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-GSK3ß 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-ß-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-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: 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.

Reversal of High-Fat Diet-Induced Non-Alcoholic Fatty Liver Disease by Metformin Combined with PGG, an Inducer of Glycine N-Methyltransferase.

Nonalcoholic fatty liver disease (NAFLD) is a major cause of liver-related morbidities and mortality, and no effective drug treatment currently exists. We aimed to develop a novel treatment strategy to induce the expression of glycine N-methyltransferase (GNMT), which is an important enzyme regulating S-adenosylmethionine metabolism whose expression is downregulated in patients with NAFLD. Because 1,2,3,4,6-pentagalloyl glucose (PGG) is a GNMT inducer, and metformin was shown to upregulate liver mitochondrial GNMT protein expression, the effect of PGG and metformin was evaluated. Biochemical analysis, histopathological examination, immunohistochemical staining, reverse transcription-quantitative PCR (RT-qPCR), Western blotting (WB), proteomic analysis and Seahorse XF Cell Mito Stress Test were performed. The high-fat diet (HFD)-induced NAFLD mice were treated with PGG and metformin. Combination of PGG and metformin nearly completely reversed weight gain, elevation of serum aminotransferases, and hepatic steatosis and steatohepatitis. In addition, the downregulated GNMT expression in liver tissues of HFD-induced NAFLD mice was restored. The GNMT expression was further confirmed by RT-qPCR and WB analysis using both in vitro and in vivo systems. In addition, PGG treatment was shown to increase oxygen consumption rate (OCR) maximum capacity in a dose-dependent manner, and was capable of rescuing the suppression of mitochondrial OCR induced by metformin. Proteomic analysis identified increased expression of glutathione S-transferase mu 4 (GSTM4), heat shock protein 72 (HSP72), pyruvate carboxylase (PYC) and 40S ribosomal protein S28 (RS28) in the metformin plus PGG treatment group. Our findings show that GNMT expression plays an important role in the pathogenesis of NAFLD, and combination of an inducer of GNMT and metformin can be of therapeutic potential for patients with NAFLD.

Pentagalloyl Glucose and Cisplatin Combination Treatment Exhibits a Synergistic Anticancer Effect in 2D and 3D Models of Head and Neck Carcinoma.

Although cisplatin is a first-line chemotherapy drug for head and neck squamous cell carcinoma (HNSCC), its therapeutic efficacy is limited owing to serious side effects and acquired drug resistance. This study determined whether combining pentagalloyl glucose (PGG) and cisplatin enhanced their anti-tumor activities on HNSCC cell lines. We investigated the anticancer effect of PGG combined with cisplatin in 2D and 3D multicellular spheroid cell culture. The results revealed that PGG combined with cisplatin inhibited cell viability and produced synergistic effects. PGG potentiates the anticancer effect of cisplatin by promoting apoptosis and inhibiting cell migration. The western blot and molecular docking analysis revealed that the synergistic effect of the combination treatment may be related to the PGG-mediated reduced expression of phosphorylated STAT3 and phosphorylated Akt. Furthermore, we found that the combined treatment of PGG and cisplatin's effect on 3D multicellular spheroid size was more potent than the monotherapies. Our findings indicated that the combination therapy of PGG and cisplatin synergistically inhibited HNSCC cancer cell viability and induced apoptosis in 2D and 3D models. The present results suggested that PGG may be a promising adjunct drug used with cisplatin for a practical therapeutic approach to head and neck cancer.

1,2,3,4,6-Pentagalloyl glucose of Pistacia lentiscus can inhibit the replication and transcription processes and viral pathogenesis of SARS-COV-2.

