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Promising Remedies for Cardiovascular Disease: Natural Polyphenol Ellagic Acid and Its Metabolite Urolithins
Abstract
Background:
Cardiovascular disease (CVD) is a significant worldwide factor contributing to human fatality and morbidity. With the increase of incidence rates, it is of concern that there is a lack of current therapeutic alternatives because of multiple side effects. Ellagic acid (EA), the natural polyphenol (C14H6O8), is abundant in pomegranates, berries, and nuts. EA and its intestinal microflora metabolite, urolithins, have recently attracted much attention as a potential novel "medicine" because of their wide pharmacological properties.
Purpose:
This study aimed to critically analyze available literature to summarize the beneficial effects of EA and urolithins, and highlights their druggability and therapeutic potential in various CVDs.
Methods:
We systematically studied research and review articles between 1984 and 2022 available on various databases to obtain the data on EA and urolithins with no language restriction. Their cardiovascular protective activities, underlying mechanism, and druggability were highlighted and discussed comprehensively.
Results:
We found that EA and urolithins may exert preventive and curative effects on CVD with negligible side effects and possibly regulate lipid metabolism imbalance, pro-inflammatory factor production, vascular smooth muscle cell proliferation, cardiomyocyte apoptosis, endothelial cell dysfunction, and Ca2+ intake and release. Potentially, this may lead to the prevention and amelioration of atherosclerosis, hypertension, myocardial infarction, cardiac fibrosis, cardiomyopathy, cardiac arrhythmias, and cardiotoxicities in vivo. Several molecules and signaling pathways are associated with their therapeutic actions, including phosphatidylinositol 3-kinase/protein kinase B, mitogen-activated protein kinase, NF-κB, nuclear factor erythroid-2 related factor 2, sirtuin1, miRNA, and extracellular signal-regulated kinase 1/2.
Conclusion:
In vitro and in vivo studies shows that EA and urolithins could be used as valid candidates for early prevention and effective therapeutic strategies for various CVDs.
... Cardiovascular diseases (CVDs) are perceived as a primary contributor to worldwide fatalities, involving concerns such as hypertension, arterial hardening, heart attacks, irregular heart rhythms, and heart failure [159,160]. Emerging research has illuminated a noticeable surge in the prevalence of heart ailments [159][160][161]. It is essential to understand that the medications often employed for cardiovascular diseases (CVDs), including statins, angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), fibrates, and β-blockers, pose a risk of causing unwanted side effects. ...
... The inflammatory response to injury is a complex biological process that reacts to harmful stimuli. Several enzymes, like cyclooxygenase (COX), lipoxygenase (LOX), tyrosine kinase (TK), phospholipase A2 (PLA2s), and protein kinase C, play an important role in the regulation of the inflammatory response [159][160][161][162]. Some specific flavonoids have been shown to directly inhibit these enzymes, thereby directly impacting inflammation [183,184]. ...
... The production of leukocytes is recognized as a crucial phase in the advancement of inflammation observed in cardiovascular diseases and other ailments. Arachidonic acid synthesis ultimately leads to the production of cytokines (IL-1) and chemokines (IL-8) by neutrophils [161,162]. This process is facilitated by both COX and LOX enzymes. ...
There are a wide variety of phytochemicals collectively known as polyphenols. Their structural diversity results in a broad range of characteristics and biological effects. Polyphenols can be found in a variety of foods and drinks, including fruits, cereals, tea, and coffee. Studies both in vitro and in vivo, as well as clinical trials, have shown that they possess potent antioxidant activities, numerous therapeutic effects, and health advantages. Dietary polyphenols have demonstrated the potential to prevent many health problems, including obesity, atherosclerosis, high blood sugar, diabetes, hypertension, cancer, and neurological diseases. In this paper, the protective effects of polyphenols and the mechanisms behind them are investigated in detail, citing the most recent available literature. This review aims to provide a comprehensive overview of the current knowledge on the role of polyphenols in preventing and managing chronic diseases. The cited publications are derived from in vitro, in vivo, and human-based studies and clinical trials. A more complete understanding of these naturally occurring metabolites will pave the way for the development of novel polyphenol-rich diet and drug development programs. This, in turn, provides further evidence of their health benefits.
... Another critical aspect of pomegranate extracts is the low oral bioavailability of ellagitannins, especially EA; indeed, it is reported to be poorly absorbed and endowed with a very low water solubility [26]. To overcome this challenging difficulty, which can jeopardize intestinal bioaccessibility, several formulations have been developed, such as cellulose ester solid dispersions [27], cyclodextrin nanosponges [28], or particle size reduction to microparticles or nanoparticles [29,30], as well as the creation of encapsulation biodegradable systems using polyvinyl alcohol or PVA associated with chitosan (80:20) [31][32][33]. ...
... The oral administration of PPE (100 mg/kg) led to a very early detection of EA in the systemic circulation ( Figure 2); indeed, the plasma concentration of EA peaked 1 h after its administration, reaching the maximal concentration of 53 ± 14 ng/mL, as previously reported, but with higher doses of EA [26]. Four hours after the administration, the concentration of the tannin was negligible. ...
... Of note, a large part of ellagitannins is represented by punicalagins, which gut microbiota transforms into EA at the gastric and colon level and into urolithins at the intestinal level [3,44,45]. A limitation to the clinical use of this interesting fruit is represented by the low bioavailability of its metabolites, among which is EA, which totals less than 1% [26]. Therefore, researchers are currently committed to improving bioavailability, creating new formulations or preparations, including through new or unconventional technologies that can combine high extraction yields and the preservation of nutrients and bioactive compounds, and have a reduced impact on the environment in terms of energy consumption and a lower or no reliance on synthetic solvents. ...
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.
... Approximately, 85% of these mortality rates were due to heart attacks and strokes (WHO site). Strokes kill 6.7 million people each year, and coronary heart disease claims 7.4 million lives [3,4]. ...
... Cardiovascular disease (CVD), encompassing conditions such as atherosclerosis, hypertension, myocardial infarction, cardiomyopathy, arrhythmia, and heart failure (HF), is a major contributor to global mortality. The incidence of CVD has experienced a notable increase [1][2][3][4]. Despite the wide range of pharmaceuticals currently utilized for the management of CVD, such as statins, angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), calcium channel blockers (CCBs), fibrates, and β-blockers, it is important to acknowledge that a significant number of these medications are associated with adverse effects in the human population [4]. ...
... The incidence of CVD has experienced a notable increase [1][2][3][4]. Despite the wide range of pharmaceuticals currently utilized for the management of CVD, such as statins, angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), calcium channel blockers (CCBs), fibrates, and β-blockers, it is important to acknowledge that a significant number of these medications are associated with adverse effects in the human population [4]. Hence, there exists a significant clinical requirement to discover and cultivate innovative therapeutic strategies for CVD [2]. ...
Fruits, vegetables, and other food items contain phytochemicals or secondary metabolites
which may be considered non-essential nutrients but have medicinal importance. These dietary phytochemicals exhibit chemopreventive and therapeutic effects against numerous diseases. Polyphenols
are secondary metabolites found in vegetables, fruits, and grains. These compounds exhibit several
health benefits such as immune modulators, vasodilators, and antioxidants. This review focuses on
recent studies on using dietary polyphenols to treat cardiovascular disorders, atherosclerosis, and
vascular endothelium deficits. We focus on exploring the safety of highly effective polyphenols to
ensure their maximum impact on cardiac abnormalities and discuss recent epidemiological evidence
and intervention trials related to these properties. Kaempferol, quercetin, and resveratrol prevent oxidative stress by regulating proteins that induce oxidation in heart tissues. In addition, polyphenols modulate the tone of the endothelium of vessels by releasing nitric oxide (NO) and reducing
low-density lipoprotein (LDL) oxidation to prevent atherosclerosis. In cardiomyocytes, polyphenols suppress the expression of inflammatory markers and inhibit the production of inflammation markers to exert an anti-inflammatory response. Consequently, heart diseases such as strokes, hypertension, heart failure, and ischemic heart disease could be prevented by dietary polyphenols
In the present review, we discuss the occurrence of ellagitannins (ETs) and ellagic acid (EA) and methods for their isolation from plant materials. We summarize analytical methods, including high-performance liquid chromatography–ultraviolet (HPLC–UV) and liquid chromatography–mass spectrometry (LC–MS), for the determination of ETs, EA and their bioactive metabolites urolithins (Uros) in samples of plant and food origin, as well as in biological samples, such as plasma, urine and feces. In addition, the current interest in the bioactivities of Uros is discussed in brief.
Objective:
Arterial hypertension (HTN) is important due to its high prevalence, morbidity, and mortality rates. Calcium channel blockers (CCBs) are the first-line antihypertensive drugs. HTN can lead to heart failure (HF) by causing hypertensive left ventricular hypertrophy (HTN LVH). CCBs are recommended for the treatment of HTN LVH. The aim of the paper is to analyze the status of CCBs regarding 1) HTN LVH treatment and 2) capability to prevent HTN-induced HF in the guidelines.
Methods:
A narrative review is used for this paper. A search of the following databases was conducted: Medline, Scopus, Science Direct, Springer, SAGE, Wiley, Oxford Journals, Cambridge, and Google Scholar.
Results:
CCBs are effective antihypertensive drugs. CCBs are also a very good therapeutic option for HTN LVH because they are capable of causing reverse LVH remodeling. Consequently, we may expect that CCBs would prevent HF. However, evidence suggests CCBs confer less protection from HF than other first-line antihypertensive drugs. A negative inotropic action of non-dihydropyridine CCBs may contribute to suboptimal protection against HF. This discrepancy is clinically relevant because CCBs are in one of the two recommended (single-pill) combinations for the initial treatment of the HTN population. HTN LVH precipitates HF.
Conclusion:
CCBs are somewhat inferior to renin-angiotensin-aldosterone system blockers but still very good in HTN LVH regression; consequently, CCBs are expected to protect from HF. On the contrary, CCBs protect from HF less than other first-line antihypertensive drugs. This discrepancy needs a clear explanation in order to improve clinical practice.
