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.

Study of the Biologically Active Properties of Medicinal Plant Cotinus coggygria

The results of the studies have shown that to obtain an extract of a complex of biologically active substances of Cotinus coggygria, ethyl alcohol (mass fraction of alcohol 70%) with a hydromodule of 1:5 should be used, and the extraction should be carried out for 60 min at a temperature of 60 °C. The investigated plant extracts with the complex of bioactive substances from the Cotinus coggygria leaves and flowers are safe from the point of view of the content of heavy metals, pesticides, aflatoxin B1, radionuclides, as well as pathogenic and opportunistic microorganisms. It has been established that the Cotinus coggygria extract contains rutin, hyperoside, ferulic acid, quercetin, kaempferol, disulphuretin, sulphurein, sulphurein, gallic acid, methyl gallate, pentagalloyl glucose, 3,3′,4′,5,6,7-hexahydroxyflavonone, 3,3′,4′,5,5′,7-hexahydroxyflavonone, 3-O-α-L-rhamnofuranoside, 3,3′,4′,5,5′,7-hexahydroxyflavulium(1+), 7-O-β-D glucopyranoside, and 3,3′,4′,7-tetrahydroxyflavonone. The tested extracts have anticancer, antigenotoxic, and antimicrobial (against E. coli, S. aureus, P. vulgaris, C. albicans, L. mesenteroides) properties. The high antioxidant status of the tested extracts was established; the antioxidant activity of the samples was 145.09 mg AA/g (AA—ascorbic acid).

Systemic delivery of targeted nanotherapeutic reverses angiotensin II-induced abdominal aortic aneurysms in mice

Abdominal aortic aneurysm (AAA) disease causes dilation of the aorta, leading to aortic rupture and death if not treated early. It is the 14th leading cause of death in the U.S. and 10th leading cause of death in men over age 55, affecting thousands of patients. Despite the prevalence of AAA, no safe and efficient pharmacotherapies exist for patients. The deterioration of the elastic lamina in the aneurysmal wall is a consistent feature of AAAs, making it an ideal target for delivering drugs to the AAA site. In this research, we conjugated nanoparticles with an elastin antibody that only targets degraded elastin while sparing healthy elastin. After induction of aneurysm by 4-week infusion of angiotensin II (Ang II), two biweekly intravenous injections of pentagalloyl glucose (PGG)-loaded nanoparticles conjugated with elastin antibody delivered the drug to the aneurysm site. We show that targeted delivery of PGG could reverse the aortic dilation, ameliorate the inflammation, restore the elastic lamina, and improve the mechanical properties of the aorta at the AAA site. Therefore, simple iv therapy of PGG loaded nanoparticles can be an effective treatment option for early to middle stage aneurysms to reverse disease progression and return the aorta to normal homeostasis.

Pentagalloyl glucose inhibits TNF‐α‐activated CXCL1/GRO-α expression and induces apoptosis‐related genes in triple-negative breast cancer cells

In triple-negative breast cancer (TNBC), the tumor microenvironment is associated with increased proliferation, suppressing apoptotic mechanisms, an altered immune response, and drug resistance. The current investigation was designed to examine the natural compound pentagalloyl glucose (PGG) effects on TNF-α activated TNBC cell lines, MDA-MB-231 and MDA-MB-468. The results obtained showed that PGG reduced the expression of the cytokine GRO-α/CXCL1. PGG also inhibited IƙBKE and MAPK1 genes and the protein expression of IƙBKE and MAPK, indicating that GRO-α downregulation is possibly through NFƙB and MAPK signaling pathway. PGG also inhibited cell proliferation in both cell lines. Moreover, PGG induced apoptosis, modulating caspases, and TNF superfamily receptor genes. It also augmented mRNA of receptors DR4 and DR5 expression, which binds to TNF-related apoptosis-induced ligand, a potent and specific stimulator of apoptosis in tumors. Remarkably, PGG induced a 154-fold increase in TNF expression in MDA-MB-468 compared to a 14.6-fold increase in MDA-MB-231 cells. These findings indicate PGG anti-cancer ability in inhibiting tumor cell proliferation and GRO-α release and inducing apoptosis by increasing TNF and TNF family receptors' expression. Thus, PGG use may be recommended as an adjunct therapy for TNBC to increase chemotherapy effectiveness and prevent cancer progression.

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.