Pentagalloylglucose Research Articles

Sulfonated Penta-Galloyl Glucose (SPGG): The Pharmacological Effects of Promiscuous Glycosaminoglycan Small Molecule Mimetic.

Sulfated glycosaminoglycans (SGAGs), such as heparin, are complex linear polysaccharides attached to core proteins via covalent bonds to form proteoglycans. SGAGs are crucial in assembling extracellular matrix, the regulation of cell signaling and cell behavior, hemostasis, development, and various diseases, including thrombosis, cancer, infectious diseases, and neurodegenerative disorders, through their binding with diverse proteins. Despite the abundant SGAG-protein interactions provided by nature, the development of small SGAG-like molecules remains underexplored. However, sulfonated penta-galloyl glucose (SPGG) represents a promising, easily synthesized, small-molecule mimetic of SGAGs, capable of harnessing these interactions. This minireview discusses the chemical synthesis and characterization of SPGG, along with its pharmacological effects derived from modulating the SGAG-protein interface.

LC-MS-based metabolomics for the profiling of bioactive compounds in tree peony flower buds with multiple bioactive potentials

Tree peonies (Paeonia suffruticosa) are important pharmaceutical and oilseed crops widely cultivated in China. Tree peony flowers, as important by-products of the industrial crops, are conventionally used as folk medicine with health-promoting effects on human. However, the in-depth understanding of biologically active compounds in tree peony flowers is scarce. In this study, an in-depth analysis of bioactive compounds in tree peony flower buds (TPFBs) from 74 cultivars was conducted using an integrated LC-MS-based metabolomic approach. Ninety-two metabolites were tentatively identified in TPFBs. The quantitative results revealed that TPFBs were abundant in bioactive compounds. Among these, paeoniflorin, albiflorin, cynaroside, and pentagalloylglucose (PGG) emerged as the primary chemical markers of TPFBs, showing significant variations based on genotype. Each extract of TPFB exhibited potent antioxidant, antibacterial, and anti-neuroinflammatory activities. Notably, TPFB extract showed the highest effectiveness in inhibiting L. monocytogenes among all tested bacteria. Cynaroside was predicted to serve as a pivotal component in TPFB for its anti-neuroinflammatory effects by interacting with toll-like receptor 4 (TRL4) and interleukin-1beta (IL-1β). This study offers novel insights into the bioactive compounds and bioactivities of TPFBs, which lays theoretical basis for the application in pharmaceutical industry.

Pentagalloylglucose alleviates acetaminophen-induced acute liver injury by modulating inflammation via cGAS-STING pathway

BackgroundThe cGAS-STING pathway is an important component of the innate immune system and plays significant role in acetaminophen-induced liver injury (AILI). Pentagalloylglucose (PGG) is a natural polyphenolic compound with various beneficial effects, including anti-cancer, antioxidant, anti-inflammatory, and liver-protective properties; however, whether it can be used for the treatment of AILI and the specific mechanism remain unclear.Materials and methodsA cell culture model was created to study the effect of PGG on cGAS-STING pathway activation using various techniques including western blotting (WB), real-time quantitative polymerase chain reaction (RT-qPCR), immunofluorescence (IF), and immunoprecipitation (IP). The effect of PGG was investigated in vivo by establishing a dimethylxanthenone acetic acid (DMXAA)-mediated activation model. An AILI model was used to evaluate the hepatoprotective and therapeutic effects of PGG by detecting liver function indicators, liver histopathology, and cGAS-STING pathway-related indicators in mice with AILI.ResultsPGG blocked cGAS-STING pathway activation in bone marrow-derived macrophages (BMDMs), THP-1 cells, and peripheral blood mononuclear cells (PBMCs) in vitro. Furthermore, PGG inhibited the generation of type I interferons (IFN-I) and the secretion of inflammatory factors in DMXAA-induced in vivo experiments. In addition, PGG also reduced serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP), improved liver tissue damage and apoptosis, and inhibited the cGAS-STING pathway activation caused by acetaminophen. In terms of the mechanism, PGG disrupted the connection between STING and TBK1.ConclusionsPGG exerts a protective effect against AILI by blocking the cGAS-STING pathway, offering a promising treatment strategy.

