Xanthorrhizol Research Articles

Curcuma xanthorrhiza extract and xanthorrhizol ameliorate cancer-induced adipose wasting in CT26-bearing mice by regulating lipid metabolism and adipose tissue browning

BackgroundCancer cachexia—characterized by anorexia, body weight loss, skeletal muscle atrophy, and fat loss—affects nearly 80% of cancer patients and accounts for 20% of cancer deaths. Curcuma xanthorrhiza, known as Java turmeric, and its active compound xanthorrhizol (XAN) exhibit anticancer, anti-inflammatory, and antioxidant properties. However, the ameliorative effects of C. xanthorrhiza extract (CXE) and XAN on cancer-associated adipose atrophy remain unexplored. This study aimed to evaluate the therapeutic effects of CXE and XAN on cancer cachexia-induced adipose tissue wasting in CT26 tumor-bearing mice. MethodsCT26 cells were injected subcutaneously into the right flank of BALB/c mice to establish a cancer cachexia model. To evaluate the inhibitory effects of CXE and XAN on cancer cachexia, 50 and 100 mg/kg CXE and 15 mg/kg XAN were administered orally every day for 1 week. ResultsCXE and XAN administration significantly attenuated the loss of body weight and epidydimal fat mass by cancer cachexia. In epididymal adipose tissues, administration of CXE or XAN inhibited white adipose tissue browning by repressing expression of the thermogenic genes. Simultaneously, CXE or XAN attenuated fat catabolism through the downregulation of lipolytic genes. The administration of CXE or XAN induced the expression of genes associated with adipogenesis and lipogenesis-related genes. Moreover, CXE or XAN treatment was associated with maintaining metabolic homeostasis; regulating the expression of adipokines and AMP-activated protein kinase (AMPK). ConclusionsCXE and XAN mitigate cancer-induced adipose tissue atrophy, primarily by modulating lipid metabolism and WAT browning, indicating their therapeutic potential for cachectic cancer patients.

Natural deep eutectic solvent extraction of xanthorrhizol and curcuminoids from Curcuma xanthorrhiza Roxb and simultaneous determination by high-performance liquid chromatography

Context: Curcuma xanthorrhiza, a native to Indonesia, has been recognized as a potential medicinal plant. Xanthorrhizol (XTZ), curcumin (Cur), bisdemethoxycurcumin (BDMC), and demethoxycurcumin (DMC) are the main major metabolites with different bioactivities. Thus, the selective extraction of these markers is required. Aims: To characterize and use natural deep eutectic solvents (NADES) for the extraction of XTZ and curcuminoids (CURS) from C. xanthorrhiza. Methods: Four NADES, comprising of glucose:lactic acid (Glu:LA, 1:3), choline chloride: malic acid (ChCl:MA, 1:1), choline chloride: glycerol (ChCl:Gly, 1:1), and choline chloride: sucrose (ChCl:Suc, 3:1) were synthesized and subjected to FTIR. The physicochemical properties of NADES were characterized, including polarity, viscosity, and density. Their antioxidant profiles were evaluated. The toxicity of NADES was assessed towards Escherichia coli by real-time growth monitoring. Tested NADES were employed to extract marker compounds from the rhizome of C. xanthorrhiza. A validated high-performance liquid chromatography (HPLC) method was applied to simultaneously quantify XTZ and CURS in NADES extracts. Results: FTIR spectra confirmed the formation of hydrogen bonds between components. Using the DPPH and FRAP methods, all NADES and NADES extracts displayed antioxidative activity, suggesting the contribution of NADES to the activity. Of the tested NADES, Glu:LA (1:3) obtained the highest content of XTZ over Cur, BDMC, and DMC, comparable to that of ethanol maceration. All tested NADES were harmless to E. coli, except for ChCl:MA (1:1). However, NADES extracts of Glu:LA (1:3) and ChCl:MA (1:1) suppressed the growth of the bacterium. Scanning electron micrographs demonstrated the destruction of the surface structure of the rhizome powder by NADES-ultrasonication. Conclusions: The study recommended the use of Glu:LA (1:3) to selectively extract XTZ to promote environmentally friendly and sustainable extraction.

