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Cancer is one of the major reasons for mortality across the globe. Many side-effects are associated with the formulations available in the market, affecting the quality of life of the patients. This has caused the researchers to find an alternative source of medications, such as herbal medicine, showing a promising effect in anticancer treatment; one such source is Pomegranate, which belongs to the family Punicaceae. Punica granatum contains many polyphenols that have antioxidant, antidiabetic, and therapeutic effects in the treatment and management of metabolic and cardiovascular diseases, as well as a favourable effect on anticancer therapy. Polyphenols like punicalin, punicalagin, and ellagic acid are a few of the many compounds responsible for the anticancer activity of pomegranate. Many preparations of pomegranate, such as Pomegranate Juice (PJ), Pomegranate seed oil (PSO), Pomegranate peel extract (PoPx), etc. are used in various clinical studies. These polyphenols show anticancer activity by either arresting the cell cycle in the G2/M phase, inducing apoptosis or damaging the DNA of tumor cells. This review explicitly discusses the role and mechanism of bioactives obtained from the pomegranate in the treatment and management of cancer. The chemical structure, properties, and role of pomegranate in the treatment of breast, lung, thyroid, colon, and prostate cancer have been focused on in detail. This review also discusses various targeted drug delivery approaches for tumour treatment as well as patented preparation of pomegranate compounds along with the ongoing clinical trials.

Severe acute respiratory syndrome coronavirus (SARS-CoV-2) main protease (Mpro) inhibitors are considered as potential treatments for coronavirus disease 2019, and dietary polyphenols show promise in SARS-CoV-2 Mpro inhibition based on in silico studies. In the present study, we utilize a combination of biochemical-, surface plasmon resonance-, and docking-based assays to evaluate the inhibition and binding affinities of a series of tannins and their gut microbial metabolites on SARS-CoV-2 Mpro. The tested compounds (2–50 μM) were hydrolyzable tannins, including ellagitannins (punicalagin and ellagic acid) and gallotannins (tannic acid, pentagalloyl glucose, ginnalin A, and gallic acid), and their gut microbial metabolites, urolithins and pyrogallol, respectively. They inhibited SARS-CoV-2 Mpro (by 6.6–100.0% at 50 μM) and bound directly to the Mpro protein (with dissociation constants from 1.1 × 10–6 to 5.3 × 10–5 M). This study sheds light on the inhibitory effects of tannins and their metabolites on SARS-CoV-2 Mpro.

Aims: This study aims to explore the efficacy of punicalagin (PG) on diabetic cardiomyopathy (DCM), with a specific focus on the mechanisms underlying the effects of PG on mitochondrial fusion/fiss...

Objectives: We aimed to investigate the protective potential of Punica granatum L. fruit rind extract (PFE) containing punicalagin (10.3% W/W), ellagic acid (EA) (2.7%W/W) in vincristine (75 µg/kg ...

Punicalagin, a bioactive ellagitannin predominantly found in Pomegranate, has a wide range of health benefits including potent antioxidant properties. The metabolism of punicalagin in human body produces urolithins and ellagic acid. Ellagic acid is a natural phenolic antioxidant and is also known for its antiproliferative activities. Terminalia ferdinandiana (Kakadu plum) was reported to be a rich source of ellagic acid. In this study, an UHPLC-MS/MS method was developed and validated for accurate determination of ellagic acid levels and bioactive ellagitannins (punicalagin and castalagin). Total ellagic acid content in the fruits and leaves were 2.76 and 9.54 g/100 g DW. Punicalagin contents in the fruits and leaves were 74 and 49 mg/100 g DW, and castalagin contents were 1.1 and 0.8 mg/100 g DW. To the best of our knowledge, this is the first report about punicalagin and castalagin concentrations in Kakadu plum fruits and leaves. The findings are very promising regarding the potential use of Kakadu plum fruit and leaf extracts as natural preservatives in the food industry.

Background Insulin resistance, defined as a diminished ability to respond to the stimulation of insulin, is the main line for a variety of metabolic-related diseases. Punicalagin (PU), a hydrolyzable tannin of pomegranate juice, exhibits multiple biological properties, including anti-oxidant, anti-cancer and anti-inflammatory activities. Objective This research study aimed at determining the protective effect of PU on insulin resistance and to uncover the underlying mechanism based on the gut microbiota, IKKβ/NF-κB pathway, and autophagy. Design An insulin resistance animal model was established using C57BL/6 mice fed with a high-fat diet (HFD) for 8 weeks. The model included two groups continuing a HFD for 12 weeks with or without administering via gavage with PU 20 mg/kg/day. Changes in fasting plasma glucose levels, fasting serum insulin levels, glucose and insulin tolerance, glycolipid metabolism, gut microbiota composition (16S rRNA gene sequencing), inflammatory responses, and autophagy in the liver were evaluated. Body weight gain, glycolipid metabolic disorder, liver injury, as well as systemic and hepatic insulin sensitivity, were significantly attenuated after supplementing with PU. Results This research study revealed that PU alleviated HFD-induced glucose and lipid disorders, liver injury and insulin resistance; decreased the Firmicutes/Bacteroides ratio, decreased the abundance of Coprococcus and Anaerotruncus, and increased Rikenellaceae; and decreased serum and liver tumor necrosis factor-alpha and interleukin-1β levels, inhibited liver IKKβ and NF-κB phosphorylation; and increased liver autophagy-related proteins LC3-II, P62, and Beclin1, and increased the number of liver autophagosomes. Conclusion PU can improve HFD-induced insulin resistance, improved liver glucose and lipid metabolism disorder and liver injury, and the potential mechanism is that PU inhibited the IKKβ/NF-κB inflammatory pathway by regulating gut microbiota homeostasis and up-regulating liver autophagy activity.