Pentagalloyl glucose enhanced the stress resistance to delay aging process in Caenorhabditis elegans

Aging is a complex biological process characterized by gradual and irreversible functional deterioration, strongly associated with oxidative stress. Pentagalloyl glucose (PGG) has attracted increasing attention due to its potent antioxidant and anti-stress properties. This study investigated the potential of PGG to mitigate the aging process under stress in RAW 264.7 cells and Caenorhabditis elegans models. The expression of vital genes associated with stress was also measured to explain the action mechanism of PGG in C. elegans. The findings showed that PGG supplementation not only significantly enhanced the stress tolerance of RAW 264.7 cells, but also prolonged lifespan and reduced the ROS and lipofuscin accumulation in C. elegans induced by stress. Meanwhile, the improvement effect of PGG on delaying aging development was also manifested in the protection of mitochondrial function and neuronal integrity. Moreover, daf-16 nuclear translocation and sod-3 expression were significantly enhanced by PGG to delay the aging process. Mechanistically, PGG might alleviate aging by improving daf-16, sod-3, ctl-1, and gst-4 levels in the DAF-16/FOXO pathway and upregulating skn-1 and gst-4 expression in the SKN-1/Nrf2 pathway. Our study provided novel insights into the role of PGG in combating stress-induced aging.

Dual-Drug Nanomedicine Assembly with Synergistic Anti-Aneurysmal Effects via Inflammation Suppression and Extracellular Matrix Stabilization.

Abdominal aortic aneurysm (AAA) represents a critical cardiovascular condition characterized by localized dilation of the abdominal aorta, carrying a significant risk of rupture and mortality. Current treatment options are limited, necessitating novel therapeutic approaches. This study investigates the potential of a pioneering nanodrug delivery system, RAP@PFB, in mitigating AAA progression. RAP@PFB integrates pentagalloyl glucose (PGG) and rapamycin (RAP) within a metal-organic-framework (MOF) structure through a facile assembly process, ensuring remarkable drug loading capacity and colloidal stability. The synergistic effects of PGG, a polyphenolic antioxidant, and RAP, an mTOR inhibitor, collectively regulate key players in AAA pathogenesis, such as macrophages and smooth muscle cells (SMCs). In macrophages, RAP@PFB efficiently scavenges various free radicals, suppresses inflammation, and promotes M1-to-M2 phenotype repolarization. In SMCs, it inhibits apoptosis and calcification, thereby stabilizing the extracellular matrix and reducing the risk of AAA rupture. Administered intravenously, RAP@PFB exhibits effective accumulation at the AAA site, demonstrating robust efficacy in reducing AAA progression through multiple mechanisms. Moreover, RAP@PFB demonstrates favorable biosafety profiles, supporting its potential translation into clinical applications for AAA therapy.

Pentagalloyl Glucose (PGG) Exhibits Anti-Cancer Activity against Aggressive Prostate Cancer by Modulating the ROR1 Mediated AKT-GSK3β Pathway.

Androgen-receptor-negative, androgen-independent (ARneg-AI) prostate cancer aggressively proliferates and metastasizes, which makes treatment difficult. Hence, it is necessary to continue exploring cancer-associated markers, such as oncofetal Receptor Tyrosine Kinase like Orphan Receptor 1 (ROR1), which may serve as a form of targeted prostate cancer therapy. In this study, we identify that Penta-O-galloyl-β-D-glucose (PGG), a plant-derived gallotannin small molecule inhibitor, modulates ROR1-mediated oncogenic signaling and mitigates prostate cancer phenotypes. Results indicate that ROR1 protein levels were elevated in the highly aggressive ARneg-AI PC3 cancer cell line. PGG was selectively cytotoxic to PC3 cells and induced apoptosis of PC3 (IC50 of 31.64 µM) in comparison to normal prostate epithelial RWPE-1 cells (IC50 of 74.55 µM). PGG was found to suppress ROR1 and downstream oncogenic pathways in PC3 cells. These molecular phenomena were corroborated by reduced migration, invasion, and cell cycle progression of PC3 cells. PGG minimally and moderately affected RWPE-1 and ARneg-AI DU145, respectively, which may be due to these cells having lower levels of ROR1 expression in comparison to PC3 cells. Additionally, PGG acted synergistically with the standard chemotherapeutic agent docetaxel to lower the IC50 of both compounds about five-fold (combination index = 0.402) in PC3 cells. These results suggest that ROR1 is a key oncogenic driver and a promising target in aggressive prostate cancers that lack a targetable androgen receptor. Furthermore, PGG may be a selective and potent anti-cancer agent capable of treating ROR1-expressing prostate cancers.

