An UHPLC/LC-MS illustrated the dynamic profiling of balanophorin B, gallic acid, and 4-hydroxycinnamic acid in rat as 3 molecular entities from Balanophora simaoensis.

An UHPLC/LC-MS was founded to detect balanophorin B (B), gallic acid (GA), 4-hydroxycinnamic acid (HC), and their in vivo profiling in rats, after oral administration of the ethanol extract of Balanophora simaoensis S. Y. Chang et Tam. The in vivo dynamic existence of 3 molecular entities in rats and the multistep biotransformation of GA were elucidated by their sensitive mass spectrometry response after efficient UHPLC and/or HPLC separation, through analyzing the bio-samples of rat plasma, bile, liver, kidneys, and excreta. The method was validated with satisfactory calibration curves having correlation coefficients r from 0.996 to 0.999 for concentration scaled from 0.100 nM to 0.100 µM, internal standard normalized matrix factors ranged from 0.923 to 0.993, sextuplicate recoveries valued from 95.0% to 103.6%, as well as accuracy and precision varied from 95.6% to 103.7%. The content of B, GA, and HC in the whole herb was of 4.66, 63.5, and 10.4 µmol/kg in dry weight, respectively. The Cmax for B, GA, and HC in rat systemic circulation was of 76.0 nM, 2.30 µM, and 51.0 µM, with tmax at 3, 2, and 2 h, respectively. B and GA stayed in rat liver over 4 hs to present a material base for the pharmacology and pharmacodynamics of the whole herb. The biotransformation of GA indicated a complicated scheme in rats. As a final metabolite from GA with total biotransformation conversion over 20%, 4-hydroxybenzaldehyde resourced from two steps of dehydroxylation and one step of reduction of GA, but not concerned with HC.

Salvianolic acid B and ferulic acid synergistically promote angiogenesis in HUVECs and zebrafish via regulating VEGF signaling.

ETHNOPHARMACOLOGICAL RELEVANCE: Induced vascular growth in the myocardium has been widely acknowledged as a promising intervention strategy for patients with ischemic coronary artery disease. Yet despite long-term efforts on gene, protein or cell-based pro-angiogenic therapies, the clinical translation remains challenging. Noticeably, multiple medicinal herbs have long-term documented effects in promoting blood circulation. Salvia miltiorrhiza and Ligusticum stratum are two representative traditional Chinese medicine herbs with suggested roles in enhancing organ blood supply, and Guanxinning Tablet (GXNT), a botanical drug which is formulated with these two herbs, exhibited significant efficacy against angina pectoris in clinical practices. AIM OF THE STUDY: This study aimed to examine the pro-angiogenic activity of GXNT and its major components, as well as to explore their pharmacological mechanism in promoting angiogenesis. MATERIALS AND METHODS: In vitro, the pro-angiogenic effects of GXNT and its major components were examined on human umbilical vein endothelial cells by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT), scratch assay, and endothelial cell tube formation assay. In vivo, the pro-angiogenic effects were examined on the ponatinib-induced angiogenesis defective zebrafish model. The active compounds were identified through phenotype-based screening in zebrafish, and their pharmacological mechanism was explored in both in vitro and in vivo models by immunofluorescent staining, cell cycle analysis, quantitative PCR and whole embryo in-situ hybridization. RESULTS: We demonstrated strong pro-angiogenic effects of GXNT in both human umbilical vein endothelial cells and zebrafish model. Moreover, through phenotype-based screening in zebrafish for active compounds, pro-angiogenic effects was discovered for salvianolic acid B (Sal B), a major component of Salvia miltiorrhiza, and its activity was further enhanced when co-administered with ferulic acid (FA), which is contained in Ligusticum stratum. On the cellular level, Sal B and FA cotreatment increased endothelial cell proliferation of sprouting arterial intersomitic vessels in zebrafish, as well as largely restored G1-S cell cycle progression and cyclin D1 expression in angiogenic defective HUVECs. Through quantitative transcriptional analysis, increased expression of vegfr2 (kdr, kdrl) and vegfr1 was detected after GXNT or SalB/FA treatment, together with upregulated transcription of their ligands including vegf-a, vegf-b, and pgfb. Bevacizumab, an anti-human VEGF-A monoclonal antibody, was able to significantly, but not completely, block the pro-angiogenic effects of GXNT or SalB/FA, suggesting their multi-targeting properties. CONCLUSIONS: In conclusion, from a traditional Chinese medicine with effects in enhancing blood circulation, we demonstrated the synergistic pro-angiogenic effects of Sal B and FA via both in vitro and in vivo models, which function at least partially through regulating the expression of VEGF receptors and ligands. Future studies are warranted to further elaborate the molecular interaction between these two compounds and the key regulators in the process of neovascularization.

