Table 2.
Biological activity of phenolic acids.1
| Test/Model | Microbial Metabolite | Concentration/Dose | Results | Ref. |
|---|---|---|---|---|
| Anti-adhesive activity | ||||
| Adherence of uropathogenic E. coli to T24 epithelial bladder cells | Catechol; BA; 3-HB; PCA; VA; GA; PA; 3-HPA; 3,4-DHPA; 3-PP; 3-HPP and 3,4-DHPP | 100–500 µM |
Catechol, BA, VA, PA and 3,4-DHPA inhibited E. coli adherence in a concentration-dependent manner. GA and PA had the strongest effect, followed by 3,4-DHPA. | [32] |
| Antidiabetic effects | ||||
| Glucose transport in human and murine 3T3-L1 adipocytes stimulated or not with insulin | PCA | 100 µmol/L | PCA reversed the oxLDL-induced drop in glucose uptake and GLUT4 translocation. PCA also prevented the oxLDL-induced reduction of adiponectin mRNA expression and secretion, as well of PPARγ mRNA expression and activity. | [33] |
| Beta cell function of rat INS-1E pancreatic beta cells and isolated rat pancreatic islets | 3,4-DHPA; 2,3-DHB and 3-HPP | 1–5 µM | 3,4-DHPA and 3-HPP significantly increased glucose-induced insulin secretion (5 and 1 µM, respectively). In presence of oxidative stress, 3,4-DHPA and 3-HPP reduced ROS and carbonyl group production, and glucose-stimulated insulin secretion was restored to control levels. The phosphorylation of PKC and ERKs was enhanced. | [34] |
| Beta cell function of Min6 pancreatic beta cells incubated with cholesterol | 3,4-DHPA | 10–250 µM | 3,4-DHPA prevented impaired insulin secretion induced by cholesterol by protecting pancreatic beta cells against oxidative stress, apoptosis and mitochondrial dysfunction. | [35] |
| Insulin signalling and glucose uptake and production in rat renal NRK-52E cells | 2,3-DHB; 3,4-DHPA; 3-HPP and VA | 20 µM | Glucose uptake and production decreased after treatment with 2,3-DHB, and PEPCK levels as well. IR and IRS-1 phosphorylated and total protein levels were increased. The inhibition of the PI3K/Akt pathway was restrained. | [36] |
| Insulin signalling and glucose uptake and production in rat renal NRK-52E cells treated with high glucose | 3,4-DHPA; 2,3-DHB and 3-HPP | 10 µM | 3,4-DHPA restored the altered glucose uptake and production caused by high glucose, and tyrosine phosphorylated and total levels of IR increased. The PI3K/Akt pathway and AMPK were activated, while the PEPCK expression was decreased. | [37] |
| Beta cell function and glucose utilization in human skeletal muscle and rat INS-1 beta cells | HA; HVA and 5-PVA | 5–100 µM | HA and 5-PVA stimulated glucose oxidation in skeletal muscle and preserved skeletal mitochondrial function after oxidative insult. In beta cells, all metabolites induced glucose-stimulated insulin secretion without affecting beta cell mitochondrial respiration or electron transport chain components’ expression. | [38] |
| Antiglycative activity | ||||
| Formation of AGEs in BSA/glucose system and glyoxal trapping ability | PG; 3,4-DHPP; DHFA; 3-HPA; 3,4-DHPA and HVA | 2.0–50 µmol/L | Only DHFA at 10 µmol/L had a significant impact inhibiting albumin glycation, and a combination of 3-HPA, 3,4-DHPA and HVA inhibited glycation at 2.0 µmol/L. PG, 3,4-DHPP and 3,4-DHPA showed a glyoxal trapping ability of approximately 60%, 90% and 65%, respectively. | [39] |
| Formation of AGEs in BSA/glucose and BSA/MGO systems | 3,4-DHPA; 3-HPA and HVA | 1 mM | The order of inhibitory activity against AGEs was: rutin > quercetin > 3,4-DHPA > aminoquanidine > 3-HPA > HVA | [40] |