Pentagalloyl Glucose and Gallotannins from Mangifera Indica L. Seed Kernel Extract as A Promising Antifungal Feed Additive, In Vitro, and In Silico Studies

Recently, the valorization of agro-industrial wastes through their exploration of their bioactive compounds has become a necessary trend to maximize their applications in various production sectors, particularly animal feeding. In the study, mango seed kernels were used as agro-industrial wastes to extract gallotannins fraction (GF) and pentagalloyl glucose (PGG). The GF and PGG were mixed with poultry feeds to investigate their potential ability to control Aspergillus flavus (A. flavus) growth and inhibit its production of aflatoxins (AFs). Ketoconazole was used as an antifungal standard. GF and PGG combat the growth of A. flavus, with minimum inhibition concentration (MIC) of 21.7 ± 1.7 and 20 ± 0 mg/mL, respectively. Moreover, GF and PGG showed promising results in preventing the production of AFs (AFB1, AFB2, AFG1, and AFG2) at 5 and 10 mg/100-gram feed. Furthermore, to explain the mode of action of PGG as an antifungal agent, a molecular docking study has been performed against Type 1 Polyketide Synthase (PKS), which is found in many toxigenic Aspergillus species and has a highly active Acyl Carrier Protein (ACP) domain that is implicated in thiol ester-bound intermediates involved in fungal polyketides, fatty acids, and other non-ribosomal peptide formation, which are highly implicated in the construction of aflatoxin biosynthesis. The promising results prompt us to use mango seed extract as a cheap source of gallotannin components as a safe feed additive for reducing fungal and mycotoxin contamination in animal feeds.

Pentagalloyl glucose induces anti-inflammatory macrophage polarization - suppressing macrophage mediated vascular cell dysfunction and TGF-β secretion.

Background: Pentagalloyl glucose (PGG) is a polyphenol with vasoprotective properties. Targeted delivery of PGG reversed aortic aneurysm growth in several rodent models associated with decreased number of macrophages and transforming growth factor-β (TGF-β) expression. Thus, we sought to determine cellular mechanisms by which PGG reduces macrophage-induced aortic pathogenicity and its relationship to TGF-β. Methods: Using THP-1 cells, primary human aortic cells, and explanted rat aortas, we assessed the anti-inflammatory effect of PGG. Expression of pro/anti-inflammatory macrophage markers was analyzed. Adhesion of monocytes as well as oxidative stress status, viability, and TGF-β expression after primary aortic cell exposure to macrophage-conditioned medium with and without PGG were assessed. The release of TGF-β was also examined in elastase-treated cultured rat aortas. Results: PGG pre-treatment of human aortic cell monolayers reduced the adhesion of THP-1 monocytes. PGG enhanced the expression of anti-inflammatory markers in THP-1-derived macrophages, and increased mitochondrial reactive oxygen species as well as mitochondrial polarization. Conditioned medium from THP-1-derived macrophages induced reactive oxygen species, cell death, and TGF-β release from human aortic cells, which was suppressed by PGG. In explanted rat aortas, PGG reduced elastase mediated TGF-β release. Conclusions: Combining anti-inflammatory, cytotoxic, and oxidative effects, PGG has high cardiovascular therapeutic potential. We confirmed previous in vivo observations whereby PGG suppressed TGF-β response associated with disease resolution.

Comparative analysis of chemical components in fruits of Chebulae Fructus and its pulp based on chromatographic technology coupled with multivariate chemometric methods

