(a) Upon infection (bacterial, viral, parasitic, etc.) recognized by pattern recognition receptors (PRR; e.g., TLRs, RIRs, etc.), it often triggers inflammation with elevated cytokine and/or chemokine release by innate immune cells such as M$\mathrm{\Phi }$s and neutrophils; in this regard, inflammation is part of innate immune for activating and proceeding adaptive immunity. Without proper control, inflammation, however, often leads to pathological consequence. For instance, cytokine storm without proper antiinflammation and resolution of inflammation damages tissues developing pathological manifestations. (b) Non-infectious conditions such as trauma, surgery, environmental insults, etc. also often trigger inflammatory responses. For instance, tissue injuries (e.g., ischemic heart attack or myocardial infarction) and the one triggered by microbes, often cause necrotic/apoptotic cell death and matrix damages, which releases host danger products such as high mobility group protein 1 (HMGB1), IL-1/33, mtDNA, or mitochondrial N-formyl-peptide (f-Met-Leu-Phe; fMLP) for triggering local inflammation through DAMP receptors [101]. Upon injury or infection, HMGB1 is released passively from necrotic cells or by active secretion from M$\mathrm{\Phi }$s and monocytes via IFN$\beta$-mediated JAK/STAT pathway, which is readily responsible for triggering inflammatory responses in lethal endotoxemia and sepsis. (c) Autoimmunity has long been proposed to lead to chronic inflammation. Autoantibodies activate complements, which could contribute to acute/chronic inflammation. The elevated autoantibodies, for instance, anti-CRP in systemic lupus erythematosus, often target opsonins to form ternary pyrogenic immune complex with apoptotic materials, which shifts from classical opsonin functions in facilitating phagocytosis of apoptotic/necrotic cells toward promoting release of proinflammatory cytokines (e.g., IL-8, TNF) by M$\mathrm{\Phi }$s [102]. In an experimental model, anti-CD3/CD28 (HIT3A/CD28.2) could result in I$\kappa$B$\alpha$ degradation, an inflammatory prerequisite. (d) Furthermore, blood coagulation-inflammation axis [103, 104, 105, 106] and oxidative stress-induced inflammation [107] make inflammation occurring for diverse pathological manifestations. For instance, coagulants (FVIIa, FXa, FXIIa, KK, thrombin, etc.) trigger inflammatory cytokine elevation. Oxidation (ROS) readily contributes to the initiation of inflammation [95, 96, 97, 98, 99, 100]; namely, ROS is essential for NLRP3 activation.

Inflammation occurs when pro- and anti- inflammation systems are out of balance plus defects in resolution of inflammation [108]. (a) Overwhelming proinflammation includes signaling activations (upregulated NF$\kappa$B, HIF, mTORC1, PI3K/AkT, Ras/Raf/MEK/ERK, and JAK/STAT), complement activation, autophagy inactivation, and ER stress as well as elevated inflammatory mediators (e.g., cytokines, chemokines, TNF, leptin, extracellular ATP, clotting factors, BK, arachidonate (AA) metabolites, ATII, AGE, PAF, CRP, plasmin, ROS, calpains, CD40/CD40L, growth factors, histamine, other endogenous DAMP (HMGB1, mtDNA, TSLP), etc. Interestingly, several extracellular matrix components such as MMP2, TNF converting enzyme, and proteoglycan play activating roles in inflammation, while protease Omi suppresses inflammation. (b) Anti-inflammatory events mainly involve AMPK activation, FOXO activation, SirT1 activation, autophagy activation, NF$\kappa$B inactivation, mTORC1 inhibition, M2 polarization, PI3K/AkT inhibition, JAK/STAT inhibition, complement inhibition, anticoagulation, PAR inhibition, PPAR agonism, HDAC inhibition, PDE4 inhibition, cytokine/mediator antagonisms (e.g., anti-TNF, receptor antagonists, anti-cytokine, LPS antagonism), etc. (c) Resolution of inflammation is largely achieved by endogenous anti-inflammatory lipid mediators (lipoxin A4 (LXA4) derived from AA, 15-epi-LXA4 derived from AA, Rvs derived from EPA or DHA, RvD1/2/3/4 derived from DHA, protectin and maresin derived from DHA). Other pro-resolving lipid mediators are also of resolution and antiinflammation: (i) endogenous electrophilic nitrated fatty acids [109] (naturally occurring E-9/E-10 NO${}_2$-oleic acid and E-10/E-12 NO${}_2$-linoleic acid) suppressing IKK phosphorylation, NF$\kappa$B nuclear translocation, TRAF6 recruitment (TLR4 signaling), STAT-1 phosphorylation and nuclear translocation, neutrophil/platelet activation, AT1 receptor, BcL-xL, xanthine oxidoreductase (O${}_2$•${}^{\mathrm{-}}$production), NOX (p47${}^{phox}$ and gp91${}^{phox}$), 5-LOX, and the expression of TLR4, cytokine (TNF-$\alpha$ and IL-1$\beta$), VCAM-1/ICAM-1, MMP, and iNOS. The abilities to activate Nrf2/keap1, PPAR$\gamma$, AMPK, ERK1/2, CaMKK$\beta$, caspase-8/9, Bad, MAPK phosphatase-1, eNOS phosphorylation at Ser1179, and the expression of eNOS, HO-1, and heat shock factors are consistent with the antiinflammatory potentials. Independent of cGMP-mediated NO actions, nitrated fatty acids undergoing nitroalkylation modify protein functions and enzyme activities, which is similar to direct protein S-nitrosylation consequences in mediating antiinflammation. Nitrated fatty acids are also proposed to release NO; (ii) lysophospholipid inactivates ERK/p38, thereby showing antiinflammation by the consequent suppression of NF$\kappa$B activation and TNF$\alpha$ expression. Sphingosine-1-phosphate promotes NO release, presenting its anti-inflammatory action; (iii) PGI2 blocks NF$\kappa$B translocation/activation, while PGJ2 confers anti-inflammatory effect via inactivating NF$\kappa$B by forming an adduct with NF$\kappa$B; (iv) conjugated linoleic acid, a PPAR$\alpha$ agonist, decreases TNF$\alpha$ and IL-6 production, which is accompanied by FOXp3+ Treg expansion, increases in ex vivo lymphocyte proliferation, and IL-2 or IFN$\gamma$ production in stimulated T cells; (v) short chain fatty acids, main metabolic products of anaerobic bacteria fermentation in the intestine, inhibit HDAC and act on leukocytes and endothelial cells through GPR41 and GPR43 receptors to reduce production of cytokines (TNF$\alpha$, IL-2, IL-6, and IL-10), NO, and chemokines (e.g., MCP-1 and CXCLs). Its suppression of HMGB1 release thereby attenuates septic risk; (vi) n-3 FA, n-6 AA, and PGD2-derived cyclopentenone-containing lipid peroxidation products offer anti-inflammatory actions [110]; and (vii) possible anti-inflammatory and pro-resolving roles of PGF2$\alpha$ remain largely unclear and elusive. PGF2$\alpha$ could reverse exacerbation of inflammation by functioning as an endogenous agonist (selective FP receptor agonist fluprostenol) during the resolution phase after inhibition of COX-2 with a highly selective COX-2 inhibitor.