| Anti-inflammatory activity | ||||
| NO production in LPS-activated RAW264.7 cells | 3-HPP; CA and 3,4-DHPP | IC50 = 224.85–689.91 µM | CA and 3,4-DHPP inhibited the NO production significantly stronger than 3-HPP. | [41] |
| Inflammatory response in LPS-stimulated human THP-1 monocytic cells | 4-HBA; BA-glucuronide; BA-sulfate; PCA; PCA-3-glucuronide; PCA-4-glucuronide; PCA-3-sulfate; PCA-4-sulfate; VA; VA-glucuronide and VA-sulfate | 0.1–10 µM | LPS-induced TNF-α secretion was inhibited by BA-sulfate, VA-glucuronide and PCA-3-sulfate, as well as by four combinations of metabolites that included 4-HBA and/or PCA with a stronger effect than the individual metabolites. 4-HBA significantly reduced IL-1ß secretion. | [42] |
| Inflammatory response in LPS-stimulated BV2 microglia | PCA | 5–20 µM | PCA dose-dependently inhibited LPS-induced TNF-α, IL-6, IL-1ß and PGE2 production, and suppressed LPS-induced TLR4 expression, NF-κB and MAPKs activation. | [43] |
| Inflammatory response in LPS-stimulated human gingival fibroblasts | PCA | 5–20 µM | PCA inhibited LPS-induced IL-6 and IL-8 production and NF-κB activation. PPAR-γ antagonist GW9662 reversed the prevention of IL-6 and IL-8 production by PCA. | [44] |
| Colitis mice model induced by 2,4,6-trinitrobenzenesulfonic acid (TNBS) | PCA | 30 and 60 mg/kg | PCA improved TNBS-induced colitis in mice, reduced the GSSG/GSH ratio and expression of proinflammatory cytokines, and increased the expression of antioxidant enzymes and Nrf2. The SphK/S1P axis and the related NF-κB and STAT3 signaling pathway were abrogated. | [45] |
| NO production in LPS-Stimulated RAW 264.7 macrophages and dendritic D2SC/I cells | p-CoA; HVA; 4-HB; HA; FA; PCA; CA; VA; 3-HPA; 3,4-DHPA | 0.1–100 µM | CA, 3,4-DHPA and PCA were the most active metabolites inhibiting NO production in RAW 264.7 cells. In D2SC/I cells, 3,4-DHPA, CA, and p-CoA were the most potent metabolites. | [46] |
| Inflammatory response of HIEC-6 human intestinal epithelial cells after IL-1β-induced ulcerative colitis, and of mice after TNBS-induced ulcerative colitis | GA | 20–60 mg/kg | Anti-inflammatory cytokines (IL-4 and IL-10) increased and the proinflammatory ones (IL-1, IL-6, IL-12, IL-17, IL-23, TGF-β and TNF-α) decreased in HIEC-6 cells and in mice. Apoptosis was reduced in GA treated groups and the colonic inflammation in mice was attenuated. GA inhibited NF-κB activation. | [47] |
| Antioxidant activity | ||||
| DPPH radical scavenging activity | 3-HPP; CA and 3,4-DHPP | IC50 = 5.02–5.91 µM | CA and 3,4-DHPP had the stronger scavenging radical activity, while 3-HPP had no antioxidant activity. | [41] |
| ABTS assay | 4-HPA; 3,4-DHPA; PCA; 2,3-DHB; PG and GA | IC50 = 4.332–852.713 µM | The ability to scavenge 50% of free radical ABTS• + was stronger for GA, PG and 3,4-DHPA but weaker for 4-HPA. | [48] |
| Ferric-reducing antioxidant potential (FRAP) | 4-HPA; 3,4-DHPA; PCA; 2,3-DHB; PG and GA | 1.00 x 10-3 mg/mL | The strongest antioxidant activity was shown by 3,4-DHPA, PG, GA and PCA. | [48] |
| DPPH radical scavenging activity | 3,4-DHPA; 3-HPA and HVA | 1 mM | The order of antioxidant activity was: quercetin > rutin = 3,4-DHPA > HVA >> 3-HPA. | [40] |
| Ferric-reducing antioxidant potential (FRAP) | 3,4-DHPA; 3-HPA and HVA | 1 mM | The order of reducing activity was: quercetin > HVA > 3,4-DHPA > rutin >> 3-HPA. | [40] |
