Biphasic Fermentation of Trapa bispinosa Shells by Ganoderma sinense and Characterization of Its Polysaccharides and Alcoholic Extract and Analysis of Their Bioactivity.

BACKGROUND: Trapa bispinosa shells (TBs) and its flesh (TBf) have been recognized for their medicinal properties, including antioxidant, antitumor, and immunomodulatory effects. Despite these benefits, TBs are often discarded as waste material, and their applications remain to be further explored. METHODS: In this study, we optimized the solid-state fermentation process of Ganoderma sinense (GS) with TBs using a response surface experiment methodology to obtain the fermented production with the highest water extract rate and DPPH free radical scavenging activity. We prepared and characterized pre-fermentation purified polysaccharides (P1) and post-fermentation purified polysaccharides (P2). Alcoholic extracts before (AE1) and after (AE2) fermentation were analyzed for active components such as polyphenols and flavonoids using UPLC-QTOF-MS/MS (ultra-performance liquid chromatography-quadrupole time-of-flight tandem mass spectrometry). Mouse macrophages (RAW 264.7) were employed to compare the immune-stimulating ability of polysaccharides and the antioxidant activity of AE1 and AE2. RESULTS: Optimal fermentation conditions comprised a duration of 2 days, a temperature of 14 °C, and a humidity of 77%. The peak water extract yield and DPPH free radical scavenging rate of the water extract from TBs fermented by GS were observed under these conditions. The enhanced activity may be attributed to changes in the polysaccharide structure and the components of the alcoholic extract. The P2 treatment group indicated more secretion of RAW 264.7 cells of NO, iNOS, IL-2, IL-10, and TNF-α than P1, which shows that the polysaccharides demonstrated increased immune-stimulating ability, with their effect linked to the NF-кB pathway. Moreover, the results of the AE2 treatment group indicated that secretion of RAW 264.7 cells of T-AOC and T-SOD increased and MDA decreased, which shows that the alcoholic extract demonstrated enhanced antioxidant activity, with its effect linked to the Nrf2/Keap1-ARE pathway. CONCLUSIONS: Biphasic fermentation of Trapa bispinosa shells by Ganoderma sinense could change the composition and structure of the polysaccharides and the composition of the alcoholic extract, which could increase the products' immunomodulatory and antioxidant activity.

Changes in the pasting and rheological properties of wheat, corn, water caltrop and lotus rhizome starches by the addition of Annona montana mucilage.

Annona montana mucilage (AMM) is a novel mucilage with unique but limited information. This study investigated the effects of AMM addition on the pasting and rheological properties of wheat starch (WS), corn starch (CS), water caltrop starch (WCS), and lotus rhizome starch (LRS). The addition of AMM generally increased the pasting temperature and peak viscosity, but reduced the setback value of all starches to varying degrees, and the initiation of viscosity-increase for cereal starch/AMM systems during pasting occurred at lower temperatures, accompanied with a distinctive two-stage swelling process as well as lower peak and final hot paste viscosity at 50 °C. AMM significantly increased the pseudoplasticity and entanglement of the systems to varying degrees (LRS > WS > WCS > CS). Under a constant shear rate of 50 s-1, the consistency level was found to fall in honey-like for cereal starch/AMM groups, and honey-like to extremely thick levels for WCS and LRS/AMM groups. Except for the WCS/AMM systems, the storage and loss modulus as well as tan increased with increasing AMM concentration. Short-term retrogradation of starch at 4 °C was pronouncedly retarded by the addition of AMM for WS, CS and WCS groups, but was less affected for LRS group.

Identification of Candidate Expansin Genes Associated with Seed Weight in Pomegranate (Punica granatum L.).