Urolithin A is an active compound of gut-microbiota-derived metabolites of polyphenol ellagic acid that has anti-aging, antioxidative, and anti-inflammatory effects. However, the effects of urolithin A on polyinosinic acid-polycytidylic acid (poly(I:C))-induced inflammation remain unclear. Poly(I:C) is a double-stranded RNA (dsRNA) similar to a virus and is recognized by Toll-like receptor-3 (TLR3), inducing an inflammatory response in immune cells, such as macrophages. Inflammation is a natural defense process of the innate immune system. Therefore, we used poly(I:C)-induced RAW264.7 cells and attenuated the inflammation induced by urolithin A. First, our data suggested that 1–30 μM urolithin A does not reduce RAW264.7 cell viability, whereas 1 μM urolithin A is sufficient for antioxidation and the decreased production of tumor necrosis factor-α (TNF-α), monocyte chemoattractant protein-1 (MCP-1), and C-C chemokine ligand 5. The inflammation-related proteins cyclooxygenase-2 and inducible nitric oxide synthase were also downregulated by urolithin A. Next, 1 μM urolithin A inhibited the levels of interferon (INF)-α and INF-β. Urolithin A was applied to investigate the blockade of the TLR3 signaling pathway in poly(I:C)-induced RAW264.7 cells. Moreover, the TLR3 signaling pathway, subsequent inflammatory-related pathways, and antioxidation pathways showed changes in nuclear factor-κB (NF-κB) signaling and blocked ERK/mitogen-activated protein kinase (MAPK) signaling. Urolithin A enhanced catalase (CAT) and superoxide dismutase (SOD) activities, but decreased malondialdehyde (MDA) levels in poly(I:C)-induced RAW264.7 cells. Thus, our results suggest that urolithin A inhibits TLR3-activated inflammatory and oxidative-associated pathways in macrophages, and that this inhibition is induced by poly(I:C). Therefore, urolithin A may have antiviral effects and could be used to treat viral-infection-related diseases.
Abstract Camellia osmantha is a new species of the genus Camellia and is an economically important ornamental plant. Its activity and ingredients are less studied than other Camellia plants. This study investigated the antithrombotic effect and chemical components of C. osmantha fruit cores using platelet aggregation assays and coagulation function tests. The cores of C. osmantha fruits were extracted with ethanol to obtain a crude extract. The extract was dissolved in water and further eluted with different concentrations of methanol on an MCI resin column to obtain three fractions. These samples were used for antithrombotic activity tests and phytochemical analysis. The results showed that the extract and its fractions of C. osmantha have strong antithrombotic activity, significantly reducing the platelet aggregation rate and prolonging the thrombin time (TT). The total saponins, flavonoids, and polyphenols in the active fractions may be responsible for the antithrombotic activity. The chemical constituents were analyzed by ultra‐performance liquid chromatography‐quadrupole time‐of‐flight mass spectrometry (UPLC‐QTOF/MS). Twenty‐three compounds were identified rapidly and accurately. Among them, ellagic acid, naringenin, and quercetin 3‐O‐glucuronide may be important antithrombotic constituents. Furthermore, interactions between these compounds and the P2Y1 receptor were investigated via molecular modeling, because the P2Y1 receptor is a key drug target of antiplatelet aggregative activity. The molecular docking results suggested that these compounds could combine tightly with the P2Y1R protein. Our results showed that C. osmantha fruit cores are rich in polyphenols, flavonoids, and saponins, which can be developed into a promising antithrombotic functional beverage for the prevention and treatment of cardiovascular and cerebrovascular diseases.
Zizyphus spina-christi L. has antimicrobial properties because of the presence of biologically active compounds. Alternaria is an opportunistic pathogen that causes leaf spots, rots, and blights on a variety of plant parts. This study aimed to reduce the usage of synthetically derived fungicides. Identification of the bioactive components present in leaves and fruits methanolic extracts of Z. spina-christi was performed using high-performance liquid chromatography (HPLC) and gas chromatography-mass spectrometry (GC-MS). The efficacy of the two methanol extracts was tested against (a) in vitro fungal growth and (b) pathogenicity control on non-wounded and wounded tomato fruits. The results revealed that gallic acid and ellagic acid were the major components in leaves extract while quercetin was the major component in fruits extract. In addition, Phenol, 2,5-bis(1,1-dimethylethyl) (40.24%) and Decane, 2-methyl-(18.53%) were the most abundant components in the leaf extract, and the presence of D-mannonic acid, 2,3,5,6-tetrakis-o-(trimethylsilyl), and γ-lactone (22.72%) were major components in fruits extract. The methanolic extracts of Z. spina-christi leaves and fruits demonstrated significant antifungal activity against the growth of Alternaria alternata, A. citri, and A. radicina with variable inhibition percentages at different concentrations. Pathogenicity was increased when the skin was injured, as expected. Both extracts reduced the percentage of infected fruits.
Background:
Myocardial fibrosis after myocardial infarction (MI) is one of the leading causes of cardiovascular diseases. Cardiac fibroblasts (CFs) are activated and promoted by MI to undergo myofibroblast transformation (CMT). Urolithin A (UA) is an active and effective gut metabolite derived from polyphenolics of berries and pomegranate fruits, which has been reported to have anti-inflammatory and anti-oxidant functions. However, whether UA affects the CMT process during myocardial fibrosis remains unclear.
Methods:
TGF-β1-treated primary rat cardiac fibroblasts were used for in vitro study. Cell proliferation ability was evaluated by MTT assay. Cell migration and invasion abilities were tested by wound healing and Transwell assays. The expression of CMT process-related markers were measured by qRT-PCR and western blot. The rat MI model was established by left anterior descending coronary artery (LAD) ligation and evaluated by H&E and Masson staining.
Results:
Our data demonstrated that UA treatment could inhibit the CMT process in TGF-β1-induced CFs, including cell proliferation, migration and invasion abilities. Knocking down of Nrf2, which was activated by UA treatment, could mitigate the effects of UA treatment on CMT process. Moreover, in vivo administration of UA in rat MI model successfully up-regulated Nrf2 expression and improved the myocardial damage and fibrosis.
Conclusions:
The study discovered the function and mechanism of UA on myocardial fibrosis and demonstrated the protective effects of UA administration through activation of Nrf2 pathway.
Cardiomyocyte apoptosis, neural remodeling, and gap junction channel change play critical roles in ventricular arrhythmia (VA) after acute myocardial infarction (AMI). Urolithin B (UB), one of the gut metabolites of ellagitannins, a class of antioxidant polyphenols, has various biological activities, but its direct role in cardiomyocyte apoptosis, neural remodeling, and gap junction channel change after AMI remains elusive. We investigated whether urolithin B reduced susceptibility of myocardial arrhythmic after myocardial infarction (MI). In vitro, the cardiomyocytes were subjected to hypoxia (94% N2/5% CO2/1% O2) for 3 hours. Cardiomyocyte apoptosis was assessed by TUNEL staining and western blotting. Urolithin B was found to decrease the number of apoptotic cells after hypoxia. Moreover, there was a substantial decrease in the expression of neural remodeling markers in the urolithin B treatment group. Urolithin B significantly increased the expression level of gap junction channel protein. Mechanistically, urolithin B inhibited cardiomyocyte apoptosis by activating Akt/the mammalian target of rapamycin (mTOR) pathway, and the protection of urolithin B against cardiomyocyte apoptosis was compromised with Akt gene silencing. Furthermore, urolithin B suppressed nuclear translocation of nuclear factor-kB (NF-κB) to facilitate nerve remodeling. Taken together, our findings suggested that UB reduced the occurrence of myocardial arrhythmias after hypoxia via regulation of the Akt/mTOR pathway and NF-κB nuclear translocation, which highlights the potential of UB as a novel therapy for ischemic heart disease.
Inflammatory infiltration has been implicated in the pathogenesis of cardiovascular diseases (CVDs). The NLRP3 inflammasome is involved in the development of several types of CVDs, including myocardial infarction, myocardial ischemia–reperfusion damage, heart failure, atrial fibrillation, and hypertension. Inhibiting the activity of NLRP3 inflammasome can inhibit the progress of CVDs. However, there is no NLRP3 inflammasome inhibitor in clinic, and it is very important to find a safe and effective NLRP3 inhibitor. Phenols and terpenoids are naturally natural products that have many anti-inflammatory effects in CVDs by modulating the NLRP3 inflammatory pathway. Thus, 20 natural products from phenols and terpenoids for the treatment of cardiovascular disease based on the inhibition of NLRP3 inflammasome were summarized and screened. Docking results showed salvianolic acid B and ellagic acid in phenols, and oridonin and triptolide in terpenoids had a better binding activity with NLRP3, which can provide theoretical support for finding novel NLRP3 inflammasome inhibitors or lead compounds in the future.
Background
Quercus acuta Thunb. (Fagaceae) or Japanese evergreen oak is cultivated as an ornamental plant in South Korea, China, Japan, and Taiwan and used in traditional medicine. The acorn or fruit of Quercus acuta Thunb. (QAF) is the main ingredient of acorn jelly, a traditional food in Korea. Its leaf was recently shown to have potent xanthine oxidase inhibitory and anti-hyperuricemic activities; however, there have been no studies on the biological activity of QAF extracts. Solar ultraviolet light triggers photoaging of the skin, which increases the production of reactive oxygen species (ROS) and expression of matrix metalloproteinase (MMPs), and destroys collagen fibers, consequently inducing wrinkle formation. The aim of this study was to investigate the effect of water extracts of QAF against UVB-induced skin photoaging and to elucidate the underlying molecular mechanisms in human keratinocytes (HaCaT).
Methods
In this study, we used HPLC to identify the major active components of QAF water extracts. Anti-photoaging effects of QAF extracts were evaluated by analyzing ROS procollagen type I in UVB-irradiated HaCaT keratinocytes. Antiradical activity was determined using 2,2-diphenyl-1-picrylhydrazyl and 2,20-azino-bis (3-ethylbenzothiazoline-6-sulphonic acid) assays. The expression of MMP-1 was tested by western blotting and ELISA kits. QAF effects on phosphorylation of the MAPK (p38, JNK, and ERK) pathway and transcription factor AP-1, which enhances the expression of MMPs, were analyzed by western blots.
Results
We identified two major active components in QAF water extracts, gallotannic acid and ellagic acid. The QAF aqueous extracts recovered UVB-induced cell toxicity and reduced oxidative stress by inhibiting intracellular ROS generation in HaCaT cells. QAF rescued UVB-induced collagen degradation by suppressing MMP-1 expression. The anti-photoaging activities of QAF were associated with the inhibition of UVB-induced phosphorylation of extracellular signal-regulated kinase (ERK) and activator protein 1 (AP-1). Our findings indicated that QAF prevents UVB-induced skin damage due to collagen degradation and MMP-1 activation via inactivation of the ERK/AP-1 signaling pathway. Overall, this study strongly suggests that QAF exerts anti-skin-aging effects and is a potential natural biomaterial that inhibits UVB-induced photoaging.