Chebulae Fructus, was extensively used as a food supplement and medicinal herb, which contained two medicinal forms corresponding to the mature fruit of Chebulae Fructus (CF) and CF pulp. They were widely used in the Chinese clinical medicine and it played a significant role in the Mongolian and Tibetan medicine for the treatment of sore throat, asthma, diarrhea and other diseases. Both of them were recorded in the 2020 Edition (Volume I) of the Chinese Pharmacopoeia. However, the chemical components of CF and CF pulp have not been holistically explored, which seriously hindered its quality evaluation. This study investigated the overall chemical profile of the CF and CF pulp using ultra high-performance liquid chromatography coupled with quadrupole time of flight mass spectrometry (UHPLC-Q-TOF/MS) and ultra high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). Sixty-four chemical components were tentatively identified, and 13 components were quantified in Chebulae Fructus. Furthermore, multivariate chemometric methods were applied to compare the differences among CF samples, and all samples were classified by orthogonal partial least squares-discriminant analysis (OPLS-DA) based on the 13 quantified compounds. The results showed that CF and CF pulp were clustered in two different areas. Ellagic acid, chebulagic acid, chebulinic acid, corilagin and pentagalloyl glucose were selected as the significant constituents to different of CF and CF pulp. LC-MS coupled with chemometrics strategy analysis could comprehensively evaluate the holistic quality of CF, which provided a necessary information for the rational development and utilization of CF and CF pulp resource.

Enrichment, analysis, identification and mechanism of antioxidant components in Toona sinensis

• Toona sinensis has strong antioxidant activity. • Liquid-liquid-refining extraction was developed to enrich antioxidants from extract. • Pentagalloyl glucose and ethyl gallate were the main antioxidants. • Single electron transfer followed by proton transfer is main antioxidant mechanism. The tender leaves of Toona sinensis not only taste delicious, but also have a wide range of biological activities, including strong antioxidant activity. In this study, a method based on liquid-liquid-refining extraction and bioassay-guided separation were established and developed for enrichment, analysis and identification of antioxidant components in T. sinensis . Two main antioxidants, 1,2,3,4,6-penta-O-galloyl-β-D-glucose (PGG) and ethyl gallate (EG) with strong antioxidant capacity were responsible for the antioxidant activity of T. sinensis . The EC 50 of EG scavenging ABTS· + and DPPH· were 4.46 ± 0.05 μg/mL and 7.61 ± 0.13 μg/mL, and the EC 50 of PGG were 12.90 ± 0.16 μg/mL and 16.29 ± 0.20 μg/mL. The thermodynamic parameters of various pathways indicated that single electron transfer followed by proton transfer (SET-PT) was the main antioxidant mechanism of PGG and EG. Furthermore, the results of frontier molecular orbital theory and reaction kinetics showed that PGG had low energy gap and reaction energy barrier, which was the fundamental reason why its antioxidant activity was better than EG. Graphical Abstract. .

Pentagalloyl Glucose-Targeted Inhibition of P-Glycoprotein and Re-Sensitization of Multidrug-Resistant Leukemic Cells (K562/ADR) to Doxorubicin: In Silico and Functional Studies.

Combining phytochemicals with chemotherapeutic drugs has demonstrated the potential to surmount drug resistance. In this paper, we explore the efficacy of pentagalloyl glucose (PGG) in modulating P-gp and reversing multidrug resistance (MDR) in drug-resistant leukemic cells (K562/ADR). The cytotoxicity of PGG was evaluated using a CCK-8 assay, and cell apoptosis was assessed using flow cytometry. Western blotting was used to analyze protein expression levels. P-glycoprotein (P-gp) activity was evaluated by monitoring the kinetics of P-gp-mediated efflux of pirarubicin (THP). Finally, molecular docking, molecular dynamics simulation, and molecular mechanics with generalized Born and surface area solvation (MM-GBSA) calculation were conducted to investigate drug-protein interactions. We found that PGG selectively induced cytotoxicity in K562/ADR cells and enhanced sensitivity to doxorubicin (DOX), indicating its potential as a reversal agent. PGG reduced the expression of P-gp and its gene transcript levels. Additionally, PGG inhibited P-gp-mediated efflux and increased intracellular drug accumulation in drug-resistant cells. Molecular dynamics simulations and MM-GBSA calculation provided insights into the binding affinity of PGG to P-gp, suggesting that PGG binds tightly to both the substrate and the ATP binding sites of P-gp. These findings support the potential of PGG to target P-gp, reverse drug resistance, and enhance the efficacy of anticancer therapies.