Seed weight is an important target trait in pomegranate breeding and culture. Expansins act by loosening plant cell walls and cellulosic materials, permitting turgor-driven cell enlargement. However, the role of expansin genes (EXPs) in pomegranate seed weight remains elusive. A total of 29 PgrEXPs were identified in the 'Dabenzi' genome. These genes were classified into four subfamilies and 14 subgroups, including 22 PgrEXPAs, 5 PgrEXPBs, 1 PgrEXPLA, and 1 PgrEXPLB. Transcriptome analysis of PgrEXPs in different tissues (root, leaf, flower, peel, and seed testa) in 'Dabenzi', and the seed testa of the hard-seeded pomegranate cultivar 'Dabenzi' and soft-seeded cultivar 'Tunisia' at three development stages showed that three PgrEXPs (PgrEXPA11, PgrEXPA22, PgrEXPA6) were highly expressed throughout seed development, especially in the sarcotesta. SNP/Indel markers of these PgrEXPs were developed and used to genotype 101 pomegranate accessions. The association of polymorphic PgrEXPs with seed weight-related traits (100-seed weight, 100-kernel weight, 100-sarcotesta weight, and the percentage of 100-sarcotesta to 100-seed weight) were analyzed. PgrEXP22 was significantly associated with 100-seed weight and 100-sarcotesta weight and is a likely candidate for regulating seed weight and sarcotesta development in particular. This study provides an effective tool for the genetic improvement of seed weight in pomegranate breeding programs.

Improved Cardiovascular Effects of a Novel Pomegranate Byproduct Extract Obtained through Hydrodynamic Cavitation.

The healthy properties of pomegranate fruit, a highly consumed food, have been known for a long time. However, the pomegranate supply chain is still rather inefficient, with the non-edible fraction, whose weight is roughly half the total and is endowed with plenty of valuable bioactive compounds, either disposed of or underutilized. A novel extract obtained from non-edible byproducts (called PPE), using hydrodynamic cavitation, a green, efficient, and scalable technique, was investigated for its cardiovascular effects in vivo. PPE showed efficacy in an acute phenylephrine (PE)-induced hypertensive rat model, similar to the extract of whole fruit (PFE) obtained using the same extractive technique, along with good intestinal bioaccessibility after oral administration. Finally, when chronically administered for 6 weeks to spontaneously hypertensive rats, PPE was shown to significantly contain the increase in systolic blood pressure, comparable to the reference drug Captopril, and at a dose remarkably lower than the reported effective dose of ellagic acid. The extract from the non-edible fraction of the pomegranate fruit also showed good anti-inflammation and anti-fibrotic effects. The findings of this study, along with the extraction technique, could contribute to enhancing the value of the pomegranate supply chain, relieve the related environmental burden, and potentially improve public health.

Engineering Yarrowia lipolytica for Sustainable Production of the Pomegranate Seed Oil-Derived Punicic Acid.

Punicic acid is a conjugated linolenic acid with various biological activities including antiobesity, antioxidant, anticancer, and anti-inflammatory effects. It is often used as a nutraceutical, dietary additive, and animal feed. Currently, punicic acid is primarily extracted from pomegranate seed oil, but it is restricted due to the extended growth cycle, climatic limitations, and low recovery level. There have also been reports on the chemical synthesis of punicic acid, but it resulted in a mixture of structurally similar isomers, requiring additional purification/separation steps. In this study, a comprehensive strategy for the production of punicic acid in Yarrowia lipolytica was implemented by pushing the supply of linoleic acid precursors in a high-oleic oil strain, expressing multiple copies of the fatty acid conjugase gene from Punica granatum, engineering the acyl-editing pathway to improve the phosphatidylcholine pool, and promoting the assembly of punicic acid in the form of triglycerides. The optimal strain with high oil production capacity and a significantly increased punicic acid ratio accumulated 3072.72 mg/L punicic acid, accounting for 6.19% of total fatty acids in fed-batch fermentation, providing a viable, sustainable, and green approach for punicic acid production to substitute plant extraction and chemical synthesis production.

The potential of postharvest zinc treatment for preservation of pomegranate aril quality.