| Cyclic voltammetry (CV) | 3,4-DHPA; 3-HPA and HVA | 1 mM | The order of reducing activity was: quercetin > rutin > 3,4-DHPA > HVA > 3-HPA. | [40] |
| Ferrozine assay | 3,4-DHPA; 3-HPA and HVA | 1 mM | The order of chelating activity was: rutin > quercetin > HVA >> 3-HPA >> 3,4-DHPA. | [40] |
| DPPH radical scavenging assay | 3,4-DHPA; 3-HPA; PCA and HA | 2–10 µM | The order of antioxidant activity was: 3,4-DHPA = quercetin > PCA > 3-HPA ≅ HA. | [49] |
| Superoxide scavenging assay | 3,4-DHPA; 3-HPA; PCA and HA | 50 µM | The order of superoxide scavenging activity was: quercetin > 3,4-DHPA > PCA >> 3-HPA ≅ HA. | [49] |
| DPPH radical scavenging assay | 3,4-DHPA; p-CoA; VA and FA | 25 µM | The order of antioxidant activity was: 3,4-DHPA > VA > FA > p-CoA. | [50] |
| Ferric-reducing antioxidant potential (FRAP) | 3,4-DHPA; p-CoA; VA and FA | 5 µM | The order of reducing activity was: 3,4-DHPA > VA > FA > p-CoA. | [50] |
| ABTS assay | 3,4-DHPA; p-CoA; VA and FA | 5 µM | The order of antioxidant activity was: 3,4-DHPA > FA > p-CoA > VA. | [50] |
| ORAC assay | 3,4-DHPA; p-CoA; VA and FA | 3 µM | The order of antioxidant activity was: p-CoA > 3,4-DHPA > VA > FA. | [50] |
| Anti-proliferative activity and cytotoxicity | ||||
| Apoptosis and cellular oxidative stress of oxLDL-exposed J774A.1 cells | PCA | 25 µM | OxLDL-induced cell death was prevented, as well as ROS production and GSH depletion. The activation of p53 was prevented, and therefore the overexpression of p53-target genes decreased. p38MAPK and PKC∂ activation was reversed. PCA induced JNK activation and increased nuclear Nrf2 content. | [51] |
| TGF-ß1-induced proliferation and migration of human airway smooth muscle cells (ASMCc) | PCA | 1–50 nM | PCA inhibited the proliferation and migration of ASMCs and the expression of type I collagen and fibronectin. The Smad2/3 activation in ASMCs exposed to TGF-ß1 was downregulated. | [52] |
| Cardiovascular protective effect | ||||
| Antithrombotic efficacy under high shear stress in vitro in human platelets as well as in an in vivo arterial thrombosis model | PCA | 5–25 µM | PCA significantly decreased stress-induced platelet aggregation by blocking the interaction between von Willebrand factor (vWF) and glycoprotein Ib. Intracellular calcium increase was attenuated, shear-induced granular secretion from dense and α-granules was inhibited and glycoprotein IIb/IIIa activation was attenuated. The antithrombotic effects of PCA were confirmed in vivo. | [53] |
| Cardiac function and cardiac autonomic balance in STZ-induced diabetic rats | PCA | 50 and 100 mg/kg | %FS and %LVEF increased and LF:HF decreased compared with untreated diabetic rats. Plasma HbA1c decreased as well as cardiac MDA and cardiac mitochondrial ROS. Mitochon-drial membrane depolarization and swelling was prevented and cardiac anti-apoptotic BCL2 protein levels increased | [54] |
| Vasodilation of pre-contracted isolated aortic rings; blood pressure in normotensive and spontaneously hypertensive rats | 3-PP; 4-HPP; 3,4-DHPP; 4-HPA; 3,4-DHPA; HVA; 3-HB; PhG; 4-MC; m-CoA; 3-HPP and 3-HPA | 100 nM; 2.5–25 mg/kg and 5 mg/kg/50 µL/min |
3-HPP had the highest vasodilatory activity, which was NO and endothelium-dependent. In vivo, 3-HPP lowered arterial blood pressure in normotensive and spontaneously hypertensive rats. | [55] |
| Diabetic cardiomyopathy in type 2 diabetic rats | PCA | 50 and 100 mg/kg | PCA was protective against diabetic cardiomyopathy through hypoglycemic, insulin-sensitizing, anti-inflammatory and antioxidant effects. | [56] |