In Vitro Replication Inhibitory Activity of Xanthorrhizol against Severe Acute Respiratory Syndrome Coronavirus 2

In spite of the large number of repositioned drugs and direct-acting antivirals in clinical trials for the management of the ongoing COVID-19 pandemic, there are few cost-effective therapeutic options for severe acute respiratory syndrome (SARS) coronavirus 2 (SCoV2) infection. In this paper, we show that xanthorrhizol (XNT), a bisabolane-type sesquiterpenoid compound isolated from the Curcuma xanthorrhizza Roxb., a ginger-line plant of the family Zingiberaceae, displays a potent antiviral efficacy in vitro against SCoV2 and other related coronaviruses, including SARS-CoV-1 (SCoV1) and a common cold-causing human coronavirus. XNT reduced infectious SCoV2 titer by ~3-log10 at 20 μM and interfered with the replication of the SCoV1 subgenomic replicon, while it had no significant antiviral effects against hepatitis C virus and noroviruses. Further, XNT exerted similar antiviral functions against SCoV2 variants, such as a GH clade strain and a delta strain currently predominant worldwide. Neither SCoV2 entry into cells nor the enzymatic activity of viral RNA polymerase (Nsp12), RNA helicase (Nsp13), or the 3CL main protease (Nsp5) was inhibited by XNT. While its CoV replication inhibitory mechanism remains elusive, our results demonstrate that the traditional folk medicine XNT could be a promising antiviral candidate that inhibits a broad range of SCoV2 variants of concern and other related CoVs.

Xanthorrhizol inhibits non-small cell carcinoma (A549) cell growth and promotes apoptosis through modulation of PI3K/AKT and NF-κB signaling pathway.

Xanthorrhizol (XNT) is a sesquiterpenoid agent isolated from Curcuma xanthorrhiza; It is known to exhibit various pharmacological activities including anti-cancer. We investigated the anti-cell proliferative and proapoptotic effects of XNT on Non-small cell carcinoma (A549) cells were analyzed by the generation of reactive oxygen species (ROS), alteration of mitochondrial membrane potential (ΔΨm), oxidative DNA damage, and apoptosis morphological changes were explored by Hoechst and AO/EtBr staining. Our study demonstrated that XNT treatment significantly reduced the viability of A549 cells in a concentration-dependent manner. We observed that XNT-induced oxidative stress-mediated apoptotic cell death by increasing intracellular ROS generation, depleting antioxidant levels, enhancing lipid peroxidation, increased apoptotic morphological changes, and % of DNA damage on human lung cancer cells. Furthermore, we observed that the XNT induce apoptosis through inhibits phosphorylation of PI3K, AKTand inhibit NF-κBp65 transcriptional signaling activity. In addition, XNT treatment alters the ΔΨm, thereby induces apoptosis was closely coordinated with the induction of pro-apoptotic markers Bax, Bad, caspase- 3, 9 and cytochrome c, and suppression of anti-apoptotic (Bcl-2, Bcl-XL) protein expression. According to our results, XNT-inducing apoptosis in A549 cells by causing oxidative damage and modulating apoptotic signaling events. Finally, XNT-induced apoptotic cell death was confirmed by the TUNEL assay. Therefore, XNT might be used as a chemotherapeutic agent for the treatment of lung cancer.

Comprehensive computational target fishing approach to identify Xanthorrhizol putative targets

Xanthorrhizol (XNT), is a bioactive compound found in Curcuma xanthorrhiza Roxb. This study aimed to determine the potential targets of the XNT via computational target fishing method. This compound obeyed Lipinski’s and Veber’s rules where it has a molecular weight (MW) of 218.37 gmol-1, TPSA of 20.23, rotatable bonds (RBN) of 4, hydrogen acceptor and donor ability is 1 respectively. Besides, it also has half-life (HL) values 3.5 h, drug-likeness (DL) value of 0.07, oral bioavailability (OB) of 32.10, and blood–brain barrier permeability (BBB) value of 1.64 indicating its potential as therapeutic drug. Further, 20 potential targets were screened out through PharmMapper and DRAR-CPI servers. Co-expression results derived from GeneMANIA revealed that these targets made connection with a total of 40 genes and have 744 different links. Four genes which were RXRA, RBP4, HSD11B1 and AKR1C1 showed remarkable co-expression and predominantly involved in steroid metabolic process. Furthermore, among these 20 genes, 13 highly expressed genes associated with xenobiotics by cytochrome P450, chemical carcinogenesis and steroid metabolic pathways were identified through gene ontology (GO) and KEGG pathway analysis. In conclusion, XNT is targeting multiple proteins and pathways which may be exploited to shape a network that exerts systematic pharmacological effects.

