Effects of Statin and Annatto-extracted Tocotrienol Supplementation on Glucose Homeostasis, Bone Microstructure, and Gut Microbiota Composition in Obese Mice.

BACKGROUND/AIM: This study examined the effects of tocotrienols (TT) in conjunction with statin on glucose homeostasis, bone microstructure, gut microbiome, and systemic and liver inflammatory markers in obese C57BL/6J mice. MATERIALS AND METHODS: Forty male C57BL/6J mice were fed a high-fat diet (HFD) and assigned into four groups in a 2 (no statin vs. 120 mg statin/kg diet)×2 (no TT vs. 400 mg TT/kg diet) factorial design for 14 weeks. RESULTS: Statin and TT improved glucose tolerance only when each was given alone, and only statin supplementation decreased insulin resistance. Consistently, only statin supplementation decreased serum insulin levels and HOMA-IR. Pancreatic insulin was also increased with statin treatment. Statin and TT, alone or in combination, reduced the levels of serum IL-6, but only TT attenuated the increased serum leptin levels induced by a HFD. Statin supplementation increased bone area/total area and connectivity density at LV-4, while TT supplementation increased bone area/total area and trabecular number, but decreased trabecular separation at the distal femur. Statin supplementation, but not TT, reduced hepatic inflammatory cytokine gene expression. Neither TT supplementation nor statin supplementation statistically altered microbiome species evenness or richness. However, they altered the relative abundance of certain microbiome species. Most notably, both TT and statin supplementation increased the relative abundance of Lachnospiraceae UCG-006. CONCLUSION: TT and statin collectively benefit bone microstructure, glucose homeostasis, and microbial ecology in obese mice. Such changes may be, in part, associated with suppression of inflammation in the host.

Raspberry polyphenols target molecular pathways of heart failure.

Approximately 650,000 new cases of heart failure (HF) are diagnosed annually with a 50% five-year mortality rate. HF is characterized by reduced left ventricular (LV) ejection fraction and hypertrophy of the LV wall. The pathophysiological remodeling of the heart is mediated by increased oxidative stress and inflammation. Raspberries are rich in polyphenols which may favorably impact enzymes involved in redox homeostasis while also targeting inflammatory signaling. Thus, the objective of this study was to investigate whether raspberry polyphenols could attenuate HF. Sprague Dawley rats consumed a 10% (w/w) raspberry diet for 7 weeks. At week 3, HF was surgically induced via coronary artery ligation. Hemodynamics and morphology of the heart were assessed. Expression of cardiac proteins involved in oxidative stress, inflammation, apoptosis, and remodeling were examined, and histological analysis was conducted. Additionally, human cardiomyocytes were treated with raspberry polyphenol extract (RBPE) followed by CoCl2 to chemically induce hypoxia. Redox status, apoptosis, and mitochondrial dysfunction were measured. Raspberries attenuated reductions in cardiac function and reduced morphological changes which coincided with reduced toll-like receptor (TLR)4 signaling. Reductions in oxidative stress, apoptosis, and remodeling occurred in vivo. Incubation of cardiomyocytes with RBPE attenuated CoCl2-induced oxidative stress and apoptosis despite pronounced hypoxia-inducible factor (HIF)-1α expression. These data indicate that consumption of raspberries can reduce the underlying molecular drivers of HF; thus, leading to the observed improvements in cardiac functional capacity and morphology. This dietary strategy may be an effective alternative strategy for treating HF. However, further investigation into alternative models of HF is warranted.

Blackberry consumption protects against e-cigarette-induced vascular oxidative stress in mice.