(a) Endogenous and exogenous glucocorticoids are common anti-inflammatory agents, reducing cytokine-induced genes or mediators [111]. (i) Glucocorticoids inhibit the production of TSLP, cytokines, chemokines, adhesion molecules, and other inflammatory mediators. They suppress NF$\kappa$B-dependent transcription by upregulating MAPK phosphatase-1 to dephosphorylate p38 MAPK; otherwise, p38 MAPK transactivating NF$\kappa$B via p65 serine phosphorylation in turn leading to NF$\kappa$B-dependent transcription is essential for proinflammatory cytokine gene expression. (ii) As a result of downregulated NF$\kappa$B, glucocorticoids also suppress COX-2, iNOS, and ICAM-1 expression. (iii) From immunology viewpoints, glucocorticoids suppress T effectors; T effector proliferation requires IL-2, IL-4, IL-5, IL-17, and IFN$\gamma$. (iv) Glucocorticoids activate M$\mathrm{\Phi }$ phagocytosis of apoptotic cells while increasing the expression of IL-1 decoy receptor and promoting M$\mathrm{\Phi }$ to release anti-inflammatory IL-10 and TGF$\beta$. (v) Corticosteroids induce MAPK phosphatase 1, inhibit JNK, inactivate NF$\kappa$B and AP-1, block PLA2, COX-2, and lipocortin-1, and reduce PG and LT biosyntheses. As the result of suppressed production of IL-1, TNF-$\alpha$, GM-CSF, IL-3, IL-4, IL-5, and CXCL 8, corticosteroids readily exhibit antiinflammation. (b) Anti-inflammatory IVIG contains diverse soluble proteins that could neutralize cytokines and chemokines and antagonize their corresponding receptors. Clinically, (i) IVIG readily improves glucocorticoid response/sensitivity possibly mediated by its improved receptor binding or suppressed proinflammatory cytokine production. (ii) Mediated by Fab, IVIG suppresses or neutralizes autoantibodies and cytokines, neutralizes activated complement components, restores idiotypic-antiidiotypic networks, blocks leukocyte-adhesion-molecule binding, targets specific immune cell-surface receptors, and modulates DC maturation and function. (iii) Through Fc domain, IVIG confers anti-inflammatory actions by blockade of the FcRn and Fc$\gamma$R activation, upregulation of inhibitory Fc$\gamma$RIIB, and immunomodulation by anti-inflammatory sialylated IgG segments. (iv) IVIG also lowers systemic HMGB1 release [112]. (c) Extracellular adenosine dampens inflammation, which is mediated by four distinct adenosine receptors: A1, A2A, A2B, and A3. Concerning clinical anti-inflammatory functions, A1 receptor activation during intravenous administration of adenosine for the treatment of supraventricular tachycardia. A2A activation on inflammatory cells such as neutrophils or lymphocytes attenuates inflammation. A2B activation in response to tissue hypoxic adaptation suppresses ischemia and reperfusion. A3 adenosine receptor activation may relief inflammatory dry eye syndrome. (d) Statins are recognized anti-inflammatory based upon AMPK activation [113], IKK inhibition, IKK-independent NF$\kappa$B inactivation, JAK/STAT inhibition [114, 115], PI3K/AkT/mTOR inhibition, FOXO upregulation, eNOS activation, Nrf2 activation, HO-1 activation, increased IL-10, attenuated proinflammatory biomarkers (e.g., CRP, IL-6, and TNF) [115, 116], suppressed CD40 expression [117], decreased MHC II expression, depressed tissue factor expression and its initiated blood coagulation, and Treg accumulation [118]. Statins also promote efferocytosis and cysteine S-nitrosylation of COX-2 for Rvs (e.g., 15-epi-LXA4) production [119], both of which are considerably anti-inflammatory. The ability to promote S-nitrosylation of thioredoxin at Cys69 subsequently stimulates the antioxidative activity to facilitate ROS scavenging. In the context of its classical effects on cholesterol lowering, statins eventually prevent inflammasome (NLRP3) activation from cholesterol accumulation. Statins attenuate T cell activation by depleting membrane cholesterol and disrupting the integrity of lipid rafts that are essential to TCR and costimulatory molecule assemblies [120]. On the contrary, there is evidence for PI3K/AkT/mTOR and AkT/$\beta$-catenin activation by statins [121, 122]; further research is needed to verify such discrepancies in relation to anti-inflammatory mechanism(s). (e) Aspirin, a member of phytochemical family, is currently recommended for cancer prevention, cardioprotection, and antiinflammation in addition to its classical roles in COX inhibition and minor pain/fever relief. Apart from COX inhibition for attenuating inflammatory PGs and LTs species, aspirin effects include AMPK activation, suppressed TNF secretion, and the serine acetylation of COX-2 for the formation of antiinflammatory Rvs (e.g., 15-epi-LXA4) [123]. Other COX inhibitors (e.g., NS-398, celecoxib, etc.) block PGE2 production; recent studies have revealed that COX inhibitors could relieve influenza infection [124]. (f) Low NO concentration (400 nM or under hypoxia) essentially facilitates HIF degradation and impairs HIF1$\alpha$ signaling. NO antagonizes EC adhesion and inhibits caspase (suppressed IL-1$\beta$/18 expression) while enhancing T cell expansion. The abilities of low level of NO to reduce BcL-2 family member expression and increase cytochrome C release certainly contribute to proapoptosis, thereby representing resolution of inflammation. Apopototic immune cells are phagocytosized by M$\mathrm{\Phi }$s, reducing the production of inflammatory mediators. Mechanistically, post-translational modification (S-nitrosylation) not only mediates NO actions, but also serves as antiinflammatory mechanisms [125, 126, 127]. (i) S-nitrosylation of NF$\kappa$B p65 (Cys38)/p50 (Cys62) results in suppressed NF$\kappa$B binding to iNOS promoter, thereby attenuating iNOS expression. (ii) S-nitrosylation of AP-1 c-Jun and c-Fos DNA binding domains blocks AP-1 binding to DNA promoters of various proinflammatory target genes. (iii) S-nitrosylated IKK at Cys179 inhibits IKK activity and suppresses NF$\kappa$B nuclear translocation, thus diminishing cytokine and COX expression. (iv) S-nitrosylation of MyD88 at Cys216 blocks its recruitment to TLR for proceeding TLR signaling. (v) S-nitrosylation has negative effects on EGF receptor (Cys166 and Cys305) and AkT (Cys224), thereby attenuating growth factor-mediated inflammation. (vi) S-nitrosylation suppresses CD40L-induced CD40 activation, leading to attenuated IL-1$\beta$, IL-12, and TNF$\alpha$ production. (vii) S-nitrosylation enhances SOCS1 expression. Clinically, endogenous or exogenous S-nitrosylating agents (e.g., ethyl nitrite, S-nitroglutathione, etc.) and NO donors (e.g., atorvastatin) are used for treating inflammation such as Crohn’s disease, bronchopulmonary dysplasia, acute lung injury/acute respiratory distress syndrome, asthma, COPD, etc. (g) By blocking the ability of TRAF6 to phosphorylate IKK, miR-146b and miR-155 serve as negative feedback regulators in TLR-mediated signaling following the canonical LPS/MyD88/IRAKs/TRAF6 pathway. miR-125b directly inhibits TNF-$\alpha$ expression and NF$\kappa$B transcription, while miR-let7 and miR-21 target TLR4 mRNA at the post-transcriptional level preceding MyD88 signaling. miR-21 also shows positive regulation on IL-10 production [128]. (h) Complement inhibition attenuates tissue injury/destruction, septic shock, multiple organ failure, hyperacute graft rejection, and various disorders [129]. (i) Endogenous soluble C-1 inhibitor is an anti-inflammatory reagent with therapeutic potential. (ii) Eculizumab and soliris (monoclonal antibodies against complement C5) suppress complement activation. (iii) Other antagonisms include C1-recombinant soluble complement receptor, antibodies to C3/C5 blocking the cascade reaction, neutralization of the complement-derived anaphylatoxin C3aR/C5aR/CD88, CD18/11b interference with C3R, and regulatory membrane-bound complement receptors (e.g., CR1/CD35, complement receptor-related gene y (crry; CR2/CD21), membrane cofactor protein (MCP/CD46), DAF/CD55, and CD59-protective receptors) [129]. (i) Heat shock response attenuates proinflammatory mechanisms and iNOS activity; it essentially stabilizes I$\kappa$B$\alpha$ by depleting IKK-$\alpha$ and phosphorylated IKK-$\alpha$. Such inhibition on NF$\kappa$B-dependent transcription makes HSP anti-inflammatory [130]. Accordingly, heat shock blocks AT II-induced expression of IL-6 and ICAM-1. Immunologically, Treg induction and maintenance promoted by stress-induced HSP certainly contributes to antiinflammation. Specifically, (i) HSP90 activates eNOS [131] with concomitant reduction in O${}_2$•${}^{\mathrm{-}}$. (ii) In addition to reduced oxidative damages, HSP70 downregulates CD86 and MHC II expression while inhibiting TNF-$\alpha$ production [131]. HSP70 can also inhibit IFN-$\gamma$production by monocytes. HSP70 through TLR2 activates MyD88 and subsequent ERK phosphorylation that triggers IL-10 production [131]. HSP70 also exerts its anti-apoptotic function downstream of caspase-3-like proteases. (iii) HSP60 facilitates the maturation of pro-caspase-3 to its active form, while HSP32 functions as HO-1, an antioxidant enzyme.