A short shelf life usually limits the distribution and supply of pomegranate arils. Since zinc (Zn) has an indispensable role in the nutrient integrity of our diet and is effective in suppressing pathogens, this study was done as two separate experiments of pre-harvest spraying and postharvest dipping of arils with two zinc supplements, including nano zinc oxide (nZnO) and zinc sulfate (ZnSO4). The optimized concentration of both sources was used in the experiment. The pre-harvest treatment failed to extend the shelf life of arils, and, ultimately, the arils decayed after 15 days. However, the postharvest zinc treatment significantly (P < 0.01) affected all measured indices. Also, zinc sulfate was more effective than nZnO. Zn uptake was higher in postharvest treatments because exogenous Zn was in direct contact with the aril surface. After dissolving in water, Zn ions in sulfate bind to the membrane of microorganisms and thus delay cell division and microbial growth cycle. The solubility of zinc oxide nanoparticles in water is poor. Using the ZnSO4 treatment (0.8%W/V) effectively maintained the values of titratable acidity (TA), total phenolic content (TPC), total soluble solids (TSS), anthocyanin content, and antioxidant activity. Also, this treatment significantly controlled weight loss in the arils.

Effective application of citric acid treated Trapa natans and Citrullus lanatus lignocellulosic macromolecules for adsorptive remediation of acid Violet-7 dye.

The peels of Trapa natans (TRA) and Citrullus lanatus (CIT), were modified with a variety of chemicals to boost their surface for the optimization of adsorption performance by providing a greater number of additional active binding sites. Citric acid-processed peels (TRAC and CITC) had shown more favorable adsorption performance to eradicate acid violet 7 dye (AVS). Extra and additional active sites generated after chemical processing, including hydroxyl (OH), carboxyl (COOH), amines NH2, carbonyl, and ester (-O-CO-) groups, as evidenced from FTIR and SEM characterizations, may boost the potential of physicochemical integration of adsorbent surface activity in order to promote and encourage the retention of hazardous and risky AVS molecules from the water. The Langmuir isotherm assessed the qmax for the adsorption of AVS on TRAC, CITC, TRA, and CIT to be 212.8, 294, 24.3, and 60.6 mg/g, respectively, whereas the correlation coefficients assessed for both TRAC and CITC were 0.98 and for TRA and CIT were 0.97, closer to unity reflecting monolayer physio-sorption. According to Temkin, the adsorption of AVS on TRAC, TRA, CITC, and CIT gives "BT" values of 1.275, 0.947, 1.085, and 1.211 mg/g, also suggesting physio-sorption. Therefore, chemically modified peels can be employed for detoxification of AVS.

Pomegranate juice-containing serum inhibits migration of hepatocellular carcinoma cells and promotes apoptosis by induction of mitochondrial dysfunction.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide, with an insidious onset and poor prognosis. Pomegranate is a fruit rich in many natural products with anti-cancer potential; however, its direct biological effects are difficult to evaluate in vitro because of changes in its active components after absorption and metabolism. This study was conducted to prepare pomegranate juice-containing serum (PJ serum) by gavage of pomegranate juice (PJ) in rats and to collect serum. The aim was to investigate the components and the effects of PJ serum on HCC cells by serum pharmacology. 56 compounds were identified in the PJ serum, including 6 prototype components. PJ serum selectively inhibited HCC cells proliferation and migration, and it promoted apoptosis of HCC cells without affecting LO2 cells activity. Furthermore, PJ serum reduced the mitochondrial membrane potential and increased the calcium ion concentration in HCC cells. Mechanistically, PJ serum up-regulated the expression of the Bax family, Caspases and TIMP2/MMP2, and down-regulated the expression of MMP9. This study revealed that PJ serum inhibited HCC cell migration by regulating the TIMP2/MMP2 balance and MMP9 expression and promoted HCC cell apoptosis by inducing mitochondrial dysfunction and causing a Caspase cascade. The polyphenols and flavonoids in PJ may be important components responsible for its anti-HCC activity after metabolism.

The Modulatory Bioeffects of Pomegranate (Punica granatum L.) Polyphenols on Metabolic Disorders: Understanding Their Preventive Role against Metabolic Syndrome.

