kaurane diterpenoids (kauran-13-ol (D1), xylopic acid (D2) and kauran-16α-ol (D3)) from the fruit of X. aethiopica. Methodology In vitro alpha amylase and alpha glucosidase inhibitory assays were performed on D1, D2 and D3 (0.03125, 0.0625, 0.125, 0.25, 0.5, 1.0 and 2.0 mg/mL) and acarbose (0.003125, 0.00625, 0.0125, 0.025, 0.05 and 0.1 mg/mL) followed by molecular docking studies, molecular dynamics simulation and MMPBSA to examine their mode of interaction, binding affinity, binding mode and binding energy established with the enzymes. Also, ADMET properties of the studied diterpenes were examined to explain their druggability potential. Result The in vitro alpha-amylase and alpha-glucosidase studies identified D3 as the most promising inhibitor among the kaurane diterpenes with lower IC50 values of 0.65 and 0.17 mg/mL. The molecular docking analysis showed that D1, D2 and D3 established vital hydrogen bond, hydrophobic and pi-interaction with the receptors, while the molecular dynamics simulation showed the kaurane diterpenes exhibited good stability at the enzymes’ binding pocket. The MMPBSA binding energy values showed the diterpenes had good binding energies that corroborated that of molecular docking. The ADMET properties identified the compounds as promising drug candidate. Conclusion The study demonstrated that the kaurane diterpenoids have good inhibitory effect on the diabetes enzymes. Further comprehensive investigation into the antidiabetic properties of the diterpenes may lead to the identification of new hit molecule.

Investigation of Herb-Drug Interactions between Xylopia aethiopica, Its Principal Constituent Xylopic Acid, and Antidepressants.

Depression affects an estimated 350 million people worldwide and is implicated in up to 60% of suicides. Only about 60-70% of patients respond to antidepressant therapy. One of the factors causing patients to not attain therapeutic goals is herb-drug interactions. To investigate any potential herb-drug interaction that might exist between Xylopia aethiopica extract (XAE) or xylopic acid (XA) and selected conventional antidepressants (imipramine, fluoxetine, and venlafaxine) in mice. Dried, powdered fruits of Xylopia aethiopica were cold macerated in 70% ethanol to obtain XAE. XA was isolated by cold macerating dried fruits of Xylopia aethiopica in petroleum ether, crystallising impure XA with ethyl acetate, and purifying XA crystals with 96% ethanol. Pharmacodynamic interaction was assessed via isobolographic analysis of tail suspension tests of the agents individually and in their respective combinations. Pharmacokinetic interaction was assessed by monitoring the effect of coadministrations on the plasma concentration of antidepressants and xylopic acid via HPLC analysis. XAE and XA in mice showed significant antidepressant-like activity in the tail suspension test. With interaction indices less than one, synergism of antidepressant effect was observed in the Xylopia aethiopica extract/fluoxetine (γXAE/FL = 0.502), Xylopia aethiopica extract/imipramine (γXAE/IP = 0.322), Xylopia aethiopica extract/venlafaxine (γXAE/VL = 0.601), xylopic acid/imipramine (γXA/IP = 0.556), xylopic acid/venlafaxine (γXA/VL = 0.451), and xylopic acid/fluoxetine (γXA/FL = 0.298) combinations, which may be potentially due to elevation of serotonergic neurotransmission via varying mechanisms. The AUC of imipramine (AUCIP = 1966 ± 58.98 µg/ml.h) was significantly (P < 0.0001) reduced by Xylopia aethiopica extract (AUCIP = 1228 ± 67.40 µg/ml.h) and xylopic acid (AUCIP = 1250 ± 55.95 µg/ml.h), while the AUC of xylopic acid (AUCXA = 968.10 ± 61.22 µg/ml.h) was significantly (P < 0.0001) reduced by venlafaxine (AUCXA = 285.90 ± 51.92 µg/ml.h) and fluoxetine (AUCXA = 510.60 ± 44.74 µg/ml.h), possibly due to the effect of interfering agents on gastric emptying hence reducing oral absorption. Xylopia aethiopica extract and xylopic acid interacted synergistically with imipramine, fluoxetine, and venlafaxine and reduced the systemic circulation of imipramine.