COMPARISON OF ANTIFUNGAL EFFECT OF XANTHORRHIZOL (CURCUMA XANTHORRHIZA ROXB.) AND 2% CHLORHEXIDINE AGAINST CANDIDA ALBICANS AMERICAN TYPE CULTURE COLLECTION 10231 BIOFILM

Objective: Several studies suggest that 2% chlorhexidine (CHX), an effective irrigation solution against Candida albicans biofilm, is toxic to host cells,thus an effective and safe alternative irrigation solution is needed. Java turmeric (Curcuma xanthorrhiza Roxb.) containing xanthorrhizol (XNT) hasbeen reported to have an antifungal effect, yet no studies to date have reported the optimum dose of XNT in inhibiting C. albicans biofilm, so the aimof this study was to determine the optimum dose of XNT against C. albicans biofilm.Methods: C. albicans American Type and Culture Collection (ATCC) 10231 biofilm was exposed to XNT for 15 min. Then, the antifungal effect wastested using 3-[4,5-dimethyl-thiazol-2-yl]-2,5-diphenytetrazolium bromide reduction assay and total plate count (TPC).Results: There was no statistically significant difference between the percentage of biofilm eradication and TPC results following exposure ofC. albicans ATCC 10231 biofilm to 1% XNT, 1.25% XNT, and 2% CHX.Conclusion: Our results suggest that 1% XNT and 1.25% XNT have an antifungal effect against C. albicans ATCC 10231 biofilm equivalent to that of2% CHX.

COMPARISON OF ANTIBACTERIAL EFFICACY BETWEEN XANTHORRHIZOL (CURCUMA XANTHORRHIZA ROXB.) AND CHLORHEXIDINE 2% AGAINST ENTEROCOCCUS FAECALIS CLINICAL ISOLATE BIOFILM

Objective: In root canal treatments, chlorhexidine (CHX) is widely used for irrigation and is effective in killing Enterococcus faecalis. CHX is a syntheticchemical and is toxic to host cells; therefore, natural or herbal irrigation solutions, which are safer but still effective, are necessary. The aim of thisstudy is to analyze the effect of xanthorrhizol (XNT) derived from Curcuma xanthorrhiza Roxb. on E. faecalis clinical isolate biofilm formation (0.5%,0.75%, 1%, 1.25%, and 1.5%).Methods: The MTT assay and total plate count were performed for assessing the effectiveness of herbal ingredients, while CHX (2%) was used as apositive control. Data were analyzed using one-way ANOVA and Bonferroni post-hoc tests for analyzing differences between groups.Results: Xanthorrhizol concentrations of 0.5%, 0.75%, 1%, 1.25%, and 1.5% reduced the amount of bacteria that grew as biofilms in vitro. We foundthat the ability of xanthorrhizol 1% to inhibit E. faecalis biofilm formation was not significantly different compared with that of CHX 2% (p>0.05).Conclusion: Xanthorrhizol 1% can inhibit biofilm formation by E. faecalis. Further studies are required to confirm this preliminary result.

Expansion of antibacterial spectrum of xanthorrhizol against Gram-negatives in combination with PMBN and food-grade antimicrobials.

