Publications by authors named "Subbaraju Gottumukkala"

38 Publications

Dehydroxyhispolon Methyl Ether, A Hispolon Derivative, Inhibits WNT/β-Catenin Signaling to Elicit Human Colorectal Carcinoma Cell Apoptosis.

Int J Mol Sci 2020 Nov 22;21(22). Epub 2020 Nov 22.

Ph.D. Program in Translational Medicine, National Chung Hsing University, Taichung 40227, Taiwan.

Colorectal cancer (CRC) is the fourth leading cause of cancer mortality worldwide. Aberrant activation of WNT/β-catenin signaling present in the vast majority of CRC cases is indispensable for CRC initiation and progression, and thus is a promising target for CRC therapeutics. Hispolon is a fungal-derived polyphenol with a pronounced anticancer effect. Several hispolon derivatives, including dehydroxyhispolon methyl ether (DHME), have been chemically synthesized for developing lead molecules with stronger anticancer activity. Herein, a DHME-elicited anti-CRC effect with the underlying mechanism is reported for the first time. Specifically, DHME was found to be more cytotoxic than hispolon against a panel of human CRC cell lines, while exerting limited toxicity to normal human colon cell line CCD 841 CoN. Additionally, the cytotoxic effect of DHME appeared to rely on inducing apoptosis. This notion was evidenced by DHME-elicited upregulation of poly (ADP-ribose) polymerase (PARP) cleavage and a cell population positively stained by annexin V, alongside the downregulation of antiapoptotic B-cell lymphoma 2 (BCL-2), whereas the blockade of apoptosis by the pan-caspase inhibitor z-VAD-fmk attenuated DHME-induced cytotoxicity. Further mechanistic inquiry revealed the inhibitory action of DHME on β-catenin-mediated, T-cell factor (TCF)-dependent transcription activity, suggesting that DHME thwarted the aberrantly active WNT/β-catenin signaling in CRC cells. Notably, ectopic expression of a dominant-active β-catenin mutant (∆N90-β-catenin) abolished DHME-induced apoptosis while also restoring BCL-2 expression. Collectively, we identified DHME as a selective proapoptotic agent against CRC cells, exerting more potent cytotoxicity than hispolon, and provoking CRC cell apoptosis via suppression of the WNT/β-catenin signaling axis.
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http://dx.doi.org/10.3390/ijms21228839DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7700694PMC
November 2020

Co-Delivery of Hispolon and Doxorubicin Liposomes Improves Efficacy Against Melanoma Cells.

AAPS PharmSciTech 2020 Nov 4;21(8):304. Epub 2020 Nov 4.

Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, Alabama, 36849, USA.

Hispolon is a small molecular weight polyphenol that has antioxidant, anti-inflammatory, and anti-proliferative activities. Our recent study has demonstrated hispolon as a potent apoptosis inducer in melanoma cell lines. Doxorubicin is a broad spectrum first-line treatment for various kinds of cancers. In this study, co-delivery of doxorubicin and hispolon using a liposomal system in B16BL6 melanoma cell lines for synergistic cytotoxic effects was investigated. Liposomes were prepared using a lipid film hydration method and loaded with doxorubicin or hispolon. The formulations were characterized for particle size distribution, release profile, and encapsulation efficiency (EE). In addition, in vitro cytotoxicity, in vitro cell apoptosis, and cellular uptake were evaluated. Liposomes exhibited small particle size (mean diameter ~ 100 nm) and narrow size distribution (polydispersity index (< 0.2) and high drug EE% (> 90%). The release from liposomes showed slower release compared to free drug solution as an additional time required for the release of drug from the liposome lipid bilayer. Liposome loaded with doxorubicin or hispolon exhibited significantly higher cytotoxicity against B16BL6 melanoma cells as compared to doxorubicin solution or hispolon solution. Likewise, co-delivery of hispolon and doxorubicin liposomes showed two-fold and three-fold higher cytotoxicity, as compared to hispolon liposomes or doxorubicin liposomes, respectively. In addition, co-delivery of doxorubicin and hispolon in liposomes enhanced apoptosis more than the individual drugs in the liposome formulation. In conclusion, the co-delivery of hispolon and doxorubicin could be a promising therapeutic approach to improve clinical outcomes against melanoma.
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http://dx.doi.org/10.1208/s12249-020-01846-2DOI Listing
November 2020

Elucidating the anti-melanoma effect and mechanisms of Hispolon.

Life Sci 2020 Sep 6;256:117702. Epub 2020 May 6.

Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, AL 36849. Electronic address:

There is a rapid increase in the incidence of melanoma which has led to a global crisis. Thus, there is a great need for developing novel, safe and effective drugs for the treatment of melanoma. Hispolon is a small molecular weight polyphenol derived from Phellinus linteus, which has antioxidant, anti-inflammatory and anti-proliferative activities. Hispolon has been reported to induce apoptosis in gastric cancer, hepatocellular carcinoma, and myeloid leukemia. However, the anticancer effect in melanoma is not well elucidated. Thus, our present study was to investigate the anti-cancer effect of hispolon on melanoma cancer cells. B16BL6 cells were treated with different concentrations of hispolon for 24 h and the effect on oxidative stress, mitochondrial functions, apoptosis and cell proliferation were studied. Hispolon is a potent generator of reactive oxygen species, nitrite and lipid peroxide levels. Furthermore, it significantly inhibits the expression of Bcl-2 and promotes the expression of Bax, increases the activity of caspase 1 and 3, inhibits mitochondrial Complex I and IV activities. By the above mechanisms, hispolon dose-dependently exhibited the antimelanoma effect similar to the well established pharmacological agent, curcumin. Thus, hispolon can be a potent anti-melanoma drug in the future if the pharmacodynamic effects and the toxicological studies are appropriately carried out.
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http://dx.doi.org/10.1016/j.lfs.2020.117702DOI Listing
September 2020

X-ray crystal structures, density functional theory and docking on deacetylase enzyme for antiproliferative activity of hispolon derivatives on HCT116 colon cancer.

Bioorg Med Chem 2019 09 5;27(17):3805-3812. Epub 2019 Jul 5.