Conclusion
These results show that QAF water extract effectively prevents skin photoaging by enhancing collagen deposition and inhibiting MMP-1 via the ERK/AP-1 signaling pathway.
This study evaluated the in vitro antineoplastic and antiviral potential and in vivo toxicity of twelve extracts with different polarity obtained from the herbaceous perennial plant Geum urbanum L. (Rosaceae). In vitro cytotoxicity was determined by ISO 10993-5/2009 on bladder cancer, (T-24 and BC-3C), liver carcinoma (HEP-G2) and normal embryonic kidney (HEK-293) cell lines. The antineoplastic activity was elucidated through assays of cell clonogenicity, apoptosis induction, nuclear factor kappa B p65 (NFκB p65) activation and total glutathione levels. Neutral red uptake study was applied for antiviral activity. The most promising G. urbanum extract was analyzed by UHPLC–HRMS. The acute in vivo toxicity analysis was carried out following OEDC 423. The ethyl acetate extract of aerial parts (EtOAc-AP) exhibited the strongest antineoplastic activity on bladder cancer cell lines (IC50 = 21.33–25.28 µg/mL) by inducing apoptosis and inhibiting NFκB p65 and cell clonogenicity. EtOAc and n-butanol extracts showed moderate antiviral activity against human adenovirus type 5 and human simplex virus type I. Seventy four secondary metabolites (gallic and ellagic acid derivatives, phenolic acids, flavonoids, etc.) were identified in EtOAc-AP by UHPLC–HRMS. This extract induced no signs of acute toxicity in liver and kidney specimens of H-albino mice in doses up to 210 mg/kg. In conclusion, our study contributes substantially to the detailed pharmacological characterization of G. urbanum, thus helping the development of health-promoting phytopreparations.
The widespread use of chemical control agents and pesticides for plant-pathogen control has caused many human health and environmental issues. Plant extracts and biocontrol agents have robust antimicrobial activity against different plant pathogens. However, their antiviral activities are still being investigated. In the present study, the methanol extract of Paronychia argentea was characterized and evaluated for its protective activity against the tobacco mosaic virus (TMV) infection in tomato plants under greenhouse conditions at 21 days post-inoculation. The results showed that the foliar application of P. argentea extract (10 µg/mL) enhanced tomato plant growth, resulting in significant increases in shoot and root parameters and total chlorophyll contents. Moreover, a significant reduction in TMV accumulation level in P. argentea-treated plants of 77.88% compared to non-treated plants was reported. Furthermore, induction of systemic resistance with significant elevation in production of antioxidant enzymes (PPO, CAT, and SOD) and transcriptional levels of the pathogenesis-related proteins (PR-1 and PR-7) and polyphenolic genes (CHS and HQT) were also observed. Out of 16 detected compounds, HPLC analysis revealed that the most abundant polyphenolic compounds found in P. argentea extract were gallic acid (5.36 µg/mL), kaempferol (7.39 µg/mL), quercetin (7.44 µg/mL), ellagic acid (7.89 µg/mL), myricetin (8.36 µg/mL), and ferulic acid (8.69 µg/mL). The findings suggest that the use of P. argentea extract as an effective and safe source for the production of bioactive compounds may offer a solution for a promising approach for the management of plant viral infections. To the best of our knowledge, this is the first report of the protective activity of P. argentea extract against plant viral diseases.
This study examined the cardiac anti-cardiomyopathy (DC) protective effect of urolithin A in streptozotocin (STZ)-treated rats and investigated if this protection involves activation of SIRT1 signaling. Diabetes was induced first STZ (65 mg/kg, i.p.) before starting the experiments. Adult male rats (n = 8/group) were treated for 8 weeks as control (non-diabetic), control + urolithin A (2.5 mg/kg/i.p.), STZ, STZ + urolithin A, and STZ + urolithin A + Ex-527 (1 mg/kg/i.p.) (a SIRT1 inhibitor). With no effect on fasting glucose and insulin levels, urolithin A improved left ventricular (LV) function and structure and reduced heart weight and serum levels of cardiac markers in STZ-treated rats. Also, it prevented collagen deposition, reduced mRNA levels of Bax, cleaved caspaspe3, collagen 1A1, transforming growth factor-β1 (TGF-β1), and Smad3 but enhanced those of Bcl2 in the LVs of diabetic rats. However, urolithin A suppressed the generation of reactive oxygen species (ROS), activated the nuclear factor erythroid 2–related factor 2 (Nrf2), and increased the levels of manganese superoxide dismutase (MnSOD) and total glutathione (GSH) in the LVs of the non-diabetic and diabetic rats, In parallel, it suppressed the cardiac activity of NF-nuclear factor-kappa beta p65 (κB p65) and reduced levels of tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6). Coincided with these events, urolithin A promoted higher activity, mRNA, and total/nuclear protein levels of SIRT1 and lowered the levels of acetyl-FOXO1, Nrf2, NF-κB, and p53. All these benefits of urolithin A were prevented by Ex-527. In conclusion, urolithin A protects against DC by activating SIRT signaling.
Background:
Cerebral ischemia/reperfusion (I/R) could increase the reactive oxidative stress in the cardiomyocytes. Also, some studies report cardiac arrhythmias following oxidative stressor such as I/R. Hence, this study was aimed to investigate the effects of ellagic acid (EA) against arrhythmias in a cerebral I/R model.
Materials and methods:
Thirty-two male rats were randomly allocated into four groups: Sham (normal saline, 10 days), EA (100 mg/kg EA, 10 days), I/R (20 min ischemia followed by 30 min reperfusion, 10 days), and EA + I/R (100 mg/kg EA before I/R). In all animals, electrocardiogram (ECG) was recorded pre-ischemia and postischemia on the first and 11th days, respectively.
Results:
The I/R group showed an abnormally prolonged QTc interval after ischemia compared to the preischemia and control groups. EA administration in the EA+I/R group significantly reduced this prolonged QTc interval (P< 0.01). In the I/R group, ischemic/reperfusion resulted in a prolonged QRS complex and an elevated ST, which EA significantly prevented (P<0.01). In addition, EA significantly prevented the dramatically shortened RR interval induced by reperfusion (P<0.01). The incidence of ventricular fibrillation significantly increased in the I/R group; then it dramatically decreased following the administration of EA (P<0.0001).
Conclusion:
EA pretreatment repaired the adverse effects of I/R on the ECG parameters, which can be attributed to its negative chronotropic effects. EA pretreatment can prevent the cerebral I/R-induced heart arrhythmias.
Pomegranate juice (Punica granatum) has been used since ancient times in traditional medicine (Unani Medicine, Ayurveda); its main compounds are anthocyanins and ellagic acid, which have anti-inflammatory, antioxidant, hepatoprotective, and cardiovascular health effects. The objective was to evaluate the effect of pomegranate juice on inflammation, blood pressure, and vascular and physiological markers associated with obesity induced by a high-fat diet in a murine model. The results show that pomegranate juice reduces the concentration of low-density lipoprotein cholesterol (cLDL) 39% and increases the concentration of high-density lipoprotein cholesterol (cHDL) by 27%, leading to a 12%–18% decrease in the risk of cardiovascular diseases (CVD). In addition to reducing blood pressure by 24%, it also had an antiatherogenic effect by decreasing sE-selectin levels by 42%. On the other hand, the juice significantly increased adiponectin levels in adipose tissue, decreased levels of inflammation markers (tumor necrosis factor-α (TNF-α), plasminogen activator inhibitor-1 (PAI-1), interleukin-17A (IL-17A), interleukin-6 (IL-6), interleukin-1β (IL-1β)), and inhibited the monocyte chemoattractant protein-1 (MCP-1). Pomegranate juice requires clinical studies to prove its immunoregulatory and therapeutic effects on cardiovascular and atherogenic risks.
This study aimed to investigate the antioxidant, antimicrobial, and immunomodulatory activities of a Cleome droserifolia (Forssk.) Del. (Cd) shoot methanolic extracts considering the biological activity of its phytogenic compounds. For this purpose, the Cd phenolic compounds were detected, and an in vitro evaluation of the antioxidant and antimicrobial activities of the Cd extract was performed. For a biological evaluation, 30 v-line rabbits were randomly distributed into three groups with treatments including: a basal diet without Cd shoots powder supplement (C group) or supplemented with 1.25- (Cdl group) or 2.5 (Cdh group)-mg Cd/kg dry matter (DM). The Cd extract showed a linear scavenging activity for 2,2-diphenyl-1-picrylhydrazyl and 2,2′-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid), with the maximal activity observed at a concentration of 1 mg/mL. A total of 16 phenolic compounds were identified by reverse-phase high-performance liquid chromatography (RP-HPLC) in the Cd methanolic extract, among which benzoic acid, rutin, ellagic acid, naringenin, and o-coumaric acid were the major compounds. The methanolic extract of Cd showed inhibitory actions against microbial pathogen species. The in vivo study showed that the two concentrations of Cd significantly improved the redox status of the blood plasma and lysozyme activity. Treatment with Cdh significantly decreased the levels of interleukin-β1 in the blood plasma compared with the control. Moreover, the two concentrations of Cd significantly increased the counts of intestinal and cecal yeast and Lactobacillus species and decreased the Salmonella and Coliform species compared with the control. The aerial parts of the Cd shrub had strong antioxidant, antimicrobial, and immunomodulatory activities, which can improve the overall health status and seem to be related to its impressive range of biologically active phenolic compounds.
Herbal tea of Lagerstroemia speciosa Pers., commonly known as banaba, has been traditionally used to treat various ailments including diabetes and obesity due to its antioxidant and anti-inflammatory efficacies. Drug-induced liver injury is a common cause of acute liver failure. Isoniazid (INH) is used as the first-line treatment for tuberculosis; clinical and experimental studies have reported an abnormal liver function after INH therapy. Dapsone (DDS) is used for leprosy and other infections. This study investigates the hepatoprotective effect of ethanolic banaba leaves extract (EBLE) against simultaneously administered INH- and DDS-induced hepatotoxicity in rats. DDS (30 mg/kg, i.p.) and INH (50 mg/kg. p.o.) were administered simultaneously for 30 days. In separate groups, rats were posttreated orally with EBLE (500 mg/kg) and silymarin (100 mg/kg) for 30 days after INH + DDS administration. The marker enzymes of hepatotoxicity, oxidative stress markers, inflammatory markers, and histopathology were done. Simultaneous administration of INH- and DDS-induced significant elevation of marker enzymes of hepatotoxicity in the serum. This treatment also increased lipid peroxidation and pro-inflammatory markers (tumor necrosis factor alpha, transforming growth factor beta, and nuclear factor kappa B) expressions and decreased intracellular antioxidants such as superoxide dismutase, catalase, and glutathione in the liver tissue. All these abnormalities were significantly mitigated after EBLE and SIL posttreatments. The results of this study suggest that EBLE and silymarin can be protective against INH + DDS-induced hepatotoxicity.