Modern research achievements support the health-promoting effects of natural products and diets rich in polyphenols. Pomegranate (PG) (Punica granatum L.) contains a considerable number of bioactive compounds that exert a broad spectrum of beneficial biological activities, including antimicrobial, antidiabetic, antiobesity, and atheroprotective properties. In this context, the reviewed literature shows that PG intake might reduce insulin resistance, cytokine levels, redox gene expression, blood pressure elevation, vascular injuries, and lipoprotein oxidative modifications. The lipid parameter corrective capabilities of PG-ellagitannins have also been extensively reported to be significantly effective in reducing hyperlipidemia (TC, LDL-C, VLDL-C, and TAGs), while increasing plasma HDL-C concentrations and improving the TC/HDL-C and LDL-C/HDL-C ratios. The health benefits of pomegranate consumption seem to be acheived through the amelioration of adipose tissue endocrine function, fatty acid utilization, GLUT receptor expression, paraoxonase activity enhancement, and the modulation of PPAR and NF-κB. While the results from animal experiments are promising, human findings published in this field are inconsistent and are still limited in several aspects. The present review aims to discuss and provide a critical analysis of PG's bioeffects on the components of metabolic syndrome, type-2 diabetes, obesity, and dyslipidemia, as well as on certain cardiovascular-related diseases. Additionally, a brief overview of the pharmacokinetic properties, safety, and bioavailability of PG-ellagitannins is included.

Pomegranate (Punica granatum L.) and Its Rich Ellagitannins as Potential Inhibitors in Ulcerative Colitis.

Ulcerative colitis, an immune-mediated inflammatory disease of the gastrointestinal tract, places a significant financial burden on patients and the healthcare system. Recently, reviews of the pomegranate and the abundant medicinal applications of its ellagitannins, as well as its pharmacological action, phytochemicals, metabolism, and pharmacokinetics, have been completed. However, summaries on their anti-ulcerative colitis effects are lacking. Numerous preclinical animal investigations and clinical human trial reports demonstrated the specific therapeutic effects of pomegranate and the effect of its ellagitannins against ulcerative colitis. According to the literature collected by Sci-finder and PubMed databases over the past 20 years, this is the first review that has compiled references regarding how the rich ellagitannins found in pomegranate have altered the ulcerative colitis. It was suggested that the various parts of pomegranates and their rich ellagitannins (especially their primary components, punicalagin, and ellagic acid) can inhibit oxidant and inflammatory processes, regulate the intestinal barrier and flora, and provide an anti-ulcerative colitis resource through dietary management.

Punica granatum peel extract modulates levofloxacin-induced oxidative stress and testicular damage in rats.

Levofloxacin (LEV) is one of the Fluoroquinolones antibiotic groups, which are utilized in the therapy of numerous diseases, particularly in reproductive organs. Punica granatum peel is a waste byproduct rich in phytochemicals that are known for their different biological activities. The current research was designed to assess the capability of pomegranate peel extract (PGPE) in counteracting LEV-induced oxidative stress and testicular injury in rats. Rats groups were divided as follows: control, PGPE (500 mg/kg BW), LEV (300 mg/kg BW), and PGPE plus LEV. Rats were treated orally for two weeks daily. The chemical and nutritional content of Punica granatum peel (PGP) were investigated. GC/MS analysis showed the major phytochemical constituents in PGPE as gallic acid, ellagic acid, 4H-Pyran-4-one, 2,3-dihydro-3,5-dihydroxy-6-methyl, and caffeic acid with DPPH, ABTS, and NO radical scavenging activity, as well as Fe3+- reducing antioxidant activity. Results revealed that LEV increased TBARS and H2O2 concentrations and LDH activity in rat testes significantly. While the activities of antioxidant enzymes, phosphatases, aminotransferases, and reduced glutathione content as well as protein levels, were significantly reduced. Worthy changes in testosterone, luteinizing, and follicle-stimulating hormone levels, as well as sperm characteristics, were also discovered. LEV was also found to trigger apoptosis, as evidenced by elevated p53 and caspase-3 levels and decreased Bcl2 levels. Furthermore, alterations in histological and immunohistochemical PCNA expression were observed in rat testes, confirming the biochemical findings. Furthermore, PGPE pretreatment of LEV-treated rats restored the majority of the tested parameters when compared to the LEV-treated group. In conclusion, pomegranate peel extract had a powerful modulating role against the adverse effects of levofloxacin in rat testes and represents a perspective of the utilization of food waste by-products.