Hypolipidemic and reduced nitrergic effects of p-hydroxycinnamic diesters extracted from Copernicia prunifera in mice challenged by a high-fat diet.

Dyslipidemia is a chronic non-transmissible condition that has increased due to an unhealthy lifestyle. Statins have been used as the standard treatment to control hyperlipidemia. However, side effects and high costs may be associated with its prolonged treatment, so plants derivatives have been an attractive therapy to overcome these problems. Among the compounds extracted from plants, the p-hydroxycinnamic diesters (HCE), present in carnauba wax (CW), have been found with good pharmacological properties. Therefore, this study aimed to evaluate the potential anti-hypercholesterolemic and possible toxicological effects of HCE in C57BL/6J mice under a high-fat (HF) diet. Male C57BL/6J mice were fed during 60 days under the HF diet and therefore were either treated with HCE (200 and 400 mg/kg) or simvastatin (20 mg/kg) or received saline (controls) by gavage for 30 days under the same diet. HCE treatment was able to reduce serum total cholesterol and LDL levels. Besides, this compound increased liver X receptor (LXR) and but not significantly affected IL-1ß and TNF-α liver mRNA transcription activity. In conclusion, HCE treatment was found safe and may attenuate the deleterious effects of dyslipidemia due to chronic feeding with western diets.

Ferulic Acid Supplementation Increases Lifespan and Stress Resistance via Insulin/IGF-1 Signaling Pathway in C. elegans.

Ferulic acid (FA) is a naturally-occurring well-known potent antioxidant and free radical scavenger. FA supplementation is an effective strategy to delay aging, but the underlying mechanism remains unknown. In the present study, we examined the effects of FA on lifespan extension and its mechanism of FA in Caenorhabditis elegans (C. elegans). Results suggested that FA increased the lifespan of C. elegans, rather than altering the growth of E. coli OP50. Meanwhile, FA promoted the healthspan of C. elegans by improving locomotion and reducing fat accumulation and polyQ aggregation. FA increased the resistance to heat and oxidative stress through reducing ROS. The upregulating of the expression of the hlh-30, skn-1, and hsf-1 were involved in the FA-mediated lifespan extension. Furthermore, FA treatment had no impact on the lifespan of daf-2, hlh-30, skn-1, and hsf-1 mutants, confirming that insulin/IGF-1 signaling pathway and multiple longevity mechanisms were associated with the longevity mechanism of FA. We further found that mitochondrial signaling pathway was modulation involved in FA-mediated lifespan extension. With the results from RNA-seq results and mutants lifespan assay. These findings contribute to our knowledge of the lifespan extension and underlying mechanism of action of FA in C. elegans.

Effects of dietary ferulic acid supplementation on growth performance and skeletal muscle fiber type conversion in weaned piglets.