Practical applications
Herbal tea contain Lagerstroemia speciosa leaves are used in several Southeast Asian countries due to its rich antioxidant and inflammatory properties. This study showed the hepatoprotective efficacy of L. speciosa ethanolic extract against simultaneously administered dapsone- and isoniazid-induced hepatotoxicity in rats. L. speciosa administration was found to decrease dapsone- and isoniazid-induced oxidative stress and hepatic inflammation. L. speciosa herbal tea can reduce drug-induced hepatic complications as it contains phytochemicals such as corosolic acid, gallic acid, ellagic acid and berberine and are implicated for its hepatoprotective effect. Therefore, L. speciosa extract can be used for drug-induced liver injury.
Mitochondrial dysfunction is a fundamental challenge in septic cardiomyopathy. Mitophagy and the mitochondrial unfolded protein response (UPRmt) are the predominant stress-responsive and protective mechanisms involved in repairing damaged mitochondria. Although mitochondrial homeostasis requires the coordinated actions of mitophagy and UPRmt, their molecular basis and interactive actions are poorly understood in sepsis-induced myocardial injury. Our investigations showed that lipopolysaccharide (LPS)-induced sepsis contributed to cardiac dysfunction and mitochondrial damage. Although both mitophagy and UPRmt were slightly activated by LPS in cardiomyocytes, their endogenous activation failed to prevent sepsis-mediated myocardial injury. However, administration of urolithin A, an inducer of mitophagy, obviously reduced sepsis-mediated cardiac depression by normalizing mitochondrial function. Interestingly, this beneficial action was undetectable in cardiomyocyte-specific FUNDC1 knockout (FUNDC1CKO) mice. Notably, supplementation with a mitophagy inducer had no impact on UPRmt, whereas genetic ablation of FUNDC1 significantly upregulated the expression of genes related to UPRmt in LPS-treated hearts. In contrast, enhancement of endogenous UPRmt through oligomycin administration reduced sepsis-mediated mitochondrial injury and myocardial dysfunction; this cardioprotective effect was imperceptible in FUNDC1CKO mice. Lastly, once UPRmt was inhibited, mitophagy-mediated protection of mitochondria and cardiomyocytes was partly blunted. Taken together, it is plausible that endogenous UPRmt and mitophagy are slightly activated by myocardial stress and they work together to sustain mitochondrial performance and cardiac function. Endogenous UPRmt, a downstream signal of mitophagy, played a compensatory role in maintaining mitochondrial homeostasis in the case of mitophagy inhibition. Although UPRmt activation had no negative impact on mitophagy, UPRmt inhibition compromised the partial cardioprotective actions of mitophagy. This study shows how mitophagy modulates UPRmt to attenuate inflammation-related myocardial injury and suggests the potential application of mitophagy and UPRmt targeting in the treatment of myocardial stress.
Background
Hyperactivation of mechanistic target of rapamycin (mTOR) signaling pathway is involved in the regulation of cellular growth, proliferation, and more in general, is a common phenomenon in most types of cancers. Thus, natural substances targeting this pathway can be of great therapeutic potential in supporting the treatment of tumor patients. Rhus tripartita (Ucria) Grande is a plant growing in desertic areas which is traditionally used for the treatment of several diseases in Tunisia. In the present work, the biochemical profile of the main compounds present in the plant leaf extract was determined and the anti-leukemic potential of the plant extracts against acute monocytic leukaemia (AML) THP-1 cells was investigated.
Methods
After HPLC identification of some phenolic compounds present in the plant extract and the quantification of saponin content, the cytotoxic effect of Rhus tripartita extracts on THP-1 cell culture was evaluated using the colorimetric MTT assay for cell viability. THP-1 cells were incubated with medium containing the relative IC 50 concentrations of total plant extract, saponin extract and some standard compounds (rutin (R); kaempferol (K); mixture of catechin, epicatechin, and epicatechin-gallate (CEEG); ellagic acid (EA). Finally, qRT-PCR and western blotting analysis were used to evaluate the effect of some flavonoids present in a crude extract of polyphenols and the total extract of saponins on cell survival and apoptosis.
Results
Analysis of expression level of some gene ( PIK3CA, PTEN, AKT1, mTOR, EIF4E, RPS6KB1 , and TSC1 ) involved in the mTOR pathway and the phosphorylation of S6 and AKT proteins allowed to observe that a total Rhus tripartita extract and some of the compounds found in the extract controls THP-1 cell proliferation and apoptosis via regulation of the PI3K-Akt-mTOR signaling pathway.
Conclusion
Rhus tripartita -induced inhibition of cell cycle and induction of apoptosis may involve the mTOR pathway. Therefore, Rhus tripartita extract may be a useful candidate as a natural anti-cancer drug to support the treatment of AML.
The paracetamol-induced injuries of liver and kidneys in animals are mostly used to screen out the hepato and nephroprotective effect of extract or other therapeutic agents. In the present study total phenolic and flavonoid contents, in vitro antioxidant, and in vivo hepato/nephroprotective (on paracetamol-induced intoxication in experimental rabbits) potentials of the Daphne mucronata leaves methanolic extract were determined. For the identification of possible phytochemicals, HPLC (high performance liquid chromatography) analysis was carried out and a total of eight phenolic compounds; malic acid, gallic acid, chlorogenic acid, epigallocatechin gallate, quercetin, morin, ellagic acid, and rutin were identified. D. mucronata extract at doses of 250 and 500 mg/kg body weight were given for eight days to paracetamol intoxicated rabbits and the observed results were compared with standard Silymarin. The level of liver enzymes like aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, serum triglyceride, serum cholesterol, serum bilirubin, and kidneys biomarkers like serum urea, uric acid, and creatinine, as well as lipid peroxidation malondialdehyde contents were increased while the antioxidant enzymes like reduced glutathione and total antioxidant capacity were decreased. Furthermore, histopathological analysis of the liver and kidney tissues of control and treated groups also confirmed the hepatoprotective and nephroprotective effect of the D. mucronata which was most probably due to its high antioxidant phenolic and flavonoid phytoconstituents.
The aim of this study was to investigate whether ellagic acid (EA) treatment can prevent changes in contractile function and Ca²⁺ regulation of cardiomyocytes in pathologic cardiac hypertrophy. Groups were assigned as Con group; an ISO group in which the rats received isoproterenol alone (5 mg/kg/day); and an ISO + EA group in which the rats received isoproterenol and EA (20 mg/kg/day) for 4 weeks. Subsequently, fractional shortening, intracellular Ca²⁺ signals, and L-type Ca²⁺ currents of isolated ventricular myocytes were recorded. Protein expression levels were also determined by the Western blotting method. The survival rate was increased, and the upregulated cardiac hypertrophy markers were significantly attenuated with the EA treatment. The fractional shortening and relaxation rate of myocytes was decreased in the ISO group, whereas EA significantly improved these changes. Ventricular myocytes of the ISO + EA rats displayed lower diastolic Ca²⁺ levels, higher Ca²⁺ transients, shorter Ca²⁺ decay, and higher L-type Ca²⁺ currents than those of ISO rats. Protein expression analyses indicated that the upregulated p-PLB and p-CaMKII expressions were restored by EA treatment, suggesting improved calcium handling in the ISO + EA rat heart. Moreover, ISO rats displayed significantly increased expression of p-22phox and p47phox subunits of NOX2 protein. Expression of the p22phox subunit was reduced with EA administration, while the decrease in p47phox did not reach a significant level. The increased ROS impairs Ca²⁺ homeostasis and contractile activity of cardiac myocytes, whereas chronic EA administration prevents Ca²⁺ dysregulation and functional abnormalities associated with pathological cardiac hypertrophy via the diminution of oxidative stress.
This study investigated the protective effect of ellagic acid (EA) against diabetic cardiomyopathy (DC) in streptozotocin (STZ)-treated rats and examined if the mechanism of protection involves modulating silent information regulator 1 (SIRT1). Adult male rats were divided into 5 groups (n = 12/each) as control, control + EA, diabetes mellitus (DM), STZ + EA, and STZ + EA + EX-527 (a SIRT1 inhibitor). With a hypoglycemic and insulin-releasing effect, EA preserved cardiomyocyte structure and suppressed the increase in heart weights and collagen deposition in the left ventricle (LV) of DM rats. Concomitantly, EA improved LV systolic and diastolic functions; reduced serum levels of creatinine kinase-MB (CK-MB), brain natriuretic peptide (BNP), and troponin-I, downregulated transforming growth factor beta 1 (TGF-β1), smad3, and cleaved caspase-3, and increased Bax/Bcl-2 ratio. Of note, EA increased the expression and activity of SIRT1 and suppressed the acetylation of nuclear factor erythroid-derived 2-like 2 (Nrf2), nuclear factor kappa B (NF-κB), smad2, and forkhead box, class O (FOXO1) in the LVs of both the control and diabetic groups. These effects were associated with a significant reduction in the levels of reactive oxygen species (ROS), malondialdehyde (MDA), tumor necrosis factor kappa (TNF-κ), and interleukin 6 (IL-6) levels and activity of NF-κB but with increased activity Nrf2 and levels of glutathione (GSH), superoxide dismutase (SOD), and Bcl-2. All these effects were abolished by EX-527. In conclusion, EA protected against DC by its hypoglycemic, antioxidant, anti-inflammatory, and anti-fibrotic, and anti-apoptotic effects through upregulation and activation of SIRT1.
Bauhinia coccinea is a tropical woody plant widely distributed in Vietnam and Unnan in southern China. Although many studies have shown the biological activities of extracts from various other species in the genus, no studies have investigated the effects of B. coccinea extracts on biological systems. In the present study, a quantitative analysis of four marker compounds of ethanol extracts of B. coccinea branches (EEBC) was performed using the high performance liquid chromatography (HPLC)-photodiode array (PDA) method. Among gallic acid, (+)-catechin, ellagic acid, and quercitrin contained in EEBC, the most abundant compound was (+)-catechin (18.736 mg/g). In addition, we investigated the EEBC on neuroprotection, antioxidation, and Alzheimer’s disease (AD) marker molecules, acetylcholinesterase (AChE), and amyloid-β (Aβ). EEBC significantly inhibited hydrogen peroxide (H2O2)-induced cell death in a HT22 neuronal cell line and increased 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) and 2,2-diphenyl-1-picrylhydrazyl scavenging activity markedly. EEBC also inhibited AChE and Aβ aggregation. Among the four compounds, gallic acid exhibited strong inhibitory effects against AChE activation. In the Aβ aggregation assay, the four marker compounds exhibited inhibitory effects lower than 30%. According to the results, EEBC could exert anti-AChE activation and Aβ aggregation activities based on the interactive effects of the marker compounds. Our findings suggest that EEBC are sources of therapeutic candidates for application in the development of AD medication based on AChE and Aβ dual targeting.