Pentagalloyl glucose-stabilized decellularized bovine jugular vein valved conduits as pulmonary conduit replacement

Congenital heart diseases (CHD) are one of the most frequently diagnosed congenital disorders, affecting approximately 40,000 live births annually in the United States. Out of the new patients diagnosed with CHD yearly, an estimated 2,500 patients require a substitute, non-native conduit artery to replace structures congenitally absent or hypoplastic. Devices used for conduit replacement encounter limitations exhibiting varying degrees of stiffness, calcification, susceptibility to infection, thrombosis, and a lack of implant growth capacity. Here, we report the functionality of pentagalloyl glucose (PGG) stabilized decellularized valved bovine jugular vein conduit (PGG-DBJVC). The PGG-DBJVC tissues demonstrated mechanical properties comparable to native and glutaraldehyde fixed tissues, while exhibiting resistance to both collagenase and elastase enzymatic degradation. Subcutaneous implantation of tissues established their biocompatibility and resistance to calcification, while implantation in sheep in the pulmonary position demonstrated adequate implant functionality, and repopulation of host cells, without excessive inflammation.In conclusion, this PGG-DBJVC device could be a favorable replacement option for pediatric patients, reducing the need for reoperations required with current devices. Statement of significanceCongenital Heart Disease (CHD) is a common congenital disorder affecting many newborns in the United States each year. The use of substitute conduit arteries is necessary for some patients with CHD who have missing or underdeveloped structures. Current conduit replacement devices have limitations, including stiffness, susceptibility to infection and thrombosis, and lack of implant growth capacity. Pentagalloyl glucose-stabilized bovine jugular vein valved tissue (PGG-DBJVC) offers a promising solution as it is resistant to calcification, and biocompatible. When implanted in rats and as pulmonary conduit replacement in sheep, the PGG-DBJVC demonstrated cellular infiltration without excessive inflammation, which could lead to remodeling and integration with host tissue and eliminate the need for replacement as the child grows.

Binding of Pentagalloyl Glucose to Aortic Wall Proteins: Insights from Peptide Mapping and Simulated Docking Studies.

Pentagalloyl glucose (PGG) is currently being investigated as a non-surgical treatment for abdominal aortic aneurysms (AAAs); however, the molecular mechanisms of action of PGG on the AAA matrix components and the intra-luminal thrombus (ILT) still need to be better understood. To assess these interactions, we utilized peptide fingerprinting and molecular docking simulations to predict the binding of PGG to vascular proteins in normal and aneurysmal aorta, including matrix metalloproteinases (MMPs), cytokines, and fibrin. We performed PGG diffusion studies in pure fibrin gels and human ILT samples. PGG was predicted to bind with high affinity to most vascular proteins, the active sites of MMPs, and several cytokines known to be present in AAAs. Finally, despite potential binding to fibrin, PGG was shown to diffuse readily through thrombus at physiologic pressures. In conclusion, PGG can bind to all the normal and aneurysmal aorta protein components with high affinity, potentially protecting the tissue from degradation and exerting anti-inflammatory activities. Diffusion studies showed that thrombus presence in AAAs is not a barrier to endovascular treatment. Together, these results provide a deeper understanding of the clinical potential of PGG as a non-surgical treatment of AAAs.

Elastin stabilization prevents impaired biomechanics in human pulmonary arteries and pulmonary hypertension in rats with left heart disease

Pulmonary hypertension worsens outcome in left heart disease. Stiffening of the pulmonary artery may drive this pathology by increasing right ventricular dysfunction and lung vascular remodeling. Here we show increased stiffness of pulmonary arteries from patients with left heart disease that correlates with impaired pulmonary hemodynamics. Extracellular matrix remodeling in the pulmonary arterial wall, manifested by dysregulated genes implicated in elastin degradation, precedes the onset of pulmonary hypertension. The resulting degradation of elastic fibers is paralleled by an accumulation of fibrillar collagens. Pentagalloyl glucose preserves arterial elastic fibers from elastolysis, reduces inflammation and collagen accumulation, improves pulmonary artery biomechanics, and normalizes right ventricular and pulmonary hemodynamics in a rat model of pulmonary hypertension due to left heart disease. Thus, targeting extracellular matrix remodeling may present a therapeutic approach for pulmonary hypertension due to left heart disease.

Pentagalloyl Glucose: A Review of Anticancer Properties, Molecular Targets, Mechanisms of Action, Pharmacokinetics, and Safety Profile.