Synergistic antidepressant-like effect of xylopic acid co-administered with selected antidepressants

BackgroundXylopic acid (XA), a kaurene diterpene from the dried fruits of Xylopia aethiopica, has anxiolytic- and antidepressant-like activity in mice and zebrafish. We aimed to assess the potential synergistic antidepressant-like effects of XA when combined with selected antidepressants in the mouse forced-swim test. Materials and methodsThe antidepressant-like effect of xylopic acid (XA) (10, 30, 100 mgkg−1), fluoxetine (Flx) (3, 10, 30 mgkg−1), sertraline (Sert) (3, 10, 30 mgkg−1), imipramine (Imi) (10, 30, 100 mgkg-1) and ketamine (Ket) (0.1, 0.3, 1.0 mgkg−1), was evaluated in forced swim test. The dose (ED50) that achieved a 50% reduction in immobility time was determined from the respective log-dose response curves. XA and the selected antidepressants were co-administered in fixed-dose ratio combinations (1/2:1/2, 1/4:1/4, 1/8:1/8) of the ED50 to identify the experimental ED50 (ED50mix). The theoretical ED50(ED50add), of all combinations was determined using isobolograms and compared with the ED50mix to identify the nature of the interaction. The effect of dose combinations on general locomotor activity was assessed in the open-field test. ResultsThe interaction index (γ) for the following XA combinations, XA/Flx, XA/Sert, XA/Imi and XA/Ket were 0.42, 0.41, 0.31 and 0.34. An independent sample t-test revealed that the experimental ED50 (ED50mix) was significantly lower than the theoretical ED50 (ED50add) in all combinations of XA, indicative of a synergistic antidepressant-like effect. However, combinations of XA with ketamine significantly reduced general locomotor activity at all dose combinations. ConclusionThe co-administration of xylopic acid and fluoxetine, imipramine, sertraline and ketamine produces a synergistic antidepressant-like effect in mice.

Isolation, characterization and modulatory potentials of β-stigmasterol, ergosterol and xylopic acid from Anchomanes difformis on mitochondrial permeability transition pore in vitro

ObjectiveSecondary metabolites and polyphenolic compounds from medicinal plants have been demonstrated to have multiple biological functions with promising research and development prospects. This study examined the effect of β-stigmasterol (with ergosterol) and xylopic acid isolated from Anchomanes difformis on liver mitochondrial permeability transition pore (mPTP). MethodsThe compounds were isolated by vacuum liquid chromatography. Mitochondrial swelling was assessed as changes in absorbance under succinate-energized conditions. Results1H and 13C NMR spectroscopic elucidation of the isolates affirmed the presence of β-stigmasterol with ergosterol (1:0.3) and xylopic acid. The isolates reversed the increase in lipid peroxidation and inhibited the opening of mitochondrial permeability transition pores caused by calcium and glucose. Pharmacological inhibition of mPTP offers a promising therapeutic target for the treatment of mitochondrial-associated disorders. ConclusionReduction in the activity of calcium ATPase and the expression of Caspase-3 and −9 were observed, suggesting that they could play a role in protecting physicochemical properties of membrane bilayers from free radical-induced severe cellular damage and be useful in the management of diseases where much apoptosis occurs.

Forced Degradation Studies, Elucidation of Degradation Pathways and Degradation Kinetics of Xylopic Acid via LC and LC-MS/MS Analyses