Mingcheng Huang,1,* Keping Wu,1,* Shan Zeng,2,* Wenfen Liu,1 Tianjiao Cui,1 Zhiqing Chen,1 Lian Lin,1 Dongying Chen,3 Hui Ouyang1 1Department of Nephrology, Kidney and Urology Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, ShenZhen, Guandong, People’s Republic of China; 2Department of Rheumatology, The First Affiliated Hospital of Jinan University, Guangzhou, Guandong, People’s Republic of China; 3Department of Rheumatology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guandong, People’s Republic of China*These authors contributed equally to this workCorrespondence: Dongying Chen; Hui Ouyang Email chendy3@mail.sysu.edu.cn; ouyh23@mail.sysu.edu.cnBackground: The aggressive phenotype of fibroblast-like synoviocytes (FLSs) is essential in the synovitis and bone destruction in rheumatoid arthritis (RA). Punicalagin is a natural polyphenol extracted in pomegranate juice, which possesses antioxidant, anti-inflammatory and anti-tumor properties suggesting it may be a potent drug for RA therapy. However, there is paucity of information on its effect in RA.Objective: To investigate the effects of punicalagin on synovial inflammation and bone destruction in RA.Methods: FLSs were isolated from synovial tissue of RA patients. The mRNA levels were evaluated by quantitative real-time PCR. Western blot was used for protein level measurements. The secretion of pro-inflammatory cytokines and metalloproteinases (MMPs) was detected by ELISA assays. Edu staining assays were carried out to investigate the proliferation of FLSs. Cell migration was assessed by Boyden chambers, wound scratch assays and F-actin staining in vitro. The intracellular translocation of nuclear factor kappa B (NF-κB) was investigated using immunofluorescence. The effects of punicalagin in vivo were measured by using collagen-induced arthritis (CIA) mice.Results: Punicalagin treatments significantly reduced the TNF-α induced expressions of pro-inflammatory cytokines (IL-1β, IL-6, IL-8 and IL-17A) and MMPs (MMP-1 and MMP-13) of RA FLSs. Punicalagin also suppressed the proliferation and migration of RA FLSs. Moreover, punicalagin (50mg/kg/d) alleviated arthritis severity and bone destruction, and decreased serum IL-6 and TNF-α in CIA mice. Further mechanism studies indicated that punicalagin blocked NF-κB activation via suppressing phosphorylation of IKK and IkBα, and preventing the translocation of 65.Conclusion: Our findings suggested that punicalagin might be one of natural therapeutic compounds for relieving RA progress via suppressing FLSs inflammation and migration through modulating NF-κB pathways.Keywords: rheumatoid arthritis, punicalagin, fibroblast-like synoviocytes, migration, pro-inflammatory cytokines

Background Ultraviolet (UV) rays are the major environmental factor that damage skin physiology causing deleterious effects such as oxidation, photoaging and pigmentation. There has been considerable interest in using botanicals to prevent skin damages caused by UV irradiation. Aim In this study, three plant extracts were tested either individually or combined together (mixture) as well as their corresponding main active compound: pomegranate/punicalagin, osmanthus/verbascoside and olive/hydroxytyrosol. We evaluated the whitening and anti-photoaging properties of the nutritional mixture using 2D human culture model and a 3D full-thickness pigmented skin model exposed to UVB and UVA. Methods For exploring skin pigmentation, oxidation and aging, we performed cell viability, tyrosinase activity and melanin content assays as well as histology analysis (Whartin–Starry staining), immunodetection (PMEL, MDA, collagen type I and elastin) and carbonylated proteins analysis by electrophoresis separation. Results Results showed that the pomegranate extract and the active molecule punicalagin could reduce the tyrosinase activity and melanin content in melanocytes (P < 0.05). The mixture, pomegranate extract and punicalagin inhibited the melanin production and pre-melanosomal protein (PMEL) expression in the 3D skin pigmented model (P < 0.001). Furthermore, the mixture treatment repaired the expressions of collagen I and elastin decrease by UV exposure (P < 0.01). The mixture also significantly decreased lipid peroxidation (P < 0.001) and carbonylated proteins (P < 0.05) in the skin model compared to the UV-exposed condition. Conclusion To conclude, the mixture composed of pomegranate, osmanthus and olive extracts protects human skin from UV rays deleterious effects and exhibits antioxidative, anti-aging and skin whitening properties. Our data suggested pomegranate contributed to the whitening properties of the mixture notably through its main active compound, punicalagin. The mixture might be a good candidates for further development as natural antioxidant and skin care product.

In recent years, consumption of pomegranate products have increased with the understanding of its benefits to human health, and pomegranate peel has become one of the most common wastes in the food industry. In this study, some physicochemical, antioxidant, in vitro bioaccessibility and antidiabetic properties of peels of Hicaz, Devedisi, and Zivzik pomegranate varieties were determined. The average values of total phenolic contents, total flavonoid contents, Punicalagin A, Punicalagin B, Ellagic acid, DPPH and ABTS of pomegranate peels were 26916.66 mg GA eq./100 g dw, 17316.37 mg QE/100 g dw, 15847.74 mg/100 g dw, 14693.31 mg/100 g dw, 783.82 mg/100 g dw, 188.59 mmol Trol. eq./g dw, and 99.01 mmol Trol. eq./g dw respectively. Their average values in vitro bioaccessibilities were 43.13, 27.82, 62.61, 73.79, 16.96, 57.22 and 31.71%, respectively. It was determined that the initial total phenolic content, total flavonoid content, ellagic acid and antioxidant activity levels of the samples significantly decreased after digestion. Nevertheless, bioaccessibility of Punicalagin A and Punicalagin B significantly protected after digestion. alpha-amylase and alpha-glucosidase inhibitory activities of pomegranate peels range from 0.06 to 0.14 mg/L and 3.01 to 3.64 mg/L respectively. It was determined that all three varieties showed higher antidiabetic activity compared to acarbose. As a result, pomegranate peel ellagitannins after in vitro digestion had high bioaccessibility. Pomegranate peel with high antioxidant and antidiabetic activities is a natural source that can be used in the pharmacology, food and cosmetics industry.

Pomegranate cv. ‘Wonderful’ fruit are susceptible to chilling injuries of the peel (CIp) when stored at 7 °C in modified-atmosphere bags for more than 3 months. The damage, manifested as superficial browning, is restricted to the fruit skin, i.e., the outer colored layer of the peel. To characterize possible causes of CIp development, fruit were collected at early harvest—when the premature fruit are poorly colored and susceptible to CIp development, and at late harvest—when mature fruit have fully red skin and less susceptibility to CIp. Skin samples were collected on day of harvest and at different time points during storage. Anatomical study of skin with CIp disorder showed a broken cuticle layer with underlying degenerated cells. A high total phenol content, which is associated with high antioxidant capacity, was not sufficient to prevent the development of CIp in the premature fruit. The concentration of punicalagin was the same for premature and mature skin at harvest and during storage, and therefore not associated with CIp development in the premature fruit skin. Furthermore, the expression of antioxidant-related genes CAT2, SOD and GR2 was similar for both premature and mature fruit skin. Poor pigmentation of the premature fruit skin and chilling-induced downregulation of key anthocyanin-biosynthesis genes were associated with CIp development. High total phenol concentration combined with high expression of the gene encoding PPO was also associated with CIp; however, high expression ratio of PAL to PPO was found in mature skin, and may be associated with reduced CIp disorder. The results presented suggest future possibilities for controlling the CIp phenomenon.