HSP inducers include ischemia-reperfusion, physical exercise, heavy metals, toxins, radiation, UV-light, laser, decreased ATP levels, and pH/osmolarity changes. The pharmacological HSP inducers include bimoclomol, geranylgeranylacetone, $\alpha$-lipoic acid, ansamycins, butyrate, prostaglandins, celastrol, terrecyclin-A, BRX-220, PLA2, and NO. TGF$\beta$ could induce HSP70 and HSP90 expression, which in part confers the antiinflammation of TGF$\beta$ [132]. It is also noted that AT II induces HSP27 and HSP70 expression and their phosphorylation; phosphorylated HSP27 and HSP70 in turn protect against AT II-induced inflammation [132, 133]. (j) In the context of coagulation-triggered inflammation [103, 104, 105, 106], anticoagulation could arrest inflammatory signaling. (i) Anticoagulants (e.g., inactivated FVIIa, direct FXa inhibitors, direct thrombin inhibitors, LMWH, heparins, and natural anticoagulants (TFPI, activated protein C (APC), and AT III) all suppress the extrinsic coagulation pathway and the generation of proinflammatory coagulant mediators (e.g., FVIIa, FXa, and thrombin). APC directly inhibits FVa, FVIIIa, and PAI; it broadly targets blood coagulation system including the extrinsic and intrinsic pathways as well as fibrinolysis, which makes it the most efficient anti-sepsis. Decreased IL-6 production and inhibited iNOS account for APC anti-inflammatory nature. Recombinant human APC (drotrecogin alfa; DrotAA) is recommended in severe sepsis and DIC, resulting in dose-dependent reduced D-dimer and IL-6 without an increase in serious bleeding. APC inhibits HMGB1 release and its receptor (TLR2/4 and RAGE) expression [112]. ATIII also attenuates HMGB1 accumulation. Interestingly, anticoagulant protein soluble thrombomodulin functions as an antibody binding HMGB1, thereby reducing HMGB1 transmission. (ii) Concerning the intrinsic pathway, PA (urokinase) readily downregulates contact system with the consequence of lowering BK production and complement inactivation, preventing inflammation. C-1 inhibitor downregulates contact coagulation by inactivating KK and FXIIa, showing antiinflammation. Eecallantide (DX88) is a potent and specific inhibitor of plasma KK; DX88 reverses the increased vascular permeability. Aprotinin inhibits KK and suppresses BK release. ATIII-bound heparin and heparin sulfate inhibit FXII activation. Ecotin is a potent inhibitor for FXIIa and KK. Warfarin inhibiting vitamin K-dependent protease activations generally exhibits anti-inflammatory action [106]. (iii) PAR antagonism blocks the signal transmission of coagulant mediators that activates cells for eliciting proinflammatory cytokines, adhesion molecules, and growth factors. For instance, PAR-1 antagonist (SCH 79797) offsets plasmin-induced IL-8 expression and PGE2 release [134]. Refluden${}^{\mathrm{\circledR }}$ suppresses M$\mathrm{\Phi }$ adhesion [135]. A thrombin receptor antagonist (E5510) diminishes VEGF [136] or PDGF [136] expression. SCH79797 by blocking ERK activation also inhibits lung inflammation and influenza A virus replication [137], while PAR-2 antagonism via IFN-$\gamma$-dependent pathway prevents influenza infection [138]. PAR-2 peptide antagonists (FSLLRY-NH${}_2$ and LSIGRL-NH${}_2$) suppress Serratia marcescens serralysin-induced IL-6/8 expression [139]. Anti-PAR-2 antibodies and tryptase inhibitors (GW-45 and GW-61) cause significant decreases in IL-6 and IL-8 release from human peripheral blood eosinophils [140]. ENMD-1068 suppresses cytokine production, benefiting to inflammatory arthritis [141]. FUT-175 (6-amidino-2-naphthyl 4-guanidino-benzoate) consistent with PAR-deficiency eases IBD/IBS [142]. PAR-4 antagonist (P4pal-10) dose-dependently diminishes the severity of endotoxemia, systemic inflammation, and DIC [143]. (k) PPARs are antiinflammatroy [144]. Clinically, PPARs present protections from CNS, EC dysfunction, liver (e.g., NAFLD), and white adipose tissue inflammation, endotoxemia, LPS-induced cardiac and pulmonary inflammation, IBD (e.g., Crohn’s disease), etc. (i) PPAR$\alpha$ increases I$\kappa$B expression and downregualtes NF$\kappa$B, AP-1, and NFAT. PPAR$\alpha$ favors switching to M$\mathrm{\Phi }$ M2 polarization. PPAR$\alpha$ agonist (Wy) decreases mRNA of tnfa, mcp-1, mac-1, etc. For instance, conjugate linoleic acid shows antiinflammation via PPAR$\alpha$ agonism. (ii) PPAR$\beta$$\gamma$ prevents LPS-induced NF$\kappa$B activation by downregulating ERK1/2. PPAR$\beta$$\gamma$ prevents M2 switching back to M$\mathrm{\Phi }$ M1 polarization. M1 M$\mathrm{\Phi }$s display enhanced microbicidal capacity and secrete high levels of proinflammatory cytokines (TNF$\alpha$, IL-1$\beta$, and, IL-6) and increased O${}_2$•${}^{-}$ and ROS/RNS radicals to increase their killing activity. In contrast, M2 M$\mathrm{\Phi }$s are pro-resolving and anti-inflammatory by dampening proinflammatory cytokine levels, secreting ECM components, and promoting efferocytosis. (iii) PPAR$\gamma$ decreases not only cytokine expression, but also PMN infiltration. For instance, 15-deoxy-$\mathrm{\Delta }$-(12,14)-PGJ2, a specific ligand of the nuclear receptor PPAR$\gamma$, reduces multiple organ failure and inhibits the expression of proinflammatory genes. Pharmacological PPAR$\gamma$ ligand (rosiglitazone) readily reduces the expression of iNOS, COX-2, ICAM-1, and P-selectin; thiazolidinediones (PPAR-$\gamma$ agonists; e.g., rosiglitazone) reduces inflammation by activating glucocorticoid nuclear translocation and/or downregulating NF$\kappa$B-mediated pathways. (l) Histone deacetylase (HDAC) inhibitors (e.g., valproic acid, sodium butyrate, and suberylanilide hydroxamic acid) suppress cytokine production, exhibiting immunosuppression and antiinflammation. HDAC inhibitors ensure acetylation of proiflammatory transcription factors (e.g., NF$\kappa$B, AP-1, or NFAT-1) and their nuclear exclusion. It is also proposed that HDAC inhibitor is involved in caspase-1 suppression for blocking IL-1$\beta$ release. (m) By increasing cAMP levels, PDE4 inhibitors (e.g., rolipram, piclamilast, roflumilast, analog cilomilast, phthalazinones, etc.) present a broad spectrum of anti-inflammatory effects. (i) Notably, the inhibitors attenuate LPS-induced TNF release from monocytes and M$\mathrm{\Phi }$s. (ii) The inhibitors prevent NF$\kappa$B from binding to DNA promoter and thus decrease VEGF expression and cytokine production. Clinically, they are used for treatment of inflammatory asthma, COPD, psoriasis, IBD, RA, etc. (n) Anti-IL-6 mAb (sarilumab) or decoy could relief SARS-CoV2 symptom (cytokine storm).