SARS-COV-2 stands as the source of the most catastrophic pandemic of this century, known as COVID-19. In this regard, we explored the effects of five Pistacia sp. active ingredients on the most crucial targets of SARS-COV-2, including 3CLpro, PLpro, RdRp, helicase, NSP15, and E protein. The results of molecular docking determined 1,2,3,4,6-pentagalloyl glucose (PG) as the most effective compound of Pistacia sp, which also confirmed its excellent binding affinities and stable interactions with helicase (-10.76 kcal/mol), RdRp (-10.19 kcal/mol), E protein (-9.51 kcal/mol), and 3CLpro (-9.47 kcal/mol). Furthermore, MD simulation was conducted to investigate the stability of all complexes throughout a 100 ns. In contrast to PLpro and NSP15, the analyses of Lennard-Jones potential, RMSDas, PCA, and SASA verified the ability of PG in forming stable and adequate interactions with RdRp, helicase, 3CLpro, and E protein due to standing as an effective inhibitor among the six targets, these data proposed the capability of PG, the most important compound of Pistacia sp., in inducing antiviral, anti-inflammatory, and antioxidant impacts on RdRp, helicase, 3CLpro, and E protein. Therefore, the possibility of inhibiting the replication and transcription processes and viral pathogenesis of SARS-COV-2 may be facilitated through the application of PG.

Pentagalloyl Glucose, a Major Compound in Mango Seed Kernel, Exhibits Distinct Gastroprotective Effects in Indomethacin-Induced Gastropathy in Rats via Modulating the NO/eNOS/iNOS Signaling Pathway.

Gastric ulcers are a common health disorder that affect up to 10% of the world's population. The gastroprotective potential of pentagalloyl glucose (PGG) against indomethacin-induced ulcer in rats and the possible underlying mechanisms were investigated. Gastric ulceration was induced by indomethacin (single dose, 60 mg/kg). Pretreatment with PGG (100 or 200 mg/kg, orally) for 8 days prior to the administration of indomethacin furnished significant reductions in gastric mucosal lesions as well as a significant increase in mucus concentration. Also, PGG significantly declined the elevations in gastric mucosal MDA, TNF-α, IL-6, PECAM-1, VEGF, and iNOS expression. It also mitigated the decrease in GSH and GPx and eNOS expression observed with indomethacin. The protective effects furnished by PGG were comparable to that of famotidine. The obtained results suggested that the anti-ulcer effects of PGG are mediated by increasing mucus production, scavenging free radicals, decreasing inflammation, and attenuating the NO/NOS signaling in favor of eNOS. To sum up, PGG could provide a potential therapy for gastric ulcer after evaluating its efficacy and effectiveness.

Hepatitis C Virus NS3/4A Inhibition and Host Immunomodulation by Tannins from Terminalia chebula: A Structural Perspective.

Terminalia chebula Retz. forms a key component of traditional folk medicine and is also reported to possess antihepatitis C virus (HCV) and immunomodulatory activities. However, information on the intermolecular interactions of phytochemicals from this plant with HCV and human proteins are yet to be established. Thus, by this current study, we investigated the HCV NS3/4A inhibitory and host immune-modulatory activity of phytocompounds from T. chebula through in silico strategies involving network pharmacology and structural bioinformatics techniques. To start with, the phytochemical dataset of T. chebula was curated from biological databases and the published literature. Further, the target ability of the phytocompounds was predicted using BindingDB for both HCV NS3/4A and other probable host targets involved in the immune system. Further, the identified targets were docked to the phytochemical dataset using AutoDock Vina executed through the POAP pipeline. The resultant docked complexes with significant binding energy were subjected to 50 ns molecular dynamics (MD) simulation in order to infer the stability of complex formation. During network pharmacology analysis, the gene set pathway enrichment of host targets was performed using the STRING and Reactome pathway databases. Further, the biological network among compounds, proteins, and pathways was constructed using Cytoscape 3.6.1. Furthermore, the druglikeness, side effects, and toxicity of the phytocompounds were also predicted using the MolSoft, ADVERpred, and PreADMET methods, respectively. Out of 41 selected compounds, 10 were predicted to target HCV NS3/4A and also to possess druglike and nontoxic properties. Among these 10 molecules, Chebulagic acid and 1,2,3,4,6-Pentagalloyl glucose exhibited potent HCV NS3/4A inhibitory activity, as these scored a lowest binding energy (BE) of -8.6 kcal/mol and -7.7 kcal/mol with 11 and 20 intermolecular interactions with active site residues, respectively. These findings are highly comparable with Asunaprevir (known inhibitor of HCV NS3/4A), which scored a BE of -7.4 kcal/mol with 20 key intermolecular interactions. MD studies also strongly suggest that chebulagic acid and 1,2,3,4,6-Pentagalloyl glucose as promising leads, as these molecules showed stable binding during 50 ns of production run. Further, the gene set enrichment and network analysis of 18 protein targets prioritized 10 compounds and were predicted to potentially modulate the host immune system, hemostasis, cytokine levels, interleukins signaling pathways, and platelet aggregation. On overall analysis, this present study predicts that tannins from T. chebula have a potential HCV NS3/4A inhibitory and host immune-modulatory activity. However, further experimental studies are required to confirm the efficacies.