Pentagalloyl glucose (PGG) is a natural hydrolyzable gallotannin abundant in various plants and herbs. It has a broad range of biological activities, specifically anticancer activities, and numerous molecular targets. Despite multiple studies available on the pharmacological action of PGG, the molecular mechanisms underlying the anticancer effects of PGG are unclear. Here, we have critically reviewed the natural sources of PGG, its anticancer properties, and underlying mechanisms of action. We found that multiple natural sources of PGG are available, and the existing production technology is sufficient to produce large quantities of the required product. Three plants (or their parts) with maximum PGG content were Rhus chinensis Mill, Bouea macrophylla seed, and Mangifera indica kernel. PGG acts on multiple molecular targets and signaling pathways associated with the hallmarks of cancer to inhibit growth, angiogenesis, and metastasis of several cancers. Moreover, PGG can enhance the efficacy of chemotherapy and radiotherapy by modulating various cancer-associated pathways. Therefore, PGG can be used for treating different human cancers; nevertheless, the data on the pharmacokinetics and safety profile of PGG are limited, and further studies are essential to define the clinical use of PGG in cancer therapies.

Divya-WeightGo combined with moderate aerobic exercise remediates adiposopathy, insulin resistance, serum biomarkers, and hepatic lipid accumulation in high-fat diet-induced obese mice

Obesity has become an unprecedented epidemic worldwide owing to a prolonged imbalance between energy intake and expenditure. Available therapies primarily suppress energy intake but often fail to produce sustained fat loss, necessitating a more efficacious strategy to combat obesity. In this study, a polyherbal formulation, Divya-WeightGo (DWG) has been investigated for its anti-obesity activity using in-vitro and in-vivo assays. Ultra-high performance liquid chromatography (UHPLC) analysis revealed the presence of phytocompounds including gallic acid, methyl gallate, corilagin, ellagic acid, pentagalloyl glucose, withaferin A and hydroxycitric acid, proven to aid in weight loss. The exposure of 3T3-L1 cells to DWG at cytosafe concentrations inhibited lipid and triglyceride accumulation and downregulated the expression of several adipogenic and lipogenic markers like PPARy, C/EBPα, C/EBPβ, SREBP-1c, FASN and DGAT1. DWG reduced LPS-induced pro-inflammatory cytokine release and NF-κB activity in THP-1 cells. The in-vivo anti-obesity activity of DWG, both alone and in combination with moderate aerobic exercise, was assessed in a high fat diet-induced obese mouse model. DWG mitigated the obesity associated increased body weight gain, feed efficiency ratio, glucose intolerance, diminished insulin sensitivity, dyslipidemia, altered liver function profile, lipid accumulation and adiposopathy in obese mice, alone as well as in combination intervention, with better efficacy in the combination approach. Thus, the findings of this study suggest that DWG could be a promising therapeutic avenue to treat obesity through attenuation of lipid and fat accumulation in liver and adipose tissues and could be utilized as an adjunct with lifestyle interventions to combat obesity and associated complications.

Phenological and Environmental Factors' Impact on Secondary Metabolites in Medicinal Plant Cotinus coggygria Scop.

Cotinus coggygria Scop. (smoketree) is a phytotherapeutically valuable shrub growing in specific areas in many Eurasian countries. Exploring the intrinsic and extrinsic (abiotic) factors that modulate its secondary metabolism has fundamental and applicative importance. Three smoketree plants from the same population were studied for a period of 4.5 months. Their extracts were characterized using LC-MS/MS, HPLC-UV-VIS-DAD and colorimetric assays to determine the chemical composition and antioxidant potential. Multivariate analysis was applied to correlate the metabolomic data with registered habitat variables and phenological stages. The identified and quantified compounds belonged to the flavonoids (myricetin-3-O-galactoside, myricitrin) and hydrolysable tannins groups (pentagalloyl glucose, methyl gallate, methyl digallate I). Phenolic compounds and tannins were synthesized abundantly in the flowering and fruit stages, whereas flavonoids and triterpenes accumulated during senescence. The antioxidant activities varied between detection methods, samplings and individuals and were only punctually correlated with the compound contents in certain phenological stages. Based on the HCAbp analysis, the samples clustered under four groups, according to their metabolic profile. The CCA analysis revealed that during the reproductive stages (flower, fruit or seed), the secondary metabolism of the plants' leaves is sensitive to the action of abiotic factors, while in senescence, the metabolic content is according to the phenological phase. This study provides a first attempt at understanding the interplay between the habitat and the metabolome of smoketree.

