Cellular protein synthesis is accelerated in human colorectal cancer (CRC), and high expression of protein synthesis regulators in CRC patients is associated with poor prognosis.Thus, inhibition of protein synthesis may be an effective therapeutic strategy for CRC.We previously demonstrated that the quassinoid bruceantinol (BOL) had antitumor activity against CRC.Herein, potent tumor growth suppression (>80%) and STAT3 inhibition was observed in two different mouse models following BOL administration.Loss of body and spleen weight was observed but was eliminated upon nanoparticle encapsulation while maintaining strong antitumor activity.STAT3 siRNA knockdown exhibited modest suppression of cell proliferation.Surprisingly, STAT3 inhibition using a PROTAC degrader (SD-36) had little effect on cancer cell proliferation suggesting the possibility of addnl. mechanism(s) of action for quassinoids.BOL-resistant (BR) cell lines, HCT116^BR and HCA7^BR, were equally sensitive to standard CRC therapeutic agents and known STAT3 inhibitors but resistant to homoharringtonine (HHT), a known protein synthesis inhibitor.The ability of quassinoids to inhibit protein synthesis was dependent on the structure of the C15 sidechain.Of note, BOL did not inhibit protein synthesis in normal human colon epithelial cells whereas HHT and napabucasin remained effective in these normal cells.Novel quassinoids were designed, synthesized, and evaluated in pre-clin. CRC models.Treatment with the most potent analog, 5c, resulted in significant inhibition of cell proliferation and protein synthesis at nanomolar concentrationsThese quassinoid analogs may represent a novel class of protein synthesis inhibitors for the treatment of human CRC.

2023-02-01·Phytomedicine

Quassinoids from Eurycoma longifolia with antiviral activities by inhibiting dengue virus replication

Article

作者: Fang, Xiaochuan ; Fan, Chunlin ; Yu, Jingtao ; He, Xuemei ; Yang, Tangjia ; Liu, Junshan ; Wen, Ting ; Tian, Chunyang ; Zheng, Yuanru ; Yu, Linzhong

BACKGROUNDDengue caused by dengue virus (DENV) spreads rapidly around the world. However, there are no worldwide licensed vaccines or specific antivirals to combat DENV infection. Quassinoids are the most characteristic components of Eurycoma longifolia, which have been reported to display a variety of biological activities. However, whether quassinoids exert anti-DENV activities remains unknown.PURPOSETo test the quassinoids of E. longifolia for their activity against DENV and to clarify the potential mechanisms.METHODSThe quassinoids from E. longifolia were isolated by chromatography techniques, and their chemical structures were elucidated by spectroscopic analysis. The anti-DENV activities of quassinoids on baby hamster kidney cells BHK-21 were determined by lactate dehydrogenase (LDH) assay. The synthesis of progeny virus was measured by plaque assay. The expression levels of envelope protein (E) and non-structural protein 1 (NS1) were evaluated by qRT-PCR, Western blot and immunofluorescence assays. Molecular docking was used to screen the potential targets of the most active quassinoid against DENV-2, and surface plasmon resonance analysis was employed to confirm the direct binding between the most active quassinoid and potential target.RESULTSTwenty-four quassinoids, including three new quassinoids (1 - 3), were isolated from the ethanol extract of E. longifolia. Quassinoids 4, 5, 9, 11, 12, 15, 16, 17, 19 and 20 significantly reduced the LDH release at the stages of viral binding and entry or intracellular replication. Among them, 19 (6α-hydroxyeurycomalactone, 6α-HEL) exhibited the best anti-DENV-2 activities with an EC₅₀ value of 0.39 ± 0.02 μM. Further experiments suggested that 6α-HEL remarkably inhibited progeny virus synthesis and mRNA and protein expression levels of E and NS1 of DENV-2. Time-of-drug-addition assay suggested that 6α-HEL inhibited intracellular replication of DENV-2 at an early stage. Moreover, 6α-HEL was shown to interact with NS5-RdRp domain at a binding affinity of -8.15 kcal/mol. SPR assay further verified 6α-HEL bound to RdRp protein with an equilibrium dissociation constant of 1.49 × 10^-7 M.CONCLUSIONTen quassinoids from E. longifolia showed anti-DENV activities at processes of virus binding and entry or intracellular replication. The most active quassinoid 6α-HEL exerts the anti-DENV-2 activities at intracellular replication stage by directly targeting the NS5-RdRp protein. These results suggest that 6α-HEL could be a promising candidate for the treatment of DENV-2 infection.