Combinational Anti-tumor Effects of Chemicals from Paeonia lutea Leaf Extract in Oral Squamous Cell Carcinoma Cells.

AIM: We identified chemical components that exhibited antitumor activity against oral squamous cell carcinoma (OSCC) cells and examined their effective concentrations and additive and/or synergistic effects in combinational usage on the proliferation, apoptosis and cell cycle of OSCC cells. MATERIALS AND METHODS: Using high-performance liquid chromatography, nuclear magnetic resonance spectroscopy and electrospray ionization-mass spectrometry, we identified the main chemical components of the methanol extracts from Paeonia lutea. We investigated the pharmaceutical effects of those components on the proliferation, apoptosis, and cell cycle of an OSCC cell line, SAS, using the tetrazolium salt 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) and caspase assays, as well as flow cytometry cell cycle analysis. We also examined the effects of those components on the mitogen-activated protein kinase signal transduction pathway by western blotting. Finally, the effects on normal human epidermal keratinocyte cells were also examined in similar experiments. RESULTS: Three chemicals have been identified in P. lutea leaves using high performance liquid chromatography: gallic acid methyl ester (GAME), pentagalloyl glucose (PGG) and paeoniflorin (PF). Both GAME and PGG significantly suppressed cell proliferation, and their combined effects were synergistic, while the effect of PF was minimal. However, those chemicals did not induce apoptosis. Cell cycle and western blotting analysis showed that the suppressive effects on cell proliferation resulted from G2 arrest and the suppression of phosphorylation of Akt/PKB. No effect was identified on normal human epidermal keratinocyte cells. CONCLUSION: These results indicate that GAME and PGG are the main chemical components of P. lutea leaves that have potential anti-cancer therapeutic effects.

A Systematic Review and Meta-Analysis of the Effect of Pentagalloyl Glucose Administration on Aortic Expansion in Animal Models.

BACKGROUND: The aim of this systematic review was to pool evidence from studies testing if pentagalloyl glucose (PGG) limited aortic expansion in animal models of abdominal aortic aneurysm (AAA). METHODS: The review was conducted according to the PRISMA guidelines and registered with PROSPERO. The primary outcome was aortic expansion assessed by direct measurement. Secondary outcomes included aortic expansion measured by ultrasound and aortic diameter at study completion. Sub analyses examined the effect of PGG delivery in specific forms (nanoparticles, periadventitial or intraluminal), and at different times (from the start of AAA induction or when AAA was established), and tested in different animals (pigs, rats and mice) and AAA models (calcium chloride, periadventitial, intraluminal elastase or angiotensin II). Meta-analyses were performed using Mantel-Haenszel's methods with random effect models and reported as mean difference (MD) and 95% confidence intervals (CIs). Risk of bias was assessed with a customized tool. RESULTS: Eleven studies reported in eight publications involving 214 animals were included. PGG significantly reduced aortic expansion measured by direct observation (MD: -66.35%; 95% CI: -108.44, -24.27; p = 0.002) but not ultrasound (MD: -32.91%; 95% CI: -75.16, 9.33; p = 0.127). PGG delivered intravenously within nanoparticles significantly reduced aortic expansion, measured by both direct observation (MD: -116.41%; 95% CI: -132.20, -100.62; p < 0.001) and ultrasound (MD: -98.40%; 95% CI: -113.99, -82.81; p < 0.001). In studies measuring aortic expansion by direct observation, PGG administered topically to the adventitia of the aorta (MD: -28.41%; 95% CI -46.57, -10.25; p = 0.002), studied in rats (MD: -56.61%; 95% CI: -101.76, -11.46; p = 0.014), within the calcium chloride model (MD: -56.61%; 95% CI: -101.76, -11.46; p = 0.014) and tested in established AAAs (MD: -90.36; 95% CI: -135.82, -44.89; p < 0.001), significantly reduced aortic expansion. The findings of other analyses were not significant. The risk of bias of all studies was high. CONCLUSION: There is inconsistent low-quality evidence that PGG inhibits aortic expansion in animal models.