(a) The effective polyphenolic anti-oxidative stress (please refer to 3.1 (1) to (6) & 4.1) readily suppresses ROS-inflammation axis, achieving antiinflammation. (b) Polyphenols target multiple inflammatory components [145] by antioxidant potentials (please refer to 3.1 (1) to (6)), AMPK activation (please refer to 3.2 (7)), inhibitions on PI3K/AkT, mTORC1, IKK/JNK, and JAK/STAT (please refer to 3.3 (22), (33), (29), and (28), respectively), suppressed HMGB1 release (please refer to 3.4 (40)), and TLR suppression (please refer to 3.4 (40)). As a result, polyphenols readily lead to NF$\kappa$B, AP-1, HIF, and STAT inactivation (please refer to 3.2 (11), 3.2 (18), 3.3 (26)) with reduced proinflammatory mediators (e.g., PGE2, cytokines, adhesion molecules, growth factors, etc.). (c) Polyphenols sustain resolution of inflammation by SirT1 activation (please refer to 3.2 (8)), eNOS activation (please refer to 3.2 (11)), FOXO upregulation (please refer to 3.2 (9), 3.3 (24)), PDE inhibition (please refer to 3.3 (32)), and adiponectin elevation (please refer to 3.2 (21)). (d) In addition, polyphenol-induced anticoagulation (e.g., TF suppression, inhibited FVIIa/Xa amidolytic activities) and anti-platelet aggregation (e.g., COX inhibition; reduced TxA2) could arrest the coagulation-thrombosis-inflammation circuit [103, 104, 105, 106]. (e) Polyphenols are also able to decrease Th1/Th2 for pro/anti-inflammatory cytokine secretion ratios in vitro, implying anti-immunoinflammatory potentials [86, 145]. (f) Decrease in Bacteroides acidifaciens, but increase in Ruminococcus gnavus and Akkermansia mucinphilia [85] in turn induces Tregs while suppressing inflammatory Th1/Th17 cells, also showing antiinflammation by polyphenols.

Such a wide range targeting the initiation (please refer to 4.2.1) and pathophysiology (please refer to 4.2.1) of inflammation by polyphenols (Fig. 2) is analogous to common pharmacological approaches (please refer to 4.2.2 and Table 1) including glucocorticoids (suppressing NF$\kappa$B for COX-2, iNOS, and ICAM-1 expression, and T effectors for IL-2, IL-4, IL-5, IL-17, and IFN), AMPK activation-dependent aspirin and statins (inhibiting inflammatory events: NF$\kappa$B, mTOR, PGE2, HIF, etc.), oral anticoagulants, PAR-2/4 antagonist, and complement inhibitors (suppressing coagulation-triggered inflammation, HMGB1 release, etc.), PPAR angonists (downregulating NF$\kappa$B/AP-1/NFAT, shifting to M$\mathrm{\Phi }$ M2 polarization, etc.), PDE4 inhibitors (downregulating NF$\kappa$B, TNF release, etc.), etc.