Natsol Laboratories Private Limited, Research & Development Building, Ramky Commercial Hub, J. N. Pharmacity, Visakhapatnam 531019, India. Electronic address:

The antiproliferative action of hispolon derivatives is stronger than that of related curcumin against several tumor cell lines. Hispolon size, smaller than curcumin, fits better than curcumin into the active site of HDAC6, an enzyme involved in deacetylation of lysine residues. HDACs are considered potential targets for tumor drug discovery and hydroxamates are known inhibitors of HDACs. One of them, SAHA (Vorinostat) is used in clinical studies. Investigations into possible mechanisms for hispolon derivatives active against the HCT116 colon tumor cell line are done after examining the structural results obtained from hispolon X-ray crystal structures as well as performing associated computational docking and Density Functional Theory techniques on HDAC6. These studies show preference for the HDAC6 active site by chelating the Zn center, in contrast with other ineffective hispolon derivatives, that establish only a single bond to the metal center. Structure activity relationships make clear that hydrogenation of the hispolon bridge also leads to single bond (non chelate) hispolon-Zn binding, and consistently nullifies the antiproliferative action against HCT116 tumor.
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http://dx.doi.org/10.1016/j.bmc.2019.07.008DOI Listing
September 2019

Synthesis, Screening and Docking Analysis of Hispolon Pyrazoles and Isoxazoles as Potential Antitubercular Agents.

Curr Top Med Chem 2019 ;19(9):662-682

Medicinal Chemistry Research Labs, College of Pharmaceutical Sciences, Andhra University, Visakhapatnam- AP, India.

Background: Hispolons are natural products known to possess cytoprotective, antioxidant and anti-cancer activities. We have found recently anti TB activity in these compounds. Efforts were made to optimize the structure with bioisosteric replacement of 1,3-diketo functional group with the corresponding pyrazole and isoxazole moieties.

Objective: The goal of this paper is designing new hispolon isoxazole and pyrazole and the evaluation of their biological activities.

Methods: The designed compounds were prepared using classical organic synthesis methods. The anti- TB activity was evaluated using the MABA method.

Results: A total of 44 compounds were synthesized (1a- 1v and 2a-2v) and screened for anti TB activity and antibacterial activity. The compounds 1b and 1n showed the highest potency with MIC 1.6µg/mL against M. tuberculosis H37Rv.

Conclusion: Bioisosteric replacement of 1,3-diketo functional group in hispolons with pyrazole or isoxazole rings have resulted in potent anti TB molecules. Docking simulations of these compounds on mtFabH enzyme resulted in a clear understanding of bioactivity profiles of these compounds. Docking scores are in good agreement with the anti TB activity obtained for these compounds. Computational studies and in vitro screening results indicate mtFabH as the probable target of these compounds.
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http://dx.doi.org/10.2174/1568026619666190305124954DOI Listing
July 2019

Toxicity and Antigenotoxic Effect of Hispolon Derivatives: Role of Structure in Modulating Cellular Redox State and Thioredoxin Reductase.

ACS Omega 2018 Jun 1;3(6):5958-5970. Epub 2018 Jun 1.

Radiation & Photochemistry Division and Chemistry Division, Bhabha Atomic Research Centre, Mumbai 400085, India.

Hispolon (HS), a bioactive polyphenol, and its derivatives such as hispolon monomethyl ether (HME), hispolon pyrazole (HP), and hispolon monomethyl ether pyrazole (HMEP) were evaluated for comparative toxicity and antigenotoxic effects. The stability of HS derivatives in biological matrices followed the order HS < HP ≈ HME < HMEP. The cytotoxicity analysis of HS derivatives indicated that HP and HMEP were less toxic than HS and HME, respectively, in both normal and tumor cell types. The mechanisms of toxicity of HS and HME involved inhibition of thioredoxin reductase (TrxR) and/or induction of reductive stress. From the enzyme kinetic and docking studies, it was established that HS and HME interacted with the NADPH-binding domain of TrxR through electrostatic and hydrophobic bonds, resulting in inhibition of the catalytic activity. Subsequently, treatment with HS, HP, and HMEP at a nontoxic concentration of 10 μM in Chinese Hamster Ovary (CHO) cells showed significant protection against radiation (4 Gy)-induced DNA damage as assessed by micronuclei and γ-H2AX assays. In conclusion, the above results suggested the importance of phenolic and diketo groups in controlling the stability and toxicity of HS derivatives. The pyrazole derivatives, HP and HMEP, may gain significance in the development of functional foods.
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http://dx.doi.org/10.1021/acsomega.8b00415DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6045486PMC
June 2018

Diketo modification of curcumin affects its interaction with human serum albumin.

Spectrochim Acta A Mol Biomol Spectrosc 2018 Jun 3;199:394-402. Epub 2018 Apr 3.

Chemistry Division, Bhabha Atomic Research Centre, Trombay, Mumbai 400085, India.

Curcumin isoxazole (CI) and Curcumin pyrazole (CP), the diketo modified derivatives of Curcumin (CU) are metabolically more stable and are being explored for pharmacological properties. One of the requirements in such activities is their interaction with circulatory proteins like human serum albumin (HSA). To understand this, the interactions of CI and CP with HSA have been investigated employing absorption and fluorescence spectroscopy and the results are compared with that of CU. The respective binding constants of CP, CI and CU with HSA were estimated to be 9.3×10, 8.4×10 and 2.5×10M, which decreased with increasing salt concentration in the medium. The extent of decrease in the binding constant was the highest in CP followed by CI and CU. This revealed that along with hydrophobic interaction other binding modes like electrostatic interactions operate between CP/CI/CU with HSA. Fluorescence quenching studies of HSA with these compounds suggested that both static and dynamic quenching mechanisms operate, where the contribution of static quenching is higher for CP and CI than that for CU. From fluorescence resonance energy transfer studies, the binding site of CU, CI and CP was found to be in domain IIA of HSA. CU was found to bind in closer proximity with Trp214 as compared to CI and CP and the same was responsible for efficient energy transfer and the same was also established by fluorescence anisotropy measurements. Furthermore docking simulation complemented the experimental observation, where both electrostatic as well as hydrophobic interactions were indicated between HSA and CP, CI and CU. This study is useful in designing more stable CU derivatives having suitable binding properties with proteins like HSA.
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http://dx.doi.org/10.1016/j.saa.2018.03.085DOI Listing
June 2018

Hispolon Suppresses LPS- or LTA-Induced iNOS/NO Production and Apoptosis in BV-2 Microglial Cells.