Targeted delivery of pentagalloyl glucose inhibits matrix metalloproteinase activity and preserves elastin in emphysematous lungs.

BACKGROUND: Elastin degradation has been established as one of the driving factors of emphysema. Elastin-derived peptides (EDPs) are shown to act as a chemoattractant for monocytes. Effectively shielding elastin from elastolytic damage and regenerating lost elastin are two important steps in improving the mechanical function of damaged lungs. Pentagalloyl glucose (PGG) has been shown to preserve elastin in vascular tissues from elastolytic damage in vivo and aid in elastin deposition in vitro. METHODS: We created emphysema by elastase inhalation challenge in mice. Albumin nanoparticles loaded with PGG, conjugated with elastin antibody, were delivered to target degraded elastin in lungs. We investigated matrix metalloproteinase-12 activity and lung damage by measuring dynamic compliance and tidal volume changes. RESULTS: Ex-vivo experiments demonstrated elastin preservation in PGG treated samples compared to controls. Inhaled nanoparticles conjugated with elastin antibody retained for extended periods in lungs. Further, mice treated with PGG nanoparticles showed a significant suppression of MMP-12 activity measured in the lungs. We observed suppression of emphysema in terms of dynamic lung compliance and tidal volume change compared to the control group. The histological examination further confirmed elastin preservation in the lungs. CONCLUSION: These results demonstrate successful targeted delivery of nanoparticles loaded with PGG to inhibit MMP-12 activity and preserve elastin in the lungs. Such targeted PGG therapy has potential therapeutic use in the management of emphysema.

Reversal of elastase-induced abdominal aortic aneurysm following the delivery of nanoparticle-based pentagalloyl glucose (PGG) is associated with reduced inflammatory and immune markers.

OBJECTIVE: An Abdominal aortic aneurysm (AAA), a deadly disease in elderly population, is featured by expansion of aortic diameter, degradation and weakening of vasculature. Its common and significant characteristics are disarray and inflammation in vasculature. We tested the hypothesis that the reversal of abdominal aortic aneurysm by pentagalloyl glucose-loaded nanoparticles (PGG-NPs) therapy that targets degraded elastin suppresses inflammatory and immune markers to ameliorate the pathophysiology of the disease in advance stage aneurysm in a porcine pancreatic elastase (PPE)-induced mouse model of AAA. METHODS AND RESULTS: After induction of aneurysm in pathogen-free C57BL/6 male mice by applying PPE peri-adventitially to the abdominal aorta, once a week for two doses of intravenous injections of pentagalloyl glucose-loaded nanoparticles (PGG-NPs) conjugated with elastin targeted antibody were used to reverse the aneurysms. We showed that PGG-NPs therapy could suppress infiltration of macrophages, CD8 and CD4 subsets of T cells, matrix metalloproteinases (MMPs), inflammatory cytokines interferon (IFN-γ) and interleukin (IL)-6 at the local and systemic level. Moreover, such PGG-NPs therapy increases the induction of anti-inflammatory cytokines IL-13, IL-27 and IL-10 at the local and systemic level. The therapy also led to remodeling of elastic lamina at the aneurysm site. CONCLUSION: Nanoparticles-loaded pentagalloyl glucose therapy can be an effective treatment option against advanced stage aneurysms to reverse the disease by ameliorating inflammation and restoring arterial homeostasis.