Stability studies of active pharmaceutical ingredients (APIs) remain an essential quality requirement of the pharmaceutical industry. Stability data of an API could guide in the choice of its processing technique, packaging method and storage conditions. Here, we sought to determine the stability or otherwise of xylopic acid (XA) under various stress conditions as stipulated by the International Conference on Harmonization (ICH). XA is a diterpene kaurene isolate of the African spice, Xylopia aethiopica (Annonaceae) that is credited with diverse biological activities. XA was subjected to various stress conditions (hydrolytic, oxidative, photolytic and thermal) and its degradation products characterized. Seven degradation products were identified and tentatively characterized by LC-MS/MS analysis. The probable degradation pathways for the seven degradation products were then predicted. Using a simple and validated UHPLC-DAD method, the degradation kinetics of XA under the different stress conditions were comprehensively assessed. The degradation of XA under all the stress conditions followed the first order reaction kinetics. XA was found to be less stable in strongly acidic or strongly basic solutions as well as in an oxidizing agent (hydrogen peroxide). The stability of XA was also found to be pH- and temperature-dependent. Its stability was however not affected by UV-light irradiation.

Pharmacokinetics and in vitro liver microsomal enzyme metabolism of Xylopic acid

Xylopic acid (XA) is a bioactive diterpene kaurene isolate of the Guinea pepper fruit, Xylopia aethiopica (Annonaceae) with numerous well-established biological effects. In this study, we aimed to fill certain scientific voids in terms of the scientific literature on XA, specifically, its pharmacokinetic (PK) parameters and in vitro liver microsomal enzyme metabolism. A new LC–MS/MS method was developed and validated for the determination of the plasma concentration–time profile of XA. The method was found to be accurate, precise, selective and repeatable with lowest limit of quantification (LLOQ) of 10 ng/mL and run time of 15 min. The maximum plasma concentration (Cmax), time at which maximum plasma concentration was attained (Tmax), half-life (t1/2), clearance (CL) and mean residence time (MRT) of XA were 167.03 ± 6.18 ng/mL; 10 h; 13.03 ± 7.33 h; 0.04 ± 0.01 mL/h/kg and 23.83 ± 11.02 h respectively. Six metabolites (M1–M6) were tentatively identified after XA was subjected to in vitro liver microsomal enzyme metabolism. The metabolites were the products of methylation (M1), glucuronidation (M2), deacetylation (M3), glucosylation (M4), hydroxylation and glutamic acid addition (M5) and glutathionylation (M6). The outcome of this study provides useful insights that could guide further research on XA.

In vitro efficacy of isoflavonoids and terpenes against Leishmania (Leishmania) infantum and L. amazonensis

The main form of control of leishmaniasis is the treatment, however various side effects and poor efficacy are associated with presently available drugs. The investigation of bioactive natural products for new antileishmanial drugs is a valid approach. The present study reports the in vitro efficacy of natural isoflavonoids and terpenes against Leishmania infantum and L. amazonensis and their cytotoxicity against HepG2 cells. L. infantum and L. amazonensis promastigotes were exposed to the terpenes kaurenoic acid, xylopic acid, and (−)-α-bisabolol and to the isoflavonoids (−)-duartin and (3R)-claussequinone for antileishmanial activity and to cytotoxicity to HepG2 cells. The most effective substance against both L. infantum and L. amazonensis species was (3R)-claussequinone (IC50 = 3.21 μg/mL and 2.47 μg/mL, respectively) that disclosed low cytotoxicity against HepG2 cells (CC50 = 387.79 μg/mL). The efficacy of (3R)-claussequinone against intracellular amastigotes of L. infantum and the externalization of phosphatidylserine in promastigotes of this isoflavanoid were investigated by infection of Raw 264.7 macrophages and marking with Annexin V-FITC and propidium Iodide for flow cytometry analysis. The results for amastigotes showed that (3R)-claussequinone was able to reduce the rate of infection with IC50 = 4.61 μg/mL and did not alter the externalization of phosphatidylserine. In conclusion it is presently reported, for the first time, the striking antileishmanial activity of (3R)-claussequinone against L. infantum and L. amazonensis associated to low cytotoxicity. Furthermore, these results suggest that (3R)-claussequinone is a new hit aiming to develop new therapeutic alternatives.