Pomegranate (Punica granatum L.) and its phytochemicals as anxiolytic; an underreported effect with therapeutic potential: A systematic review.

Anxiety is a mental disorder characterized by excessive concern about possible future threats that, if prolonged, becomes a pathology that must be controlled through psychotherapy and medication. Currently, the pharmacological treatment for anxiety involves the use of antidepressants and benzodiazepines; however, these treatments often come with adverse effects. Thus, there is a need to seek natural compounds that can help alleviate anxiety and reduce these side effects. On the other hand, pomegranate (PG) fruit is known to have important health benefits, which have been compiled in several reviews. However, its anxiolytic effect has not been thoroughly studied, and clinical research on this topic is lacking. The aim of this work was to conduct a systematic review of studies exploring the anxiolytic-like effect of PG and its phytochemicals. Databases such as Pubmed, ScienceDirect, Springer link, Google scholar, Worldwide science, and Web of science were searched for articles using predetermined terms. Inclusion criteria were established, and original articles that met these criteria were selected. The data collected included information on PG part and variety, species, sample size, anxiety model, dose, route and time of administration, reference drug, main results, and the mechanisms of action. Fifty-nine studies were found that reported the anxiolytic-like effect of PG and its phytochemicals such as anthocyanins, flavonoids, tannins, organic acids, and xanthonoids. The literature suggests that the mechanisms of action behind this effect involved the inhibition of the GABAergic receptor, NMDA, CaMKII/CREB pathway; the reduction of oxidative stress, inhibiting TLR4 and nNOS; modulation of cytokines and the expression of NFkB, GAD67, and iNOS, as well as the activation of Nrf2 and AMPK. PG and some of its phytochemicals could be considered as a novel alternative for the treatment of pathological anxiety. This review is the first to document the anxiolytic-like effect of PG.

A comprehensive genus-level phylogeny and biogeographical history of the Lythraceae based on whole plastome sequences.

BACKGROUND AND AIMS: The Lythraceae are a mainly subtropical to tropical family of the order Myrtales with 28 currently accepted genera and approximately 600 species. There is currently no well-supported phylogenetic and biogeographical hypothesis of the Lythraceae incorporating all currently accepted genera, which we sought to provide. METHODS: Plastomes of representative species of 18 distinct Lythraceae genera were sequenced and annotated. Together with existing sequences, plastomes of all 28 currently accepted genera in the Lythraceae were brought together for the first time. The plastomes were aligned and a Bayesian phylogenetic hypothesis was produced. We then conducted a time-calibrated Bayesian analysis and a biogeographical analysis. KEY RESULTS: Plastome-based Bayesian and maximum-likelihood phylogenetic trees are generally congruent with recent nuclear phylogenomic data and resolve two deeply branching major clades in the Lythraceae. One major clade concentrates shrubby and arboreal South American and African genera that inhabit seasonally dry environments, with larger, often winged seeds, adapted to dispersal by the wind. The second major clade concentrates North American, Asian, African and several near-cosmopolitan herbaceous, shrubby and arboreal genera, often inhabiting humid or aquatic environments, with smaller seeds possessing structures that facilitate dispersal by water. CONCLUSIONS: We hypothesize that the Lythraceae dispersed early in the Late Cretaceous from South American to North American continents, with subsequent expansion in the Late Cretaceous of a North American lineage through Laurasia to Africa via a boreotropical route. Two later expansions of South American clades to Africa in the Palaeocene and Eocene, respectively, are also hypothesized. Transoceanic dispersal in the family is possibly facilitated by adaptations to aquatic environments that are common to many extant genera of the Lythraceae, where long-distance dispersal and vicariance may be invoked to explain several remarkable disjunct distributions in Lythraceae clades.