Electronic cigarettes (e-cigarettes) have gained popularity; however, evidence for their safety with chronic use is lacking. Acute e-cigarette exposure induces systemic oxidative stress in users and contributes to vascular endothelial dysfunction through reduction in nitric oxide (NO). Polyphenols, abundant in blackberries (BL), mitigate cardiovascular damage. We aimed to determine whether BL was protective against e-cigarette-induced cardiopulmonary detriments. Mice were fed a diet supplemented with or without 5% freeze-dried BL (w/w) for 16 weeks. E-cigarette exposure (1 h, 5 days per week) began at week 4. Additionally, human microvascular endothelial cells (HMVECs) were treated with BL polyphenol extract (200 µg mL-1) and e-cigarette condensate (0.5% v/v). Twelve weeks of e-cigarette exposure induced multi-organ oxidative stress. E-cigarette exposure increased expression of pro-oxidant enzymes in the endothelium resulting in increased superoxide production diminishing NO bioavailability. Additionally, e-cigarettes reduced the phosphorylation of endothelial NO synthase, contributing to decreases in NO. Mice supplemented with BL were protected against decreases in NO and BL pre-treatment in vitro reduced superoxide production. However, BL was not able to attenuate oxidative stress responses in the heart or lungs. These studies demonstrate the contribution of e-cigarettes to vascular pathologies through an increase in superoxide-producing enzymes and the ability of BL polyphenols to mitigate these deleterious effects in the vasculature. Further studies should explore the role of polyphenol-rich foods in protecting against cardiopulmonary conditions induced by chronic e-cigarette use and explore their use in the recovery period post-e-cigarette cessation to properly align with current public health messaging.

Angiotensin II-Mediated Neuroinflammation in the Hippocampus Contributes to Neuronal Deficits and Cognitive Impairment in Heart Failure Rats.

BACKGROUND: Heart failure (HF) is a debilitating disease affecting >64 million people worldwide. In addition to impaired cardiovascular performance and associated systemic complications, most patients with HF suffer from depression and substantial cognitive decline. Although neuroinflammation and brain hypoperfusion occur in humans and rodents with HF, the underlying neuronal substrates, mechanisms, and their relative contribution to cognitive deficits in HF remains unknown. METHODS: To address this critical gap in our knowledge, we used a well-established HF rat model that mimics clinical outcomes observed in the human population, along with a multidisciplinary approach combining behavioral, electrophysiological, neuroanatomical, molecular and systemic physiological approaches. RESULTS: Our studies support neuroinflammation, hypoperfusion/hypoxia, and neuronal deficits in the hippocampus of HF rats, which correlated with the progression and severity of the disease. An increased expression of AT1aRs (Ang II [angiotensin II] receptor type 1a) in hippocampal microglia preceded the onset of neuroinflammation. Importantly, blockade of AT1Rs with a clinically used therapeutic drug (Losartan), and delivered in a clinically relevant manner, efficiently reversed neuroinflammatory end points (but not hypoxia ones), resulting in turn in improved cognitive performance in HF rats. Finally, we show than circulating Ang II can leak and access the hippocampal parenchyma in HF rats, constituting a possible source of Ang II initiating the neuroinflammatory signaling cascade in HF. CONCLUSIONS: In this study, we identified a neuronal substrate (hippocampus), a mechanism (Ang II-driven neuroinflammation) and a potential neuroprotective therapeutic target (AT1aRs) for the treatment of cognitive deficits in HF.

Effects of biological sex and oral contraceptive pill use on cutaneous microvascular endothelial function and nitric oxide-dependent vasodilation in humans.

The purpose of this study was to evaluate in vivo endothelial function and nitric oxide (NO)-dependent vasodilation between women in either menstrual or placebo pill phases of their respective hormonal exposure [either naturally cycling (NC) or using oral contraceptive pills (OCPs)] and men. A planned subgroup analysis was then completed to assess endothelial function and NO-dependent vasodilation between NC women, women using OCP, and men. Endothelium-dependent and NO-dependent vasodilation were assessed in the cutaneous microvasculature using laser-Doppler flowmetry, a rapid local heating protocol (39°C, 0.1 °C/s), and pharmacological perfusion through intradermal microdialysis fibers. Data are represented as means ± standard deviation. Men displayed greater endothelium-dependent vasodilation (plateau, men: 71 ± 16 vs. women: 52 ± 20%CVCmax, P < 0.01), but lower NO-dependent vasodilation (men: 52 ± 11 vs. women: 63 ± 17%NO, P = 0.05) compared with all women. Subgroup analysis revealed NC women had lower endothelium-dependent vasodilation (plateau, NC women: 48 ± 21%CVCmax, P = 0.01) but similar NO-dependent vasodilation (NC women: 52 ± 14%NO, P > 0.99), compared with men. Endothelium-dependent vasodilation did not differ between women using OCP and men (P = 0.12) or NC women (P = 0.64), but NO-dependent vasodilation was significantly greater in women using OCP (74 ± 11%NO) than both NC women and men (P < 0.01 for both). This study highlights the importance of directly quantifying NO-dependent vasodilation in cutaneous microvascular studies. This study also provides important implications for experimental design and data interpretation.NEW & NOTEWORTHY This study supports differences in microvascular endothelial function and nitric oxide (NO)-dependent vasodilation between women in low hormone phases of two hormonal exposures and men. However, when separated into subgroups of hormonal exposure, women during placebo pills of oral contraceptive pill (OCP) use have greater NO-dependent vasodilation than naturally cycling women in their menstrual phase and men. These data improve knowledge of sex differences and the effect of OCP use on microvascular endothelial function.