Anti‐inflammatory activity of xylopic acid may be attributed to the modulation of Nrf2 and NF‐kB activities

For a long time, non‐resolving inflammation has been the bane of our existence [1]. Currently, there are varying treatment and management options for inflammatory conditions. However, the search for newer, alternative management options continues unabated. A key focus of our research is the identification of lead compounds and therapeutically viable compounds from plants. One such compound isolated from Xylopia aethiopica is the kaurene diterpene, xylopic acid (XA). The anti‐inflammatory potential of XA has been established from our previous studies [2, 3]. This current work sets out to identify potential molecular targets of xylopic acid in in vitro and cell‐based assays. The selection of these investigated targets was based on the proven bioactivity of xylopic acid as a potential anti‐inflammatory agent and on predictions from the Spider target prediction webtool. Reporter gene assays were used to test for altered NF‐kB and Nrf2 activities in transfected HEK or CHO cells, respectively. XA at 30 µM significantly (p&lt;0.001) inhibited the NF‐kB‐dependent reporter gene expression (Fig. 1) and enhanced activation of Nrf2 in a concentration‐dependent manner when compared to the control (Fig. 2). Our findings suggest that the anti‐inflammatory mechanism of XA entails the inhibitory effect on NF‐kB and an increased activity of Nrf2.

Extract of Xylopia aethiopica and its kaurene diterpene, xylopic acid, improve learning and memory in mice

BackgroundCognitive dysfunction, presenting as learning and memory impairment, is a common manifestation in many chronic diseases of the nervous system. Some of these diseases include depression, epilepsy, and Alzheimer’s disease. To date, few drugs or medicinal products have shown ability to improve learning and memory deficits. Neuroprotection is one of the mechanisms by which memory could be improved. The extract of Xylopia aethiopica and its kaurene derivative, xylopic acid, have previously demonstrated neuroprotective effects in animal models. The aim of the present study was to investigate the effect of an extract of Xylopia aethiopica fruit and xylopic acid, on learning and memory using murine models.Materials and methodsUnripe Xylopia aethiopica fruits were collected, dried, and extracted using 70% v/v ethanol. Xylopic acid was isolated from the fruits using petroleum ether, concentrated with ethyl acetate and then recrystallized with petroleum ether before purifying with ethanol (96%v/v). Institute of Cancer Research (ICR) mice received oral doses of the extract of Xylopia aethiopica (XAE; 30, 100 and 300 mg/kg), xylopic acid (XA; 30, 100 and mg/kg), citicoline (300 mg/kg), piracetam (300 mg/kg) or ketamine (30 mg/kg) and saline (vehicle). The animals were then taken through the Morris water maze test (MWM), spontaneous alternation Y-maze test (Y-maze), and novel object recognition test (NOR), to assess learning and memory.ResultsIn the NOR test, XAE (30, 100 and 300 mg/kg) and XA (30, 100 and 300 mg/kg) increased the percentage exploration and recognition index (p = 0.0005 and p < 0.0001, respectively) when compared to both vehicle and ketamine groups. Similarly, doses of XAE and XA as used in the NOR test increased the percentage alternation in the Y-maze test. Although XAE and XA treatments decreased the latencies to find hidden platform in the MWM test, it was not significantly different from the vehicle group. However, this decrease in latency differed significantly when compared to the ketamine group. Interestingly, both XAE and XA treatments increased the percentage frequency to the target quadrant in the probe trial of the MWM. It is noteworthy that in all the three models used, both the extract and xylopic acid performed better than piracetam and citicoline, the reference drugs.ConclusionThe ethanolic extract of Xylopia aethiopica fruit and xylopic acid improved exploratory learning and recognition memory, spatial working, recognition, and reference memories in the behavioral tests.

Regulation of Nrf2 and NF-κB activities may contribute to the anti-inflammatory mechanism of xylopic acid.