(a) ROS initiates and progresses CVD. (i) ROS has been proposed to mediate arrhythmia, while NOX plays a role in AF. (ii) ROS activates NF$\kappa$B and favors hypertrophic gene program. (iii) ROS can promote the initiation of coagulation by targeting the tissue factor (TF)-FVII complex. (iv) ROS also inhibits the production of natural anticoagulant APC, thus favoring coagulation and formation of thrombin and thrombus. (v) ROS is a known factor for endothelial dysfunction. (vi) Classical lipid hypothesis proposes lipid in the form of LDL accumulating in the intima; LDL-C is not only a classical biomarker, but also a risk factor and driver. LDL particle containing over 80% cholesterol and esters is oxidized. The uptake of OxLDL by M$\mathrm{\Phi }$ CD36 scavenger receptor is not subject to cholesterol homeostasis; OxLDL activates PPAR$\gamma$ to stimulate its own uptake. OxLDL including oxidized PC activates ROS generation, thereby promoting actin polymerization. As a result, foam cells are immobilized and trapped in the intima [100, 148]. Interestingly, OxLDL stimulates NOX [7, 148]; therefore, it establishes a forward-feed loop of oxidative stress refueling atherogenesis. AT II per se induces NOX and mitochondrial-derived ROS [149] in VSMCs, directly linking hypertensive risk to lipid oxidative stress (OxLDL) in atherogenesis [100]. Atherogenesis typically features such OxLDL uptake, which is the hallmark for foam cell formation in the intima (phase I, fatty streak formation in the vascular lumen), which continues with phase II of fibrous plaque formation involving various cell adhesion followed by phase III of plaque rupture involving inflammation and matrix turnover. Severe atherosclerosis will lead to MI progressing as congestive heart failure. (b) Atherosclerosis is a chronic inflammatory disease [150, 151]; inflammation sets in and results in monocyte adhesion followed by penetration into endothelial layer, and leukocyte recruitment by rolling and adhesion. Various inflammatory signals activate VSMC, EC, etc. (i) Not only does inflammation set in atherogenesis, but also OxLDL per se in the intima is proinflammatory including the stimulation of expression of TNF, CRP, VCAM, ICAM, MCP-1, E-selectin, etc., all of which facilitate VSMC proliferation, fibrous cap formation, etc. (ii) Saturated fats and accumulated intracellular cholesterol crystals are proinflammatory, which activates inflammasome NLRP3 that in turn leads to procaspase-1 activation, thereby consequently maturing pro-IL1$\beta$/18 for their secretion. NLRP3 activation also leads to pyroptosis, an inflammatory cell death. Such positive feedback loops of inflammation result in severe atherosclerosis that could lead to MI possibly followed by congestive heart failure [152, 153]. (iii) Furthermore, other risk factor such as ATII or CD40/D40L driving the “ROS-inflammation axis” [95, 96, 97, 98, 99, 100] readily encourages CVD development.

A growing list of innovative treatments (US-FDA approved drugs) are available for CVD. (a) For hypolipidemic actions, statins, ezetimibe, ApoB100 inhibitor, ApoC3 inhibitors, PCSK-9 inhibitors/mAb, bile acid sequestrants, hypoTG agents or LPL up-regulators (ApoC2 and ApoA5 activators and ApoC1/3 (ISIS 304801) inhibition), ANGPTL3/4 blockade (anti-ANGPTL3 mAb (evinacumab; REGN1500), anti-ANGPTL4 mAb (REGN1001)), microsomal triglyceride transfer protein (MTP) inhibitor (lomitapide/implitapide), and fibrate derivatives (e.g., bezafibrate), and Apo[a] lowering agents (ISIS-Apo(a)Rx and PCSK-9 inhibitors). (b) In anti-thrombosis approaches: aspirin, anticoagulants (e.g., anti-FXa, heparin, low molecular weight heparin (LMWH), and warfarin), tissue plasminogen (tPA) activators (e.g., streptokinase, urokinase, alteplase, reteplase, tenecteplase, anistreplase, desmoteplase, or viprinex), and antiplatelet agents (aspirin, clopidogrel, prasugrel, dipyridamol, abciximab, cilostazol, and ticagrelor as well as ADP receptor inhibitors (ticagrelor, prasugrel, clopidogrel, or cangrelor) are often employed. In addition, TM5007 [154] inhibits PAI-1 activity, while TAFI inhibitors [155] include guanidinoethyl-mercaptosuccinic acid, $ϵ$-amino caproic acid, potato tuber carboxypeptidase inhibitor, DL-2-mercapto methyl-3-guanidinoethyl-thiopropanoic acid, leech carboxypeptidase inhibitor, tick carboxypeptidase inhibitor, SAR-104772, compound-8/14, UK-396,082, AZD-9684, BX 528, EF6265, etc. (c) Anti-hypertension approaches involve drug combinations (renin inhibitor/calcium-channel blocker, AT${}_1$R antagonist/diuretic, AT${}_1$R antagonist/calcium-channel blocker, AT${}_1$R antagonist/calcium-channel blocker/diuretic, or calcium-channel blocker/renin inhibitor/diuretic), RAAS-targeting diuretics (e.g., hydrochlorothiazide), $\beta$-blockers, ACE inhibitors, AT-II inhibitors, rennin inhibitors, AT-II receptor blockers, Ca2${}^{+}$ channel blockers (e.g., amlodipine), $\alpha$-blockers, and $\alpha$/$\beta$-blockers. PDE5 inhibitors (sildenafil and vardenafil), PGI2 analogues (epoprostenol or iloprost), vasodialator (andrenomedullin), etc. (d) In view of inflammation elevating Lp[a], anti-IL-6 mAb (tocilizumab) delivers efficicay in treating atherosclosis by blocking LPA promoter activity, thus suppressing hepatic apo[a] expression and Lp[a] synthesis. STAT3/JAK2 inhibitor (WP1066) also diminishes IL-6-induced LPA promoter activity. (e) Others such as amiodarone and dronedarone are effective, while $\beta$-blockers, digoxin, ACE inhibitors, and AT receptor blockers are classical treatments for anti-arrhythmia.