Sleep deprivation has deteriorating effects on cognitive functions and activation of brain inflammation mechanisms has been reported by some studies following total sleep deprivation. Some studies have reported the health benefits of punicalagin, a main abstract from Punica granatum L., including those for the treatment of Alzheimer’s disease. The antioxidant characteristic of punicalagin and the fact that sleep deprivation accelerates mediators of inflammation led us to further explore the possible neuroprotective role of punicalagin in total sleep deprivation memory impairment in a rat model. In this study, male Wistar rats were implanted with a canula in the lateral ventricle to receive intracerebroventricular injections (drug or vehicle). The animals were trained for the passive avoidance test and then received intracerebroventricular injections of different doses of punicalagin (0.001, 0.01, or 0.1 μg/rat). Then, they were placed in the sleep deprivation apparatus for 24 hours and tested afterwards for memory retrieval and locomotion. Our results indicated that 24 hours of total sleep deprivation impaired memory processes. PG microinjection before TSD did not prevent the deteriorating effect of total sleep deprivation on memory, and only showed a tendency of restoring the memory impairment. Comparison of the locomotor activity between the animals in different groups showed a significant increase in the total sleep deprivation sham groups that received two of the highest doses of punicalagin. Considering the reported beneficial actions of PG by other studies, further investigation is needed into the possible effects of PG in memory alterations.

The present study investigated to know whether the pomegranate polyphenol punicalagin (PU) can ameliorate oxidative stress and pathological alterations induced by a calorie rich diet comprised of fat and fructose. Male Swiss albino mice were fed normal pellet (Control) or high fat-high fructose diet (HFFD) for 60 days. PU (30 or 60 mg/kg bw) was administered orally for the last 15 days for both dietary groups. Measurement of TBARS, AOPP and FRAP in plasma, histopathology of liver and brain, assessment of oxidative damage in brain tissues, and blood brain barrier function were carried out. HFFD mice showed an increase in the levels of TBARS and AOPP, and a decline in FRAP. PU administration to HFFD mice reduced the levels of TBARS and AOPP and improved FRAP significantly. Histopathology results showed fatty changes and inflammatory infiltration in the liver of HFFD mice. Cortex and hippocampus of HFFD mice confirmed the presence of degenerating neurons with shrunken cytoplasm and pyknotic nuclei. PU treatment caused significant hepato and neuroprotective effects, and among the two doses the high dose of PU (60 mg/kg) showed more pronounced effects than the low dose (30 mg/kg). The immunohistochemical localization of the markers of oxidative damage to proteins (3-NT), lipids (4-HNE) and DNA (8-OHG) was increased in brain tissues of HFFD mice and upon PU administration (60 mg/kg) the levels of these oxidative stress markers were significantly decreased. Our findings clearly suggest that PU can modulate oxidative stress and could be a potential candidate for treating neurodegenerative processes associated with calorie excess.

Punicalagin is the most popular ellagitannin found in pomegranate husk and is well known to reduce the risk of cancer and cardiovascular diseases (CVDs). The present work describes a novel method for the preparation of nanoparticles of Punicalagin using pomegranate (Punica granatum) since the use of Punicalagin in bulk form is associated with many problems. In this study, nanoparticles of Punicalagin were synthesized, characterized using various techniques, and further evaluated for their antioxidant, antibacterial, and antiproliferative potential using HepG2 cancer cells. DLS analysis revealed that the average size of nanoparticles of Punicalagin was 87 nm, whereas SEM analysis confirmed spherical shaped nanoparticles with size ranging from 90 to 116 nm. HPLC studies confirmed the presence of Punicalagin in synthesized nanoparticles. The results also revealed that nanoparticles of Punicalagin were nearly four times more potent antioxidants than bulk and possessed an inhibition zone of about 13 mm. The response of antiproliferative assay showed that the nanoparticles of Punicalagin caused nearly 44% reduction while bulk form showed only a 15% reduction in cell viability of cancerous cells at 100 µg/mL. The study suggests a great potential for use of the herbal drug in nano form to treat cancer as compared to its bulk counterparts.

Antimicrobial resistance poses a serious threat to human health worldwide. Plant compounds may help to overcome antibiotic resistance due to their potential resistance modifying capacity. Several botanical extracts and pure polyphenolic compounds were screened against a panel of eleven bacterial isolates with clinical relevance. The two best performing agents, Cistus salviifolius (CS) and Punica granatum (GP) extracts, were tested against 100 Staphylococcus aureus clinical isolates, which resulted in average MIC50 values ranging between 50–80 µg/mL. CS extract, containing hydrolyzable tannins and flavonoids such as myricetin and quercetin derivatives, demonstrated higher activity against methicillin-resistant S. aureus isolates. GP extract, which contained mostly hydrolyzable tannins, such as punicalin and punicalagin, was more effective against methicillin-sensitive S. aureus isolates. Generalized linear model regression and multiple correspondence statistical analysis revealed a correlation between a higher susceptibility to CS extract with bacterial resistance to beta-lactam antibiotics and quinolones. On the contrary, susceptibility to GP extract was related with bacteria sensitive to quinolones and oxacillin. Bacterial susceptibility to GP and CS extracts was linked to a resistance profile based on cell wall disruption mechanism. In conclusion, a differential antibacterial activity against S. aureus isolates was observed depending on antibiotic resistance profile of isolates and extract polyphenolic composition, which may lead to development of combinatorial therapies including antibiotics and botanical extracts.