| Insulin-stimulated NO production by human aortic endothelial cells under high glucose conditions | 3-HPP | 1 µM | Under glucotoxic conditions, 3-HPP preserved insulin-stimulated increases in NO production, and phosphorylation of Akt and eNOS. The rise in ROS and RNS was prevented. | [57] |
| Endothelial function and oxidative stress in human Ea.hy926 endothelial cells | 3,4-DHPA; 2,3-DHB and 3-HPP | 10–12 µM | 3,4-DHPA and a mix of the metabolites increased the NO generation and phosphorylation of eNOS, Akt and AMPK. Under oxidative stress, metabolites enhanced cell viability and prevented reduced eNOS phosphorylation. ROS generation and phosphorylation of ERK and JNK were prevented. | [58] |
| Relaxation of pre-contracted rat artery rings and blood pressure in spontaneously hypertensive rats | 3,4-DHPA; 4-MC and 3-HPP | EC50 = 22.4–49.1 µM; 0.5–25 mg/kg and 5 mg/kg/min |
The vasorelaxant activity of 3,4-DHPA and 4-MC was similar in aorta and mesenteric artery. The effect of 3,4-DHPA depended on endothelium, NO, prostaglandin and Ca2+-activa-ted K+ channels. Both metabolites dose-dependently decreased blood pressure after bolus and infusion administration. | [59] |
| Whole blood platelet aggregation induced by arachidonic acid and ex ovo hen’s egg model of thrombosis | 4-MC and PG | IC50 = 3–25 µM; 5 mM |
PG showed a comparable anti-platelet effect to that of acetylsalicylic acid, while that of 4-MC was significantly lower. 4-MC interfered with calcium intracellular signalling, being this the possible mechanism of action. In the ex vivo experiment, the anti-platelet effect of 4-MC was confirmed by significantly increasing the survival of the eggs. | [60] |
| Chemopreventive effect | ||||
| ATP production by HCT-116 colon cancer cells | 3,4-DHPA; 3-HPA; 4-HPA; HVA and 3-OMGA | IC50 = 260 µmol/L | 3-OMGA inhibited cell proliferation. Combining 3,4-DHPA (100, 200 and 300 µmol/L) and EGCG (40 µmol/L) increased the anti-proliferative effect compared to individual treatments. | [61] |
| Apoptosis of HT-29 colon cancer cells | 4-HPA and VA | 100 µM | 4-HPA enhanced the late-stage apoptosis and the percentage of dead cells compared to control cells. | [62] |
| Angiogenesis in HUVEC cells treated with VEGF and in zebrafish model | PCA | 6.25–100 μM; 25 µM |
PCA inhibited the proliferation, migration, invasion and capillary structure formation of HUVECs, and blocked the VEGFR2-dependent Akt/MMP2 and ERK pathways. In vivo, the anti-angiogenic effect of PCA was possibly due to downregulation of VEGFα-VEGFR2 and Ang2-Tie2 pathways. | [63] |
| Proliferation and apoptosis of HT-29 colon cancer cells | 3,4-DHPA; p-CoA; VA and FA | 0.1–100 µM | 3,4-DHPA had the strongest effect reducing cell viability. All metabolites reduced cell number in S phase, and p-CoA and FA increased apoptosis. | [50] |
| Proliferation, cell-cycle arrest and apoptosis of Caco-2 cell | CA; 3-PP and BA | 100–1000 µM and EC50 = 460–500 µM | Only CA reduced cell proliferation by 50%, while 3-PPA and BA decreased it at 1000 μM. CA and 3-PP induced cell-cycle arrest at the S-phase. CA activated caspase-3 and 3-PPA decreased mitochondrial DNA content. | [64] |
| Apoptosis and autophagy in OVCAR-3 ovarian cancer cells | PCA | 5–30 µM | PCA inhibited cell proliferation by inducing apoptosis and autophagy. PCA modulated proapoptotic and anti-apoptotic proteins (Bax, Bcl-2, PARP and caspase-3) and upregulated autophagy-related protein LC3-II. | [65] |