1011 Potent antifungal activity of pentagalloyl glucose against drug-resistant candida albicans, candida auris, and other non-albicans candida species

1011 Potent antifungal activity of pentagalloyl glucose against drug-resistant candida albicans, candida auris, and other non-albicans candida species

Targeting UBE2T Potentiates Gemcitabine Efficacy in Pancreatic Cancer by Regulating Pyrimidine Metabolism and Replication Stress

Although small patient subsets benefit from current targeted strategies or immunotherapy, gemcitabine remains the first-line drug for pancreatic cancer (PC) treatment. However, gemcitabine resistance is widespread and compromises long-term survival. Here, we identified ubiquitin-conjugating enzyme E2T (UBE2T) as a potential therapeutic target to combat gemcitabine resistance in PC. Proteomics and metabolomics were combined to examine the effect of UBE2T on pyrimidine metabolism remodeling. Spontaneous PC mice (LSL-KrasG12D/+, LSL-Trp53R172H/+, Pdx1-Cre; KPC) with Ube2t-conditional knockout, organoids, and large-scale clinical samples were used to determine the effect of UBE2T on gemcitabine efficacy. Organoids, patient-derived xenografts (PDX), and KPC mice were used to examine the efficacy of the combination of a UBE2T inhibitor and gemcitabine. Spontaneous PC mice with Ube2t deletion had a marked survival advantage after gemcitabine treatment, and UBE2T levels were positively correlated with gemcitabine resistance in clinical patients. Mechanistically, UBE2T catalyzes really interesting new gene 1 (RING1)-mediated ubiquitination of p53 and relieves the transcriptional repression of ribonucleotide reductase subunits M1 and M2, resulting in unrestrained pyrimidine biosynthesis and alleviation of replication stress. Additionally, high-throughput compound library screening using organoids identified pentagalloylglucose (PGG) as a potent UBE2T inhibitor and gemcitabine sensitizer. The combination of gemcitabine and PGG diminished tumor growth in PDX models and prolonged long-term survival in spontaneous PC mice. Collectively, UBE2T-mediated p53 degradation confers PC gemcitabine resistance by promoting pyrimidine biosynthesis and alleviating replication stress. This study offers an opportunity to improve PC survival by targeting UBE2T and develop a promising gemcitabine sensitizer in clinical translation setting.

STRUCTURE-ACTIVITY-RELATIONSHIP OF THE POLYPHENOLS INHIBITION OF α-AMYLASE AND α-GLUCOSIDASE

Background: Diabetes mellitus (DM) is a serious public health challenge, projected by WHO to be one of the 7 leading cause of death by 2030. Medicinal plants have been demonstrated to be useful in DM local management because of polyphenols present in these plants. For an alternative treatment approach especially with polyphenols-rich herbs, knowledge of comparative efficacy of the polyphenols will lead to enhanced therapy especially in postprandial hyperglyceamic control. Materials and Methods:Vegetative parts of Anacardium occidentale, Abelmoschus ecsulentus and Ceiba pentandra, prominent in the local management of DM were identified, collected and subjected to alcoholic extraction. From the crude extracts were isolated agathisflavone, quercetin 3-O-glucoside, quercetin 3-O-diglycoside, mangiferin, isomangiferin and pentagalloyl glucose, belonging to flavonoid, xanthones and tannins structural classes. These polyphenols were evaluated for their potentials to inhibit both α-glucosidase and α-amylase. Physicochemical parameters of the polyphenols were evaluated and molecular docking experiments were carried out to gain insight into the observed inhibitory activity. Results: quercetin 3-O-glucosidewas the most potent of the polyphenols against the two enzymes. Increase in the number of phenolic hydroxyl group did not increase the inhibitory activity and neither computation of the binding energies with the enzymes nor physicochemical parameters of the polyphenols could explain the observed inhibitory activity against the enzymes, across the structural classes. Thus, only the bioassay against the enzymes α-glucosidase and α-amylase correlated well with the use of the plants in treating diabetic mellitus Conclusion: Medicinal plants rich in quercetin 3-O-glycoside may have better treatment outcomes in postprandial hyperglycaemia control.