DownoadedFomP125171694ondaed27Oc2021 According to the World Health Organization, the novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) or COVID 19 has caused a pandemic around the world. The rapid infection has posed significant threats to international health and the economy. Till now, there is no treatment available. This contribution focuses on specific phytochemicals, essential oils and probiotics against SARS-CoV-2. Different electronic scientific databases and search engines were employed. The potential effects of phenolics, flavonoids, tannins, alkaloids, saponins and essential oils from different edible sources as well as probiotics against SARS-CoV-2 and coronaviruses have been reviewed. Inhibition mechanisms on SARS-CoV-2 and other coronaviruses either experimented or predicted by molecular docking modeling software were presented. The confirmed compounds belong to the alkaloids, tannins and terpenoides bioactive classes as pedunculagin, tercatain, punicalin, punicalagin, punicalin, geraniin, chebulagic acid, punicalagin, emetine and ginkgolide A can be preventing the infection or introducing treatments against SARS-CoV-2 and other coronaviruses. Lactobacillus plantarum strain N4, Enterococcus faecium NCIMB 10415, Lactobacillus salivarius prevented the infection by trapping the coronavirus or stimulated the cellular defense by the production of nitric oxide. Utilize the rich plants with bioactive compounds or use them in the preparation of functional foods is a simple way to provide people with protection against SARS-COV-2.

Alcohol consumption is a tradition in most cultures but are increasingly being arised as possessing a potential for misuse. Punicalagin is a phenolic compound that is found in forms alpha and beta in pomegranates. In this study, the protective role of punicalagin on oxidative stress, inflammation and DNA damage caused by ethanol (EtOH) in liver tissue were examined. Wistar albino rats were divided into 4 groups as control, eth, punicalagin, EtOH EtOH + punicalagin. In EtOH groups, rats were treated with EtOH (4g/kg) for 21 days, in punicalagin groups, rats were treated with punicalagin (4 mg/ kg) for 21 days. In the liver tissue, superoxide dismutase (SOD), catalase (CAT) activities and malondialdehyde (MDA) and glutathione (GSH) levels, in serum AST, ALT, LDH activities and TNF-alpha, IL-6 levels were measured. Genotoxicity was evaluated using comet assay. Based on these experimental results, while EtOH increased ALT, AST and LDH enzyme activies and induced inflammation and oxidative stress. Punicalagin reduced IL6, TNF-alpha, MDA levels, ALT, AST, LDH enzyme activities and increased SOD, CAT activities and GSH levels. EtOH significantly increased the percentage of damaged cells (type II, III and IV) and genetic damage index compared to the other groups (control, punicalagin and EtOH +punicalagin). Punicalagin was not genotoxic compared to the control. Furthermore, punicalagin reduced the genotoxic effect, induced by EtOH, with the sharp decrease in damaged cells (from 14.00 +/- 1.22 to 2.20 +/- 1.30) and genetic damage index (from 1.20 +/- 0.05 to 0.14 +/- 0.05). Punicalagin has antioxidant, anti-inflammatory and protective role against to ethanol induced liver toxicity.

Salmonella, a bacterial foodborne pathogen, can contaminate meat, milk, and vegetables. While appropriate measures are available to control Salmonella, the inhibitory phytochemicals from plants are gaining increased attention. Punicalagin, a natural antimicrobial, is one of the main active tannins isolated from Punica granatum L. To obtain a broader understanding of the effect of punicalagin on the cell membranes of Salmonella Typhimurium, the growth curves, extracellular potassium concentration, release of cell constituents, intracellular pH, membrane potential, and morphological features were characterized to elucidate the mechanisms of action. Treatment with punicalagin induced an increase in the extracellular concentrations of potassium and a release of cell constituents. A higher pH gradient, an increase in the intracellular pH, and cell membrane depolarization were observed after punicalagin treatment. Electron microscopy observations showed that the cell membrane structures of Salmonella Typhimurium were damaged by punicalagin. It is concluded that punicalagin inhibits the proliferation of Salmonella Typhimurium and destroys the integrity of the cell membrane, leading to a loss of cell homeostasis. These findings indicate that punicalagin has the potential to be developed as a future alternative to control Salmonella Typhimurium contamination in foods and reduce the risk of salmonellosis.

Influenza A virus (IAV) causes great morbidity and mortality worldwide every year. However, there are only a limited number of drugs clinically available against IAV infection. Further, emergence of drug-resistant strains can render those drugs ineffective. Thus there is an unmet medical need to develop new anti-influenza agents. In this study, we show that punicalagin from plants possesses strong anti-influenza activity with a low micromolar IC50 value in tissue culture. Using a battery of bioassays such as single-cycle replication assay, neuraminidase (NA) inhibition assay, and virus yield reduction assay, we demonstrate that the primary mechanism of action (MOA) of punicalagin is the NA-mediated viral release. Moreover, punicalagin can inhibit replication of different strains of influenza A and B viruses, including oseltamivir-resistant virus (NA/H274Y), indicating that punicalagin is a broad spectrum antiviral against both IAV and IBV. Further, although punicalagin targets NA like oseltamivir, it has a different MOA. These results suggest that punicalagin is an influenza NA inhibitor that may be further developed as a novel antiviral against influenza viruses.

Lipid metabolism balance plays a vital role in maintaining normal levels of sterols, triglycerides, and free fatty acids (FFA). Inhibiting FFA-induced lipotoxicity is considered a highly potential treatment for non-alcoholic fatty liver disease (NAFLD) and other lipid metabolism diseases. Punicalagin (PU), a pomegranate-derived polyphenol, has been found to effectively regulate lipid metabolism and prevent fatty liver, cardiovascular and other chronic diseases caused by lipid metabolism disorders. In the present study, we found that PU protects HepG2 cells from palmitic acid (PA)-induced lipapoptosis. Silent information regulator 1 (SIRT1) plays a key role in protecting against lipapoptosis in HepG2 cells. Knockdown of SIRT1 significantly diminished the protective effect of PU. Besides, PU could be able to reactivate weakened autophagy and inhibit PA-induced ER stress. Our findings supported that PU can effectively attenuate FFA-induced lipotoxicity via activating SIRT1/autophagy and inhibiting ER stress.