Inflammation is a natural defense process of the innate immune system, associated with the release of proinflammatory cytokines such as interleukin-1β, interleukin-6, interleukin-12 and TNFα; and enzymes including iNOS through the activation and nuclear translocation of NF-κB p65 due to the phosphorylation of IκBα. Regulation of intracellular Ca2+ is considered a promising strategy for the prevention of reactive oxygen species (ROS) production and accumulation of DNA double strand breaks (DSBs) that occurs in inflammatory-associated-diseases. Among the metabolites of ellagitannins that are produced in the gut microbiome, urolithin A (UA) has received an increasing attention as a novel candidate with anti-inflammatory and anti-oxidant effects. Here, we investigated the effect of UA on the suppression of pro-inflammatory molecules and NF-κB activation by targeting TLR4 signalling pathway. We also identified the influence of UA on Ca2+ entry, ROS production and DSBs availability in murine bone-marrow-derived macrophages challenged with lipopolysaccharides (LPS). We found that UA inhibits IκBα phosphorylation and supresses MAPK and PI3K activation. In addition, UA was able to reduce calcium entry, ROS production and DSBs availability. In conclusion, we suggest that urolithin A is a promising therapeutic agent for treating inflammatory diseases through suppression of NF-κB and preserving DNA through maintaining intracellular calcium and ROS homeostasis.
Urolithin A (UroA) is a gut metabolite produced from ellagic acid-containing foods such as pomegranates, berries, and walnuts. UroA is of growing interest due to its therapeutic potential for various metabolic diseases based on immunomodulatory properties. Recent advances in UroA research suggest that UroA administration attenuates inflammation in various tissues, including the brain, adipose, heart, and liver tissues, leading to the potential delay or prevention of the onset of Alzheimer’s disease, type 2 diabetes mellitus, and non-alcoholic fatty liver disease. In this review, we focus on recent updates of the anti-inflammatory function of UroA and summarize the potential mechanisms by which UroA may help attenuate the onset of diseases in a tissue-specific manner. Therefore, this review aims to shed new insights into UroA as a potent anti-inflammatory molecule to prevent immunometabolic diseases, either by dietary intervention with ellagic acid-rich food or by UroA administration as a new pharmaceutical drug.
Alchornea cordifolia (Schumach. & Thonn.) Müll. Arg. is a well-known African medicinal plant tra-ditionally used for various healing purposes. In the present study, methanolic, ethyl acetate and infusion extracts of A. cordifolia leaves were studied for their total phenolic and flavonoid contents and screened for their chemical composition. Moreover, the enzyme (acetyl- and butyr-yl-cholinesterases, α-amylase, α-glucosidase and tyrosinase) inhibitory and cytotoxicity activities on HepG2: human hepatocellular carcinoma cells, B16 4A5: murine melanoma cells, S17: murine bone marrow (normal) cells of extracts were evaluated. Finally, components-targets and docking analyses were conducted with the aim to unravel the putative mechanisms underlying the ob-served bio-pharmacological effects. Interestingly, the infusion and methanolic extracts showed significantly higher total phenolic and flavonoid contents compared with the ethyl acetate extract (TPC: 120.38-213.12 mg GAE/g and TFC: 9.66-57.18 mg RE/g). Besides, the methanolic, followed by the infusion extracts were revealed to contain higher number of compounds (84 and 74 compounds, respectively), while only 64 compounds were observed for the ethyl acetate extract. Gallic acid, ellagic acid, shikimic acid, rutin, quercetin, myricetin, vitexin, quercitrin, kaempferol and naringenin were among the compounds commonly identified in all the studied extracts. Addi-tionally, the methanolic and infusion extracts displayed higher antioxidant capacity than ethyl acetate extract in all assays performed. In ABTS and DPPH radical scavenging assays, the methanol extract (500.38 mg TE/g for DPPH and 900.64 mg TE/g for ABTS) exhibited the best ability, followed by the water and ethyl acetate extracts. Furthermore, the extracts exhibited differential enzyme inhibitory profiles. In particular, the methanolic and infusion extracts showed better cytotoxic selectivity activity against human hepatocellular carcinoma cells. Overall, this study demonstrated A cordifolia to be a species worthy of further investigations, given its richness in bioactive phy-tochemicals and wide potentialities as antioxidants and pharmacological agents.
Among bioactive phytochemicals, ellagic acid (EA) is one of the most controversial because its high antioxidant and cancer-preventing effects are strongly inhibited by low gastrointestinal absorption and rapid excretion. Strategies toward an increase of solubility in water and bioavailability, while preserving its structural integrity and warranting its controlled release at the physiological targets, are therefore largely pursued. In this work, EA lysine salt at 1:4 molar ratio (EALYS), exhibiting a more than 400 times increase of water solubility with respect to literature reports, was incorporated at 10% in low methoxylated (LM) and high methoxylated (HM) pectin films. The release of EA in PBS at pH 7.4 from both film preparations was comparable and reached 15% of the loaded compound over 2 h. Under simulated gastric conditions, release of EA from HM and LM pectin films was minimal at gastric pH, whereas higher concentrations—up to 300 μM, corresponding to ca. 50% of the overall content—were obtained in the case of the HM pectin film after 2 h incubation at the slightly alkaline pH of small intestine environment, with the enzyme and bile salt components enhancing the release. EALYS pectin films showed a good prebiotic activity as evaluated by determination of short chain fatty acids (SCFAs) levels following microbial fermentation, with a low but significant increase of the effects produced by the pectins themselves. Overall, these results highlight pectin films loaded with EALYS salt as a promising formulation to improve administration and controlled release of the compound.
Antidesma bunius (L.) spreng (Mamao) is widely distributed in Northeastern Thailand. Antidesma bunius has been reported to contain anthocyanins, which possess antioxidant and antihypertensive actions. However, the antidiabetic and antiglycation activity of Antidesma bunius fruit extract has not yet been reported. In this study, we investigated the inhibitory activity of anthocyanin-enriched fraction of Antidesma bunius fruit extract (ABE) against pancreatic α-amylase, intestinal α-glucosidase (maltase and sucrase), protein glycation, as well as antioxidant activity. A liquid chromatography-tandem mass spectrometry (LC-MS/MS) chromatogram revealed that ABE contained phytochemical compounds such as cyanidin-3-glucoside, delphinidin-3-glucoside, ellagic acid, and myricetin-3-galactoside. ABE inhibited intestinal maltase and sucrase activity with the IC50 values of 0.76 ± 0.02 mg/mL and 1.33 ± 0.03 mg/mL, respectively. Furthermore, ABE (0.25 mg/mL) reduced the formation of fluorescent AGEs and the level of Nε-carboxymethyllysine (Nε-CML) in fructose and glucose-induced protein glycation during four weeks of incubation. During the glycation process, the protein carbonyl and β-amyloid cross structure were decreased by ABE (0.25 mg/mL). In addition, ABE exhibited antioxidant activity through DPPH radical scavenging activity and Trolox equivalent antioxidant capacity (TEAC) with the IC50 values 15.84 ± 0.06 µg/mL and 166.1 ± 2.40 µg/mL, respectively. Meanwhile, ferric reducing antioxidant power (FRAP) showed an EC50 value of 182.22 ± 0.64 µg/mL. The findings suggest that ABE may be a promising agent for inhibiting carbohydrate digestive enzyme activity, reducing monosaccharide-induced protein glycation, and antioxidant activity.
Previously, we demonstrated that a 5% ethanol extract of unripe Rubus coreanus (5-uRCK) and ellagic acid has hypocholesterolemic and antiobesity activity, at least partially mediated by the downregulation of adipogenic and lipogenic gene expression in high-fat diet (HFD)-fed animals. The present study investigated the thermogenic and lipolytic antiobesity effects of 5-uRCK and ellagic acid in HFD-induced obese C57BL/6 mice and explored its mechanism of action. Mice fed an HFD received 5-uRCK or ellagic acid as a post-treatment or pretreatment. Both post-treated and pretreated mice showed significant reductions in body weight and adipose tissue mass compared to the HFD-fed mice. The protein levels of lipolysis-associated proteins, such as adipose triglyceride lipase (ATGL), phosphorylated hormone-sensitive lipase (p-HSL), and perilipin1 (PLIN1), were significantly increased in both the 5-uRCK- and ellagic acid-treated mouse epididymal white adipose tissue (eWAT). Additionally, thermogenesis-associated proteins, such as peroxisome proliferator-activated receptor α (PPARα), carnitine palmitoyl transferase-1 (CPT1), uncoupling protein 1 (UCP1), and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC1α), in inguinal white adipose tissue (ingWAT) were clearly increased in both the 5-uRCK- and ellagic acid-treated mice compared to HFD-fed mice. These results suggest that 5-uRCK and ellagic acid are effective for suppressing body weight gain and enhancing the lipid profile.
Background
Gunnera tinctoria has been collected by Mapuche-Pewenche people for food and medicinal purposes. The high polyphenol content of methanolic extract from G. tinctoria leaves with chemical constituents such as ellagic acid and quercetin derivatives suggests its application to prevent endothelial dysfunction and oxidative stress. The aim of this study was to provide evidence of the protective effect of this extract on endothelial function by reducing oxidative stress induced by high d -glucose and H 2 O 2 , as well as by stimulating nitric oxide (NO) levels in human umbilical vein endothelial cells (HUVECs).
Results
A methanolic extract with a high content of polyphenols (520 ± 30 mg gallic acid equivalents/g dry extract) was obtained from G. tinctoria leaves. Its main constituent was ellagic acid. The results of Ferric reducing antioxidant power and 2,2-diphenyl-1-picrylhydrazyl radical scavenging assays of the extract confirmed its antioxidant activity by inhibition pathway of radical species. The incubation of HUVECs with the extract decreased the apoptosis and reactive oxygen species (ROS) synthesis induced by high extracellular concentration of d -glucose or hydrogen peroxide. The extract increased endothelial NO levels and reduced vasoconstriction in human placental vessels.