Gallotannin from Bouea macrophylla Seed Extract Suppresses Cancer Stem-like Cells and Radiosensitizes Head and Neck Cancer.

Cancer stem cells (CSCs) play a critical role in radiation resistance and recurrence. Thus, drugs targeting CSCs can be combined with radiotherapy to improve its antitumor efficacy. Here, we investigated whether a gallotannin extract from Bouea macrophylla seed (MPSE) and its main bioactive compound, pentagalloyl glucose (PGG), could suppress the stemness trait and further confer the radiosensitivity of head and neck squamous cell carcinoma (HNSCC) cell lines. In this study, we evaluate the effect of MPSE or PGG to suppress CSC-like phenotypes and radiosensitization of HNSCC cell lines using a series of in vitro experiments, tumorsphere formation assay, colony formation assay, apoptosis assay, and Western blotting analysis. We demonstrate that MPSE or PGG is able to suppress tumorsphere formation and decrease protein expression of cancer stem cell markers. MPSE or PGG also enhanced the radiosensitivity in HNSCC cells. Pretreatment of cells with MPSE or PGG increased IR-induced DNA damage (γ-H2Ax) and enhanced radiation-induced cell death. Notably, we observed that pretreatment with MPSE or PGG attenuated the IR-induced stemness-like properties characterized by tumorsphere formation and the CD44 CSC marker. Our findings describe a novel strategy for increasing therapeutic efficacy for head and neck cancer patients using the natural products MPSE and PGG.

Immunomodulatory effect of pentagalloyl glucose in LPS-stimulated RAW264.7 macrophages and PAO1-induced Caenorhabditis elegans.

Pentagalloyl glucose (PGG) is a valuable natural compound with an array of biological activities, but the immunomodulatory effect and mechanism have not been fully validated yet. In this study, to elucidate comprehensively the function of immunomodulation and its underlying mechanism of PGG in vitro and in vivo, two model systems were conducted, which including lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages cells and Pseudomonas aeruginosa (PAO1)-induced Caenorhabditis elegans (C. elegans). Current results showed that PGG significantly inhibited secretions of tumor necrosis factor-α (TNF-α), interleukin-1 beta (IL-1ß), interleukin-6 (IL-6) and mediator nitric oxide (NO) in LPS-stimulated RAW264.7 cells. In addition, the expression of genes nitric oxide synthase (iNOS), TNF-α, IL-1ß and IL-6 in LPS- stimulated RAW264.7 cells was reduced by PGG. In vivo assay showed that lifespan of PAO1-induced C. elegans was enhanced significantly by 14.1% under the pre-treatment of PGG, which was abrogated in toxin sensitive mdt-15 mutant. Similarly, the PGG showed a benefit on 41.2% significant extension longevity in C. elegans under pathogenic PA14. And the nuclear localization of DAF-16 of strain TJ356 was significantly increased in PAO1-induced C. elegans by PGG. Further, PGG modulated several signaling pathways to enhance immunomodulation in C. elegans including DBL-1, DAF-2/DAF-16, and mitogen-activated protein (MAP) kinase pathways. Furthermore, other genes involved in immunomodulatory response in C. elegans were remarkably regulated such as lys-1, lys-2, spp-18, egl-9, and hif-1. Our study suggested that PGG have potential to develop into novel immunomodulatory nutraceutical.

Pentagalloyl Glucose-Laden Poly(lactide-co-glycolide) Nanoparticles for the Biomechanical Extracellular Matrix Stabilization of an In Vitro Abdominal Aortic Aneurysm Model.