Am J Chin Med 2017 9;45(8):1649-1666. Epub 2017 Nov 9.

§ Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan.

Hispolon (HIS) is an active polyphenol compound derived from Phellinus linteus (Berkeley & Curtis), and our previous study showed that HIS effectively inhibited inflammatory responses in macrophages [Yang, L.Y., S.C. Shen, K.T. Cheng, G.V. Subbaraju, C.C. Chien and Y.C. Chen. Hispolon inhibition of inflammatory apoptosis through reduction of iNOS/NO production via HO-1 induction in macrophages. J. Ethnopharmacol. 156: 61-72, 2014]; however, its effect on neuronal inflammation is still undefined. In this study, HIS concentration- and time-dependently inhibited lipopolysaccharide (LPS)- and lipoteichoic acid (LTA)-induced inducible nitric oxide (NO) synthase (iNOS)/NO production with increased heme oxygenase (HO)-1 proteins in BV-2 microglial cells. Accordingly, HIS protected BV-2 cells from LPS- or LTA-induced apoptosis, characterized by decreased DNA ladder formation, and caspase-3 and poly(ADP ribose) polymerase (PARP) protein cleavage in BV-2 cells. Similarly, the NOS inhibitor, N-nitro-L-arginine methyl ester (NAME), inhibited LPS- or LTA-induced apoptosis of BV-2 cells, but neither NAME nor HIS showed any inhibition of NO production or cell death induced by the NO donor, sodium nitroprusside (SNP), indicating the involvement of NO in the inflammatory apoptosis of microglial cells. Activation of c-Jun N-terminal kinase (JNK) and nuclear factor (NF)-[Formula: see text]B contributed to LPS- or LTA-induced iNOS/NO production and apoptosis of BV-2 cells, and that was suppressed by HIS. Additionally, HIS possesses activity to induce HO-1 protein expression via activation of extracellular signal-regulated kinase (ERK) in BV-2 cells, and application of the HO inhibitor, tin protoporphyrin (SnPP), or knockdown of HO-1 protein by HO-1 small interfering (si)RNA significantly reversed HIS inhibition of NO production and cell death in BV-2 cells stimulated by LPS. Results of an analysis of the effects of HIS and two structurally related chemicals, i.e. dehydroxy-HIS (D-HIS) and HIS-methyl ester (HIS-ME), showed that HIS expressed the most potent inhibitory effects on iNOS/NO production, JNK activation, and apoptosis in BV-2 microglial cells activated by LPS with increased HO-1 protein expression. Overall these results suggested that HIS possesses inhibitory activity against LPS- or LTA-induced inflammatory responses including iNOS/NO production and apoptosis in BV-2 microglial cells and that the mechanisms involve upregulation of the HO-1 protein and downregulation of JNK/NF-[Formula: see text]B activation. A critical role of hydroxyl at position C3 in the anti-inflammatory actions of HIS against activated BV-2 microglial cells was suggested.
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http://dx.doi.org/10.1142/S0192415X17500896DOI Listing
February 2018

Synthesis, screening and docking analysis of hispolon analogs as potential antitubercular agents.

Bioorg Med Chem Lett 2017 01 18;27(1):11-15. Epub 2016 Nov 18.

Medicinal Chemistry Research Labs, College of Pharmaceutical Sciences, Andhra University, Visakhapatnam 530 003, India. Electronic address:

A series of 20 hispolons/dihydrohispolons were synthesized and characterized by spectral data. These compounds were subjected to in vitro antitubercular activity screening against Mycobacterium tuberculosis (H37Rv) strain. The synthesized compounds showed varied antitubercular activity ranging from 100 to 1.6μg/mL. Among the screened compounds, four compounds (H1, H2, H3 and H15) have shown moderate activity with MIC 25μg/mL. Potent activities were observed for the dihydrohispolon derivative H14 (MIC 1.6μg/mL) followed by H13 (6.25μg/mL) and H17 (12.5μg/mL), H19 (3.125μg/ML). Docking simulations gave good insights on the possible interactions between the tested compounds and β-keto acyl synthase enzyme (mtbFabH). Drug-inhibitor combination studies showed no synergism with the drugs targeting mycolic acid biosynthesis (isoniazid, ethambutol and thiolactomycin, a specific inhibitor of KAS-B enzyme) but showed significant synergism with other drugs including rifampicin and ciprofloxacin ascertaining the drug target for hispolons as inhibition of mycolic acid biosynthesis, probably via mtbFabH.
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http://dx.doi.org/10.1016/j.bmcl.2016.11.047DOI Listing
January 2017

Free radical reactions of isoxazole and pyrazole derivatives of hispolon: kinetics correlated with molecular descriptors.

Free Radic Res 2016 Dec 7;50(12):1361-1373. Epub 2016 Nov 7.

a Radiation and Photochemistry Division , Bhabha Atomic Research Centre , Trombay , Mumbai , India.

Hispolon (HS), a natural polyphenol found in medicinal mushrooms, and its isoxazole (HI) and pyrazole (HP) derivatives have been examined for free radical reactions and in vitro antioxidant activity. Reaction of these compounds with one-electron oxidant, azide radicals ([Formula: see text]) and trichloromethyl peroxyl radicals ([Formula: see text]), model peroxyl radicals, studied by nanosecond pulse radiolysis technique, indicated formation of phenoxyl radicals absorbing at 420 nm with half life of few hundred microseconds (μs). The formation of phenoxyl radicals confirmed that the phenolic OH is the active centre for free radical reactions. Rate constant for the reaction of these radicals with these compounds were in the order k ≅ k>k. Further the compounds were examined for their ability to inhibit lipid peroxidation in model membranes and also for the scavenging of 2,2'-diphenyl-1-picrylhydrazyl (DPPH) radical and superoxide ([Formula: see text]) radicals. The results suggested that HP and HI are less efficient than HS towards these radical reactions. Quantum chemical calculations were performed on these compounds to understand the mechanism of reaction with different radicals. Lower values of adiabatic ionization potential (AIP) and elevated highest occupied molecular orbital (HOMO) for HI and HP compared with HS controlled their activity towards [Formula: see text] and [Formula: see text] radicals, whereas the contribution of overall anion concentration was responsible for higher activity of HS for DPPH, [Formula: see text], and lipid peroxyl radical. The results confirm the role of different structural moieties on the antioxidant activity of hispolon derivatives.
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http://dx.doi.org/10.1080/10715762.2016.1247955DOI Listing
December 2016

The in vitro antitumor activity of arene-ruthenium(II) curcuminoid complexes improves when decreasing curcumin polarity.