(a) Fig. 2 predicts that polyphenols offer a host of benefits to CVD, suppressing CVD features by antagonizing hyperlipidemia, thrombosis, hypertension, and hyperhomocysteinia (please refer to 4.3.3.1 to 4.3.3.4). (b) Improved EC function (e.g., anti-hypertension, reduced PAI-1/2, ET-1 attenuation, and ACE inhibition), hypolipidemic effects (please refer to 4.3.3.1), anti-oxidation (please refer to 4.1.3), antiinflammation (please refer to 4.2.3), and anti- hypertensive and thrombotic events readily fight against atherosclerosis, MI, and HF. (c) For protection from hypertrophy, polyphenols alleviate its pathogenesis by FOXO upregulation (atrophic gene: atrogin-1 expression), PI3K/AkT/mTORC1 inhibition (please refer to 3.3 (22)), $\beta$-catenin inactivation (please refer to 3.3 (23)), and downregulated [Ca2${}^{+}$]i (please refer to 3.2 (7)) and its consequent calcineurin-dependent NFAT activation. The exhibited EC- dependent or independent VSMC relaxation and improved EC functions attenuate hypertrophy. (d) The abilities to inhibit ACE (please refer to 3.3 (30)), PDE (please refer to 3.3 (32)), blood coagulation (please refer to 3.3 (35)), PAI-1 production (please refer to 3.4 (43)), and platelet aggregation (please refer to 3.2 (7) & (11)) along with K${}^{+}$ channel activation (please refer to 3.4 (41)) and the classical anti-oxidative potentials (please refer to 4.1) are capable of combating fibrosis and arrhythmia and its manifestation (e.g., AF and angina).

(a) Hyperglycemia, through various mechanisms, per se leads to increased ROS production. Excessive ROS can feedback and contribute to the pathogenesis of insulin-resistance and impaired insulin secretion, not to mention about the oxidation-inflammation axis [95, 96, 97, 98, 99, 100] in diabetes initiation and progression. (b) Inflammation confers insulin resistance. Inflammation, cytokines (IL-1$\beta$, IL-6, TNF, IFN), and metabolic stress are capable of inducing $\beta$ cell apoptosis mediated by IRS-2 ubiquitination, exhibiting insulin deficiency in diabetes II. Hyperglycemia and hyperlipidemia lead to insulin resistance and $\beta$ cell apoptosis, which is consistent with the notion that obesity likely develops diabetes II. (i) In fact, AGE per se is inflammatory; hyperglycemia with elevated AGE that induces EC apoptosis, iNOS, and COX-2. AGE signal transduced through its receptor (RAGE) is similar to TLR-dependent cytokine signaling, which activates inflammatory kinase JNK or IKK and in turn blocks IRS tyrosine phosphorylation, leading to insulin resistance. In addition, diabetes as manifestation of obesity receiving adipocytokines (e.g., TNF$\alpha$, IL-6, leptin, etc.) leads to insulin resistance. (ii) Proinfammatory cytokines encourage insulin resistance by activating suppressor of cytokine signaling-3 (SOCS-3). SOCS-3 directly binds insulin receptor and blocks the receptor recognition of IRS, thus suppressing signaling initiation. SOCS-3 is also able to bind IRS and function as E3 ligase, inducing IRS degradation and reducing insulin signaling. (iii) A nonreceptor-type phosphotyrosine phosphatase (PTP1B) dephosphorylates the receptor, limiting its activity. However, the receptor auto-phosphorylation and signaling produces H${}_2$O${}_2$ that inhibits PTP1B, leading to prolonged insulin signaling. (iv) An SH2-containing adaptor protein, Grb10, binds and inhibits the receptor kinase activity. Recently, mTORC1 has been shown to phosphorylate and enhance the inhibitory effect of Grb10 on the receptor. (v) Serine/threonine kinases (e.g., JNK or IKK) phosphorylate IRS in response to proinflammatory cytokines and thus inhibit the recognition of IRS proteins by the receptor tyrosine phosphorylation. Namely, inflammation (e.g., IL-6 or TNF) through its corresponding receptor autophosphorylation activates JNK1 and STAT3 that in turn facilitates IRS serine phosphorylate to compete with IRS tyrosine phosphorylation of initiating insulin signaling. Similarly, TLR-mediated IKK activation in response to inflammation competes with IRS tyrosine phosphorylation to block insulin signaling [157].

Several common anti-diabetes strategies have been reported [158]. (a) Sulfonylurea binds and closes K${}^{+}$ channels for $\beta$ cell depolarization and insulin granule secretion. (b) Na${}^{+}$/glucose symport inhibitors (e.g., dapagliflozin, canagliflozin and empagliflozin) block glucose reuptake/reabsorption from urine during Na${}^{+}$ recovery from the kidney, lowering blood glucose level for a better glycemic control. (c) GLP-1 analogs (exenatide and liraglutide)/GLP-1 receptor agonists (liraglutide, semaglutide, lixisenatide, and once-weekly extended-release exenatide)/GLP-1 ligands mainly promote insulin secretion. GLP-1 released in response to ingestion of nutrients essentially acts on pancreatic $\beta$ cells to stimulate insulin secretion. Through GLP receptor, GLP-1 activates adenylate cyclase causing increased levels of intracellular cAMP and activation of PKA. As a consequence, PKA activation closes K${}^{+}$ channel causing Ca2${}^{+}$ influx for insulin secretion from $\beta$ cells. In addition, (i) GLP-1 activates AMPK, mediating insulin sensitivity via eNOS phosphorylation and activation for Glut-4 translocation and resulting in enhanced glucose utilization by peripheral tissues (muscle, adipose tissue, liver, heart, etc.); (ii) GLP-1 inhibits glucagon release from $\alpha$ cell; and (iii) GLP-1 receptor activation and its downstream EPac2 recruitment to membrane (increased cAMP) cause natriuretic peptide secretion from atrial cardiomyocytes; natriuretic peptide also stimulates glucose-stimulated insulin secretion. (d) DPP-4 inhibitors (e.g., gliptins, saxagliptin, alogliptin, and sitagliptin) prevent GLP-1 rapid degradation by DPP-4. (e) In addition to AMPK activation, metformin inhibits cAMP production, blocking the action of glucagon, and thereby reducing fasting glucose levels. Metformin also induces a profound shift in the microbiota profile that may contribute to its mode of action possibly through an effect on GLP-1 secretion. Apart from suppressing hepatic glucose production, metformin increases insulin sensitivity, enhances peripheral glucose uptake (inducing the phosphorylation of GLUT4 enhancer factor), decreases insulin-induced suppression of fatty acid oxidation, and decreases the absorption of glucose from the GI tract. Increased peripheral use of glucose may be due to improved insulin binding to insulin receptors. (f) Thiazolidinediones (PPAR-$\gamma$ agonists; e.g., rosiglitazone) increase storage of FFAs (carbohydrate utilization) in adipocytes, thus decreasing circulating glucose levels. (g) Basal/long lasting -insulin replacement supplements insulin and $\beta$ cell death-induced insulin deficiency in diabetes I and II, respectively.