Conclusions
This study provides evidence about the antioxidant and endothelial protective properties of methanolic G. tinctoria leaf extract. The extract improves the availability of NO in HUVECs, inhibiting the production of ROS and vasoconstriction.
Oxidative stress (OS) refers to the physiological imbalance between oxidative and antioxidative processes leading to increased oxidation, which then results in the inflammatory infiltration of neutrophils, increased protease secretion, and the production of a large number of oxidative intermediates. Oxidative stress is considered an important factor in the pathogenesis of cardiovascular disease (CVD). At present, active components of Chinese herbal medicines (CHMs) have been widely used for the treatment of CVD, including coronary heart disease and hypertension. Since the discovery of artemisinin for the treatment of malaria by Nobel laureate Youyou Tu, the therapeutic effects of active components of CHM on various diseases have been widely investigated by the medical community. It has been found that various active CHM components can regulate oxidative stress and the circulatory system, including ginsenoside, astragaloside, and resveratrol. This paper reviews advances in the use of active CHM components that modulate oxidative stress, suggesting potential drugs for the treatment of various CVDs.
Our recent studies have demonstrated multiple health-promoting benefits from black walnut kernels. These biological functions of black walnuts are likely associated with their bioactive constituents. Characterization of phenolic compounds found in black walnut could point out underexplored bioactive activities of black walnut extracts and promote the development of novel applications of black walnut and its by-products. In the present study, we assessed bioactivity profiles of phenolic compounds identified in the kernels of black walnuts using a high-throughput screening (HTS) approach. Black walnut phenolic compounds were evaluated in terms of their total antioxidant capacity, antioxidant response element (ARE) induction, and anticancer activities. The anticancer activities were identified by evaluating the effects of the phenolic compounds on the growth of the tumorigenic alveolar epithelial cells (A549) and non-tumorigenic lung fibroblast cells (MRC-5). Out of 16 phenolic compounds tested, several compounds (penta-O-galloyl-β-d-glucose, epicatechin gallate, quercetin, (-)-epicatechin, rutin, quercetin 3-β-d-glucoside, gallic acid, (+)-catechin, ferulic acid, syringic acid) exerted antioxidant activities that were significantly higher compared to Trolox, which was used as a control. Two phenolic compounds, penta-O-galloyl-β-d-glucose and quercetin 3-β-d-glucoside, exhibited antiproliferative activities against both the tumorigenic alveolar epithelial cells (A549) and non-tumorigenic lung fibroblast cells (MRC-5). The antioxidant activity of black walnut is likely driven not only by penta-O-galloyl-β-d-glucose but also by a combination of multiple phenolic compounds. Our findings suggested that black walnut extracts possibly possess anticancer activities and supported that penta-O-galloyl-β-d-glucose could be a potential bioactive agent for the cosmetic and pharmaceutical industries.
In this study, we carried out a comparative evaluation of antiaging and anti‐melanogenesis activities of raspberry extracts (Rubus occidentalis L.) according to their stage of ripening (uRo: unripe raspberry, Ro: ripe raspberry), and analyzed the active component (ellagic acid) present in these extracts. Our results showed higher inhibitory effects of the uRo extract in terms of elastase and collagenase activities than Ro extract. In the CCD‐986sk cells, uRo extract significantly inhibited MMP‐1 activity by 18% and increased the rate of type 1 pro‐collagen synthesis by 25%. Besides, treatment with uRo extract significantly inhibited α‐melanocyte‐stimulating hormone‐induced melanin synthesis and tyrosinase activity in B16F10 mouse melanoma cells. Overall, uRo was a more potent mediator of antiaging and anti‐melanogenesis effects than Ro extract. Further analysis showed that the functional effects of uRo could be attributed to its 18.5 times higher ellagic acid content than that in Ro extract.
Practical applications
This study reported the differential effect of the raspberry extracts depending on their stage of ripening. To the best of our knowledge, this was the first study to report the antiaging, anti‐wrinkle, and anti‐pigmentation effects of the uRo extracts. We showed that the extracts from the uRo have an overall better antiaging and skin‐whitening effect than ripe ones. The effects were attributed to high ellagic acid content in uRo. We believed that our study makes a significant contribution to the literature because the outcome of the study has both, cosmetic as well as therapeutic implications.
BACKGROUND
Cycas circinalis leaves are used to treat diabetes mellitus in local medicinal systems without any scientifically proved information on their medicinal potential and phytochemicals. In this study, the total phenolic contents, total flavonoid contents, and 2,2‐diphenyl‐1‐picrylhydrazyl (DPPH) scavenging and inhibitory effects on α‐glucosidase and α‐amylase were determined for optimized hydroethanolic leaf extracts. Secondary metabolites were identified using ultra‐high‐performance liquid chromatography–quadrupole time‐of‐flight mass spectrometry (UHPLC–QTOF‐MS/MS). In vivo studies on diabetic albino mice were also carried out to evaluate the impact of the most active extract on their blood glucose levels.
RESULTS
The 60% ethanolic extract showed the highest extract yield (209.70 ± 0.20 g kg⁻¹) and total phenolic (154.24 ± 3.28 mg gallic acid equivalent) and flavonoid (78.52 ± 1.65 mg rutin equivalent per gram dried extract) contents and exhibited the maximum DPPH scavenging activity (IC50 = 59.68 ± 2.82 μg mL⁻¹). The IC50 values for inhibition of α‐glucosidase (58.42 ± 2.22 μg mL⁻¹) and α‐amylase (74.11 ± 1.70 μg mL⁻¹) were also significant for the 60% ethanolic extract. The untargeted UHPLC–QTOF‐MS/MS‐based metabolite profiling confirmed the presence of iridoid glucoside, gibberellin A4, O‐β‐d‐glucosyl‐4‐hydroxy‐cinnamate, 3‐methoxy‐2‐phyenyl‐4H‐furo[2,3‐h]chromen‐4‐one, kaempferol, withaferin A, amentoflavone, quercitin‐3‐O‐(6″‐malonyl glucoside), ellagic acid, and gallic acid. Plant extract at a dose of 500 mg kg⁻¹ body weight reduced the blood glucose level by a considerable extent and also improved the lipid profile of diabetic mice after a 28‐day trial.
CONCLUSION
The findings revealed the medicinal potential of C. circinalis leaves to treat diabetes mellitus and provided the nutraceutical leads for functional food development. © 2020 Society of Chemical Industry
The stem barks and leaves of Cenostigma macrophyllum are used in Brazilian folk medicines in the treatment of stomach and intestinal diseases. However, there are no reports of chromatographic methods used to evaluate the bioactives of its standardized extracts and for biological evaluation. An analytical method was developed and validated for simultaneous determination and quantification of the bioactive phenolics gallic acid, methyl gallate, ellagic acid and, the biflavonoids agathisflavone and amentoflavone in the leaves and stem bark of C. macrophyllum. HPLC operating conditions were optimized and the parameters such as selectivity, linearity, precision, accuracy, LOD, LOQ and, robustness of the method were also evaluated. Robustness was evaluated using a multivariate optimization technique. Linear relationships within the range of investigated concentrations were observed with their correlation coefficients greater than 0.9991. The method was validated for repeatability (RSD # 2.88%), intermediate precision (RSD # 3.38%) with recovery between 84.12 and 106.64% and the RSD less than 3.40% and proved to be robust. Besides, antioxidant, acetylcholinesterase inhibition, anti-inflammatory and antinociceptive activities of the standardized hydromethanolic extracts of leaves and stem bark of this species were evaluated. The method was successfully applied in the quantification of the gallic acid, methyl gallate, ellagic acid, agathisflavone and amentoflavone of standardized extracts. The results showed the present method developed was simple, sensitive, reproducible, accurate and precise. The standardized hydromethanolic extracts of leaves and stem bark of C. macrophyllum showed antioxidant activity (EC 50 69.09 and 83.06 mg mL À1), acetylcholinesterase inhibition (52.23 and 83.36%) and they were able to inhibit the formalin-induced nociception and also reduced the edema formations at 100 mg kg À1 doses. The anti-inflammatory potentials were evaluated by the decrease of the Cg-induced neutrophils migrations at the same doses.
Aim: We conducted a systematic review and meta-analysis to assess all-cause mortality and heart failure (HF) hospitalization with sacubitril/valsartan (S/V) compared to standard HF therapy in patients with HF with reduced ejection fraction (HFrEF) using real-world data.
Methods: We performed a systematic review and meta-analysis following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We searched PubMed and Google Scholar for the observational studies published in English exploring the clinical outcomes of S/V use in HFrEF till 14/03/2022. Two independent reviewers assessed the quality and risk of bias of the included studies. A random-effect model was used to combine data. The outcomes assessed were all-cause mortality and HF hospitalization associated with S/V use in comparison to standard HF therapy.
Results: A total of nine observational studies comparing S/V to Angiotensin-converting enzyme inhibitors (ACE-I)/Angiotensin II receptor blockers (ARB) in HFrEF were included in the systematic review, with more than 32000 patients included in the final analysis. Overall, S/V use was associated with a significant reduction in all-cause mortality (Risk Ratio [RR]= 0.70, 95% CI 0.53-0.93, I2= 83%) and HF hospitalization (RR= 0.62; 95% CI, 0.48-0.80, I2= 94%).
Conclusion: Similar to the landmark controlled evidence, real-world data of S/V use in HFrEF demonstrated a significant reduction in all-cause mortality and HF hospitalization.
Metabolic cardiomyopathy (MC) is characterized by intracellular lipid accumulation and utilizing fatty acids as a foremost energy source, thereby leading to excess oxidative stress and mitochondrial dysfunction. There is no effective therapy available yet. In this study we investigated whether defective mitophagy contributed to MC and whether urolithin A (UA), a naturally occurring microflora-derived metabolite, could protect against MC in experimental obese mice. Mice were fed high fat diet for 20 weeks to establish a diet-induced obese model. We showed that mitochondrial autophagy or mitophagy was significantly downregulated in the heart of experimental obese mice. UA (50 mg·kg−1·d−1, for 4 weeks) markedly activated mitophagy and ameliorated MC in obese mice by gavage. In PA-challenged H9C2 cardiomyocytes, UA (5 μM) significantly increased autophagosomes and decreased autolysosomes. Furthermore, UA administration rescued PINK1/Parkin-dependent mitophagy and relieved mitochondrial defects in the heart of obese mice, which led to improving cardiac diastolic function and ameliorating cardiac remodelling. In PA-challenged primarily isolated cardiomyocytes, both application of mitophagy inhibitor Mdivi-1 (15 μM) and silencing of mitophagy gene Parkin blunted the myocardial protective effect of UA. In summary, our data suggest that restoration of mitophagy with UA ameliorates symptoms of MC, which highlights a therapeutic potential of UA in the treatment of MC. UA, a naturally-occurring compound, protects against diastolic dysfunction and cardiac remodelling in the obese mice, without altering the blood glucose level. Mechanistically, UA activated PINK1/Parkin dependent mitophagy, by which the mitochondrial defects including reduced respiratory capacity, MMP collapse and mitochondrial oxidative stress were alleviated.