J Inorg Biochem 2016 09 4;162:44-51. Epub 2016 Jun 4.

Natsol Laboratories Private Limited, Commercial Hub, J.N. Pharma City, Visakhapatnam 531019, India. Electronic address:

The antitumor activity of ruthenium(II) arene (p-cymene, benzene, hexamethylbenzene) derivatives containing modified curcumin ligands (HCurcI=(1E,4Z,6E)-5-hydroxy-1,7-bis(3,4-dimethoxyphenyl)hepta-1,4,6-trien-3-one and HCurcII=(1E,4Z,6E)-5-hydroxy-1,7-bis(4-methoxyphenyl)hepta-1,4,6-trien-3-one) is described. These have been characterized by IR, ESI-MS and NMR spectroscopy. The X-ray crystal structure of HCurcI has been determined and compared with its related Ru complex. Four complexes have been evaluated against five tumor cell lines, whose best activities [IC (μM)] are: breast MCF7, 9.7; ovarian A2780, 9.4; glioblastoma U-87, 9.4; lung carcinoma A549, 13.7 and colon-rectal HCT116, 15.5; they are associated with apoptotic features. These activities are improved when compared to the already known corresponding curcumin complex, (p-cymene)Ru(curcuminato)Cl, about twice for the breast and ovarian cancer, 4.7 times stronger in the lung cancer and about 6.6 times stronger in the glioblastoma cell lines. In fact, the less active (p-cymene)Ru(curcuminato)Cl complex only shows similar activity to two novel complexes in the colon cancer cell line. Comparing antitumor activity between these novel complexes and their related curcuminoids, improvement of antiproliferative activity is seen for a complex containing CurcII in A2780, A549 and U87 cell lines, whose IC are halved. Therefore, after replacing OH curcumin groups with OCH, the obtained species HCurcI and its Ru complexes have increased antitumor activity compared to curcumin and its related complex. In contrast, HCurcII is less cytotoxic than curcumin but its related complex [(p-cymene)Ru(CurcII)Cl] is twice as active as HCurcII in 3 cell lines. Results from these novel arene-Ru curcuminoid species suggest that their increased cytotoxicity on tumor cells correlate with increase of curcuminoid lipophilicity.
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http://dx.doi.org/10.1016/j.jinorgbio.2016.06.002DOI Listing
September 2016

Design, synthesis and in vitro cell-based evaluation of the anti-cancer activities of hispolon analogs.

Bioorg Med Chem 2015 May 21;23(9):2148-2158. Epub 2015 Mar 21.

Department of Biomedical Sciences, CVMNAH, Tuskegee University, Tuskegee, AL, USA.

Phytochemicals play an important role in cancer therapy. Hispolon and 26 of its analogs (9 known and 17 new) were synthesized and evaluated for their antiproliferative activities in a panel of six independent human cancer cell lines using the in vitro cell-based MTT assay. Among the hispolon analogs tested, compound VA-2, the most potent overall, produced its most significant effect in the colon cancer cell lines HCT-116 (IC₅₀ 1.4 ± 1.3 μM) and S1 (IC₅₀ 1.8 ± 0.9 μM) compared to its activity in the normal HEK293/pcDNA3.1 cell line (IC₅₀ 15.8±3.7 μM; p<0.01 for each comparison). Based on our results, VA-2 was about 9- to 11-times more potent in colon cancer cells and 2- to 3-times more potent in prostate cancer cells compared to HEK293/pcDNA3.1 cells. Morphological analysis of VA-2 showed significant reduction of cell number, while the cells' sizes were also markedly increased and were obvious at 68 h of treatment with 1 μM in HCT-116 (colon) and PC-3 (prostate) cancer cells. A known analog, compound VA-4, prepared by simple modifications on the aromatic functional groups of hispolon, inhibited prostate and colon cancer cell lines with IC₅₀ values <10 μM. In addition, hispolon isoxazole and pyrazole analogs, VA-7 and VA-15 (known), respectively, have shown significant activity with the mean ICv values in the range 3.3-10.7 μM in all the cancer cell lines tested. Activity varied among the analogs in which aromatic functional groups and β-diketone functional groups are modified. But the activity of analogs VA-16 to VA-27 was completely lost when the side chain double-bond was hydrogenated indicating the crucial role of this functionality for anticancer activity. Furthermore, many of the compounds synthesized were not substrates for the ABCB1-transporter, the most common cause of multidrug resistance in anti-cancer drugs, suggesting they may be more effective anticancer agents.
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http://dx.doi.org/10.1016/j.bmc.2015.03.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4398655PMC
May 2015

Hispolon inhibition of inflammatory apoptosis through reduction of iNOS/NO production via HO-1 induction in macrophages.

J Ethnopharmacol 2014 Oct 14;156:61-72. Epub 2014 Aug 14.

Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan; Cancer Research Center and Orthopedics Research Center, Taipei Medical University Hospital, Taipei, Taiwan. Electronic address:

Ethnopharmacological Relevance: Phellinus linteus (Berkeley & Curtis), a well-known medical fungus, has long been used as a traditional medicine in Oriental countries to treat various diseases, and hispolon (HIS) is one of its bioactive components. HIS is known to possess potent antineoplastic and antiviral properties; however, its effect on inflammatory apoptosis is still undefined.

Materials And Methods: RAW264.7 macrophages were incubated with HIS for 30 min followed by LPS, LTA, or PGN stimulation for 12h. The expression of indicated proteins AP-1 and NF-κB transcriptional activities was examined by Western blotting using specific antibodies. Levels of NO and ROS were examined by Griess reaction, and DCHF-DA staining via flow cytometric analysis, respectively. AP-1 and NF-κB transcriptional activities were detected by luciferase reporter assay. Knockdown of HO-1 protein expression was performed by transfection of macrophages with HO-1 siRNA. Pharmacological inhibitors including ROS scavenger NAC, JNK inhibitor SP600125, NF-κB inhibitor BAY117082 were applied for mechanism study.