Assessment of sports nutrition knowledge, dietary intake, and nutrition information source in female collegiate athletes: A descriptive feasibility study.

Objective: This descriptive feasibility study aimed to assess dietary intake, sports nutrition knowledge, and nutrition information source in collegiate athletes. Participants: Fourteen indoor volleyball female collegiate athletes from a National Collegiate Athletic Association Division I university. Methods: Participants completed a Nutrition for Sports Knowledge Questionnaire (NSKQ) once and dietary and body composition assessments over four time points. Results: Pre-season mean energy and carbohydrate intake were lower than the American College of Sports Medicine Recommendations (25 ± 6.4 vs 37-41 kcal/kg BW/day and 3 ± 0.9 vs 6-10 g/kg BW/day; respectively). Off-season carbohydrate intake followed similar trends. The average score on the NSKQ was 45 ± 9.6% out of 100. Athletic trainers were identified as a top nutrition source followed by strength and conditioning coaches and nutritionists. Conclusion: Female volleyball athletes have inadequate dietary intake and sports nutrition knowledge and may benefit from nutrition education and counseling by trained sports nutrition experts.Supplemental data for this article can be accessed online at https://doi.org/10.1080/07448481.2021.1987919.

Berry consumption mitigates the hypertensive effects of a high-fat, high-sucrose diet via attenuation of renal and aortic AT1R expression resulting in improved endothelium-derived NO bioavailability.

Dysregulation of the renin-angiotensin system (RAS) is a contributor to high-fat diet-related blood pressure (BP) increases. Deleterious effects of dysregulated RAS result in an overproduction of reactive oxygen species and a decrease in endothelial nitric oxide (NO) bioavailability due to increased NADPH oxidase (NOX) expression. Dietary polyphenols have been shown to mitigate the imbalance in the redox state and protect against endothelial dysfunction induced by a high-fat diet. Thus, we aim to determine whether polyphenol-rich blackberry and raspberry, alone and in combination, attenuate the detrimental effects of a high-fat, high-sucrose (HFHS) diet on the vascular endothelium and kidneys of mice. We show that a HFHS diet increased the expression of renal and aortic angiotensin type 1 receptor (AT1R). Further, NOX1 and NOX4 expression were increased in the kidney contributing to fibrotic damage. In human aortic endothelial cells (HAECs), palmitic acid increased the expression of NOX4, potentially driving oxidative damage in the aorta, as evidenced by increased nitrotyrosine expression. Berries reduced the expression of renal and aortic AT1R, leading to a subsequent decrease in renal NOX expression and reduced aortic oxidative stress evidenced by reduced nitrotyrosine expression. Blackberry and raspberry in combination increased the expression of NRF2 and its downstream proteins in HAECs, thereby reducing the oxidative burden to the endothelium. In combination, blackberry and raspberry also increased serum levels of NO metabolites. These findings indicate that blackberry and raspberry unique polyphenols may act synergistically to favorably modulate the abovementioned pathways and attenuate HFHS diet-induced increases in BP.

Altered PVN-to-CA2 hippocampal oxytocin pathway and reduced number of oxytocin-receptor expressing astrocytes in heart failure rats.