Hydrolyzable tannins are incorporated into the endocarp during sclerification of the water caltrop Trapa natans.

The water caltrop (Trapa natans) develops unique woody fruits with unusually large seeds among aquatic plants. During fruit development, the inner fruit wall (endocarp) sclerifies and forms a protective layer for the seed. Endocarp sclerification also occurs in many land plants with large seeds; however, in T. natans, the processes of fruit formation, endocarp hardening, and seed storage take place entirely underwater. To identify potential chemical and structural adaptations for the aquatic environment, we investigated the cell-wall composition in the endocarp at a young developmental stage, as well as at fruit maturity. Our work shows that hydrolyzable tannins-specifically gallotannins-flood the endocarp tissue during secondary wall formation and are integrated into cell walls along with lignin during maturation. Within the secondary walls of mature tissue, we identified unusually strong spectroscopic features of ester linkages, suggesting that the gallotannins and their derivatives are cross-linked to other wall components via ester bonds, leading to unique cell-wall properties. The synthesis of large amounts of water-soluble, defensive aromatic metabolites during secondary wall formation might be a fast way to defend seeds within the insufficiently lignified endocarp of T. natans.

Chromosome-level assemblies of cultivated water chestnut Trapa bicornis and its wild relative Trapa incisa.

Water chestnut (Trapa L.) is a floating-leaved aquatic plant with high edible and medicinal value. In this study, we presented chromosome-level genome assemblies of cultivated large-seed species Trapa bicornis and its wild small-seed relative Trapa incisa by using PacBio HiFi long reads and Hi-C technology. The T. bicornis and T. incisa assemblies consisted of 479.90 Mb and 463.97 Mb contigs with N50 values of 13.52 Mb and 13.77 Mb, respectively, and repeat contents of 62.88% and 62.49%, respectively. A total of 33,306 and 33,315 protein-coding genes were predicted in T. bicornis and T. incisa assemblies, respectively. There were 159,232 structural variants affecting more than 11 thousand genes detected between the two genomes. The phylogenetic analysis indicated that the lineage leading to Trapa was diverged from the lineage to Sonneratia approximately 23 million years ago. These two assemblies provide valuable resources for future evolutionary and functional genomic research and molecular breeding of water chestnut.

Influence of microwave heating on bioactive properties, phenolic compounds and fatty acid profiles of pomegranate seed oil.

In this study, the effects of different microwave powers on the bioactive properties, fatty acid and phenolic profiles of pomegranate seed oil were reported using various analytical methods, GC and HPLC. Antioxidant capacity and total phenolic values of pomegranate seed oils were established between 14.16% (control) and 19.18% (720 and 900 W) to 0.00 (900 W) and 3.61 mgGAE/100 g (control), respectively. The viscosity values of pomegranate seed oil increased with the heat treatment. But, the viscosity of the oils increased with the applied Watt increase. The p-coumaric acid amounts of the seed oils heated at 180, 720 and 900 W in the microwave were found to be statistically similar. In general, phenolic compounds of pomegranate seed oils did not show a constant increase or decrease depending on microwave power. The key fatty acid of pomegranate seed oil was punisic acid (30.49-36.10%). followed by linoleic acid (25.95-30.01%).

Anti-COVID-19 Potential of Ellagic Acid and Polyphenols of Punica granatum L.

Pomegranate (Punica granatum L.) is a rich source of polyphenols, including ellagitannins and ellagic acid. The plant is used in traditional medicine, and its purified components can provide anti-inflammatory and antioxidant activity and support of host defenses during viral infection and recovery from disease. Current data show that pomegranate polyphenol extract and its ellagitannin components and metabolites exert their beneficial effects by controlling immune cell infiltration, regulating the cytokine secretion and reactive oxygen and nitrogen species production, and by modulating the activity of the NFκB pathway. In vitro, pomegranate extracts and ellagitannins interact with and inhibit the infectivity of a range of viruses, including SARS-CoV-2. In silico docking studies show that ellagitannins bind to several SARS-CoV-2 and human proteins, including a number of proteases. This warrants further exploration of polyphenol-viral and polyphenol-host interactions in in vitro and in vivo studies. Pomegranate extracts, ellagitannins and ellagic acid are promising agents to target the SARS-CoV-2 virus and to restrict the host inflammatory response to viral infections, as well as to supplement the depleted host antioxidant levels during the stage of recovery from COVID-19.