Results: HIS showed concentration-dependent inhibition of LPS, LTA, and PGN-induced iNOS protein expressions and NO production by RAW264.7 macrophages. Accordingly, HIS protected RAW264.7 cells from LPS-, LTA-, and PGN-induced apoptosis. Increased HO-1 by HIS was detected at both protein and mRNA levels along with an increase in intracellular peroxide, and this was inhibited by the translational inhibitor, cycloheximide (CHX), the transcriptional inhibitor, actinomycin D (Act D), and the reactive oxygen species scavenger, N-acetylcysteine (NAC). A mechanistic study indicated that inhibition of c-Jun N-terminal kinase (JNK) protein phosphorylation, and activator protein (AP)-1 and nuclear factor (NF)-κB activation were involved in the anti-inflammatory actions of HIS in macrophages. A structure-activity relationship analysis showed that HIS expressed the most potent effect of inhibiting iNOS and apoptosis elicited by LPS, LTA, and PGN with a significant increase in HO-1 protein in macrophages.

Conclusions: Evidence supporting HIS prevention of inflammatory apoptosis via blocking NO production and inducing HO-1 protein expression in macrophages is provided, and the hydroxyl at position C3 is a critical substitution for the anti-inflammatory actions of HIS.
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http://dx.doi.org/10.1016/j.jep.2014.07.054DOI Listing
October 2014

Determination of Catechin and Epicatechin Content in Chocolates by High-Performance Liquid Chromatography.

Int Sch Res Notices 2014 28;2014:628196. Epub 2014 Oct 28.

Natsol Laboratories Private Limited, 2nd Floor, Research & Development Building, Ramky Commercial Hub, Jawaharlal Nehru Pharma City, Visakhapatnam 531 019, India.

A simple and sensitive reversed phase high-performance liquid chromatographic (HPLC) method has been developed for the determination of catechin and epicatechin in cocoa powder and chocolates. The separation was achieved on a reversed phase C 18 column (TARGA) 5 μm by gradient elution with a flow rate of 1.0 mL/minute with an operating temperature of 30°C and detection with a UV-Visible detector was at 280 nm. The method was validated for linearity, precision, intra- and interday precision, and accuracy. The developed method is successfully applied for the determination of catechin and epicatechin content in chocolates. The Godiva brand chocolate contains high concentration of epicatechin.
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http://dx.doi.org/10.1155/2014/628196DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4897191PMC
July 2016

Design of a novel nucleoside analog as potent inhibitor of the NAD dependent deacetylase, SIRT2.

Syst Synth Biol 2010 Dec 23;4(4):257-63. Epub 2011 Feb 23.

Aptuit Laurus Private Limited, ICICI Knowledge Park, Turkapally, Shameerpet, Hyderabad, 500078 India.

Sirtuins (class III histone deacetylase) are evolutionarily conserved NAD(+)-dependent enzymes that catalyze the deacetylation of acetyl-lysine residues of histones and other target proteins. Because of their associations in various pathophysiological conditions, the identification of small molecule modulators has been of significant interest. In the present study, virtual screening was carried out with NCI Diversity Set II using crystal structure of hSIRT2 (PDB ID: 1J8F) as a model for the docking procedure to find potential compounds, which were then subjected to experimental tests for their in vitro SIRT2 inhibitory activity. One of the 40 compounds tested, NSC671136 (IUPAC name: 6-Acetyl-4-oxo-1,3-diphenyl-2-thioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-5-yl 2,4-dichlorobenzoate) has structurally unique scaffold, showed strong inhibitory activity towards SIRT2 with IC(50) of ~8.7 μM and to a lesser extent on SIRT1 activity. The reported compound is substantially potent compared to the published SIRT2 inhibitors and serves as an excellent base for future lead development.
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http://dx.doi.org/10.1007/s11693-011-9069-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3065595PMC
December 2010

Bisdemethylcurcumin and structurally related hispolon analogues of curcumin exhibit enhanced prooxidant, anti-proliferative and anti-inflammatory activities in vitro.

Biochem Pharmacol 2010 Jun 4;79(11):1658-66. Epub 2010 Feb 4.

Department of Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston, 77030, USA.

Curcumin, a component of turmeric (Curcuma longa), exhibits anti-inflammatory and anti-proliferative activities through the generation of reactive oxygen species (ROS). Curcumin (diferuloylmethane) contains two hydroxyl, two methoxy and two phenyl groups but how these groups contribute to its activity is poorly understood. We synthesized analogues that varied in inclusion of these groups and compared their activity. We found that bisdemethylcurcumin (BDC) was more potent than curcumin as an anti-inflammatory agent as indicated by suppression of TNF-induced NF-kappaB activation, more potent as an anti-proliferative agent, and more potent in inducing ROS. Hispolon, which lacks one aromatic unit in relation to curcumin, also exhibited enhanced anti-inflammatory and anti-proliferative activities. When synthetic curcumin (Cur-S) was compared with bisdemethylcurcumin (BDC), hispolon, hispolon methyl ether (HME), dehydroxy hispolon (DH), hydroxy hispolon (HH), methoxy hispolon methyl ether (MHME), and methoxy hispolon (MH), we found that following order of anti-inflammatory activity: BDC=Hispolon>HME>HH>Cur-S>MHME>MH>DH; for anti-proliferative: Hispolon>BDC>MHME>Cur-S>MH>HME=HH>DH; and for prooxidant: BDC>Cur-S=MHME>HH>MH+HME>DH (254-1414 mean fluorescence intensity). Thus, dehydroxy hispolon was least potent for all three activities. Overall the results indicate that the substitution of a hydroxyl group for a methoxy group at the meta positions of the phenyl rings in curcumin significantly enhanced the anti-inflammatory activity, and the removal of phenyl ring at the 7(th) position of the heptadiene back bone and addition of hydroxyl group significantly increased the anti-proliferative activity of curcumin.
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http://dx.doi.org/10.1016/j.bcp.2010.01.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2846970PMC
June 2010

Withanolide sulfoxide from Aswagandha roots inhibits nuclear transcription factor-kappa-B, cyclooxygenase and tumor cell proliferation.

Phytother Res 2009 Jul;23(7):987-92

Bioactive Natural Products and Phytoceuticals, Department of Horticulture and National Food, Safety and Toxicology Center, Michigan State University, East Lansing, Michigan, USA.