Oxytocinergic actions within the hippocampal CA2 are important for neuromodulation, memory processing and social recognition. However, the source of the OTergic innervation, the cellular targets expressing the OT receptors (OTRs) and whether the PVN-to-CA2 OTergic system is altered during heart failure (HF), a condition recently associated with cognitive and mood decline, remains unknown. Using immunohistochemistry along with retrograde monosynaptic tracing, RNAscope and a novel OTR-Cre rat line, we show that the PVN (but not the supraoptic nucleus) is an important source of OTergic innervation to the CA2. These OTergic fibers were found in many instances in close apposition to OTR expressing cells within the CA2. Interestingly, while only a small proportion of neurons were found to express OTRs (~15%), this expression was much more abundant in CA2 astrocytes (~40%), an even higher proportion that was recently reported for astrocytes in the central amygdala. Using an established ischemic rat heart failure (HF) model, we found that HF resulted in robust changes in the PVN-to-CA2 OTergic system, both at the source and target levels. Within the PVN, we found an increased OT immunoreactivity, along with a diminished OTR expression in PVN neurons. Within the CA2 of HF rats, we observed a blunted OTergic innervation, along with a diminished OTR expression, which appeared to be restricted to CA2 astrocytes. Taken together, our studies highlight astrocytes as key cellular targets mediating OTergic PVN inputs to the CA2 hippocampal region. Moreover, they provide the first evidence for an altered PVN-to-CA2 OTergic system in HF rats, which could potentially contribute to previously reported cognitive and mood impairments in this animal model.

Raspberry and blackberry act in a synergistic manner to improve cardiac redox proteins and reduce NF-κB and SAPK/JNK in mice fed a high-fat, high-sucrose diet.

BACKGROUND AND AIMS: Increased cardiac inflammation and oxidative stress are common features in obesity, and toll-like receptor (TLR)4 signaling is a key inflammatory pathway in this deleterious process. This study aimed to investigate whether berries could attenuate the detrimental effects of a high-fat, high-sucrose (HFHS) diet on the myocardium at the molecular level. METHODS AND RESULTS: Eight-week-old male C57BL/6 mice consumed a low-fat, low-sucrose (LFLS) diet alone or supplemented with 10% blackberry (BL), 10% raspberry (RB) or 10% blackberry + raspberry (BL + RB) for four weeks. Animals were then switched to a HFHS diet for 24 weeks with or without berry supplementation or maintained on a LFLS control diet without berry supplementation. Left ventricles of the heart were isolated for protein and mRNA analysis. Berry consumption, particularly BL + RB reduced NADPH-oxidase (NOX)1 and NOX2 and increased catalase (CAT) and superoxide dismutase (SOD)2, expression while BL and RB supplementation alone was less efficacious. Downstream TLR4 signaling was attenuated mostly by both RB and BL + RB supplementation, while NF-κB pathway was attenuated by BL + RB supplementation. Stress-activated protein kinase (SAPK)/Jun amino-terminal kinase (JNK) was also attenuated by BL + RB supplementation, and reduced TNF-α transcription and protein expression was observed only with BL + RB supplementation. CONCLUSION: The synergistic effects of BL + RB may reduce obesity-induced cardiac inflammation and oxidative stress to a greater extent than BL or RB alone.

Blueberry Polyphenols Increase Nitric Oxide and Attenuate Angiotensin II-Induced Oxidative Stress and Inflammatory Signaling in Human Aortic Endothelial Cells.

Accumulating evidence indicate that blueberries have anti-hypertensive properties, which may be mainly due to its rich polyphenol content and their high antioxidant capacity. Thus, we aimed to investigate the mechanisms by which blueberry polyphenols exert these effects. Human aortic endothelial cells (HAECs) were incubated with 200 µg/mL blueberry polyphenol extract (BPE) for 1 h prior to a 12 h treatment with angiotensin (Ang) II, a potent vasoconstrictor. Our results indicate that Ang II increased levels of superoxide anions and decreased NO levels in HAECs. These effects were attenuated by pre-treatment with BPE. Ang II increased the expression of the pro-oxidant enzyme NOX1, which was not attenuated by BPE. Pre-treatment with BPE attenuated the Ang II-induced increase in the phosphorylation of the redox-sensitive MAPK kinases, SAPK/JNK and p38. BPE increased the expression of the redox-transcription factor NRF2 as well as detoxifying and antioxidant enzymes it transcribes including HO-1, NQO1, and SOD1. We also show that BPE attenuates the Ang II-induced phosphorylation of the NF-κB p65 subunit. Further, we show that inhibition of NRF2 leads to a decrease in the expression of HO-1 and increased phosphorylation of the NF-κB p65 subunit in HAECs treated with BPE and Ang II. These findings indicate that BPE acts through a NRF2-dependent mechanism to reduce oxidative stress and increase NO levels in Ang II-treated HAECs.

Skeletal muscle proteome expression differentiates severity of cancer cachexia in mice and identifies loss of fragile X mental retardation syndrome-related protein 1.