BACKGROUND: Ferulic acid (FA) is a common polyphenolic compound. The purpose of this study was to explore the effect of dietary FA supplementation on growth performance and muscle fiber type conversion in weaned piglets. In this study, eighteen 21-day-old DLY (Duroc × Landrace × Yorkshire) weaned piglets were randomly divided into control, 0.05% FA, and 0.45% FA groups. RESULTS: Our study showed that dietary FA supplementation had no effect on growth performance, but it could upregulate the expression of slow myosin heavy chain (MyHC) protein, increase the activities of succinic dehydrogenase and malate dehydrogenase, and downregulate the expression of fast MyHC protein. Dietary FA supplementation also increased the expression levels of phosphorylated AMP-activated protein kinase, sirtuin 1 (Sirt1), peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), myocyte enhancer factor 2C, and troponin I-SS, increased the proportion of slow-twitch fiber, and decreased the proportion of fast-twitch fiber. In addition, our results showed that dietary FA supplementation increased the messenger RNA abundance of mitochondrial nuclear transcription genes, including ATP synthase membrane subunit c locus 1, cytochrome oxidase subunit 1, nuclear respiratory factor 1, mitochondrial transcription factor A, mitochondrial transcription factor B1, and cytochrome c. CONCLUSION: We provided the first evidence that FA could promote muscle fiber type conversion from fast-twitch to slow-twitch via the Sirt1/AMP-activated protein kinase/PGC-1α signaling pathway and could improve the mitochondrial function in weaned piglets. This means that FA can be used as a dietary supplement to improve the quality of pork. © 2021 Society of Chemical Industry.

Comprehensive dietary evaluation of Italian primary school children: food consumption and intake of energy, nutrients and phenolic compounds.

Information on children's diet including bioactive compounds is quite scarce. This observational study investigated the composition of the diet of children living in Parma (Italy; n = 172, 8-10 years) using 3-day food records completed in winter and spring. Mean daily intakes of food groups, energy and nutrients were obtained using the national food database, while (poly)phenol contents were estimated from Phenol-Explorer or by specific literature searches. Food consumption, energy and nutrient intakes decreased in spring and were partially in line with national data. Adherence to the nutritional recommendations was not satisfied for the majority of nutrients. Main contributors to the phenolic intake were flavonoids (flavan-3-ols) and phenolic acids (hydroxycinnamic acids), while main dietary sources were fruit, chocolate-based products, vegetables, and tea & coffee (decaffeinated). This study provided the first comprehensive analysis of the nutritional composition of children's diet. Future research should look at the health implications of dietary choices in children.

Free ferulic acid supplementation of heat-stressed hair ewe lambs: Oxidative status, feedlot performance, carcass traits and meat quality.

Twenty-two Katahdin × Dorper ewe lambs (average weight = 23.5 ± 2.8 kg) were individually housed during a 40-d feeding study and then slaughtered to evaluate effects of free ferulic acid (FA; 0 and 250 mg/kg of feed) on oxidative status, feedlot growth, carcass and non-carcass traits, wholesale cut yields and meat quality under heat stress conditions. Overall feeding FA decreased protein oxidation without affecting oxidative stress index, while growth rate and feed efficiency increased only in the hottest period (i.e., 28 to 45 °C). The FA supplementation increased kidney-pelvic-heart and mesenteric fat deposition, as well as yields of forequarter, shoulder, ribs, loin, and breast and flank, but decreased yields of hindquarter, neck, plain loin and leg. Carcass characteristics and meat quality were unaffected by FA. Overall, FA supplementation of heat-stressed hair ewe lambs enhanced feedlot performance under extreme heat stress and increased internal fat reserves, while changing muscle mass deposition, possibly because it prevented protein oxidation.

Hydroxycinnamic Acid from Corncob and Its Structural Analogues Inhibit Aß40 Fibrillation and Attenuate Aß40-Induced Cytotoxicity.