Xanthorrhizol (XTZ), isolated from Curcuma xanthorrhiza, has potent antifungal and antibacterial activity. It shows very strong activity against Gram-positive bacteria, such as Streptococcus mutans and Staphylococcus aureus, but is generally not active against Gram-negative bacteria. In this study, we explored the possibility of using a combination strategy for expanding the antimicrobial spectrum of XTZ against Gram-negative bacteria. To take advantage of XTZ being a food-grade material, 10 food-grade or generally recognized as safe (GRAS) antimicrobial compounds with low toxicities were selected for combination therapy. In addition, polymyxin B nonapeptide (PMBN), which is less toxic than polymyxin B, was also selected as an outer membrane permeabilizer. The antibacterial activity of various double or triple combinations with or without XTZ were assayed in vitro against four Gram-negative bacterial species (Escherichia coli, Salmonella enterica serovar Typhi, Salmonella enterica serovar Typhimurium, and Vibrio cholerae), with synergistic combinations exhibiting clear activity subjected to further screening. The combinations with the greatest synergism were XTZ + PMBN + nisin, XTZ + PMBN + carvacrol, and XTZ + PMBN + thymol. These combinations also showed potent antimicrobial activity against Shigella spp., Yersinia enterocolitica, and Acinetobacter baumannii. In time-kill assays, the three combinations achieved complete killing of E. coli within 2 h, and S. Typhi and V. cholera within 15 min. This is the first report on expanding the activity spectrum of XTZ against Gram-negative bacteria through combination with PMBN and food-grade or GRAS substances, with the resulting findings being particularly useful for increasing the industrial and medical applications of XTZ.

Inhibitory Effects of Curcuma xanthorrhiza Supercritical Extract and Xanthorrhizol on LPS-Induced Inflammation in HGF-1 Cells and RANKL-Induced Osteoclastogenesis in RAW264.7 Cells.

Periodontal disease is triggered by the host immune response to pathogens in the microbial biofilm. Worsening of periodontal disease destroys the tooth-supporting tissues and alveolar bone. As oral inflammation can induce systemic diseases in humans, it is important to prevent periodontal disease. In this study, we demonstrated that Curcuma xanthorrhiza supercritical extract (CXS) and its active compound, xanthorrhizol (XAN), exhibit anti-inflammatory effects on lipopolysaccharide (LPS)-treated human gingival fibroblast-1 cells and anti-osteoclastic effects on receptor activator of nuclear factor kappa B ligand (RANKL)-treated RAW264.7 cells. LPS-upregulated inflammatory factors, such as nuclear factor kappa B p65 and interleukin-1β, were prominently reduced by CXS and XAN. In addition, RANKL-induced osteoclastic factors, such as nuclear factor of activated T-cells c1, tartrate-resistant acid phosphatase, and cathepsin K, were decreased in the presence of CXS and XAN. CXS and XAN inhibited the mitogen-activated protein kinase (MAPK)/activator protein-1 (AP-1) signaling pathway. Collectively, these results provide evidence that CXS and XAN suppress LPS-induced inflammation and RANKL-induced osteoclastogenesis by suppressing the MAPK/AP-1 pathway.

Simultaneous quantification of curcuminoids and xanthorrhizol in Curcuma xanthorrhiza by high-performance liquid chromatography

ABSTRACTA new method for simultaneous quantification of curcuminoids and xanthorrhizol (XNT) in Curcuma xanthorrhiza was developed and validated using high-performance liquid chromatography with diode-array UV–Vis detector. The chromatographic separation was achieved on a Phenomenex C18 at room temperature with the mobile-phase acetonitrile −0.001% formic acid in gradient elution system and delivered at a flow rate of 1 mL/min. Detection wavelength 425 nm was used for curcuminoids and 224 nm for XNT. System suitability, linearity, precision, accuracy, limit of detection, limit of quantitation, and stability were evaluated and were found in good agreement with Association of Official Analytical Chemists guidelines for single-laboratory validation. The proposed method was found to be precise, accurate, and reliable and also could be applied for the simultaneous quantitative analysis of curcuminoids and XNT in C. xanthorriza raw material and its herbal medicinal product.