Investigation of the methanol extract of Aswagandha (Withania somnifera) roots for bioactive constituents yielded a novel withanolide sulfoxide compound (1) along with a known withanolide dimer ashwagandhanolide (2) with an S-linkage. The structure of compound 1 was established by extensive NMR and MS experiments. Compound 1 was highly selective in inhibiting cyclooxygenase-2 (COX-2) enzyme by 60% at 100 microm with no activity against COX-1 enzyme. The IC(50) values of compound 1 against human gastric (AGS), breast (MCF-7), central nervous system (SF-268) and colon (HCT-116) cancer cell lines were in the range 0.74-3.63 microm. Both S-containing dimeric withanolides, 1 and 2, completely suppressed TNF-induced NF-kappaB activation when tested at 100 microm. The isolation of a withanolide sulfoxide from W. somnifera roots and its ability to inhibit COX-2 enzyme and to suppress human tumor cell proliferation are reported here for the first time. In addition, this is the first report on the abrogation of TNF-induced NF-kappaB activation for compounds 1 and 2.
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http://dx.doi.org/10.1002/ptr.2736DOI Listing
July 2009

Synthesis, structural revision, and antioxidant activities of antimutagenic homoisoflavonoids from Hoffmanosseggia intricata.

Bioorg Med Chem Lett 2007 Mar 15;17(5):1288-90. Epub 2006 Dec 15.

Department of Chemistry, Sri Venkateswara University, Tirupati 517 502, India.

Intricatinol and intricatin, the two homoisoflavonoids isolated from Hoffmanosseggia intricata, and two analogs have been synthesized from pyrogallol in three steps. The spectral data of synthetic intricatinol are in good agreement with those of natural metabolite, but the spectral data of intricatin are not corroborative with those of the natural product. The structure of intricatin has been thus revised to 8-methoxybonducellin, a compound isolated from Caesalpinia pulcherrima. The antioxidant activity of all the four homoisoflavonoids was determined by superoxide (NBT) and DPPH free radical scavenging methods. The synthetic analog 7,8-dihydroxy-3-[(3,4-dihydroxyphenyl)methylene]chroman-4-one displayed excellent activity in both methods.
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http://dx.doi.org/10.1016/j.bmcl.2006.12.008DOI Listing
March 2007

Ashwagandhanolide, a bioactive dimeric thiowithanolide isolated from the roots of Withania somnifera.

J Nat Prod 2006 Dec;69(12):1790-2

Laila Research Center, Unit I, Phase III, Jawahar Autonagar, Vijayawada 520 007, India.

A new dimeric withanolide, ashwagandhanolide (1), was isolated from the roots of an Ayurvedic medicinal herb, Withania somnifera. A detailed spectroscopic evaluation revealed its identity as a dimer with an unusual thioether linkage. Compound 1 displayed growth inhibition against human gastric (AGS), breast (MCF-7), central nervous system (SF-268), colon (HCT-116), and lung (NCI H460) cancer cell lines, with IC50 values in the range 0.43-1.48 microg/mL. In addition, it inhibited lipid peroxidation and the activity of the enzyme cyclooxygenase-2 in vitro.
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http://dx.doi.org/10.1021/np060147pDOI Listing
December 2006

Estimation of twelve bacopa saponins in Bacopa monnieri extracts and formulations by high-performance liquid chromatography.

Chem Pharm Bull (Tokyo) 2006 Jun;54(6):907-11

Laila Research Centre, Unit I, Phase III, Jawahar Autonagar, Vijayawada-520 007, India.

A simple and sensitive reversed phase high performance liquid chromatographic (HPLC) method has been developed for the simultaneous determination of twelve bacopa saponins present in the extracts of the Indian Medicinal Plant, Bacopa monnieri. The separation was achieved on a reversed phase C(18) column (Luna C(18)), 5 microm by isocratic elution with 0.05 M sodium sulphate buffer (pH 2.3) and acetonitrile (68.5 : 31.5, v/v) as the mobile phase at a flow rate of 1.0 ml/min with an operating temperature of 30 degrees C. The method was validated for linearity, precision, intra- and inter-day precision and accuracy. Several Bacopa samples (plant materials, extracts and commercial formulations) were successfully analyzed. Major bacopasaponins were bacosides A(3) (3), bacopaside II (4), bacopaside I (5), bacopaside X (6), bacopasaponin C (7), bacopaside N2 (9) and the minor components were bacopasaponin F (1), bacopasaponin E (2), bacopaside N1 (8) bacopaside III (10), bacopaside IV (11) and bacopaside V (12). The total saponin content in the samples, plant materials and extracts varied from 5.1 to 22.17% and 1.47 to 66.03 mg/capsule or tablet in the commercial formulations.
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http://dx.doi.org/10.1248/cpb.54.907DOI Listing
June 2006

Standardisation of Gymnema sylvestre R.Br. by high-performance thin-layer chromatography: an improved method.

Phytochem Anal 2006 May-Jun;17(3):192-6

Laila Impex Research Centre, Unit I, Phase III, Jawahar Autonagar, Vijayawada -520 007, India.

An improved high-performance thin-layer chromatographic (HPTLC) method for the standardisation of Gymnema sylvestre is reported. The method involves the initial hydrolysis of gymnemic acids, the active ingredients, to a common aglycone followed by the quantitative estimation of gymnemagenin. The present method rectifies an error found in an HPTLC method reported recently.
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http://dx.doi.org/10.1002/pca.905DOI Listing
July 2006

Regulation of vascular responses to inflammation: inducible matrix metalloproteinase-3 expression in human microvascular endothelial cells is sensitive to antiinflammatory Boswellia.

Antioxid Redox Signal 2006 Mar-Apr;8(3-4):653-60

Laboratory of Molecular Medicine, Department of Surgery, The Ohio State University Medical Center, Columbus, OH 43210, USA.