The aggregation of amyloid-ß protein (Aß) is deemed a vital pathological feature of Alzheimer's disease (AD). Hence, inhibiting Aß aggregation is noticed as a major tactic for the prevention and therapy of AD. Hydroxycinnamic acid, as a natural phenolic compound, is widely present in plant foods and has several biological activities including anti-inflammation, antioxidation, and neuroprotective effects. Here, it was found that hydroxycinnamic acid and its structural analogues (3-hydroxycinnamic acid, 2-hydroxycinnamic acid, cinnamic acid, 3,4-dihydroxycinnamic acid, 2,4-dihydroxycinnamic acid, and 3,4,5-trihydroxycinnamic acid) could inhibit Aß40 fibrillogenesis and reduce Aß40-induced cytotoxicity in a dose-dependent manner. Among these small molecules investigated, 3,4,5-trihydroxycinnamic acid is considered to be the most effective inhibitor, which reduces the ThT fluorescence intensity to 30.79% and increases cell viability from 49.47 to 84.78% at 200 µM. Also, the results with Caenorhabditis elegans verified that these small molecules can ameliorate AD-like symptoms of worm paralysis. Moreover, molecular docking studies showed that these small molecules interact with the Aß40 mainly via hydrogen bonding. These results suggest that hydroxycinnamic acid and its structural analogues could inhibit Aß40 fibrillogenesis and the inhibition activity is enhanced with the increase of phenolic hydroxyl groups of inhibitors. These small molecules have huge potential to be developed into novel aggregation inhibitors in neurodegenerative disorders.

Pharmacokinetic Study of Ferulic Acid Following Transdermal or Intragastric Administration in Rats.

Ferulic acid is contained in some Chinese herbal medicines such as Ligusticum chuanxiong or Angelica sinensis. Studies have focused on the treatment of inflammatory diseases and pain using ferulic acid. However, little is known about its pharmacokinetics after transdermal administration. The present research investigated the pharmacokinetic behavior of ferulic acid in rat plasma and skin microdialysate after ferulic acid transdermal or intragastric administration. Samples collected at predetermined time points were determined by a simple and sensitive HPLC-UV method. The pharmacokinetic parameters were estimated using non-compartmental analysis with DAS 2.0 software. The values of AUC0-t and Cmax after intragastric administration (20 mg/kg) in plasma were 281.47 ± 46.76 min mg/L and 12.20 ± 2.46 mg/L, respectively. After emulsion transdermal administration (117 mg/kg, 35 mg/4 cm2), the values of AUC0-t and Cmax in plasma and skin microdialysate were 953.90 ± 175.30 min mg/L, 7630.47 ± 1410.33 min mg/L, 3.00 ± 0.61 mg/L, and 19.08 ± 4.39 mg/L, respectively. Here, we show a promising delivery system for ferulic acid that could replace traditional administration, and a better understanding of the transdermal pharmacokinetics of ferulic acid, which may be helpful for further clinical and laboratory studies.

Danggui Buxue decoction ameliorates lipid metabolic defects involved in the initiation of diabetic atherosclerosis; identification of active compounds.

OBJECTIVE: To determine the constituent compounds of Danggui buxue decoction (DBD) involved and the potential mechanisms mediating its effects, with specific reference to lipids playing a role in the initiation of diabetic atherosclerosis. METHODS: Liquid chromatography-tandem mass spectrometry was used to identify and quantify the absorbed bioactive compounds (ABCs) present in DBD. Goto-Kakizaki (GK) rats were randomly allocated to a diabetes atherosclerosis (DA) group, a DBD group, and an ABC group (10 per group), which were all high-fat diet-fed. The treated rats were administered DBD (4 g/kg) or ABCs (in amounts equal to those present in DBD) once daily for 28 d, and a control group of Wistar rats were administered vehicle. Body mass gain, fasting blood glucose, and homeostasis assessment of insulin resistance (HOMA- IR) were measured. Serum triglyceride (TG), cholesterol (CHOL), high density lipoprotein-cholesterol (HDL-C), low-density lipoprotein-cholesterol (LDL- C) and tumor necrosis factor-α (TNF-α) concentrations were determined. Hematoxylin and eosin staining and microscopy were used to characterize the abdominal aorta and the expression of lipogenic genes was quantified in this vessel. RESULTS: Seven ABCs were identified in rat serum: ferulic acid, formononetin, calycosin, astragaloside, caffeic acid, ligustilide, and butyphthalide. DBD significantly reduced HOMA-IR, the serum concentrations of TG, CHOL, and LDL-C, and the expression of the lipogenic genes monocyte chemotactic protein 1, Fas, intercellular adhesion molecule 1, and Cd36 in aorta; and significantly increased the mRNA expression of Scd1 in aorta. CONCLUSION: DBD affects lipid metabolism in the early stage of atherosclerosis in diabetic GK rats, with the mechanism likely involving the regulation of lipid metabolic genes in vessels. The contribution of ABCs to the effect of DBD on lipid metabolism was 24%-101%.