This study aimed to explore the potential anticancer activity of phenolic-rich feijoa extracts from the flesh, peel, and whole fruit on the human prostate cancer cell line (LNCaP). Results showed that feijoa extracts had cancer-specific anti-proliferative activity on the LNCaP cell line. The anticancer activity of feijoa extracts was shown through activation of the caspase-dependent apoptosis pathway based on the increase of sub-G1 phase in the cell cycle, the decrease of mitochondrial membrane potential, as well as the elevated caspase 3, 8, and 9 activity in the treated LNCaP cells. The anti-cancer activity of feijoa extracts could be attributed to the high total phenolic contents (0.14-0.37 mg GAE/mg dw) and, in particular, the high ellagic acid content (2.662-9.119 μg/mg dw). The successful activation of the caspase-dependent apoptosis pathway indicates that phenolic-rich feijoa extracts have a good potential to be utilized as a functional ingredient in foods and nutraceuticals.
Bioactive compounds from strawberries have been associated with multiple healthy benefits. The present study aimed to assess chemical characterization of a methanolic extract of the Romina strawberry variety in terms of antioxidant capacity, polyphenols profile and chemical elements content. Additionally, potential toxicity, the effect on amyloid-β production and oxidative stress of the extract was in vivo evaluated in the experimental model Caenorhabditis elegans. Results revealed an important content in phenolic compounds (mainly ellagic acid and pelargonidin-3-glucoside) and minerals (K, Mg, P and Ca). The treatment with 100, 500 or 1000 μg/mL of strawberry extract did not show toxicity. On the contrary, the extract was able to delay amyloid β-protein induced paralysis, reduced amyloid-β aggregation and prevented oxidative stress. The potential molecular mechanisms present behind the observed results explored by RNAi technology revealed that DAF-16/FOXO and SKN-1/NRF2 signaling pathways were, at least partially, involved.
Ethnopharmacological relevance: The present study was designed to investigate the redox quenching and anti-inflammatory potentials of ethanolic leaf extract of Terminalia myriocarpa Van Heurck & Müller (ETM), inspired by the reported antioxidant potential of the plant bark and the anti-edema effect of the same genus.
Materials and methods: HPLC-DAD dereplication study was conducted to detect various
secondary metabolites. In-vitro DPPH free radical scavenging assay, nitric oxide scavenging assay, Fe2+ ion chelating ability assay and reducing power assay were conducted to evaluate the redox quenching capacity. The molecular mechanism of anti-inflammation was investigated via assessing the NO and NF-ĸB expressions in different cell lines. In-vivo carrageenan and histamine-induced edema tests were conducted using established animal models. Pro-inflammatory receptors iNOS and NF-κB were docked against isolated compounds in the in-silico study.
Results: HPLC analysis revealed the presence of considerable amount of ellagic acid, where methyl-(S)-flavogallonate was previously found in ETM. Significant antioxidant activity was found in every redox assay. NO was reduced in RAW 264.7 cells, showing 83.67±4.18% inhibitory activity. TNF-α induced NF‑κB was also observed to be reduced in 293/NF-кB-luc cells with an inhibitory activity of 66.23±0.81%. In-vivo carrageenan-induced edema test demonstrated significant anti-inflammatory activity (p<0.05; p<0.01) at both doses of 250 and 500 mg/kg with 60.10% highest reduction in rat paw volume. Using same doses, histamine-induced edema test exhibited mentionable anti-inflammatory potential (p<0.05; p<0.01) with 67.91% highest reduction
in rat paw volume. Ellagic acid and methyl-(S)-flavogallonate showed satisfactory binding affinity with iNOS (-8.5 and -8.7 Kcal/moL, respectively) and NF-κB (-7.3 and -7.3 Kcal/moL, respectively).
Conclusion: Mentionable basis was found on behalf of the anti-inflammatory and antioxidant potentials of ETM which might be correlated with its NF-ĸB inhibiting properties.
In this study, the antidiabetic and antioxidant properties of the chemical constituents of Rosa rugosa Thunb. (R. rugosa) was evaluated through analysis of spectrum-effect relationship. The ultra-performance liquid chromatography (UPLC) fingerprints of 21 batches of R. rugosa were evaluated by similarity analysis (SA) and hierarchical clustering analysis (HCA). The 28 common components were identified by ultra-high-performance liquid chromatography coupled to quadrupole-orbitrap high resolution mass spectrometry (UHPLC-Q-orbitrap-HRMS/MS). Meanwhile, the antidiabetic activities and antioxidant activities of 21 batches of R. rugosa were estimated in vitro. Besides, four chemometrics named principal component analysis (PCA), grey correlation analysis (GRA), partial least squares regression (PLSR) and the bivariate correlations analysis (BCA) were applied to construct spectrum-effect relationship between the UPLC fingerprints and biological activities of R. rugosa. The spectrum-effect relationship study revealed that di-O-galloyl-HHDP-glucoside, galloyl-HHDP-glucoside and avicularin were more relevant to antidiabetic activity. Di-O-galloyl-HHDP-glucoside, galloyl-HHDP-glucoside and ellagic acid were the main antioxidant components of R. rugosa. The current bioassay and spectrum-effect relationships are proper for associating sample quality with the active ingredient, and our finding would provide foundation and further understanding of the quality evaluation and quality control of R. rugosa.
Atherosclerosis, a chronic multifactorial disease, is closely related to the development of cardiovascular diseases and is one of the predominant causes of death worldwide. Normal vascular endothelial cells play an important role in maintaining vascular homeostasis and inhibiting atherosclerosis by regulating vascular tension, preventing thrombosis and regulating inflammation. Currently, accumulating evidence has revealed that endothelial cell apoptosis is the first step of atherosclerosis. Excess apoptosis of endothelial cells induced by risk factors for atherosclerosis is a preliminary event in atherosclerosis development and might be a target for preventing and treating atherosclerosis. Interestingly, accumulating evidence shows that natural medicines have great potential to treat atherosclerosis by inhibiting endothelial cell apoptosis. Therefore, this paper reviewed current studies on the inhibitory effect of natural medicines on endothelial cell apoptosis and summarized the risk factors that may induce endothelial cell apoptosis, including oxidized low-density lipoprotein (ox-LDL), reactive oxygen species (ROS), angiotensin II (Ang II), tumor necrosis factor-α (TNF-α), homocysteine (Hcy) and lipopolysaccharide (LPS). We expect this review to highlight the importance of natural medicines, including extracts and monomers, in the treatment of atherosclerosis by inhibiting endothelial cell apoptosis and provide a foundation for the development of potential antiatherosclerotic drugs from natural medicines.
Cardiac fibrosis remains an unresolved problem in heart diseases. After initial injury, cardiac fibroblasts (CFs) are activated and subsequently differentiate into myofibroblasts (myoFbs) that are major mediator cells in the pathological remodeling. MyoFbs exhibit proliferative and secretive characteristics, and contribute to extracellular matrix (ECM) turnover, collagen deposition. The persistent functions of myoFbs lead to fibrotic scars and cardiac dysfunction. The anti-fibrotic treatment is hindered by the elusive mechanism of fibrosis and lack of specific targets on myoFbs. In this review, we will outline the progress of cardiac fibrosis and its contributions to the heart failure. We will also shed light on the role of myoFbs in the regulation of adverse remodeling. The communication between myoFbs and other cells that are involved in the heart injury and repair respectively will be reviewed in detail. Then, recently developed therapeutic strategies to treat fibrosis will be summarized such as i) chimeric antigen receptor T cell (CAR-T) therapy with an optimal target on myoFbs, ii) direct reprogramming from stem cells to quiescent CFs, iii) “off-target” small molecular drugs. The application of nano/micro technology will be discussed as well, which is involved in the construction of cell-based biomimic platforms and “pleiotropic” drug delivery systems.
Ethnopharmacological relevance
Evaluation of plants such as Combretum racemosum with claimed traditional use in the management of sickle cell anaemia in Nigeria and other parts of West Africa could serve as a useful research strategy in the search for potential anti-sickling drugs and templates.
Aim of the study
This study aimed at evaluating the antisickling potential of C. racemosum by activity-guided purification and isolation of its active constituents.
Materials and methods
Crude methanol extract of the root of C. racemosum and the fractions obtained by partitioning with chloroform, ethyl acetate, and aqueous were investigated for anti-sickling activity against sodium metabisulphite induced sickling of sickle cell haemoglobin (HbSS). Repeated chromatographic separations were conducted on the most active chloroform fraction to purify and isolate bioactive compounds for further tests for anti-sickling activity. The characterization of the isolated compounds was done by mass spectrometry (FD⁺MS) and nuclear magnetic resonance (¹HNMR) spectroscopy.
Results
The chloroform fraction (FA) (% sickled erythrocyte ranged from 3.0-34.1) exhibited better anti-sickling activity than aqueous (% sickled erythrocyte ranged from 38.9-51.5) as well as the crude methanol (% sickled erythrocyte ranged from 19.1-30.4). Hence, the phytochemical investigation was focused on the chloroform fraction, which led to the identification of two ellagic acid derivatives (3,3′,4′-tri-O-methyl ellagic acid (A) and 3,3′-di-O- methyl ellagic acid (B). The two isolated compounds possessed good, comparable anti-sickling activities with compound A exhibiting a slightly better in vitro activity.
Conclusion
This paper reports for the first time anti-sickling principles from C. racemosum and therefore, provided some justification for the ethnomedicinal use of the plant in the management of sickle cell disease.
Doxorubicin is an anticancer agent that is commonly used to treat a number of tumors and is associated with acute and chronic changes of the cardiovascular system. Ellagic acid has strong free radical scavenging capacity, neuroprotective and hepatoprotective effects, and is known to protect against changes occurring due to diabetes, cardiovascular diseases, and cancer. Twenty-four Wistar rats were divided in four groups: control group received saline, doxorubicin group received doxorubicin in a single dose of 20 mg/kg, ellagic acid group received ellagic acid in a dose of 4 mg/kg, and doxorubicin + ellagic acid group received doxorubicin and ellagic acid in same doses as in previous groups. The effect of ellagic acid treatment, alone or in combination with doxorubicin, was studied on isolated heart frequency and strength of the contraction, and on thoracic aorta contractile responses. Application of ellagic acid to rats pre-treated with doxorubicin significantly prevented functional changes occurring in the heart, but not in the thoracic aorta tissue. Ellagic acid statistically significantly (p < 0.001) prevented doxorubicin-induced increase in heart rate, while at the same time increased single contraction force (p < 0.001) and attenuated morphological changes on heart tissue induced by doxorubicin. We can conclude that ellagic acid has potential to prevent doxorubicin-induced changes of the cardiovascular system.