Xylopic acid (XA) is a kaurene diterpene which naturally exists in African plants such as Xylopia aethiopica. It has been established to exhibit acute and chronic anti-inflammatory activities from our earlier studies. This current work sets out to shed light on the potential molecular target(s) of xylopic acid. Selection of investigated targets (NF-κB, Nrf2 and PTP1B) was based on an unbiased approach, using the SPiDER in silico prediction tool, and a candidate approach, examining well-known anti-inflammatory targets. Reporter gene assays were used to test for altered NF-κB and Nrf2 activities in transfected HEK or CHO cells, respectively, and immunoblot and flow cytometric analyses examined protein expression of the Nrf2/NF-kB target genes HO-1 and VCAM-1 in HUVEC. An effect of XA on PTP1B activity assay was studied using an in vitro enzyme assay with recombinant human enzyme and pNPP as substrate as well as by looking at insulin receptor phosphorylation in HepG2 cells. XA at 30µM significantly (p < 0.001) inhibited the NF-κB-dependent reporter gene expression and enhanced activation of Nrf2 in a concentration-dependent manner when compared to the control. XA also marginally increased HO-1 protein expression levels while expression of VCAM-1 was reduced to 70% in XA-treated endothelial cells. However, XA did not show any sign of inhibition of PTP1B or a related phosphatase. Our findings suggest that the anti-inflammatory mechanism of XA entails the inhibitory effect on NF-κB and an increased activity of Nrf2, accompanied by increased expression of HO-1 and reduced expression of VCAM-1.

In Vitro and In Vivo Effect of Xylopic Acid on Cytochrome P450 Enzymes.

Introduction Xylopic acid (XA), the major constituent of the fruit of Xylopia aethiopica, has shown several pharmacological properties. Traditionally, the plant is used to treat several diseases and is being used in the preparation of several local foods despite the lack of information about its safety, food-drug interaction, and other pharmacokinetic properties. This study, therefore, investigated the effect of XA on rat liver cytochrome P450 (CYP) enzymes in vivo and in vitro. Methods Inhibition or induction of some isoforms of CYP450 enzymes: CYP 1A1/1A2, 1A2, 2B1/2B2, 3A4, 2D6, and 2C9 were investigated using microsomal fractions of the liver obtained from rats pretreated with a low dose of xylopic acid (LDT) 30 mg/kg, high dose of xylopic acid (HDT) 100 mg/kg, phenobarbitone (PC) 80 mg/kg, and ketoconazole (NC) 100 mg/kg, and a no-treatment group received distilled water, with (n = 5) animals in each group. The in vitro inhibition of CYP 3A4 was assessed by treating rat liver microsomes with XA. Results Xylopic acid induced CYP 1A1/1A2, 1A2, 2D6, and 2C9, inhibited CYP 3A4, and had no effect on 2B1/2B2. Conclusion The findings would help mitigate toxicity and therapeutic failure especially in cases of coadministration of medications with food containing XA, with metabolism altered by the latter.

Xylopic acid from Xylopia aethiopica (Annonaceae) inhibits morphine tolerance in rats

Xylopic acid from Xylopia aethiopica (Annonaceae) inhibits morphine tolerance in rats

Pharmacokinetics and in Vitro Liver Microsomal Enzyme Metabolism of Xylopic Acid

Pharmacokinetics and in Vitro Liver Microsomal Enzyme Metabolism of Xylopic Acid

Forced Degradation Studies, Elucidation of Degradation Pathways and Degradation Kinetics of Xylopic Acid via LC and LC-MS/MS Analyses

Forced Degradation Studies, Elucidation of Degradation Pathways and Degradation Kinetics of Xylopic Acid via LC and LC-MS/MS Analyses

Molecular Docking and ADMET Prediction of Natural Compounds towards SARS Spike Glycoprotein-Human Angiotensin-Converting Enzyme 2 and SARS-CoV-2 Main Protease.