Specific Dietary (Poly)phenols Are Associated with Sleep Quality in a Cohort of Italian Adults.

BACKGROUND: Diet has been the major focus of attention as a leading risk factor for non-communicable diseases, including mental health disorders. A large body of literature supports the hypothesis that there is a bidirectional association between sleep and diet quality, possibly via the modulation of neuro-inflammation, adult neurogenesis and synaptic and neuronal plasticity. In the present study, the association between dietary total, subclasses of and individual (poly)phenols and sleep quality was explored in a cohort of Italian adults. METHODS: The demographic and dietary characteristics of 1936 adults living in southern Italy were analyzed. Food frequency questionnaires (FFQs) were used to assess dietary intake. Data on the (poly)phenol content in foods were retrieved from the Phenol-Explorer database. The Pittsburg Sleep Quality Index was used to measure sleep quality. Multivariate logistic regression analyses were used to test the associations. RESULTS: A significant inverse association between a higher dietary intake of lignans and inadequate sleep quality was found. Additionally, individuals with the highest quartile of hydroxycinnamic acid intake were less likely to have inadequate sleep quality. When individual compounds were taken into consideration, an association with sleep quality was observed for naringenin and apigenin among flavonoids, and for matairesinol among lignans. A secondary analysis was conducted, stratifying the population into normal weight and overweight/obese individuals. The findings in normal weight individuals showed a stronger association between certain classes of, subclasses of and individual compounds and sleep quality. Notably, nearly all individual compounds belonging to the lignan class were inversely associated with inadequate sleep quality. In the overweight/obese individuals, there were no associations between any dietary (poly)phenol class and sleep quality. CONCLUSIONS: The results of this study suggest that a higher dietary intake of certain (poly)phenols may be associated with better sleep quality among adult individuals.

Phenolic Acid Subclasses, Individual Compounds, and Breast Cancer Risk in a Mediterranean Cohort: The SUN Project.

BACKGROUND: Biological and epidemiological evidence supports an inverse association of phenolic acids with obesity-related chronic diseases. However, no previous study has prospectively evaluated the relationship between subclasses and individual compounds of phenolic acids and the risk of postmenopausal breast cancer, one of the most important and prevalent obesity-related cancer sites. OBJECTIVE: This study examined associations between subclasses of phenolic acids, including hydroxycinnamic and hydroxybenzoic acids intake, and risk of breast cancer. DESIGN: The Seguimiento Universidad de Navarra (SUN) Project is a dynamic, permanently open prospective cohort which started in 1999. PARTICIPANTS/SETTING: Participants were 10,812 middle-aged women. All of them were university graduates. MAIN OUTCOME MEASURES: Usual diet was assessed at baseline and after 10 years of follow-up with a 136-item food frequency questionnaire. Phenolic acid intake was calculated by matching food consumption with the Phenol-Explorer database on phenolic acids content of each reported food item. STATISTICAL ANALYSIS PERFORMED: Participants were classified according to tertiles of subclasses or individual compounds of phenolic acids. Cox regression models were fitted to estimate multivariable-adjusted hazard ratios and 95% CIs for breast cancer incidence. RESULTS: Over an average of 11.8 years of follow-up, 101 incident cases of breast cancer were confirmed. After multivariable adjustment, an inverse association between hydroxycinnamic acids intake and breast cancer was observed (hazard ratio third tertile vs first tertile 0.37, 95% CI 0.16 to 0.85; P for trend=0.029) among postmenopausal women. Specifically, chlorogenic acids (3-, 4-, and 5- caffeoylquinic acids) showed the strongest inverse association (hazard ratio third tertile vs first tertile 0.33, 95% CI 0.14 to 0.78; P for trend=0.012). CONCLUSIONS: A higher intake of hydroxycinnamic acids, especially from chlorogenic acids-present in coffee, fruits, and vegetables-was associated with a lower incidence of breast cancer among postmenopausal women. Future observational studies are needed to corroborate these results.