| Modulation of drug metabolizing enzymes | ||||
| GSTT2 and COX-2 expression in LT97 human colorectal adenoma cells | 3,4-DHPA and 3,4-DHPP | 2.5–25 µM | GSTT2 mRNA expression was enhanced up to 1.8-fold. COX-2 mRNA and protein expression were reduced, as well as CumOOH-induced DNA damage. | [66] |
| Gene expression of drug-metabolizing enzymes in Hepa1c1c7 mouse hepatoma cells | 3,4-DHPA; 3-HPA; PCA and HA | 5–250 µM | 3,4-DHPA increased GCLC, HO-1, NQO1, xCT and CYP1A1 gene expression. PCA at 50 µM increased the gene expression of NQO1. Peroxide-induced cytotoxicity was inhibited. | [49] |
| Acetaminophen-induced liver injury in mice | 3,4-DHPA | 10–50 mg/kg | Acetaminophen-induced hepatotoxicity was attenuated by 3,4-DHPA. Nrf-2 translocation to the nucleus was increased, as well as the expression of phase-II (UGT, SULT, GCLC and GCLM) and antioxidant enzymes. | [67] |
| ALDH activity and gene expression in Hepa1c1c7 mouse hepatoma cells | 3,4-DHPA | 5–50 µM | Concentration-dependent enhancement of the ALDH activity, as well as expression of ALDH1A1, ALDH2 and ALDH3A. Nuclear levels of Nrf2 and AhR increased significantly at 20 µM, while those of NF-κB decreased. | [68] |
| Menadione-induced liver damage in rats | PCA | 10 and 20 mg/kg | PCA prevented menadione mediated-alterations in hepatocellular markers and it also increased the activities of antioxidant enzymes (SOD and CAT) and phase II detoxifying enzymes (GST and NQO-1), and Nrf-2. | [69] |
| Modulation of intestinal microbiota | ||||
| Alteration of the composition in fecal microbiota of ApoE-/- mice fed on a high-fat diet | FA | 30 mg/kg | FA significantly lowered the ratio of Firmicutes to Bacteroidetes when compared to obese control group. | [70] |
| Growth inhibition of pathogenic and probiotic bacteria | GA; VA; FA and PCA | MIC = 20–35 mmol/L MBC = 20–30 mmol/L |
MIC against E.coli and Staphylococcus Typhimurium was similar among metabolites (15-20 mmol/L). VA and PCA had the lowest MBC (20 mmol/L). Lactobacillus acidophilus and L. rhamnosus were also inhibited but at higher concentrations (MIC > 35 mmol/L) and their MBC was also > 35 mmol/L. | [71] |
| Modulation of lipid metabolism | ||||
| Lipid metabolism in HFD-induced obesity in mice | FA | 25 and 50 mg/kg | FA reduced serum TC, TG and NEFA levels as compared to the obese control mice. Liver TC and TG significantly decreased as well. SREBP1c, FAS and ACC were reduced, while CPT1a and PPARα were up-regulated. | [72] |
| Lipid metabolism in HFD-induced obesity in mice | FA | 30 mg/kg | Serum TC, TG and LDL-C decreased when compared to obese control group, and liver TC and TG levels as well. FA significantly increased the mRNA expression of AHR and decreased that of FAS and SREBP-1c. | [70] |
| Neuroprotective effect | ||||
| Human neuroblastoma SK-N-MC cell viability after DMNQ-induced oxidative stress | PG; 3,4-DHPP; DHFA; 3-HPA; 3,4-DHPA and HVA | 0.1–20 µmol/L | The greatest increase in cell survival was induced by DHFA, followed by PG and 3,4-DHPA. Combination of metabolites also increased cell survival after oxidative stress. | [39] |
| Type 2 diabetes-induced neurodegeneration in rats | GA and p-CoA | 20–40 mg/kg | Treatment of diabetic rats with GA and p-CoA enhanced the histology of the hippocampus and glucose tolerance, prevented brain oxidative stress, improved antioxidant status, reduced inflammation and inhibited apoptosis. | [73] |