Hypolipidemic activities of xanthorrhizol purified from centrifugal TLC

Hyperlipidemia is defined as the presence of either hypertriglyceridemia or hypercholesterolemia, which could cause atherosclerosis. Although hyperlipidemia can be treated by hypolipidemic drugs, they are limited due to lack of effectiveness and safety. Previous studies demonstrated that xanthorrhizol (XNT) isolated from Curcuma xanthorrhizza Roxb. reduced the levels of free fatty acid and triglyceride in vivo. However, its ability to inhibit cholesterol uptake in HT29 colon cells and adipogenesis in 3T3-L1 cells are yet to be reported. In this study, XNT purified from centrifugal TLC demonstrated 98.3% purity, indicating it could be an alternative purification method. The IC50 values of XNT were 30.81 ± 0.78 μg/mL in HT29 cells and 35.07 ± 0.24 μg/mL in 3T3-L1 adipocytes, respectively. Cholesterol uptake inhibition study using HT29 colon cells showed that XNT (15 μg/mL) significantly inhibited the fluorescent cholesterol analogue NBD uptake by up to 27 ± 3.1% relative to control. On the other hand, higher concentration of XNT (50 μg/mL) significantly suppressed the growth of 3T3-L1 adipocytes (5.9 ± 0.58%) compared to 3T3-L1 preadipocytes (81.31 ± 0.55%). XNT was found to impede adipogenesis of 3T3-L1 adipocytes in a dose-dependent manner from 3.125 to 12.5 μg/mL, where 12.5 μg/mL significantly suppressed 36.13 ± 2.1% of lipid accumulation. We postulate that inhibition of cholesterol uptake, adipogenesis, preadipocyte and adipocyte number may be utilized as treatment modalities to reduce the prevalence of lipidemia. To conclude, XNT could be a potential hypolipidemic agent to improve cardiovascular health in the future.

The antibacterial effect of xanthorrhizol as an endodontic irrigant on Enterococcus faecalis

Objectives The aim of this study was to evaluate the antibacterial effect of xanthorrhizol (XTZ) on E. faecalis, compared with 2% chlorhexidine (CHX). Materials and Methods Normal physiological state (NS), starvation state (SS), and alkalization state (AS) of E. faecalis were used. A solution containing 1% XTZ in 30% ethanol, 1% dimethyl sulfoxide (DMSO), and 100 mg/ml sodium methyl cocoyl taurate was used and is referred to as Xan in this study. To determine the minimal bactericidal concentration (MBC) of Xan and CHX, 500µl of E. faecalis (NS and two stress states) was added to a microtube containing 500µl of serial 2-fold dilutions of 1% Xan and 2% CHX (1:2-1:128). The MBC of each antimicrobial was determined by the plate count method. Results The antibacterial effect of Xan was more effective on E. faecalis in AS than in the other states (NS, SS) at 0.125% Xan and 0.03325% Xan (P<0.05). In contrast, the antibacterial effect of CHX was more effective against E. faecalis in SS than the other states (NS, AS) at 0.0625% CHX (P<0.05). In SS, the antibacterial effect of CHX was more effective than that of Xan at 0.125% and 0.0625% (P<0.05). However, in AS, the antibacterial effect of Xan was more effective than that of CHX at 0.0625% and 0.03325% (P<0.05). Conclusions In endodontic retreatment cases in which it is important to effectively remove E. faecalis from the infected root canal, Xan may be more suitable when combined with NaOCl than CHX.

Xanthorrhizol: a review of its pharmacological activities and anticancer properties.

Xanthorrhizol (XNT) is a bisabolane-type sesquiterpenoid compound extracted from Curcuma xanthorrhiza Roxb. It has been well established to possess a variety of biological activities such as anticancer, antimicrobial, anti-inflammatory, antioxidant, antihyperglycemic, antihypertensive, antiplatelet, nephroprotective, hepatoprotective, estrogenic and anti-estrogenic effects. Since many synthetic drugs possess toxic side effects and are unable to support the increasing prevalence of disease, there is significant interest in developing natural product as new therapeutics. XNT is a very potent natural bioactive compound that could fulfil the current need for new drug discovery. Despite its importance, a comprehensive review of XNT’s pharmacological activities has not been published in the scientific literature to date. Here, the present review aims to summarize the available information in this area, focus on its anticancer properties and indicate the current status of the research. This helps to facilitate the understanding of XNT’s pharmacological role in drug discovery, thus suggesting areas where further research is required.