Osteosarcoma is the most common primary malignant bone tumor among children and young people and is associated with poor prognosis. Punicalagin is an antioxidant ellagitannin found in pomegranate juice with known antiproliferation and anti-angiogenesis properties. However, the antitumor effect of punicalagin on osteosarcoma requires further investigation. In the present study, the inhibitory effect of punicalagin on proliferation and invasion was evaluated in one human osteoblast cell line (hFOB1.19) and three human osteosarcoma cell lines (U2OS, MG63 and SaOS2). The cancer cell apoptosis ratio was determined using flow cytometry. NF-κB signaling in these cells was also evaluated using western blotting analysis. A subcutaneous tumor xenograft model was initiated to study the efficacy of punicalagin on osteosarcoma development and angiogenesis in vivo. Punicalagin treatment significantly decreased osteosarcoma cell proliferation and increased apoptosis. In addition, the invasion potential of these cells in a transwell assay was also dramatically suppressed in osteosarcoma cells. Punicalagin not only induced the degradation of IκBα but also the nuclear translocation of p65, suggesting the attenuation of NF-κB signaling pathway following treatment. Moreover, punicalagin markedly downregulated interleukin (IL)-6 and IL-8 levels, which was consistent with the inhibition of NF-κB signaling. An NF-κB activator could reverse these effects. Using a tumor xenograft mouse model, it was demonstrated that punicalagin exposure inhibited osteosarcoma growth and angiogenesis in vivo. These observations confirmed the suppressive effect of punicalagin against osteosarcoma malignancies. The underlying molecular mechanisms may include inhibition of the NF-κB signaling pathway.

Acrylamide (ACR) is widely used in industries. Oxidative stress and apoptosis pathways are important mechanisms behind ACR-induced hepatotoxicity and neurotoxicity. Regarding to antioxidant and antiapoptotic properties of punicalagin (PUN), the protective effect of this agent on ACR-induced toxicity in rat was evaluated. Rats were divided into seven groups: control, ACR (50 mg/kg/day, i.p.), PUN (10, 20, and 40 mg/kg/day, i.p.) plus ACR, vitamin E (200 mg/kg, i.p.) plus ACR, and PUN groups. After 11 days, the gait score test was evaluated. Then, the animals were sacrificed and the malondialdehyde (MDA) and glutathione (GSH) contents were determined in the brain and liver tissues. Apoptosis-involved factors and myelin basic protein (MBP) were determined by western blotting. Severe movement disorder, MDA enhancement, and GSH reduction in the brain and liver tissues were observed in ACR-treated animals. The Bax/Bcl2 ratio and caspase-3 levels were enhanced in the tested tissues. ACR elevated the level of aspartate aminotransferases and decreased serum protein and albumin concentration. PUN recovered movement disorders, changed the level of markers which are important in oxidative stress and reduced apoptosis. Also, PUN increased the MBP level which was reduced due to ACR toxicity. PUN can protect against ACR-induced toxicity through antioxidant and antiapoptotic properties.

Lafoensia pacari A. St.-Hil., Lythraceae, is used in Brazilian folk medicine to treat ulcer and gastritis; thus, it is important to conduct research so as to better understand its medicinal properties. The aim of this study was to assess the antisecretory and antiulcerogenic activities of lyophilized aqueous fraction and punicalagin isolated from leaves of L. pacari. Antisecretory gastric acid activity and antiulcerogenic activity were investigated by pyloric ligation-induced and indomethacin-induced gastric lesion models, respectively. Results show that the lyophilized aqueous fraction of L. pacari and punicalagin reduced the volume of gastric secretion, free acidity, and total acidity in mice 4 h after pyloric ligation, as well as the rate of gastric damage following the indomethacin administration model. Reduction percentages varied according to the dose of each treatment and showed statistical difference. This finding indicates that the lyophilized aqueous fraction of L. pacari and punicalagin exert an antiulcerogenic effect due to their acid antisecretory activity.

Increasing attention of plant derived therapeutic agents against cancer, investigating the anti-proliferative efficiency of plant derived chemicals have achieved increasing momentum for the design of anticancer drug. Punicalagin, dietary phytochemical altered the various cell signal transduction pathways associated with cell apoptosis and proliferation. This investigation was intended to examine the efficiency of punicalagin lying on cell viability so as to examine the molecular based punicalagin mechanism stimulated apoptosis via exploring the expression of Bcl-2 family proteins, and caspases also the cell cycle regulatory proteins p53 and NF-κB signaling in human cervical cancer cells. We also analyzed the morphological characteristic changes through mitochondrial membrane depolarization, reactive oxygen species (ROS) generation, TUNEL assay, AO/EtBr analysis in cervical cancer cells. Our findings demonstrated that punicalagin repressed the viability of cervical cancer cells in a dosereliant mode via stimulating mitochondrial mediated apoptosis. Moreover, our this study demonstrated that punicalagin blocked cervical cancer cell proliferation and stimulated cell apoptosis by suppressing NF-kappa B activity. Hence our study suggested that punicalagin exhibits opposing actions on NF-kappa B signaling networks to block cancer cell progression acts as a classical candidate for anticancer drug designing. Keywords: Punicalagin, Cervical cancer, Apoptosis, ME-180 cells, NF-ƙB pathway

Pomegranate juices (PJs) were clarified using hydrocolloids [albumin (A), casein (C), chitosan (CH) and xanthan gum (XG)] and in combination with each other. The lowest turbidity was observed in PJs clarified with ‘CH+XG’ and ‘A+C+CH’. Unlike ‘CH+XG’, effects of albumin and its combinations on clarity were mainly related with the contents of ellagic acid (r = −0.861), α‐punicalagin (r = −0.761), rutin (r = −0.734), β‐punicalagin (r = −0.730) and total punicalagin (r = −0.713). ‘CH+XG’ caused the highest phenolic (602 mg L⁻¹) and anthocyanin (449 mg L⁻¹) contents, and the second highest Aₘₐₓ (0.811 ABS), resulting from copigmentation of delphinidin‐3‐glucoside and delphinidin‐3,5‐diglucoside with CH. Since A showed moderate copigmentation effect, A had lower hyperchromic effect than CH. Moreover, C reduced Aₘₐₓ, anthocyanin content and colour density when combined with other hydrocolloids. As a result, ‘CH+XG’ would be the best combination to obtain high clarity, maintain phenolics and anthocyanins and provide high copigmentation effect in PJ.