Pharmacokinetic comparative study of tetramethylpyrazine and ferulic acid and their compatibility with different concentration of gastrodin and gastrodigenin on blood-stasis migraine model by blood-brain microdialysis method.

Tianma pills, a traditional formula made from Ligusticum chuanxiong and Gastrodia elata, are efficacious for the treatment of primary headache. Tetramethylpyrazine (TMP) and Ferulic acid (FA) are the bioactive ingredients of Ligusticum chuanxiong, while Gastrodin and Gastrodigenin are the bioactive ingredients of Gastrodia elata. Pharmacokinetic assessment of TMP, FA, gastrodin or gastrodigenin in blood or brain interstitial fluid (BIF) has been reported in healthy animals. However, the pharmacokinetic properties of TMP and FA have not been studied when they are co-administered in a blood-stasis migraine model. The present research investigated the pharmacokinetic behavior of TMP and FA after oral administration in the presence of different concentrations of gastrodin and gastrodigenin in a blood-stasis migraine model. Pharmacokinetic parameters were determined using blood-brain microdialysis in combination with the UHPLC-MS method. Compared to the control group, in which TMP and FA were administrated without gastrodin or gastrodigenin, the T1/2, MRT, Cmax and AUC0-∞ of TMP and FA were increased. These results indicate that varying concentrations of gastrodin and gastrodigenin play an important role in affecting the pharmacokinetics of TMP and FA. Low concentrations of gastrodin and gastrodigenin (similar to those found in Tianma pills) were more efficacious, validating the utility of the ancient formulation.

Lactobacillus fermentum and/or ferulic acid improved the immune responses, antioxidative defence and resistance against Aeromonas hydrophila in common carp (Cyprinus carpio) fingerlings.

This study investigates the possible effects of using Lactobacillus fermentum (LF) and/or ferulic acid (FA) in common carp (Cyprinus carpio) on some immunological parameters as well as resistance against Aeromonas hydrophila. Four diets were prepared including control diet and three diets supplemented with LF (108 CFU/g), FA (100 mg kg-1) or LF + FA (108 CFU/g + 100 mg kg-1). After 8 weeks, fish fed LF or/and FA had significantly higher final body weight, weight gain, and specific growth rate when compared to control group (P < 0.05). The feed conversion ratio of fish fed LF or/and FA were noticeably lower than control (P < 0.05). No alterations were observed in case of haematological parameters except red blood cells (RBCs), white blood cells (WBCs), hemoglobin (Hb), and hematocrit (HCT) which were significantly (P < 0.05) increased in fish fed FA or those fed both LF and FA. Also, the WBCs of fish treated with LF or/and FA were noticeably higher than control (P < 0.05). Feeding on LF and FA notably increased the serum total protein and albumin levels (P < 0.05). The serum respiratory burst and lysozyme activity were also enhanced (P < 0.05) in fish fed both LF or/and FA. In addition, evaluation of the serum antioxidant enzymes (catalase, glutathione peroxidase (GPX), and superoxide dismutase (SOD)) activity showed significant (P < 0.05) increase in fish fed FA or both LF and FA as compared to the control. Fish fed LF and FA supplemented diet had highest survival rate after experimental challenge with pathogenic A. hydrophila. The obtained results revealed that LF and/or FA can be used as beneficial feed additive to improve the immune responses and disease resistance in early stages of common carp culture.

p-Coumaric-Acid-Containing Adenostemma lavenia Ameliorates Acute Lung Injury by Activating AMPK/Nrf2/HO-1 Signaling and Improving the Anti-oxidant Response.