More than a decade ago, a novel coronavirus that infects humans, bats, and certain other mammals termed severe acute respiratory syndrome coronavirus (SARS-CoV) caused an epidemic with ~ 10% case fatality, creating global panic and economic damage. Recently, another strain of the virus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), caused an infectious disease (COVID-19) in humans which was detected for the first time in Wuhan, China. Presently, there is no specific therapy available for the treatment of COVID-19. However, social distancing, patient isolation, and supportive medical care make up the current management for this current infectious disease pandemic. The present in silico study evaluated the binding affinities of some natural products (resveratrol, xylopic acid, ellagic acid, kaempferol, and quercetin) to human angiotensin-converting enzyme 2 and coronavirus (SARS-CoV-2) main protease compared to chloroquine, an inhibitor known to prevent cellular entry and replication of the coronavirus. The respective binding energies of the selected natural compounds and chloroquine towards the proteins were computed using PyRx virtual screening tool. The pharmacodynamic and pharmacokinetic attributes of the selected compounds were predicted using admetSAR. Molecular docking analysis showed that the natural compounds had better scores towards the selected protein compared to chloroquine with polar amino acid residues present at the binding sites. The predicted ADMET properties revealed the lower acute oral toxicity of the natural products compared to chloroquine. The study provides evidence suggesting that the relatively less toxic compounds from the natural sources could be repositioned as anti-viral agents to prevent the entry and replication of SARS-CoV-2.

Cutaneous and systemic anti-allergic potential of xylopic acid in rodents

Cutaneous and systemic anti-allergic potential of xylopic acid in rodents

Evidence of an antidepressant-like effect of xylopic acid mediated by serotonergic mechanisms.

Depression causes significant debilitating symptoms and economic burden. Current management is challenged by slow onset of action and modest efficacies of antidepressants; thus, the search for newer antidepressants remains relevant. We evaluated the antidepressant effects of a kaurene diterpene, xylopic acid (XA), in zebrafish and mouse models. The chronic unpredictable stress (CUS) protocol in zebrafish and the tail suspension test (TST), forced swim test (FST), lipopolysaccharide-induced depression-like behaviour test (LID) and repeated open space swimming test (OSST) in mice were used. We further examined the impact of depleting monoamines on XA's antidepressant effects. The contribution of glutamatergic and nitrergic pathways on the antidepressant effect of XA in mice and XA's effects on 5-HT receptors and monoamine oxidase (MAO) enzymes were also evaluated. Finally, XA's influence on neuroprotection was evaluated by measuring BDNF and oxidative stress enzymes in whole brain. XA doses (1-10μM) in zebrafish and (10, 30, 100mgkg-1) in mice exerted potent antidepressant-like potential in FST, TST, LID and showed fast-onset antidepressant-like property in the OSST. The antidepressant-like properties in mice were reversed by blocking synthesis/release of serotonin but not noradrenaline using p-chlorophenylalanine and α-methyl-p-tyrosine, respectively. This antidepressant-like effect was potentiated by D-cycloserine and Nω-Nitro-L-arginine methyl ester (L-NAME) but not by D-serine and L-arginine. XA also evoked partial agonist-like effects on 5-hydroxytrptamine receptors on the rat fundus but it did not have MAO inhibition effect. It also increased BDNF, glutathione and antioxidant enzymes. Therefore, xylopic acid possesses antidepressant-like effects largely mediated by serotonergic and neuroprotective mechanisms.

Effect of xylopic acid on alloxan-induced diabetic neuropathy in rats

Background: Neuropathic pain is a very disturbing condition commonly found in diabetic patients. This study investigated xylopic acid (XA), the major constituent of Xylopia aethiopica in diabetic neuropathy as well as established possible toxicity of the compound on some selected tissues.Methods: Diabetes was induced in six groups of male rats with 120 mg/kg alloxan monohydrate. Diabetes was confirmed as a blood glucose level &gt;15 mmol/dl. Neuropathic pain was confirmed on day three post-diabetes induction and treatment with 10 mg/kg, 30 mg/kg or 100 mg/kg xylopic acid, 10 mg/kg glibenclamide, 10 mg/kg morphine, and 10 ml/kg normal saline were initiated and continued for the next 15 days. The effects of the treatments on cold allodynia (cold water at 4°C) and thermal hyperalgesia (hot water at 55 ± 1°C) were evaluated within the duration of treatments. Histology of the liver and kidney, as well as haematological, serum biochemical, and semen analyses, were done after the fifteenth day of the experiment.Results: Xylopic acid produced significant anti-hyperglycaemic and analgesic effects in the cold allodynia and thermal hyperalgesia tests. Sperm motility, viability and count were significantly restored at 10 mg/kg XA as compared higher doses and negative control. The outcome of haematological analysis revealed a protective effect of XA although histological damage liver and kidney due to alloxan treatment was observable.Conclusions: Xylopic acid ameliorates diabetic neuropathy in rats and does not exert detrimental effects at low doses.