The suppression of abdominal aortic aneurysm (AAA) growth by nonsurgical therapy is currently not an option, and AAA is considered an irreversible destructive disease. The formation and development of AAA is associated with the progressive deterioration of the aortic wall. Infiltrated macrophages and resident vascular smooth muscle cells oversecrete matrix metalloproteinases (MMPs), which cause the loss of crucial aortic extracellular matrix (ECM) components, thus weakening the aortic wall. Stabilization of the aortic ECM could enable the development of novel therapeutic options for preventing and reducing AAA progression. In the present work, we studied the biochemical and biomechanical interactions of pentagalloyl glucose (PGG) on mouse C2C12 myoblast cells. PGG is a naturally occurring ECM-stabilizing polyphenolic compound that has been studied in various applications, including vascular health, with promising results. With its known limitations of systemic administration, we also studied the administration of PGG when encapsulated within poly(lactide-co-glycolide) (PLGA) nanoparticles (NPs). Treatment with collagenase and elastase enzymes was used to mimic a pathway of degenerative effects seen in the pathogenesis of human AAA. PGG and PLGA(PGG) NPs were added to enzyme-treated cells in either a suppressive or preventative scenario. Biomolecular interactions were analyzed through cell viability, cell adhesion, reactive oxygen species (ROS) production, and MMP-2 and MMP-9 secretion. Biomechanical properties were studied through atomic force microscopy and quartz crystal microbalance with dissipation. Our results suggest that PGG or PLGA(PGG) NPs caused minor to no cytotoxic effects on the C2C12 cells. Both PGG and PLGA(PGG) NPs showed reduction in ROS and MMP-2 secretion if administered after enzymatic ECM degradation. A quantitative comparison of Young's moduli showed a significant recovery in the elastic properties of the cells treated with PGG or PLGA(PGG) NPs after enzymatic ECM degradation. This work provides preliminary support for the use of a pharmacological therapy for AAA treatment.

1,2,3,4,6-Pentagalloyl Glucose, a RBD-ACE2 Binding Inhibitor to Prevent SARS-CoV-2 Infection.

The outbreak of SARS-CoV-2 virus caused more than 80,155,187 confirmed COVID-19 cases worldwide, which has posed a serious threat to global public health and the economy. The development of vaccines and discovery of novel drugs for COVID-19 are urgently needed. Although the FDA-approved SARS-CoV-2 vaccines has been launched in many countries recently, the strength of safety, stringent storage condition and the possibly short-term immunized efficacy remain as the major challenges in the popularity and recognition of using vaccines against SARS-CoV-2. With the spike-receptor binding domain (RBD) of SARS-CoV-2 being responsible for binding to human angiotensin-converting enzyme 2 receptor (hACE2), ACE2 is identified as the receptor for the entry and viral infection of SARS-CoV-2. In this study, molecular docking and biolayer interferometry (BLI) binding assay were adopted to determine the direct molecular interactions between natural small-molecule, 1,2,3,4,6-Pentagalloyl glucose (PGG) and the spike-RBD of the SARS-CoV-2. Our results showed that PGG preferentially binds to a pocket that contains residues Glu 340 to Lys 356 of spike-RBD with a relatively low binding energy of -8 kcal/mol. BLI assay further confirmed that PGG exhibits a relatively strong binding affinity to SARS-CoV-2-RBD protein in comparison to hACE2. In addition, both ELISA and immunocytochemistry assay proved that PGG blocks SARS-CoV-2-RBD binding to hACE2 dose dependently in cellular level. Notably, PGG was confirmed to abolish the infectious property of RBD-pseudotyped lentivirus in hACE2 overexpressing HEK293 cells, which mimicked the entry of wild type SARS-CoV-2 virus in human host cells. Finally, maximal tolerated dose (MTD) studies revealed that up to 200 mg/kg/day of PGG was confirmed orally safe in mice. Our findings suggest that PGG may be a safe and potential antiviral agent against the COVID-19 by blockade the fusion of SARS-CoV-2 spike-RBD to hACE2 receptors. Therefore, PGG may be considered as a safe and natural antiviral agent for its possible preventive application in daily anti-virus hygienic products such as a disinfectant spray or face mask.