(a) Polyphenols mimic/reinforce insulin action: (i) AMPK-mediated eNOS activation (please refer to 3.2 (10)) increases glucose uptake/utilization through Glut-4 translocation. (ii) AMPK induces adiponectin elevation (please refer to 3.2 (21)) and increases GLP-1 production. GLP-1 and its ligand promote insulin secretion without weight gain. (iii) PI3K/AkT inhibition (please refer to 3.3 (22)) accompanying with JNK inhibition (please refer to 3.3 (29)) leads to suppressed insulin resistance and resulting mTORC1 inhibition promotes glycolysis (glucose utilization). (b) $\alpha$-Glucosidase inhibition (please refer to 3.3 (31)) reduces glucose inputs from dietary carbohydrates, certainly lowering glycemic index. (c) Recent insights reveal that flavonoids promote proliferation and reducing apoptosis of pancreatic $\beta$-cells. (d) As prebiotics (please refer to 3.4 (47)), polyphenols could alter gut microbiota, which contributes to energy harvesting from diets, satiety, insulin sensitivity, etc.

Diverse antagonisms against the initiation (please refer to 4.4.1 (a) (b)) and pathophysiology (please refer to 4.4.1) of diabetes by polyphenols (Fig. 2) are compatible to common pharmacological approaches (please refer to 4.4.2 and Table 1) including GLP-1/GLP-1L analogs/mimetics (AMPK activation, K${}^{+}$ channel closure, Ca2${}^{+}$ influx, increased insulin release, eNOS activation, etc.), AMPK-dependent metformin (depressed hepatic gluconeogenesis, shifting microbiota profiles, etc.), etc.

(a) Obesity is known as a low-grade inflammatory disease [159, 160, 161, 162], although it is not proposed that inflammation is an initial cause of obesity. Adipose tissue is a large endocrine system; adipocytes produce a variety of biologically active molecules known as adipocytokines or adipokines, including PAI-1, visfatin, resistin, leptin, and adiponectin in addition to TNF-$\alpha$, IL-6, MCP-1, and others. Metabolically, FFAs activate TLR-4 and excessive cellular ATP triggers inflammsome (NLRP3) activation, contributing to inflammation. Moreover, obesity per se drives M$\mathrm{\Phi }$s into M1 polarization that is characterized by iNOS and further produces TNF$\alpha$, IL-1$\beta$, IL-6, MCP-1, and O${}_2$•${}^{-}$ [162]. (b) In addition, increased ROS/RNS and ROI/RNI in obesity readily refuel chronic inflammation. (i) During adipogenesis (differentiation of adipogenic precursor cells (i.e., preadipocytes) into adipocytes), activated NOX and increased mitochondrial biogenesis with complex I/II/III impairment readily result in excessive ROS production [163, 164]. (ii) Consistent with such notion, Nrf2 and antioxidant enzyme (SOD2, catalase, GSH-Px) expression are upregulated in response to the increased ROS in obesity [165]. Nrf2 then induces C/EBPb followed by turning on C/EBP$\alpha$ and PPAR$\gamma$, both of which in concert are master genes for terminal adipogenesis [163, 164]. (iii) Apart from such intracellular ROS, extracellular redox state triggering intrinsic ROS production could further promote adipogenesis.

The classical approaches include (a) Orlistat (Xenical) inhibits pancreatic lipase, lowering dietary fat absorption; (b) serotogenic drugs (sibutramine) suppress appetite; other incretin mimetics or analogues fluoxetine and sertraline in the treatment of depression such as (S)-fenfluramine, fluoxetine, and sertraline are developed for satiety reducing food intake; (c) classical CCK mimetics (non-peptide benzodiapine and its derivative with indazole substitutions) block CCK signaling for food intake; (d) thermogenic drugs (Bisphenyl ethylamines (BRL 35135), triphenyl ethylamine (CL 316243), RO 40-2148, and [(S)-4(2-(hydroxyl-3-phenoxy propyl) amino)ethoxy]-N-(2-methoxyethyl)phenoxy acetamide (ZD 7114), a 1,4-dioxybenzene compound) increase thermogenesis burning fat in brown adipose tissues, thereby gradually reducing body fat; (e) naltrexone/bupropion combination enhances POMC-mediated release of MSH for reduced food intake and increased energy expenditure; (f) an MC4R agonist (setmelanotide) could be for weight loss, while amylin mimetics, leptin analogues, ghrelin antagonists, GLP-1 analogues, GLP-1 agonist (liraglutide), and NPY antagonists are also of anti-obesity in pre-clinical trials, showing promising results; and (g) bariatric surgery (e.g., gastric pouch reduction/bypass, Roux-en-Y gastric bypass) remains clinically effective by decreased ghrelin production; it also benefits to anti-diabetes by activating GLP-1 expression.

(a) The classical polyphenolic anti-oxidative stress (please refer to 3.1 (1) to (6) and 4.1) certainly blocks ROS-mediated inflammation [95, 96, 97, 98, 99, 100], a common pathogenesis of obesity. (b) Polyphenols’ hypolipidemic effects (please refer to 3.2 (7), (13), (16), etc.) also account for anti-obesity; accordingly, polyphenols reduce adipogenesis. (c) The AMPK activation-mediated consequence of SirT1 activation (please refer to 3.2 (8)) ensures the inhibitions on the genes involved in adipocyte differentiation and TG accumulation. (d) AMPK activation favors shifting M$\mathrm{\Phi }$ M1 to M2 polarization (please refer to 3.2 (7)); proinflammatory M1 polarization in white adipose tissues is one of obese characteristics. (e) Suppressed ADD1/SREBP-1c signals (please refer to 3.2 (16)) are associated with decreased levels of PPAR$\gamma$ as well as C/EBP $\alpha$/$\delta$ mRNA levels during adipogenesis resulting from mTORC1 inhibition [22, 37]. Inactivation of PPAR$\gamma$, a known master gene for adipogenesis and adipocyte differentiation, thus blocks adipogenesis, lipogenesis, and fat accumulation, contributing to anti-obesity [22, 37]. (f) PPAR$\gamma$ and C/EBP $\alpha$/$\delta$ inactivation (please refer to 3.2 (17)) also result from $\beta$-catenin inactivation independently of AMPK. (g) The AMPK-mediated adiponection elevation (please refer to 3.2 (21)) leads to food-intake suppression and weight loss in addition to antiinflammation. For instance, grape resveratrol increases serum adiponectin and downregulates inflammatory genes (PAI-1, IL-6, AP-1, JUN, CREBP, etc.) [42]. 7-O-galloyl-D-sedoheptulose increases adiponectin level while downregulating leptin, insulin, C-peptide, resistin, TNF$\alpha$, and IL-6 in serum and proinflammatory NF$\kappa$B p65, COX-2, iNOS, JNK, phospho-JNK, AP-1, TGF$\beta$1, and fibronectin [43]. Green tea extract upregulates adiponectin and its signaling, promoting BAT thermogenesis accompanied by decreasing final BW gain, adiposity index, adipocyte size and insulin resistance, induced energy expenditure, and promoted fat browning in animal models [166]. (h) As prebiotics (please refer to 3.4 (47)), polyphenols could alter gut microbiota with suppressed “obese microbiota”. However, it remains largely unknown whether polyphenols affect satiety, incretins, and food intake involving regulations on neuronal pathways.