Antihyperglycemic and Anti-Inflammatory Effects of Standardized Curcuma xanthorrhiza Roxb. Extract and Its Active Compound Xanthorrhizol in High-Fat Diet-Induced Obese Mice.

Xanthorrhizol, a natural compound isolated from Curcuma xanthorrhiza Roxb. (Java turmeric), has been reported to possess antioxidant and anticancer properties; however, its effects on metabolic disorders remain unknown. The aim of the present study was to evaluate the effects of xanthorrhizol (XAN) and C. xanthorrhiza extract (CXE) with standardized XAN on hyperglycemia and inflammatory markers in high-fat diet- (HFD-) induced obese mice. Treatment with XAN (10 or 25 mg/kg/day) or CXE (50 or 100 mg/kg/day) significantly decreased fasting and postprandial blood glucose levels in HFD-induced obese mice. XAN and CXE treatments also lowered insulin, glucose, free fatty acid (FFA), and triglyceride (TG) levels in serum. Epididymal fat pad and adipocyte size were decreased by high doses of XAN (26.6% and 20.1%) and CXE (25.8% and 22.5%), respectively. XAN and CXE treatment also suppressed the development of fatty liver by decreasing liver fat accumulation. Moreover, XAN and CXE significantly inhibited production of inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), interleukin-1β (IL-1β), and C-reactive protein (CRP) in adipose tissue (27.8–82.7%), liver (43.9–84.7%), and muscle (65.2–92.5%). Overall, these results suggest that XAN and CXE, with their antihyperglycemic and anti-inflammatory activities, might be used as potent antidiabetic agents for the treatment of type 2 diabetes.

In vitro anti-Malassezia activity of xanthorrhizol isolated from Curcuma xanthorrhiza Roxb

This study aimed at investigating the anti-Malassezia activity of xanthorrhizol (XTZ) isolated from Curcuma xanthorrhiza Roxb. against Malassezia furfur ATCC 14521 and Malassezia pachydermatis ATCC 14522. The in vitro susceptibility tests for XTZ were carried out in terms of minimum inhibitory concentration (MIC) and minimum fungicidal concentration (MFC), using broth microdilution method with endpoint after 48 h. Time-kill curves were determined at concentrations ranging from 0 to 25 microg ml(-1). The MIC values of XTZ against M. furfur and M. pachydermatis were 1.25 and 0.25 mug ml(-1), respectively. The MFC of XTZ was 5 microg ml(-1) for M. furfur and 2.5 microg ml(-1) for M. pachydermatis. Time-kill curves demonstrated that treatment with 25 microg ml(-1) of XTZ for 5 h was able to kill 100% of M. furfur, while 20 microg ml(-1) of XTZ for 15 min killed M. pachydermatis completely. XTZ shows potential as an anti-Malassezia agent for inhibiting the growth of M. furfur ATCC 14521 and M. pachydermatis ATCC 14522 in vitro. XTZ may be a useful alternative for treating Malassezia-associated diseases.

In vitro activity of xanthorrhizol against Streptococcus mutans biofilms

We determined the effect of xanthorrhizol (XTZ) purified from the rhizome of Curcuma xanthorrhiza Roxb. on the Streptococcus mutans biofilms in vitro. The biofilms of S. mutans at different phases of growth were exposed to XTZ at different concentrations (5, 10 and 50 micromol l(-1)) and for different time exposures (1, 10, 30 and 60 min). The results demonstrated that the activity of XTZ in removing S. mutans biofilm was dependent on the concentration, exposure time and the phase growth of biofilm. A concentration of 5 micromol l(-1) of XTZ completely inhibited biofilm formation by S. mutans at adherent phases of growth, whereas 50 micromol l(-1) of XTZ removed 76% of biofilm at plateau accumulated phase when exposed to S. mutans biofilm for 60 min. Xanthorrhizol isolated from an edible plant (C. xanthorrhiza Roxb.) shows promise as an antibacterial agent for inhibiting and removing S. mutans biofilms in vitro. XTZ could be used as a potential antibacterial agent against biofilm formation by S. mutans.