Breast cancer (BC) is one of the most common malignancies worldwide. Punicalagin (PN), which is a type of polyphenol, has been reported to act as a tumor suppressor. This study aimed to investigate the effects of PN on cellular process in BC and its molecular mechanism. The effects of various doses of PN on cell viability, migration, and invasion capacities of MCF-7 and MDA-MB-231 cells were detected by CCK-8, wound-healing, and Transwell assays. Golgi phosphoprotein 3 (GOLPH3) was then transfected into the cells with or without PN treatment, and GPLPH3 expression level was examined by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot, and expressions of epithelial-mesenchymal transition (EMT)-related protein matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase-9 (MMP-9), E-Cadherin, and N-Cadherin were measured by Western blot. High dose of PN treatment (50 μM or higher) significantly inhibited viability, migration, and invasion of MCF-7 and MDA-MB-231 cells, while overexpressed GOLPH3 promoted cell viability, migration, and invasion, and partially reversed the effects of PN treatment on the BC cells. PN inhibited the expressions of GOLPH3, MMP-2, MMP-9, and N-Cadherin, and promoted E-Cadherin expression, while overexpression of GOLPH3 partly reversed above effects attributing to PN. Thus, PN suppresses cell viability and metastasis

The pandemic caused by the new coronavirus has resulted in a global health emergency and has prompted an urgent need for new treatment strategies. No target-specific drugs are currently available for SARS-CoV-2, but new drug candidates targeting the viral replication cycle are being explored. A prime target of drug-discovery efforts is the SARS-CoV-2 main protease (Mpro). In this work, we identified a potential inhibitor for SARS-CoV-2 main protease using in silico methodologies. Molecular docking and molecular dynamics studies were carried out to ascertain the inhibitory action of α and β anomers of Punicalagin from fruit peel of Punica granatum against the Mpro protease. The molecular dynamics results revealed that the β-anomeric configuration of punicalagin allowed access to more hydrogen bonds and hydrophobic interaction leading to higher selectivity and specificity of β-anomer than α-anomer. Therefore, the β-anomer of Punicalagin could act as potential inhibitor against the main protease of SARS-CoV-2 and may act as a potential drug candidate.

PURPOSE This study aimed to investigate the anti-inflammatory effect and antifungal effect of punicalagin in murine fungal keratitis. METHODS We used in vitro and in vivo protocols to assess the anti-inflammatory effect and antifungal effect of punicalagin. In vitro, time kill and mycelial stain were done. In vivo, murine fungal keratitis was established and treated with PBS or PUN. clinical scores were taken on days 1, 3, and 5 post infection. The mRNA and protein levels of inflammatory factors were detected by RT-PCR and Western blot, and the number and location of macrophages were analyzed by flow cytometry and immunofluorescence. Also, fungal plate counting was used to assess the antifungal effect. DCFH-DA fluorescence Probe detected the ROS level. RESULTS In vitro, PUN showed activity against A.fumigatus. (A.F.), with MIC90 values of 250 μg/ml, and significantly reduced A.F. biofilm formation (p

Punicalagin, a major ellagitannin isolated from pomegranate, is proved to have various pharmacological activities with an undefined therapy mechanism. The objective of this research was to demonstrate the effect of punicalagin on anti-inflammatory and angiogenic activation in human umbilical vein endothelial cells (HUVECs) and their potential mechanisms. Endothelial-leukocyte adhesion assay was applied to evaluate primary cultures of HUVECs activation following tumor necrosis factor alpha (TNF-α) treatment. The endothelial cell proliferation, migration, permeability and tube formation were assessed by EdU assay, wound migration assay, trans-endothelial electrical resistances (TEER) assay, and capillary-like tube formation assay, respectively. In addition, the expression of relevant proteins was assessed using Western blot analysis. We confirmed that punicalagin could reduce the adhesion of human monocyte cells to HUVECs in vitro and in vivo. Further, punicalagin decreased the expression of mRNA and proteins of ICAM-1 and VCAM-1 in HUVECs. Moreover, punicalagin inhibited permeability, proliferation, migration, and tube formation in VEGF-induced HUVECs, suppressed IKK-mediated activation of NF-κB signaling in TNF-α-induced endothelial cells, and inhibited vascular endothelial growth factor receptor 2 (VEGFR2) activation and downstream p-PAK1. Our findings indicated that punicalagin might have a protective effect on HUVECs activation, which suggested that punicalagin functions through an endothelial mediated mechanism for treating various disorders such as, cancer, rheumatoid arthritis, and cardiovascular disease.

Pomegranate extract (PE) and its polyphenols have been reported to show skin protective effects but their cytoprotective effects against methylglyoxal (MGO)-induced DNA damage and cell dysfunctions are unclear. Herein, we evaluated whether PE, punicalagin (PA), ellagic acid (EA), and urolithin A (UA), can alleviate MGO-induced DNA damage in human keratinocytes. PE (50 µg/mL) and PA (50 µM) protected DNA integrity and reduced the formation of MGO-DNA adducts and tailed DNA by 60.2 and 49.7%, respectively, in HaCaT cells. PE and PA reduced MGO-induced cytotoxicity by increasing the cell viability (by 17.5 and 15.0%) and decreasing reactive oxygen species (by 28.3 and 30.0%), respectively. PE and PA also ameliorated MGO-induced cell dysfunction by restoring cell adhesion, migration, and wound healing capacity. Findings from this study provide insights into the skin protective effects of PE and its polyphenols supporting their applications as potential bioactive ingredients for cosmeceuticals.

Hyperlipidemia is closely associated with various liver diseases, and effective intervention for prevention and treatment is in great need. Here, we aim to explore the protective effects of punicalagin (PU), a major ellagitannin in pomegranate, on acute hyperlipidemia-induced hepatic lipid metabolic disorders. Male C57bl/6J mice were pretreated with 50 or 200 mg kg−1 day−1 PU for 9 days before the injection of poloxamer 407 to induce acute hyperlipidemia. PU significantly lowered lipids and liver damage markers in serum, reduced excessive lipid accumulation in the liver, attenuated hepatic oxidative stress by activating the NF-E2 related factor 2 (Nrf2)-mediated antioxidant pathway, and enhanced hepatic mitochondrial complex activities and mitochondrial DNA copy number by promoting the peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α)-mediated mitochondrial biogenesis pathway. Moreover, the decreased mitochondrial fusion-related proteins were also restored by PU treatment. In vitro, PU effectively decreased triglycerides and total cholesterol levels, up-regulated Nrf2 and mitochondrial biogenesis pathways and partially restored the mitochondrial morphology in palmitic acid-treated HepG2 cells. These results suggest that PU could improve acute hyperlipidemia-induced hepatic lipid metabolic abnormalities via decreasing oxidative stress and improving mitochondrial function both in vivo and in vitro, indicating that PU might be a potential intervention for hyperlipidemia-related liver diseases.