Adenostemma lavenia is a perennial herb belonging to the Compositae family and is widely distributed in the tropical parts of Asia. It has been widely used as medicine in Taiwan with the whole plant used to treat pulmonary congestion, pneumonia, bacterial infections of the respiratory tract, edema, and inflammation. This study sought to investigate the anti-inflammatory effects of A. lavenia in vitro and in animal models. The anti-inflammatory effects of ethyl acetate fractions of A. lavenia (EAAL) were stimulated with lipopolysaccharide (LPS) murine macrophages (RAW 264.7) and lung injury in mice. EAAL reduced proinflammatory cytokine responses. Preoral EAAL alleviated LPS-induced histological alterations in lung tissue and inhibited the infiltration of inflammatory cells and protein concentrations in bronchoalveolar lavage fluid (BALF). EAAL prevented protein expression of inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2); phosphorylation of IκB-α, MAPKs, and AMP-activated protein kinase (AMPK); and activated anti-oxidant enzymes (catalase, SOD, and GPx), heme oxygenase-1 (HO-1), and nuclear factor E2-related factor 2 (Nrf2) in LPS-stimulated cells and lung tissues. Fingerprinting of EAAL was performed with HPLC to control its quality, and p-coumaric acid was found to be a major constituent. This study suggests that EAAL is a potential therapeutic agent to treat inflammatory disorders.

Impact of Foods and Dietary Supplements Containing Hydroxycinnamic Acids on Cardiometabolic Biomarkers: A Systematic Review to Explore Inter-Individual Variability.

Plant-based diets rich in bioactive compounds such as polyphenols have been shown to positively modulate the risk of cardiometabolic (CM) diseases. The inter-individual variability in the response to these bioactives may affect the findings. This systematic review aimed to summarize findings from existing randomized clinical trials (RCTs) evaluating the effect of hydroxycinnamic acids (HCAs) on markers of CM health in humans. Literature searches were performed in PubMed and the Web of Science. RCTs on acute and chronic supplementation of HCA-rich foods/extracts on CM biomarkers were included. Forty-four RCTs (21 acute and 23 chronic) met inclusion criteria. Comparisons were made between RCTs, including assessments based on population health status. Of the 44 RCTs, only seven performed analyses on a factor exploring inter-individual response to HCA consumption. Results demonstrated that health status is a potentially important effect modifier as RCTs with higher baseline cholesterol, blood pressure and glycaemia demonstrated greater overall effectiveness, which was also found in studies where specific subgroup analyses were performed. Thus, the effect of HCAs on CM risk factors may be greater in individuals at higher CM risk, although future studies in these populations are needed, including those on other potential determinants of inter-individual variability. PROSPERO, registration number CRD42016050790.

Wheat Flour, Enriched with γ-Oryzanol, Phytosterol, and Ferulic Acid, Alleviates Lipid and Glucose Metabolism in High-Fat-Fructose-Fed Rats.

(1) Background: Modern dietary patterns with a high intake of fat and fructose, as well as refined carbohydrates, closely relate to lipid/glucose metabolic disorders. The main objective of this study is to provide new thoughts in designing functional food with some lipid/glucose metabolism regulating effects for obese people. (2) Methods: The alleviating abilities of γ-oryzanol, phytosterol or ferulic acid-enriched wheat flour on lipid/glucose metabolic dysfunction were evaluated in male SD rats induced by a high-fat-fructose diet. The underlying mechanisms were clarified using western blot. (3) Results: In an in vitro cell model, γ-oryzanol, phytosterol and ferulic acid regulate lipid/glucose metabolism by increasing the phosphorylation of AMPK and Akt, and PI3K expression, as well as decreasing expressions of DGAT1 and SCD. The in vivo study shows that ferulic acid and γ-oryzanol-enriched flours are beneficial for managing body weight, improving glucose metabolism, hyperlipidemia and hepatic lipid accumulation. Phytosterol-enriched flour exerted remarkable effects in regulating hyperinsulinemia, insulin resistance and hyperuricemia. Western blot analysis of proteins from liver samples reveals that these enriched flours alleviated hepatic lipid accumulation and insulin resistance through their elevation in the phosphorylation of AMPK and Akt. (4) Conclusions: Our study indicates that these enriched flours can serve as a health-promoting functional food to regulate obesity-related lipid/glucose metabolic dysfunction in rats.