Tandem mass tag (TMT)-based quantitative proteomics was used to examine protein expression in skeletal muscle from mice with moderate and severe cancer cachexia to study mechanisms underlying varied cachexia severity. Weight loss of 10% (moderate) and 20% (severe) was induced by injection of colon-26 cancer cells in 10-week old Balb/c mice. In moderate cachexia, enriched pathways reflected fibrin formation, integrin/mitogen-activated protein kinase (MAPK) signaling, and innate immune system, suggesting an acute phase response and fibrosis. These pathways remained enriched in severe cachexia; however, energy-yielding pathways housed in mitochondria were prominent additions to the severe state. These enrichments suggest distinct muscle proteome expression patterns that differentiate cachexia severity. When analyzed with two other mouse models, eight differentially expressed targets were shared including serine protease inhibitor A3N (Serpina3n), synaptophysin-like protein 2 (Sypl2), Isocitrate dehydrogenase [NAD] subunit alpha, mitochondrial (Idh3a), peroxisomal acyl-coenzyme A oxidase 1 (Acox1), collagen alpha-1(VI) chain (Col6a1), myozenin 3 (Myoz3), UDP-glucose pyrophosphorylase (Ugp2), and solute carrier family 41 member 3 (Slc41a3). Acox1 and Idh3a control lipid oxidation and NADH generation in the TCA cycle, respectively, and Col6a1 comprises part of type VI collagen with reported profibrotic functions, suggesting influential roles in cachexia. A potential target was identified in fragile X mental retardation syndrome-related protein 1 (FXR1), an RNA-binding protein not previously implicated in cancer cachexia. FXR1 decreased in cachexia and related linearly with weight change and myofiber size. These findings suggest distinct mechanisms associated with cachexia severity and potential biomarkers and therapeutic targets.

Tissue Derivation and Biological Sex Uniquely Mediate Endothelial Cell Protein Expression, Redox Status, and Nitric Oxide Synthesis.

Human endothelial cells are routinely utilized in cardiovascular research to provide a translational foundation for understanding how the vascular endothelium functions in vivo. However, little attention has been given to whether there are sex specific responses in vitro. Similarly, it is unclear whether endothelial cells derived from distinct tissues behave in a homogenous manner. Herein, we demonstrate that marked sex differences exist within, and between, commonly utilized human primary endothelial cells from healthy donors, with respect to redox status, nitric oxide synthesis, and associated proteins that can mediate their expression. Further, we demonstrate that endothelial cells respond uniquely to inflammatory insult in a sex- and tissue origin-dependent manner. Our findings suggest sex and tissue derivation may need to be considered when studying endothelial cells in vitro as cells derived from distinct tissue and sexes may not behave interchangeably.

Effects of strawberries on bone biomarkers in pre- and stage 1-hypertensive postmenopausal women: a secondary analysis.

Postmenopausal women experience an increase in bone remodeling with the rate of bone resorption superseding the rate of bone formation. This results in a net bone loss with a subsequent increased risk for osteoporosis and fractures. High blood pressure (BP) has been associated with loss of bone mineral density and increased propensity to fractures. Strawberries are rich in polyphenols, which have been shown to have anti-hypertensive and bone-protective properties. Thus, we examined whether daily intake of strawberries would positively affect biomarkers of bone metabolism in postmenopausal women with pre- and stage 1-hypertension. Participants (age: 59 ± 6 years; body mass index: 31.5 ± 4.1 kg m-2; systolic BP: 140 ± 13 mmHg) were randomly assigned to consume (1) 50 g of freeze-dried strawberry powder (FDSP), (2) 25 g FDSP + 25 g of placebo powder, or (3) 50 g placebo powder for eight weeks. Results indicate a significant time-by-treatment interaction (P = 0.04) for serum insulin-like growth factor (IGF)-1, a hormone that plays a major role in bone formation. Serum concentrations of bone-specific alkaline phosphatase, a marker of bone formation, and tartrate-resistant acid phosphatase-5b, a specific marker of bone resorption, were not affected by FDSP compared to placebo. Although not statistically significant, after eight weeks, osteocalcin increased in the 50 g FDSP group with a large effect size (d = 0.6) when compared to the placebo-control group. Adiponectin increased by 5% and 6% in the 25 g and 50 g FDSP groups, respectively, while it declined in the placebo-control group by 25% (P = 0.03 for time-by-treatment interaction). Our findings suggest that consumption of 25 g FDSP increases IGF-1 in postmenopausal women with pre- and stage 1-hypertension. However, further studies are needed to assert the effectiveness of a strawberry intervention for bone health.