Endothelial cells are critical elements in the pathophysiology of inflammation. Tumor necrosis factor (TNF) alpha potently induces inflammatory responses in endothelial cells. Recently we have examined the genetic basis of the antiinflammatory effects of Boswellia extract (BE) in a system of TNFalpha-induced gene expression in human microvascular endothelial cells (HMECs). Of the 522 genes induced by TNFalpha in HMECs, 113 genes were sensitive to BE. BE prevented the TNFalpha-induced expression of matrix metalloproteinases (MMPs). In the current work, we sought to test the effects of BE on TNFalpha-inducible MMP expression in HMECs. Acetyl-11-ketobeta- boswellic acid (AKBA) is known to be an active principle in BE. To evaluate the significance of AKBA in the antiinflammatory properties of BE, effects of BE containing either 3% (BE3%) or 30% (BE30%, 5- Loxin) were compared. Pretreatment of HMECs for 2 days with BE potently prevented TNFalpha-induced expression and activity of MMP-3, MMP-10, and MMP-12. In vivo, BE protected against experimental arthritis. In all experiments, both in vitro and in vivo, BE30% was more effective than BE3%. In sum, this work lends support to our previous report that BE has potent antiinflammatory properties both in vitro as well as in vivo.
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http://dx.doi.org/10.1089/ars.2006.8.653DOI Listing
September 2006

Synthesis, stereochemical assignments, and biological activities of homoisoflavonoids.

Bioorg Med Chem 2006 Apr 6;14(8):2545-51. Epub 2005 Dec 6.

Department of Chemistry, Sri Venkatateswara University, Tirupati 517 502, India.

A series of four naturally occurring homoisoflavonoids and eight analogs have been synthesized starting from an appropriately substituted phenol through chroman-4-one, in four steps. The products were assigned as E-isomers based on NMR spectroscopic data. The E-isomers were converted into Z-isomers by photoisomerization. The E- and Z-isomers showed distinct chemical shifts and the differences between (E) and (Z)-homoisoflavonoids in the proton NMR spectra afford a useful method for ascertaining the stereochemistry. The antioxidant activity of homoisoflavonoids was determined by superoxide (NBT) and DPPH free radical scavenging methods. The analog 7-hydroxy-3-[(3,4,5-trihydroxyphenyl)methylene]chroman-4-one displayed excellent activity followed by sappanone A in both the methods and were several times potent than the commercial antioxidants like BHA, BHT, etc. These compounds were evaluated in vitro for their inhibitory activities against 5-lipoxygenase (5-LOX) enzyme. The analog 7-hydroxy-3-[(N,N-dimethylaminophenyl)methylene]chroman-4-one was found to possess potent inhibitory activity and was comparable to that of the standard, nordihydroguiaretic acid. These results suggest that these homoisoflavonoids, with their potent antioxidant and 5-LOX inhibitory activities, may have useful applications as antioxidants and lead compounds for asthma and inflammatory diseases.
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http://dx.doi.org/10.1016/j.bmc.2005.11.031DOI Listing
April 2006

Cardioprotective activity of alcoholic extract of Tinospora cordifolia in ischemia-reperfusion induced myocardial infarction in rats.

Biol Pharm Bull 2005 Dec;28(12):2319-22

Pharmacology Division, Department of Pharmaceutical Sciences, Andhra University, Pradesh, India.

It has been suggested that the beneficial effects of reperfusing the myocardium might be in part reversed by the occurrence of reperfusion injury. Oxidative stress was suggested to be implicating in the pathogenesis of ischemia-reperfusion (I/R) injury. Many antioxidative plants were shown to be cardioprotective in experimental models of myocardial ischemia-reperfusion (I/R) injury. The present study was designed to investigate the effects of pretreatment with alcoholic extract of Tinospora cordifolia in an in vivo rat model. The model adopted was that of surgically-induced myocardial ischemia, performed by means of left anterior descending coronary artery occlusion (LAD) for 30 min followed by reperfusion for another 4 h. Infarct size was measured by using the staining agent TTC (2,3,5-triphenyl tetrazolium chloride). Lipid peroxide levels in serum and in heart tissue were estimated spectrophotometrically by the methods developed by Yagi and Ohkawa et al. respectively. A lead II electrocardiogram was monitored at various intervals throughout the experiment. A dose dependent reduction in infarct size and in lipid peroxide levels of serum and heart tissue were observed with the prior treatment of T. cordifolia with various doses for 7 d compared to control animals. Hence, the present study suggests the cardioprotective activity of T. cordifolia in limiting ischemia-reperfusion induced myocardial infarction.
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http://dx.doi.org/10.1248/bpb.28.2319DOI Listing
December 2005

Triterpenoid glycosides from Bacopa monnieri.

Phytochemistry 2005 Dec 15;66(23):2719-28. Epub 2005 Nov 15.

Laila Impex Research Center, Unit I, Phase III, Jawahar Autonagar, Vijayawada 520 007, India.

Two triterpenoid glycosides have been isolated along with 10 known saponins from Bacopa monnieri. Structures of the compounds have been elucidated as 3-O-[beta-D-glucopyranosyl-(1-->3)-beta-D-glucopyranosyl] jujubogenin (1) and 3-O-[beta-D-glucopyranosyl-(1-->3)-beta-D-glucopyranosyl] pseudojujubogenin (2) by high resolution NMR spectral data and chemical correlations. Further, the chemical compositions of bacosides A and B have been delineated.
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http://dx.doi.org/10.1016/j.phytochem.2005.09.016DOI Listing
December 2005

Synthesis and biological evaluation of polyhydroxycurcuminoids.

Bioorg Med Chem 2005 Dec 19;13(23):6374-80. Epub 2005 Aug 19.

Laila Impex Research Centre, Unit 1, Phase III, Jawahar Autonagar, Vijayawada, India.

A series of curcumin analogs (1-3, 5a-5t) was synthesized through the condensation of appropriately protected hydroxybenzaldehydes with acetylacetone, followed by deprotection. The antioxidant activity of these analogs was determined by superoxide free radical nitroblue tetrazolium and DPPH free radical scavenging methods and the polyhydroxycurcuminoids (5l-5s) displayed excellent antioxidant activity. These analogs showed cytotoxicity to lymphocytes and promising tumor-reducing activity on Dalton's lymphoma ascites tumor cells.
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http://dx.doi.org/10.1016/j.bmc.2005.06.050DOI Listing
December 2005

Bioefficacy of a novel calcium-potassium salt of (-)-hydroxycitric acid.

Mutat Res 2005 Nov 1;579(1-2):149-62. Epub 2005 Aug 1.

InterHealth Research Center, Benicia, CA, USA.