Ellagic acid from pomegranate peel: Consecutive countercurrent chromatographic separation and antioxidant effect.

Ellagic acid is one of the most representative natural antioxidants, and is rich in pomegranate peel. In this study, a consecutive countercurrent chromatographic (CCC) separation method was established to improve the preparative efficiency of ellagic acid from pomegranate peel. By optimizing the solvent system, sample size and flow rate, 280 mg of ellagic acid was obtained from 5 g of crude sample from pomegranate peel by CCC after six consecutive injections. Moreover, the values of EC50 for ellagic acid in scavenging ABTS·+ and DPPH· were 4.59 ± 0.07 and 10.54 ± 0.07 µg/ml, respectively, indicating a strong antioxidant activity. This study not only established a high-throughput method for the preparation of ellagic acid, but also provided a successful example for the development of and research on other natural antioxidants.

Impact of Pomegranate Juice on the Pharmacokinetics of CYP3A4- and CYP2C9-Mediated Drugs Metabolism: A Preclinical and Clinical Review.

The Punica granatum L. (pomegranate) fruit juice contains large amounts of polyphenols, mainly tannins such as ellagitannin, punicalagin, and punicalin, and flavonoids such as anthocyanins, flavan-3-ols, and flavonols. These constituents have high antioxidant, anti-inflammatory, anti-diabetic, anti-obesity, and anticancer activities. Because of these activities, many patients may consume pomegranate juice (PJ) with or without their doctor's knowledge. This may raise any significant medication errors or benefits because of food-drug interactions that modulate the drug's pharmacokinetics or pharmacodynamics. It has been shown that some drugs exhibited no interaction with pomegranate, such as theophylline. On the other hand, observational studies reported that PJ prolonged the pharmacodynamics of warfarin and sildenafil. Furthermore, since it has been shown that pomegranate constituents inhibit cytochrome P450 (CYP450) activities such as CYP3A4 and CYP2C9, PJ may affect intestinal and liver metabolism of CYP3A4 and CYP2C9-mediated drugs. This review summarizes the preclinical and clinical studies that investigated the impact of oral PJ administration on the pharmacokinetics of drugs that are metabolized by CYP3A4 and CYP2C9. Thus, it will serve as a future road map for researchers and policymakers in the fields of drug-herb, drug-food and drug-beverage interactions. Preclinical studies revealed that prolonged administration of PJ increased the absorption, and therefore the bioavailability, of buspirone, nitrendipine, metronidazole, saquinavir, and sildenafil via reducing the intestinal CYP3A4 and CYP2C9. On the other hand, clinical studies are limited to a single dose of PJ administration that needs to be protocoled with prolonged administration to observe a significant interaction.

Preventive and Therapeutic Effects of Punica granatum L. Polyphenols in Neurological Conditions.

Pomegranate (Punica granatum L.) is a polyphenol-rich food and medicinal plant containing flavonols, anthocyanins, and tannins. Ellagitannins (ETs) are the most abundant polyphenols in pomegranate. A growing body of research shows that polyphenol-rich pomegranate extracts and their metabolites target multiple types of brain cell and support their redox balance, proliferation and survival, as well as cell signaling. Independent studies have demonstrated that the significant neuroprotective effects of ETs are mediated by their antioxidant and anti-inflammatory effects, their chelating properties, by their ability to activate various signaling pathways, as well as the ability to influence mitochondrial damage, thus regulating autophagy, apoptosis and neurotransmitter signaling. The multitude of in vitro and in vivo studies summarized in the present review suggest that pomegranate polyphenols act on both neuronal and glial cells directly, and also affect blood-brain barrier function, restoring redox balance in the blood and brain and increasing blood flow to the brain.