Berries and Their Polyphenols as a Potential Therapy for Coronary Microvascular Dysfunction: A Mini-Review.

Ischemia with no obstructive coronary artery disease (INOCA) is a common diagnosis with a higher prevalence in women compared to men. Despite the absence of obstructive coronary artery disease and no structural heart disease, INOCA is associated with major adverse cardiovascular outcomes as well a significant contributor to angina and related disability. A major feature of INOCA is coronary microvascular dysfunction (CMD), which can be detected by non-invasive imaging and invasive coronary physiology assessments in humans. CMD is associated with epicardial endothelial-dependent and -independent dysfunction, diffuse atherosclerosis, and left-ventricular hypertrophy, all of which lead to insufficient blood flow to the myocardium. Inflammatory and oxidative stress signaling, upregulation of the renin-angiotensin-aldosterone system and adrenergic receptor signaling are major drivers of CMD. Treatment of CMD centers around addressing cardiovascular risk factors; however, there are limited treatment options for those who do not respond to traditional anti-anginal therapies. In this review, we highlight the ability of berry-derived polyphenols to modulate those pathways. The evidence supports the need for future clinical trials to investigate the effectiveness of berries and their polyphenols in the treatment of CMD in INOCA patients.

Dual Use of Electronic Cigarettes and Traditional Cigarettes Among Adults: Psychosocial Correlates and Associated Respiratory Symptoms.

BACKGROUND: Prolonged use of both electronic cigarettes (e-cigarettes) and traditional cigarettes can increase breathing difficulties and other adverse health effects. Research is needed to provide a deeper understanding of predictors of dual use, particularly given rapid changes in the e-cigarette market and related public health communications and policy. METHODS: The sample consists of subjects in the National Longitudinal Study of Adolescent to Adult Health Wave 5 (cross-sectional) subsample (N = 3,800) from 2016 to 2018. Participants were 31-42 y old. Multinomial logistic regression analyses were used to determine predictors of mutually exclusive categories: e-cigarette use only, cigarette use only, and concurrent e-cigarette and traditional cigarette use (compared to no use). Predictors included sex, age, poverty status, race/ethnicity, self-reported diagnosed depression, self-reported diagnosed anxiety, and previous experience of child maltreatment. RESULTS: Among the total sample (N = 3,800), 2% reported e-cigarette use only, 20% reported traditional cigarette use only, and 3% reported dual use of both e-cigarettes and traditional cigarettes. Among subjects who reported any e-cigarette or traditional cigarette use (n = 957), 12% reported dual use. In the final adjusted multivariable multinomial model, dual use was associated with living at or below the poverty line (odds ratio 2.49 [95% CI 1.19-5.70]), self-reported diagnosed depression (odds ratio 1.99 [95% CI 1.10-3.61]), and a history of child maltreatment (odds ratio 1.80 [95% CI 1.10-2.95]). Additionally, Hispanic-American individuals were more likely to report dual use compared to cigarette-only use. CONCLUSIONS: Prolonged dual use of both e-cigarettes and traditional cigarettes is a considerable public health problem. While our study identified a low percentage of dual usage among U.S. adults, dual use was disproportionately prevalent among those with depression, history of child maltreatment, living at or below the poverty line, and among Hispanic-American individuals. Culturally appropriate interventions and increasing access to cessation programs may help mitigate health disparities pertaining to dual use.

Protective Role of Polyphenols in Heart Failure: Molecular Targets and Cellular Mechanisms Underlying Their Therapeutic Potential.

Heart failure (HF) is a leading cause of death in the United States, with a 5-year mortality rate of 50% despite modern pharmacological therapies. Plant-based diets are comprised of a diverse polyphenol profile, which lends to their association with reduced cardiovascular disease risk. Whether a polyphenol-rich diet can slow the progression of or reverse HF in humans is not known. To date, in vitro and in vivo studies have reported on the protective role of polyphenols in HF. In this review, we will discuss the major mechanisms by which polyphenols mitigate HF in vitro and in vivo, including (1) reduced cardiac inflammation and oxidative stress, (2) reduced mitochondrial dysfunction, (3) improved Ca2+ homeostasis, (4) increased survival signaling, and (5) increased sirtuin 1 activity.