Type 2 diabetes has a series of metabolic aberrations accompanied by chronic hyperglycemia, along with various comorbidities. In recent reports, punicalagin from pomegranate has been reported to exert hypoglycemic effects against diabetes. The goal of the current research was to investigate the therapeutic effectiveness and elucidate the mechanisms of punicalagin underlying type 2 diabetes. Type 2 diabetes was induced by a high-fat diet (HFD) combined with streptozotocin (STZ) injection in C57BL/6J mice. Punicalagin was administered daily by oral gavage for 4 weeks. The results indicated that high FBG (fasting blood glucose), dyslipidemia and associated islet, liver and kidney injury were observed in the model group mice. Through metabolomics analysis, it was found that the administration of punicalagin could regulate 24 potential biomarkers and their related metabolic pathways. Moreover, the pathological changes in the liver and kidney were mainly mediated by reducing gluconeogenesis and increasing glycogenesis via stimulation of the PI3K/AKT signaling pathway and regulation of the HMGB-1/TLR4/NF-κB signaling pathway, which simultaneously interrelated to ten main pathological pathways. In addition, we confirmed the positive role of punicalagin in glucosamine-induced HepG2 cells and HG-induced HK-2 cells through related mechanistic studies in vitro. In conclusion, these findings suggested that the multi-effect and multi-target action mode of punicalagin had a significant hypoglycemic effect and a protective effect on diabetes mellitus. Punicalagin might serve as an alternative functional food or as a clinical supplemental therapy for the diabetic population to ameliorate metabolic syndrome.

The aim of this study was to investigate the protective effect of punicalagin (PU), which is a main component of pomegranate polyphenols, against liver injury induced by Type 2 diabetes mellitus (T2DM) and to explore the molecular mechanism based on autophagy in vivo and in vitro. In T2DM mice, we found that PU significantly improved liver histology, reversed serum biochemical abnormalities, and increased the autophagosome number in the liver. In HepG2 cells cultured in a high-glucose environment, PU upregulated the glucose uptake level. Both in vivo and in vitro, PU upregulated the expression of autophagy-related proteins, such as LC3b and p62, and reduced the phosphorylated Akt/total Akt and phosphorylated FoxO3a/total FoxO3a protein ratios, and these effects were enhanced by LY294002 (a PI3K/Akt inhibitor). In summary, our current findings suggest that PU protects against liver injury induced by T2DM by restoring autophagy through the Akt/FoxO3a signaling pathway.

Punicalagin and ellagic acid are the major polyphenols present in pomegranate peels. The contents of α‐punicalagin, β‐punicalagin, and ellagic acid in the pomegranate peels were approximately 75, 72, and 20 µM, respectively. The reactions of polyphenols in pomegranate peels with sodium nitrite under simulated stomach conditions were studied. The reactions decreased the polyphenolic contents of the pomegranate peels and accompanied the formation of nitroso compounds. The oxidation rates followed the order ellagic acid ＜α‐punicalagin ≈ β‐punicalagin. The results suggested that the reactions can occur in the stomach after a meal, while the pH changes from 2 to 4.5.

Elevation in the levels of reactive oxygen and nitrogen species (RONS), and downregulation of cellular antixoidants, have ubiquitously been reported from studies in animal models of neurodegenerative diseases, including Parkinson’s disease (PD) and Alzheimer’s disease (AD). Thus, plant-derived compounds are widely being investigated for their beneficial effects in these models. However, while studies have reported antioxidant potentials of several phytochemicals, a large number of studies have demonstrated different phytochemicals to be rather pro-oxidant and exaggerate oxidative stress (OS). One such study aimed to investigate possible ameliorative effect of Pomegranate juice (PJ) in rat model of toxin-induced parkinsonism revealed that PJ exacerbates OS, inflammation and promotes neurodegeneration. Thus, it remains to be investigated whether different constituents and metabolites of PJ are pro-oxidant or anti-oxidant. Using computational modeling, we investigated possible inhibitory potential of different constituents of PJ and their metabolites viz. delphinidin-3-glucoside, dimethylellagic acid-glucuronide, ellagic acid, ellagitannin, gallic acid, gallotannin 23, pelargonidin, punicalagin, urolithin A, urolithin A-glucuronide and urolithin B, on anti-oxidant defense system of the brain. The results indicate that the constituents of PJ have the potential to inhibit five key enzymes of the neuronal antioxidant defense system, viz. catalase, superoxide dismutase, glutathione peroxidase 4, glutathione reductase and glutathione-S-transferase. Thus, it is surmised that the constituents of PJ may contribute to OS and neurodegeneration by way of affecting antioxidant defense mechanism. This may particularly be more pronounced in neurodegenerative diseases, since neurons are known to be more vulnerable to OS. Thus, the present findings caution the use of PJ in patients prone to OS, especially those suffering from neurodegenerative diseases, and warrant further experimental studies to unveil the effects of individual components and metabolites of PJ on antioxidant defense system of brain. Keywords: Antioxidant, Molecular docking, Neurodegeneration, Oxidative stress, Phytochemical, Pro-oxidant

Total tannins from Punica granatum L (TPG) was obtained by aqueous-acetone extraction and was abundant in punicalagin and ellagic acid. As these compounds are known to act against inflammation and oxidative stress in synergistic fashion, this study was to investigate the protective role of TPG on the kidney in focal segmental glomerulosclerosis (FSGS) rats. In the present study, the glomerulosclerosis model was established by nephrectomy and injection of Adriamycin. The rats were treated with TPG and benazepril (BEN) for nine weeks. The results revealed that TPG and BEN pretreatment produced a significant improvement in biochemical parameters and renal pathology, and reduced the expression of PDGF, a-SMA and Ang-II. Similarly, the PCR and protein expression results showed that TPG normalized the renal expression of TGF-β1/Smad in FSGS conditions. These results suggested that the molecular mechanism of TPG ameliorated kidney injury might be associated with the inhibition of TGF-β1/Smad pathway.

To develop a more effective and safer drug for the treatment of type 2 diabetes mellitus (T2DM)-induced liver damage, we investigated the protective effects of punicalagin, a major component in pomegranate peel, on the liver of mice with T2DM. After five weeks of punicalagin treatment, blood and liver samples were obtained for the subsequent analyses. Western blotting, reverse transcription polymerase chain reaction, and immunohistochemical staining were performed to determine the expression of endoplasmic reticulum (ER) stress markers in the liver tissue. The results showed that punicalagin alleviated glucose and insulin resistance, increased insulin sensitivity, and reduced serum free fatty acids levels and hepatic steatosis in the mice with T2DM. Furthermore, punicalagin down-regulated the elevated mRNA expression of the ER stress markers eIF2α, GRP78, ATF4, and CHOP in the liver of mice with T2DM. Our results suggest that punicalagin is a potential natural agent for the prevention of T2DM-induced liver damage.