Obesity is associated with cardiovascular disease, diabetes and certain forms of cancer. Popular strategies on weight loss often fail to address many key factors such as fat mass, muscle density, bone density, water mass, their inter-relationships and impact on energy production, body composition, and overall health and well-being. (-)-Hydroxycitric acid (HCA), a natural plant extract from the dried fruit rind of Garcinia cambogia, has been reported to promote body fat loss in humans without stimulating the central nervous system. The level of effectiveness of G. cambogia extract is typically attributed solely to HCA. However, other components by their presence or absence may significantly contribute to its therapeutic effectiveness. Typically, HCA used in dietary weight loss supplement is bound to calcium, which results in a poorly soluble (<50%) and less bioavailable form. Conversely, the structural characteristics of a novel Ca2+/K+ bound (-)-HCA salt (HCA-SX or Super CitriMax) make it completely water soluble as well as bioavailable. An efficacious dosage of HCA-SX (4500 mg/day t.i.d.) provides a good source of Ca2+ (495 mg, 49.5% of RDI) and K+ (720 mg, 15% of RDI). Ca2+ ions are involved in weight management by increasing lipid metabolism, enhancing thermogenesis, and increasing bone density. K+, on the other hand, increases energy, reduces hypertension, increases muscle strength and regulates arrhythmias. Both Ca and K act as buffers in pH homeostasis. HCA-SX has been shown to increase serotonin availability, reduce appetite, increase fat oxidation, improve blood lipid levels, reduce body weight, and modulate a number of obesity regulatory genes without affecting the mitochondrial and nuclear proteins required for normal biochemical and physiological functions.
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http://dx.doi.org/10.1016/j.mrfmmm.2005.02.021DOI Listing
November 2005

Flavonoids, triterpenoids and a lignan from Vitex altissima.

Phytochemistry 2005 Jul;66(14):1707-12

Department of Pharmaceutical Chemistry, Sri Padmavathi School of Pharmacy, Tiruchanoor, Tirupati 517 503, India.

A new tetrahydrofuranoid lignan, altissinone (1) and a new acylated flavone C-glucoside, 2''-O-p-hydroxybenzoylorientin (2), were isolated in addition to several known triterpene acids and flavonoids from the ethyl acetate extractives of the leaves of Vitex altissima. The structures of the compounds were established based on interpretation of high resolution NMR (HMQC, HMBC and NOESY) spectral data. The ethyl acetate extract exhibited significant anti-inflammatory activity in rat paw edema model. The flavonoids and triterpene acids showed moderate antioxidant and 5-lipoxygenase enzyme inhibitory activities, respectively.
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http://dx.doi.org/10.1016/j.phytochem.2005.05.008DOI Listing
July 2005

Estimation of trans-resveratrol in herbal extracts and dosage forms by high-performance thin-layer chromatography.

Chem Pharm Bull (Tokyo) 2005 Jun;53(6):691-3

Laila Impex Research Centre, Unit I, Phase III, Jawahar Autonagar, Vijayawada-520 007, India.

A simple, sensitive and precise high-performance thin-layer chromatographic (HPTLC) method of analysis of trans-resveratrol in Polygonum cuspidatum root extracts and in dosage forms was developed and validated. The separation was carried out on a TLC aluminium plates precoated with silica gel 60F-254 as the stationary phase, eluted with chloroform-ethylacetate-formic acid (2.5 : 1 : 0.1) as mobile phase. Densitometric analysis of trans-resveratrol was carried out in the absorbance mode at 313 nm. This system was found to give compact spot for trans-resveratrol (Rf value of 0.40+/-0.03). A good linear regression relationship between peak areas and the concentrations was obtained over the range of 0.5-3.0 microg/spot with correlation coefficient 0.9989. The limit of detection and quantification was found to be 9 and 27 ng/spot. The method was validated for precision and recovery. The spike recoveries were within 99.85 to 100.70%. The RSD values of the precision in the range 0.37-1.84%. The proposed developed HPTLC method can be applied for identification and quantitative determination of trans-resveratrol in herbal extracts and dosage forms.
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http://dx.doi.org/10.1248/cpb.53.691DOI Listing
June 2005

Human genome screen to identify the genetic basis of the anti-inflammatory effects of Boswellia in microvascular endothelial cells.

DNA Cell Biol 2005 Apr;24(4):244-55

Laboratory of Molecular Medicine, Department of Surgery, The Ohio State University Medical Center, Columbus, Ohio 43210, USA.

Inflammatory disorders represent a substantial health problem. Medicinal plants belonging to the Burseraceae family, including Boswellia, are especially known for their anti-inflammatory properties. The gum resin of Boswellia serrata contains boswellic acids, which inhibit leukotriene biosynthesis. A series of chronic inflammatory diseases are perpetuated by leukotrienes. Although Boswellia extract has proven to be anti-inflammatory in clinical trials, the underlying mechanisms remain to be characterized. TNF alpha represents one of the most widely recognized mediators of inflammation. One mechanism by which TNFalpha causes inflammation is by potently inducing the expression of adhesion molecules such as VCAM-1. We sought to test the genetic basis of the antiinflammatory effects of BE (standardized Boswellia extract, 5-Loxin) in a system of TNF alpha-induced gene expression in human microvascular endothelial cells. We conducted the first whole genome screen for TNF alpha- inducible genes in human microvascular cells (HMEC). Acutely, TNF alpha induced 522 genes and downregulated 141 genes in nine out of nine pairwise comparisons. Of the 522 genes induced by TNF alpha in HMEC, 113 genes were clearly sensitive to BE treatment. Such genes directly related to inflammation, cell adhesion, and proteolysis. The robust BE-sensitive candidate genes were then subjected to further processing for the identification of BE-sensitive signaling pathways. The use of resources such as GenMAPP, KEGG, and gene ontology led to the recognition of the primary BE-sensitive TNF alpha-inducible pathways. BE prevented the TNF alpha-induced expression of matrix metalloproteinases. BE also prevented the inducible expression of mediators of apoptosis. Most strikingly, however, TNF alpha-inducible expression of VCAM-1 and ICAM-1 were observed to be sensitive to BE. Realtime PCR studies showed that while TNF alpha potently induced VCAM-1 gene expression, BE completely prevented it. This result confirmed our microarray findings and built a compelling case for the anti-inflammatory property of BE. In an in vivo model of carrageenan-induced rat paw inflammation, we observed a significant antiinflammatory property of BE consistent with our in vitro findings. These findings warrant further research aimed at identifying the signaling mechanisms by which BE exerts its anti-inflammatory effects.
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http://dx.doi.org/10.1089/dna.2005.24.244DOI Listing
April 2005