| Neuroinflammation model based on SIN-1 stress-induced injury in human SH-SY5Y neuroblastoma cells | 3,4-DHPA; 3-HPP and 3-HPA | 0.1–10 µM | Metabolites increased cell viability, probably through inhibition of ERK1/2, modulation of p38 MAPK kinases (3-HPA), and reduction of caspase-3 activation (3-HPP). | [74] |
| Apoptosis of human SH-SY5Y neuroblastoma cells previous or during H2O2 exposition. | 3,4-DHPP; 3,4-DHPA and GA | 5–10 µM | All metabolites decreased late apoptosis, but 3,4-DHPP had the strongest effect. ROS levels decreased and REDOX activity increased. All metabolites attenuated H2O2-induced activation of caspases-3 and -9. | [75] |
| Apoptosis of rat cerebellar granule neurons under H2O2-induced oxidative stress, nitrosative stress and excitotoxicity | 4-HBA and PCA | 10–300 µM | Both 4-HBA and PCA mitigated oxidative stress induced by H2O2. Under conditions of nitrosative stress only PCA was neuroprotective, but under conditions of excitotoxicity only 4-HBA reduced cell death. | [76] |
| Ischemia-induced hippocampal neuronal death in rats | PCA | 30 mg/kg | PCA decreased neuronal cell death, oxidative stress, microglial activation, astrocyte activation and BBB disruption compared with the control group after ischemia. GSH glutathione reduced concentration was recovered. | [77] |
| Lysolecithin (LPC)-induced model of inflammation in mouse hippocampal neurons co-cultured with glial cells | GA and VA | 0.2–1 µM | GA and VA increased neurite outgrowth and upregulated myelin protein in neurites and oligodendrocyte cell bodies. COX-2, NFκB, TN-C, CSPGs and GFAP expression in astrocytes decreased. GA and VA reversed the reduction in sustained repetitive firing induced by LPC. | [78] |
| Osteoprotective effects | ||||
| Osteoclast differentiation and function in mouse bone marrow macrophages treated with RANKL; inflammatory bone destruction in LPS-treated mice | PCA | 25 µM; 25 mg/kg |
PCA inhibited osteoclastogenesis and the bone-resorbing activity of mature osteoclasts. LPS-mediated bone loss in vivo was also restored by PCA. | [79] |
| Osteoclast differentiation and apoptosis in RAW264.7 murine macrophage cells treated with RANKL | PCA | 8 µM | PCA inhibited osteoclast differentiation by regulating oxidative stress and inflammation, and induced apoptosis in mature osteoclasts by inducing mitochondrial membrane potential, Cyt c release and caspase activation. | [80] |
| Renoprotective effects | ||||
| Redox status in high-glucose-exposed rat renal proximal tubular NRK-52E cell | 3,4-DHPA | 10 µM | 3,4-DHPA reversed the increase in ROS levels and the decreased antioxidant defense. SIRT-1 increased, and the high glucose-induced increase of phosphorylated MAPKs and NOX-4 were restored. | [81] |
| Extracellular matrix accumulation in high glucose-induced human mesangial cells | PCA | 5 and 10 µM | PCA inhibited high glucose-induced proliferation of mesangial cells and protected them against high glucose damage inhibiting the p38 MAPK signaling pathway. | [82] |