Prolong treatment with Trans-ferulic acid mitigates bioenergetics loss and restores mitochondrial dynamics in streptozotocin-induced sporadic dementia of Alzheimer's type.

Alzheimer disease has been well associated with mitochondrial dysfunctions. Numerous studies have reported changes in the activity of oxidative phosphorylation (OXPHOS) complexes and mitochondrial dynamics. Recently, dynamin-related protein 1 (Drp-1) has been conceived as a potential therapeutic target as well. We have examined the effect of prolonged treatment of Trans-ferulic acid on streptozocin-induced sporadic dementia of Alzheimer's type. We have found the Ferulic Acid (FA,100 mg/kg) can rescue memory and learning problems and also show significant antioxidant effect while preserving morphology of pyramidal cell layer in hippocampi. Furthermore, FA treatment has shown mitigation in intracerebral-ventricular streptozocin (ICV-STZ) induced bioenergetics loss and dynamic changes by regulating peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1alpha) protein levels in nucleus and hence, mitigating exacerbation of Drp-1 dependent mitochondrial fission and apoptosis by alleviating loss of mitochondrial membrane potential (ΔΨm), downregulating cytochrome-c release into the cytosol by limiting mitochondrial permeability transition pore (mPTP) opening concomitant increase in caspase3 activation, BAX expression and DNA fragmentation along with downregulating glial fibrillary acidic protein (GFAP) expression. FA also restored protein expression of mitofusin2 (Mfn2) a core component of mitochondrial fusion, necessary for mitophagy. We conclude that FA acid may have the propensity to mitigate mitochondrial dysfunction in Alzheimer's disease on prolonging dietary supplementation.

Ferulic Acid Exerts Anti-apoptotic Effects against Ischemic Injury by Activating HSP70/Bcl-2- and HSP70/Autophagy-Mediated Signaling after Permanent Focal Cerebral Ischemia in Rats.

This study assessed the anti-apoptotic effects of the administration of ferulic acid (FrA) in rats 30 min before middle cerebral artery occlusion (MCAo) followed by 3 d of ischemia and the involvement of 70 kDa heat shock protein (HSP70)-mediated signaling in the penumbral cortex. Our results demonstrated that FrA pretreatment at doses of 80 mg/kg (FrA-80 mg) and 100 mg/kg (FrA-100 mg) effectively ameliorated neurological functions and reduced the numbers of cytochrome c-, cleaved caspase-3-, and terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL)-positive cells in the penumbral cortex 3 d after ischemia. Moreover, FrA-80 mg and FrA-100 mg pretreatment markedly upregulated cytosolic HSP70, Beclin-1, microtubule-associated protein 1 light chain 3 (LC3) A/B-II and autophagy-related protein 5 (Atg5) expression; cytosolic and mitochondrial X-linked inhibitor of apoptosis (XIAP) expression and the Bcl-2/Bax ratio. FrA pretreatment downregulated cytosolic cytochrome c, apoptosis-inducing factor (AIF), procathepsin B, and cathepsin B expression and mitochondrial and cytosolic second mitochondria-derived activator of caspase/direct inhibitor of apoptosis protein-binding protein with a low isoelectric point (Smac/DIABLO) expression in the penumbral cortex. Pretreatment with VER155008, a HSP70 family inhibitor, significantly inhibited the effects of FrA-100 mg on the expression of the aforementioned proteins expression in the penumbral cortex. FrA-80 mg and FrA-100 mg pretreatment exerts neuroprotective effects against caspase-dependent and -independent apoptosis through activating HSP70/Bcl-2- and HSP70/autophagy-induced signaling pathways. Furthermore, the HSP70/Bcl-2- and HSP70/autophagy-induced anti-apoptotic effects of FrA pretreatment can be attributed to the regulation of Bax/cytochrome c/Smac/DIABLO/XIAP/ caspase-3- (or Bax/AIF-) and Beclin-1/LC3A/B-II/Atg5-mediated signaling, respectively, in the penumbral cortex 3 d after permanent MCAo.