Xylopic Acid Suppresses Adjuvant-induced Arthritis in Sprague Dawley Rats via Reduction in Serum Levels of IL-6 and TNF-alpha.

Xylopic acid (XA) is the principal constituent obtained from the biofractionation of the dried fruits of Xylopia aethiopica. Our initial reports have established the acute anti-inflammatory activity of this kaurene diterpene. Currently, we investigate the chronic anti-inflammatory activity of xylopic acid. The adjuvant-induced arthritis model in rats was employed in carrying out the study. It was observed from the study that XA significantly (P < 0.05) suppressed the oedema associated with adjuvant arthritis while preventing associated joint deformation as identified from the radiographs. Histopathological analysis of joints of treated animals revealed signs of bone reformation and re-calcification following XA administration. From the haematological analysis, xylopic acid significantly decreased eosinophil sedimentation rate (ESR) while also decreasing white blood cells (WBC), which were increased after arthritis induction. Serum analysis showed the inhibitory effect of XA on serum expression of IL-6 and TNF-alpha in arthritic rats. Our study demonstrates the anti-arthritic activity of orally administered XA while pointing to a possible mechanism of its anti-inflammatory action.

Xylopic acid-amodiaquine and xylopic acid-artesunate combinations are effective in managing malaria in Plasmodium berghei-infected mice

BackgroundEvidence of Plasmodium resistance to some of the current anti-malarial agents makes it imperative to search for newer and effective drugs to combat malaria. Therefore, this study evaluated whether the co-administrations of xylopic acid-amodiaquine and xylopic acid-artesunate combinations will produce a synergistic anti-malarial effect.MethodsAntiplasmodial effect of xylopic acid (XA: 3, 10, 30, 100, 150 mg kg−1), artesunate (ART: 1, 2, 4, 8, 16 mg kg−1), and amodiaquine (AQ: 1.25, 2.5, 5, 10, 20 mg kg−1) were evaluated in Plasmodium berghei (strain ANKA)-infected mice to determine respective ED50s. Artemether/lumefantrine was used as the positive control. XA/ART and XA/AQ were subsequently administered in a fixed-dose combination of their ED50s (1:1) and the combination fractions of their ED50s (1/2, 1/4, 1/8, 1/16, and 1/32) to determine the experimental ED50s (Zexp). An isobologram was constructed to determine the nature of the interaction between XA/ART, and XA/AQ combinations by comparing Zexp with the theoretical ED50 (Zadd). Bodyweight and 30-day survival post-treatment were additionally recorded.ResultsED50s for XA, ART, and AQ were 9.0 ± 3.2, 1.61 ± 0.6, and 3.1 ± 0.8 mg kg−1, respectively. The Zadd, Zexp, and interaction index for XA/ART co-administration was 5.3 ± 2.61, 1.98 ± 0.25, and 0.37, respectively while that of XA/AQ were 6.05 ± 2.0, 1.69 ± 0.42, and 0.28, respectively. The Zexp for both combination therapies lay significantly (p < 0.001) below the additive isoboles showing XA acts synergistically with both ART and AQ in clearing the parasites. High doses of XA/ART combination significantly (p < 0.05) increased the survival days of infected mice with a mean hazard ratio of 0.40 while all the XA/AQ combination doses showed a significant (p < 0.05) increase in the survival days of infected mice with a mean hazard ratio of 0.27 similar to AL. Both XA/ART and XA/AQ combined treatments significantly (p < 0.05) reduced weight loss.ConclusionXylopic acid co-administration with either artesunate or amodiaquine produces a synergistic anti-plasmodial effect in mice infected with P. berghei.