1ABTS: 2-azinobis-(3-ethylbenzothiazoline-6-sulphonate) radical cation; AGE: advanced glycation end-products; Akt: protein kinase B; ALDH: aldehyde dehydrogenase; AMPK: adenosine monophosphate-activated protein kinase; Ang2: angiotensin-2; AR: androgen receptor; BBB: blood-brain barrier; Bcl-2: B-cell lymphoma 2; BSA: bovine serum albumin; CAT: catalase; COX-2: cyclooxygenase-2; CSPG: chondroitin sulfate proteoglycans; CYP1A1: cytochrome P450 1A1; DMNQ: 2,3-dimethoxy-1,4-naphtoquinone; DMSO: dimethyl sulfoxide; DPPH: 2,2-diphenyl-1-picrylhydrazyl radical; EC50: half maximal effective concentration; eNOS: endothelial nitric oxide synthase; ERK: extracellular signal–regulated kinases; FS: fractional shortening; GCLC: glutamate-cysteine ligase catalytic subunit; GCLM: glutamate-cysteine ligase modifier subunit; GFAP: glial fibrillary acidic protein; GLUT: glucose transporter; GPx: glutathione peroxidase; GSH: glutathione; GSIS: glucose-stimulated insulin secretion; GSK-3: glycogen synthase kinase-3; GST: glutathione S-transferase; GSTT2: glutathione S-transferase theta-2; HO-1: heme oxygenase 1; HUVEC: human umbilical vein endothelial cells; IC50: half maximal inhibitory concentration; IL: interleukin; iNOS: inducible nitric oxide synthase; IR: insulin receptor; IRS-1: insulin receptor substrate 1; JNK: c-Jun N-terminal kinases; LC3: microtubule-associated proteins 1A/1B light chain 3B; LF:HF: low-frequency:high-frequency; LPC: lysolecithin; LPS: lipopolysaccharide; LVEF: left ventricular ejection fraction; MAPK: mitogen-activated protein kinase; MBC: minimal bactericidal concentration; MCP-1: monocyte chemoattractant protein 1; MGO: methylglyoxal; MIC: minimal inhibitory concentration; MMP2: matrix metalloproteinase-2; NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells; NK cells: natural killer cells; NO: nitric oxide; NOX-4: NADPH-oxidase-4; NQO1: NADH:quinone oxidoreductase-1; Nrf2: nuclear factor (erythroid-derived 2)-like 2; ORAC: oxygen radical absorbance capacity; oxLDL: oxidized LDL; PARP: poly (ADP-ribose) polymerase; PI3K: phosphatidylinositol-3-kinase; PEPCK: phosphoenolpyruvate carboxykinase; PGE2: prostaglandin E2; PKC: protein kinase C; PPARγ: peroxisome proliferator-activated receptor-γ; RANKL: receptor activator for nuclear factor κB ligand; RNS: reactive nitrogen species; ROS: reactive oxygen species; SGLT-2: sodium-glucose co-transporter-2; SIN-1: 3-morpholinosyndnomine; SIRT-1: sirtuin 1; SOD: superoxide dismutase; SphK/S1P: sphingosine kinase/sphingosine 1-phosphate; STAT-3: signal transducer and activator of transcription 3; STZ: streptozotocin; SULT: sulfotransferase; TGF-ß: transforming growth factor beta; Tie: tyrosine kinase receptor; TLR-4: toll-like receptor 4; TN-C: Tenascin-C; TNFα: tumor necrosis factor; UGT: UDP-glucuronosyltransferase; VCAM: vascular cell adhesion molecule; VEGF: vascular endothelial growth factor; VEGR-2: vascular endothelial growth factor receptor 2; xCT: cystine/glutamate anti-porter. Flavan-3-ols and microbial metabolites. BA: benzoic acid; CA: caffeic acid; DHFA: dihydroferulic acid; EC: (−)-epicatechin; EGC: (−)-epigallocatechin; EGCG: (−)-epigallocatechin gallate; FA: ferulic acid; GA: gallic acid; HA: hippuric acid; HVA: homovanillic acid; m-CoA: m-coumaric acid; p-CoA: p-coumaric acid; PA: phenylacetic acid; PCA: protocatechuic acid; PG: pyrogallol; PhG: phloroglucinol; VA: vanillic acid; 3-HB: 3-hydroxybenzoic acid; 4-HB:; 3-HPA: 3-hydroxyphenylacetic acid; 4-HPA: 4-hydroxyphenylacetic acid; 3-HPP: 3-hydroxyphenylpropionic acid 4-HPP: 3-(4-hydroxyphenyl)-propionic acid; 4-MC: 4-methylcatechol; 3-OMGA: 3-O-methylgallic acid; 3-PP: 3-phenylpropionic acid; 2,3-DHB: 2,3-dihydroxybenzoic acid; 3,4-DHPA: 3,4-dihydroxyphenylacetic acid; 3,4-DHPP: 3,4-dihydroxyphenylpropionic acid; 3,5-DHPP: 3-(3’,5’-dihydroxyphenyl)propionic acid.