Effect of all-trans retinoic acid and pentagalloyl glucose on smooth muscle cell elastogenesis.

BACKGROUND: The main objective of tissue engineering is to fabricate a tissue construct that mimics native tissue both biologically and mechanically. A recurring problem for tissue-engineered blood vessels (TEBV) is deficient elastogenesis from seeded smooth muscle cells. Elastin is an integral mechanical component in blood vessels, allowing elastic deformation and retraction in response to the shear and pulsatile forces of the cardiac system. OBJECTIVE: The goal of this research is to assess the effect of the vitamin A derivative all-trans retinoic acid (RA) and polyphenol pentagalloyl glucose (PGG) on the expression of elastin in human aortic smooth muscle cells (hASMC). METHODS: A polycaprolactone (PCL) and the gelatin polymer composite was electrospun and doped with RA and PGG. The scaffolds were subsequently seeded with hASMCs and incubated for five weeks. The resulting tissue-engineered constructs were evaluated using qPCR and Fastin assay for their elastin expression and deposition. RESULTS: All treatments showed an increased elastin expression compared to the control, with PGG treatments showing a significant increase in gene expression and elastin deposition.

Animal Model Dependent Response to Pentagalloyl Glucose in Murine Abdominal Aortic Injury.

Abdominal aortic aneurysms (AAAs) are a local dilation of the aorta and are associated with significant mortality due to rupture and treatment complications. There is a need for less invasive treatments to prevent aneurysm growth and rupture. In this study, we used two experimental murine models to evaluate the potential of pentagalloyl glucose (PGG), which is a polyphenolic tannin that binds to and crosslinks elastin and collagen, to preserve aortic compliance. Animals underwent surgical aortic injury and received 0.3% PGG or saline treatment on the adventitial surface of the infrarenal aorta. Seventeen mice underwent topical elastase injury, and 14 mice underwent topical calcium chloride injury. We collected high-frequency ultrasound images before surgery and at 3-4 timepoints after. There was no difference in the in vivo effective maximum diameter due to PGG treatment for either model. However, the CaCl2 model had significantly higher Green-Lagrange circumferential cyclic strain in PGG-treated animals (p < 0.05). While ex vivo pressure-inflation testing showed no difference between groups in either model, histology revealed reduced calcium deposits in the PGG treatment group with the CaCl2 model. These findings highlight the continued need for improved understanding of PGG's effects on the extracellular matrix and suggest that PGG may reduce arterial calcium accumulation.

On the Limits of Anthocyanins Co-Pigmentation Models and Respective Equations.

Anthocyanins co-pigmentation models with application on 1:1 complexes were revisited, and their limitations were critically commented. The flavylium multistate of species is dramatically simplified to a single acid-base equilibrium between flavylium cation and its conjugated base CB, equal to the sum of quinoidal base, hemiketal, and cis and trans-chalcones. Bearing this, a new equation that simultaneously allows calculation of the co-pigmentation constant with flavylium cation (KAH+CP) and with its conjugated base CB (KCBCP) was deduced. This equation can be used at a fixed co-pigment concentration with pH as a variable or at fixed pH and co-pigment concentration variable. A global fitting of all data allows us to calculate both association constants with good accuracy. The model was applied to the co-pigmentation of malvidin-3-glucoside with caffeine and pentagalloyl glucose (PGG). Caffeine gives rise to complexes not only with flavylium cation KAH+CP = 125 ± 7 M-1 but also with CB with KCBCP = 23 ± 3 M-1. PGG complexes exclusively with flavylium cation, KAH+CP = 914 ± 10 M-1, and the possible interaction with quinoidal base is lower than the detection limits that the inherent experimental error permits.