Ethnopharmcological relevance
Microbial biofilm formation, a quorum sensing (QS) regulated process, is one of the major causes of nosocomial and chronic infections, foodborne diseases, and associated deaths. Various approaches have been used to eradicate the menace of biofilm. Ethnomedicinal plants as potent antibiofilm agents are gaining a lot of interest in an era where the drug resistance is increasing and the availability of potent antibiotics is no longer promised. In this context, the methanol extract of Cuphea carthagenensis (CCMD), an ethno-medicinal and culinary herb, was evaluated as an antibiofilm and anti-QS agent against Pseudomonas aeruginosa.
Aim of the study: The aim of the study is to evaluate the antibiofilm and anti-QS activity of an ethnomedicinal plant against a strong biofilm forming microorganism, P. aeruginosa.
Methods
Antibiofilm activity of CCMD was demonstrated at different concentrations by Tissue Culture Plate, Test Tube method and other microscopic techniques. The effect of CCMD on QS and QS-related virulence factors viz. pyocyanin, exopolymeric substance matrix (EPS), total protease, elastase, pyoverdin and swimming motility in P. aeruginosa were also evaluated. Antioxidant activity (DPPH & FRAP), total phenolic and flavonoid content were also checked. In order to determine the composition of the extract HPLC analysis was also performed.
Results
In vitro study demonstrated a significant inhibition of biofilm formation (81.88 ± 2.57%) as well as production of QS-dependent virulence factors in P. aeruginosa. The extract also inhibited violacein production (83.31 ± 2.77%) in Chromobacterium violaceum which correlates with the reduction in QS-mediated virulence factors. The extract showed 64.79% ± 0.83% DPPH scavenging activity and reduction of ferricyanide complex (Fe³⁺) to the ferrous form (Fe²⁺) in DPPH and FRAP assay, respectively. Furthermore, the extract showed thermal stability and does not have any growth inhibitory effect on P. aeruginosa. The HPLC analysis demonstrated the presence of ellagic acid, ascorbic acid and hippuric acid in the extract.
Conclusion
This work is the first to demonstrate that C. carthagenensis can attenuate biofilm formation and QS-mediated virulence factors of P. aeruginosa. Further investigation is required to use this ethnomedicinal plant (CCMD) as an important source of antibiofilm agents.
The possible action of polyphenolic compounds in the reduction of reactive oxygen species (ROS) and mitochondrial toxicity may suggest them as putative agents for the treatment of drug-induced mitochondrial dysfunction and cardiotoxicity. This study was designed to explore protective effect of ellagic acid (EA) against celecoxib-induced cellular and mitochondrial toxicity in cardiomyocytes and their isolated mitochondria. In order to do this, isolated cardiomyocytes and mitochondria were pretreated with 3 different concentrations of EA (10, 50 and 100 µM), after which celecoxib (16 µg/ml) was added to promote deleterious effects on cells and mitochondria. Using flow cytometry and biochemical methods, the parameters of cellular and mitochondrial toxicity were investigated. Our results showed that celecoxib (16 µg/ml) caused a significant decrease in cell viability, mitochondrial membrane potential (MMP), glutathione (GSH) in intact cardiomyocytes and succinate dehydrogenase (SDH) activity, MMP collapse, and mitochondrial swelling, and a significant increase in reactive oxygen species (ROS) formation, lipid peroxidation (LP) and oxidative stress in isolated mitochondria. Also, our results revealed that co-administration of EA (50 and 100 µM) with celecoxib significantly attenuated the cellular and mitochondrial toxicity effects. In this study, we showed that simultaneous treatment with of EA ameliorated the cellular and mitochondrial toxicity induced by celecoxib, with cardiomyocytes presenting normal activity compared to the control group, and mitochondria retaining their normal activity.
We developed a method to evaluate the activity of the Na⁺–Ca²⁺ exchanger (NCX) and sarco-endoplasmic reticulum Ca²⁺-ATPase (SERCA) with fluorescence microscopy in mouse ventricular cardiomyocytes. In non-beating ventricular cardiomyocytes, α-adrenoceptor stimulation by phenylephrine caused a decrease in the cytoplasmic Ca²⁺ concentration, which was inhibited by SEA0400, an NCX inhibitor, but not cyclopiazonic acid, a SERCA inhibitor. β-Adrenoceptor stimulation by isoprenaline caused a decrease in the cytoplasmic Ca²⁺ concentration, which was inhibited by cyclopiazonic acid but not SEA0400. Ellagic acid, a phenolic phytochemical, also decreased the basal Ca²⁺ concentration, which was inhibited by cyclopiazonic acid, but not SEA0400. Thus, this method using fluorescent microscopy and specific inhibitors would be useful for the evaluation of pharmacological agents acting on NCX and SERCA.
Graphical Abstract Fullsize Image
Myocardial fibrosis, the expansion of the cardiac interstitium through deposition of extracellular matrix proteins, is a common pathophysiologic companion of many different myocardial conditions. Fibrosis may reflect activation of reparative or maladaptive processes. Activated fibroblasts and myofibroblasts are the central cellular effectors in cardiac fibrosis, serving as the main source of matrix proteins. Immune cells, vascular cells and cardiomyocytes may also acquire a fibrogenic phenotype under conditions of stress, activating fibroblast populations. Fibrogenic growth factors (such as TGF-β and PDGFs), cytokines (including TNF-α, IL-1, IL-6, IL-10 and IL-4), and neurohumoral pathways trigger fibrogenic signaling cascades through binding to surface receptors, and activation of downstream signaling cascades. In addition, matricellular macromolecules are deposited in the remodeling myocardium and regulate matrix assembly, while modulating signal transduction cascades and protease or growth factor activity. Cardiac fibroblasts can also sense mechanical stress through mechanosensitive receptors, ion channels and integrins, activating intracellular fibrogenic cascades that contribute to fibrosis in response to pressure overload. Although subpopulations of fibroblast-like cells may exert important protective actions in both reparative and interstitial/perivascular fibrosis, ultimately fibrotic changes perturb systolic and diastolic function, and may play an important role in the pathogenesis of arrhythmias. This review manuscript discusses the molecular mechanisms involved in the pathogenesis of cardiac fibrosis in various myocardial diseases, including myocardial infarction, heart failure with reduced or preserved ejection fraction (HFrEF and HFpEF), genetic cardiomyopathies and diabetic heart disease. Development of fibrosis-targeting therapies for patients with myocardial diseases will require not only understanding of the functional pluralism of cardiac fibroblasts and dissection of the molecular basis for fibrotic remodeling, but also appreciation of the pathophysiologic heterogeneity of fibrosis-associated myocardial disease.
Clozapine (CLZ) as an antipsychotic agent is very effective in treating of psychosis disorders and resistant schizophrenia, but the risk of severe cardiac toxicity effects restricts its clinical use. There are several interrelated hypotheses to explain clozapine-induced cardiotoxicity which all of them may be related to oxidative stress. Therefore, the current study investigated the harmful effects of clozapine on cardiomyocytes and assessed the cytoprotective effect of ellagic acid (EA). Freshly isolated adult rat ventricular cardiomyocytes were incubated for 4 h at 37 °C with 00.05% ethanol as control, CLZ (50 µM), CLZ (50 µM) + a series of EA concentrations (10, 20 and 50 µM) and EA (50 µM). To evaluate the protective effect of EA, the markers of cell viability, reactive oxygen species (ROS) formation, mitochondria membrane potential (ΔΨm) collapse, lysosomal membrane integrity, malondialdehyde (MDA) and oxidized/reduced glutathione (GSH/GSSG) content were checked by biochemical and flowcytometry techniques. Our results demonstrated that EA (10, 20 and 50 µM) effectively inhibited CLZ-induced cytotoxicity which is associated with ROS overproduction and amelioration of mitochondrial and lysosomal damages. In addition, EA (10, 20 and 50 µM) in the presence of CLZ reduced the production of MDA as a specific marker lipid peroxidation and GSSG. Collectively, these findings suggested that EA protects cardiomyocytes from oxidative injury through inhibiting ROS formation, mitochondria dysfunction, and lysosomal damages, which suggest a potential therapeutic strategy of EA for CLZ-induced oxidative stress and cardiotoxicity.
Hypertension is defined as the persistence of elevated blood pressure in the circulation system. The renin-angiotensin-aldosterone system is a major modulator of blood pressure. Among the risk factors of cardiovascular disease, hypertension is the most preventable and treatable, with drugs such as ACE inhibitors. Many ACE inhibitors are known to have undesirable side effects and hence, natural alternatives are being sought. Dietary polyphenols, particularly ellagitannins, are derived from plant products and are known to exhibit a variety of bioactivities. Geraniin, an ellagitannin has been shown to have antihypertensive activity in animal experiments. It is speculated that the metabolites of geraniin are responsible for its ACE inhibitory activity. We have performed in vitro ACE inhibition and in silico studies with geraniin and its metabolites (ellagic acid, urolithins). Our studies confirm that ellagic acid exhibited similar inhibitory potential to ACE as the positive control captopril.
Introduction:
Persons aged more than 65 years may be more prone to suffer from chronic diseases and comorbidities (as demonstrated by the recent COVID-19 pandemics) and are treated with multiple concomitant medications. This may result in drug-drug interactions (DDIs) that are often overlooked in clinical practice. Elderly patients are more affected by comorbidities increasing the risk of DDIs and adverse drug reactions (ADRs). Statins are effective in elderly patients with or at risk for cardiovascular disease (CVD) and are prescribed on a long-term basis and may undergo DDIs, particularly on pharmacokinetic bases. The risk of DDIs varies among statins, and safety and ADRs of statins are of special concern in patients affected by multiple chronic conditions requiring concomitant therapies at risk of DDIs, such as the elderly.
Areas covered:
The purpose of this manuscript is to give an update on the potential statin DDIs and related ADRs with an exclusive focus on the data available in elderly patients.
Expert opinion:
A better and more close attention to the potential DDIs among statins and other therapeutic options will help physicians in selecting the more effective and less harmful treatment for their patients. This is of importance, especially in older patients.