Nowadays, medicinal plants have been widely used everywhere to provide essential care for many disorders including diabetes. Recent reports assumed that the antidiabetic activities of pomegranate aril juice (PAJ) may be ascribed to its punicalagin (PCG). Therefore, the present study evaluated and compared the antidiabetic activities of PAJ and its PCG, and monitored some mechanisms of their actions in streptozotocin-nicotinamide (STZ-NA) type 2 diabetic rats. STZ-NA diabetic rats were given, orally/daily, PAJ (100 or 300 mg/kg body weight, containing 2.6 and 7.8 mg of PCG/kg body weight, respectively), pure PCG (2.6 or 7.8 mg/kg body weight), or distilled water (vehicle) for 6 weeks. PAJ (especially at the high dose) alleviated significantly (P

Pomegranate phenolics have been reported to exert skin beneficial effects but their mechanisms of action remain unclear. Herein, we investigated a standardized commercial pomegranate extract (PE; Pomella®) and its phenolics including punicalagin (PA), ellagic acid (EA), and urolithin A (UA) for their protective effects against hydrogen peroxide (H(2)O(2))-induced oxidative stress and cytotoxicity in human keratinocyte HaCaT cells. PE, PA, and EA reduced the production of H(2)O(2)-induced ROS in HaCaT cells by 1.03-, 1.37-, and 2.67-fold, respectively. PE, PA, and UA increased the viability of H(2)O(2)-stimulated HaCaT cells by 89.9, 94.9, and 90.0%, respectively. PE, PA, and UA reduced apoptotic cell populations by 3.39, 7.11, and 8.26%, respectively. In addition, PE, PA and UA decreased H(2)O(2)-stimulated caspase-3 level by 2.31-, 2.06-, and 2.68-fold, respectively. The ameliorative effects of this PE and its phenolics against the H(2)O(2)-induced oxidative stress and cytotoxicity in keratinocytes support their utilization as natural cosmeceuticals for skin health.

Recently, there has been much interest in the phenolics of pomegranate peels, because of their health benefits, such as antioxidant activity. Thus, the objective of this work is to optimize an efficient alternative and “green” technique for the extraction of phenolics from pomegranate peels. Microwave-assisted method was found to increase extraction yield, but mainly to shorten the treatment time by over 60 times compared to conventional extraction methods. The effects of solvent type, solvent/solid ratio, and microwave power on the yield of phenolics extraction were studied. The optimum operating conditions were found to be: solvent type, 50% aqueous ethanol; solvent/solid ratio, 60/1 mL/g; power, 600 W. The efficiency of the proposed extraction protocol was compared with that of the ultrasound-assisted extraction, another “green” extraction approach, studied in our previous work. The microwaves method had a yield about 1.7 times higher obtained in a shorter process time (4 min) in comparison to ultrasound-assisted extraction (10 min). These differences were attributed to the intense cell destruction of microwave-treated plant material observed by SEM analysis. The obtained extract presented a high antioxidant activity (radical scavenging activity of 94.91%), due to the high content of punicalagin (143.64 mg/g dry matter) measured by HPLC analysis, that was equivalent to that of the ultrasounds extract (radical scavenging activity, 94.77%; punicalagin content, 138.8 mg/g dry matter).

Alternative technologies, which have been developed in order to meet the consumers’ demand for nourishing and healthy meat and meat products, are followed by the food industry. In the present study, it was determined, using the HPLC method, that green tea contains a high level of epicatechin (EP) under optimal conditions and that pomegranate peel contains a high level of punicalagin (PN). Green tea, pomegranate peel, EP and PN were added to meatballs at different concentrations in eight groups. The antioxidant capacities of extracts were measured. The antimicrobial activity was examined for 72 h using three different food pathogens. The highest level of antimicrobial activity was achieved in the 1% punicalagin group, whereas the minimum inhibition concentration (L. monocytogenes, S. typhimurium) was found to be 1.87 mg/mL. A statistically significant decrease was found in FFA, POV and TBARS levels of meatballs on different days of storage (p &lt, 0.05). When compared to the control group, the bioactive compounds preserved the microbiological and chemical properties of meatballs during storage at +4 °C (14 days). It was concluded that the extracts with high EP and PN concentrations can be used as bio-preservative agents for meat and meat products.

BackgroundPathophysiological vascular remodeling in response to disturbed flow with low and oscillatory shear stress (OSS) plays important roles in atherosclerosis progression. Pomegranate extraction (PE) was reported having anti-atherogenic effects. However, whether it can exert a beneficial effect against disturbed flow-induced pathophysiological vascular remodeling to inhibit atherosclerosis remains unclear. The present study aims at investigating the anti-atherogenic effects of pomegranate peel polyphenols (PPP) extraction and its purified compound punicalagin (PU), as well as their protective effects on disturbed flow-induced vascular dysfunction and their underlying molecular mechanisms.MethodsThe anti-atherogenic effects of PPP/PU were examined on low-density lipoprotein receptor knockout mice fed with a high fat diet. The vaso-protective effects of PPP/PU were examined in rat aortas using myograph assay. A combination of in vivo experiments on rats and in vitro flow system with human endothelial cells (ECs) was used to investigate the pharmacological actions of PPP/PU on EC dysfunction induced by disturbed flow. In addition, the effects of PPP/PU on vascular smooth muscle cell (VSMC) dysfunction were also examined.ResultsPU is the effective component in PPP against atherosclerosis. PPP/PU evoked endothelium-dependent relaxation in rat aortas. PPP/PU inhibited the activation of Smad1/5 in the EC layers at post-stenotic regions of rat aortas exposed to disturbed flow with OSS. PPP/PU suppressed OSS-induced expression of cell cycle regulatory and pro-inflammatory genes in ECs. Moreover, PPP/PU inhibited inflammation-induced VSMC dysfunction.ConclusionPPP/PU protect against OSS-induced vascular remodeling through inhibiting force-specific activation of Smad1/5 in ECs and this mechanism contributes to their anti-atherogenic effects.