2017-12-01·Phytotherapy Research2区 · 医学

Polar Quassinoids in Standardized Eurycoma longifolia Extract Formulated into a Lipid‐Based Solid Dispersion to Improve Rat Sperm Count

2区 · 医学

Article

作者: Chan, Kit‐Lam ; Khan, Nurzalina Abdul Karim ; Ma, Hai‐Qiu ; Low, Bin‐Seng ; Ebrahimi, Forough

Eurycoma longifolia Jack is popularly sought in Southeast Asian countries for traditional remedies to improve sexual performance and fertility. 13α(21)‐Epoxyeurycomanone and eurycomanone, two major quassinoids in a root extract (TAF2) were reported to improve rat spermatogenesis and fertility. Unfortunately, these quassinoids possess low bioavailability because of high aqueous solubility and low lipid membrane permeability. Often, other possible barriers may be P‐glycoprotein (P‐gp) efflux in the gut and presystemic hepatic metabolism. The present study attempted to solve these problems by formulating a lipid‐based solid dispersion (TAF2‐SD) of optimized mixture of TAF2 and emulsifiers, which was then orally administered to rats prior to sperm count analysis. The TAF2‐SD‐treated rats showed significantly twofold (p < 0.001) and fourfold (p < 0.001) higher sperm count than did TAF2‐treated and vehicle‐treated (control) rats, respectively. The study also demonstrated no significant in vitro ileal absorption changes of the quassinoids by P‐gp efflux inhibitors and concentration change or secondary metabolite formation upon in vitro incubation with rat liver homogenates, suggesting that P‐gp‐mediated efflux and presystemic metabolism were not limiting their bioavailability. Further study on orally TAF2‐treated rats confirmed that the area under the curve and bioavailability curve of each quassinoid in the absence and presence of ketoconazole were unchanged. Copyright © 2017 John Wiley & Sons, Ltd.

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2023-06-08

·Business Wire

Gusto Global and Crohn’s & Colitis Foundation Expand Partnership to Advance Prognostic and Therapeutic Technologies for IBD

RESEARCH TRIANGLE PARK, N.C.--( BUSINESS WIRE )--Gusto Global, LLC announces an expansion of its partnership with the Crohn’s & Colitis Foundation to advance groundbreaking technical development for a prognostic linking predictive microbiome-based biomarkers to sustainable remission. With inflammatory bowel disease (IBD) affecting nearly 1 in 100 Americans and growing, the need for precision-oriented tools to gain microbiome insights and improve treatment protocols is urgent. Dr. Daniel van der Lelie, CEO of Gusto Global, illustrates the driving force accelerating the collaboration, “Our vision is to provide an unprecedented view into critical IBD biomarkers and equip patients with never-before-seen perspective to monitor disease onset, progression, and treatment response, paving a much clearer path towards interventions that lead to long-term success. Reducing the burden of taking medications that only address symptoms is not a distant goal but an immediate requirement. ” The Crohn’s & Colitis Foundation previously funded development of Gusto’s rigorously defined and systematically profiled community of bacteria aiming to treat IBD by rebalancing a healthy microbiome ( Nature Communications ). Andres Hurtado-Lorenzo, PhD, VP of Translational Research and IBD Ventures at Crohn’s & Colitis Foundation expressed enthusiasm for this unique strategy, “Through our IBD Ventures investment in Gusto Global, we are catalyzing the advancement of innovative microbiome-based therapeutics. We are excited about the potential of this technology to provide a novel approach to induce sustained remission in patients with IBD.” The expansion of the partnership recognizes that the computational platform that enables Gusto’s smart Live Biotherapeutic Product design can be advanced to also confirm microbial biomarkers indicative of IBD pathology and offer actionable patient insights. Angela Dobes, Vice President, IBD Plexus, Crohn’s & Colitis Foundation, stated, “We are delighted to expand the relationship with Gusto Global to better understand disease progression – an area of high unmet need in IBD - and generate a novel dataset to drive new insights and advance progress towards precision medicine.” The Crohn’s & Colitis Foundation is providing access to its IBD Plexus platform, one of the world’s most comprehensive collections of IBD data, information, and bio samples. Guided by the patient voice, IBD Plexus unites the research community to answer the most important questions in IBD. This access allows Gusto to further validate the pioneering sequencing and computational capabilities of its Tapestry® platform. Tapestry® aims to provide high-resolution individual microbiome signatures from stool and blood samples – advancing the promise of precision medicine for IBD. About Gusto Global Gusto Global is at the forefront of microbiome innovation, harnessing novel sequencing and computational technologies for an intricate understanding of the impact of microorganisms on human health. With over six decades of collective experience in the fields of microbiology, molecular biology and the modeling of bacterial behavior, Gusto’s team transcends conventional understanding. Gusto’s Tapestry® platform integrates well understood mechanistic interactions between microbes and humans into clinical applications that will fundamentally change healthcare. The Company’s current programs target immune-mediated diseases and oncology. Gusto’s mission is to detect and provide optimal treatment options and outcomes for conditions that impact or have been impacted by the human microbiome. For more information, visit http://www.gustoglobal.com . About the Crohn’s & Colitis Foundation The Crohn's & Colitis Foundation is the leading nonprofit organization focused on both research and patient support for inflammatory bowel disease (IBD), with the mission of curing Crohn's disease and ulcerative colitis and improving quality of life for the millions of Americans living with IBD. The Foundation’s work is dramatically accelerating the research process, while also providing extensive educational and support resources for patients and their families, medical professionals, and the public. For more information, visit crohnscolitisfoundation.org, call 888-694-8872, or email info@crohnscolitisfoundation.org . Publication Reference van der Lelie, D., Oka, A., Taghavi, S. et al. Rationally designed bacterial consortia to treat chronic immune-mediated colitis and restore intestinal homeostasis. Nat Commun 12 , 3105 (2021). https://doi.org/10.1038/s41467-021-23460-x

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