Berries as a Treatment for Obesity-Induced Inflammation: Evidence from Preclinical Models.

Inflammation that accompanies obesity is associated with the infiltration of metabolically active tissues by inflammatory immune cells. This propagates a chronic low-grade inflammation associated with increased signaling of common inflammatory pathways such as NF-κB and Toll-like receptor 4 (TLR4). Obesity-associated inflammation is linked to an increased risk of chronic diseases, including type 2 diabetes, cardiovascular disease, and cancer. Preclinical rodent and cell culture studies provide robust evidence that berries and their bioactive components have beneficial effects not only on inflammation, but also on biomarkers of many of these chronic diseases. Berries contain an abundance of bioactive compounds that have been shown to inhibit inflammation and to reduce reactive oxygen species. Therefore, berries represent an intriguing possibility for the treatment of obesity-induced inflammation and associated comorbidities. This review summarizes the anti-inflammatory properties of blackberries, blueberries, strawberries, and raspberries. This review highlights the anti-inflammatory mechanisms of berries and their bioactive components that have been elucidated through the use of preclinical models. The primary mechanisms mediating the anti-inflammatory effects of berries include a reduction in NF-κB signaling that may be secondary to reduced oxidative stress, a down-regulation of TLR4 signaling, and an increase in Nrf2.

Berry-Derived Polyphenols in Cardiovascular Pathologies: Mechanisms of Disease and the Role of Diet and Sex.

Cardiovascular disease (CVD) prevalence, pathogenesis, and manifestation is differentially influenced by biological sex. Berry polyphenols target several signaling pathways pertinent to CVD development, including inflammation, oxidative stress, and cardiac and vascular remodeling, and there are innate differences in these pathways that also vary by sex. There is limited research systematically investigating sex differences in berry polyphenol effects on these pathways, but there are fundamental findings at this time that suggest a sex-specific effect. This review will detail mechanisms within these pathological pathways, how they differ by sex, and how they may be individually targeted by berry polyphenols in a sex-specific manner. Because of the substantial polyphenolic profile of berries, berry consumption represents a promising interventional tool in the treatment and prevention of CVD in both sexes, but the mechanisms in which they function within each sex may vary.

Cornus officinalis var. koreana Kitam polyphenol extract decreases pro-inflammatory markers in lipopolysaccharide (LPS)-induced RAW 264.7 macrophages by reducing Akt phosphorylation.

ETHNOPHARMACOLOGICAL RELEVANCE: Cornus officinalis var. koreana Kitam (CO) is found predominantly in China but also in Korea and Japan and has been used in Eastern medicine for over 2000 years to treat several conditions including diabetes, cardiovascular disease and kidney disease. Chronic inflammation underlies the pathogenesis of these diseases. The mechanisms by which CO may exert its anti-inflammatory effects have not been well defined. AIM OF THE STUDY: We aimed to determine whether Cornus officinalis var. koreana Kitam extract (COE) attenuate the inflammatory response induced by lipopolysaccharide (LPS) in RAW 264.7 macrophages, and to elucidate the mechanisms which contribute to these anti-inflammatory effects. MATERIALS AND METHODS: COE was prepared using ethanolic extraction, followed by solvent evaporation and freeze-drying. RAW 264.7 macrophages were treated with 0, 50, 100, 200 and 400 µg/ml of COE. After 2 h, cells were treated with 100 ng/ml of LPS for 6 h. Cells were then collected for whole cell protein expression analysis of signaling and inflammatory molecules via western blot. RESULTS: Pre-treatment with 100, 200 and 400 µg/ml of COE significantly reduced Akt phosphorylation in LPS stimulated macrophages compared to LPS alone (P ≤ 0.003). NF-κB expression was significantly attenuated with 400 µg/ml of COE compared to LPS treatment alone (P = 0.01). LPS induced cyclooxygenase (COX)-2 and inducible nitric oxide synthase (iNOS) expression, which was significantly decreased by treatment with 400 µg/ml COE (P = 0.0001 and 0.02, respectively). COE dose-dependently decreased LPS-induced expression of interleukin (IL)-1ß (P ≤ 0.0008) and IL-6 (P = 0.01). CONCLUSION: In summary, COE attenuated the inflammatory response induced by LPS in RAW 264.7 macrophages, likely due to Akt inhibition.