Exception from genetic factors, polyphenols could offer a broad spectrum of anti-obesity. Antagonisms against the adipogenesis/risk (please refer to 4.5.1 (a) (b)) and pathophysiology (please refer to 4.5.1) of obesity by polyphenols (Fig. 2) are similar to common pharmacological approaches (please refer to 4.5.2 and Table 1) including thermogenic drugs that mainly suppress energy production. Polyphenolic anti-diabetes actions (please refer to 4.4.3) also extend to anti-obesity concerning GLP-1/GLP-1 analogs/mimetics (please refer to 4.5.2 and Table 1).

Cancer is characterized with multiple cellular malfunctions. The major cancer hallmarks include sustained proliferative signaling, evaded growth suppressors, resistance to cell death, replicative immortality, induced angiogenesis, activated invasion and metastasis, epigenetic dysfunctions, reprogrammed energy metabolism (e.g., Warburg effect, serine consumption, glycine uptake, etc.), and escaping immune destruction in addition to uncontrolled signaling upregulations. Tumor immunosuppressive microenvironment simply allows immune silencing and encourages T cell inactivation, further supporting cancer stemness, survival, and progression.

(a) Oxidative stress ensures tumorigenic progression. Activated oncogenes could promote ROS production; the resulting DNA damage leading to genomic instability and mutations plays a major role in cancer initiation [7, 101, 167, 168, 169, 170]. Further, the notion that tumor suppressors (e.g., p53, FOXO, retinoblastoma, p21, and p16,) act as antioxidants consistently supports the role of ROS in tumorigenesis [171]. It is also well established that ROS induces HIF1$\alpha$, contributing to angiogenesis and metastasis. (i) Concerning DNA damages, purine nucleoside oxidation by OH• to form 8,5’-cyclo-2’-deoxyadenosine. Similarly, 8,5’-cyclo-2’-deoxyguanosine will result from deoxyguanosine interaction with OH•. As a result, the radical derivatives significantly induce gene mutations and alter gene transcriptions. In addition, H abstraction of deoxyribose leads to single strand breakage, while activation of endonuclease cleaves phosphodiester bond triggering DNA fragmentation [7, 101, 167, 168, 169, 170]. OH• damage to pyrimidines is also mutagenic. 5-Hydroxydeoxy-cytidine (5-hydroxy-dC) induces C$\to$T and C$\to$A mutations in vitro and C$\to$T transitions in vivo. 5-Hydroxy-dC also deaminates to 5-hydroxy-deoxy-uracil, which codes as T. This provides an additional mechanism for the induction of C$\to$T transitions. Thymidine glycol causes T$\to$C mutations in vivo. Furthermore, DNA adducts with lipid peroxidation products, making more damaging DNA modification [172]. Interestingly, independent of excessive UV radiation, apart from UV exposure, endogenous pheomelanin is considered as an intrinsic carcinogen (intrinsic source of ROS), leading to DNA lesion driving melanoma [173]. Clinically, elevated pheomelanin level often associated with “red-hair” susceptible to melanoma also links to high frequency in BRAF V600E mutation, which suggests pheomelanin and the BRAF mutation together readily posing threats to melanoma risk in an UV-free environment. (ii) Tobacco smoking remains a major health risk not only limiting to lung cancer. Tobacco burning generates RNS/RNI to proceed with radical chain-reactions. For instance, deoxyguanine (dG) undergoes nitration by ONOOH or ONOOCOO${}^{-}$ to form unstable adduct 8-nitro-dG leading to DNA strand cleavage. 8-nitro-dG further reacts with ONOOH, resulting in 8-oxo-dG for mutation induction. In addition to single strand breakage, N${}_2$O${}_3$ readily reacts with dA/C/G forming diazo intermediates that are further hydrolyzed to hypoxanthine, uracil, and xanthine, causing mispairing and G$\to$A/T mutation [174]. (iii) Concerning oxidation-inflammation axis of forward feeding loop, oxidative stress readily provides a tumorigenic momentum. (b) Inflammation certainly plays crucial roles in every phase of tumorigenesis including cancer initiation, promotion, and progression [175, 176]. Diverse damaging cytokines and chemokines produced by immune cells during inflammation readily trigger signaling cascades and cell proliferation/differentiation. Inflammation essentially represents a link between intrinsic (e.g., oncogenes, tumor suppressors, and genome stability genes) and extrinsic (e.g., immune and stromal components) factors contributing to tumor development [177]. (i) Inflammatory cells initiate cancer development. ROS/RNS/RNI produced by inflammatory cells promotes mutagenesis, causing mutations in neighboring epithelial cells. Also, cytokines produced by inflammatory cells can elevate intracellular ROS/RNS/RNI in premalignant cells. In addition, inflammation upregulates NF$\kappa$B and activation-induced cytidine deaminase, leading to genomic instability and epigenetic changes that favor tumor initiation. Moreover, STAT3 activation encourages stem cell reprogramming/renewal, while NF$\kappa$B activation facilitates survival and antiapoptosis by upregulating Wnt/$\beta$-catenin pathway, for instance, for colonic tumor growth. It is also noted that oncoproteins (e.g., Ras, MyC, etc.) of initiated tumor induce inflammatory cytokine (IL-6/8/1$\beta$) and chemokine (CCL2/20) production as a positive feedback loop, ensuring tumor-associated inflammation to contribute to further ROS, RNI, and cytokine production [175, 176]. (ii) Inflammation readily prompts cancer progression. Proiflammatory cytokines (e.g., TNF$\alpha$, IL-23) produced by tumor-infiltrating immune cells activate key transcription factors (NF$\kappa$B or STAT3) in premalignant cells to control numerous pro-tumorigenic processes in a paracrine fashion, promoting premalignant cells to a primary tumor. As parts of positive feed-forward autocrine loops, NF$\kappa$B, AP-1, and STAT3 activations induce production of chemokines that attract additional immune/inflammatory cells to sustain autocrine tumor-associated inflammation, leading to survival/antiapoptosis, proliferation, growth, angiogenesis, and invasion [175, 176, 177]. (iii) Inflammation enhances angiogenesis as the result of NF$\kappa$B, STAT3, and AP-1 activations and proangiogenic factors such as angiopoetin2, VEGF, IL-8, CXCL-1/8, including HIF$\alpha$ expression all being upregulated [176, 177]. (iv) Inflammation also encourages cancer metastasis. Inflammation engages in every steps of metastatic process. Mechanistically, TNF signaling represses E-cadherin transcription; the loss of E cadherin increases tumor motility for invading epithelial layer and basal membrane. Inflammatory prostaglandins or MMPs increases vascular permeability, allowing tumor cells’ intravasation into blood circulation. In addition, chemokine receptors (CXCR4, CCR4/7/9/10) direct such intravasation. Inflammatory cytokines (e.g., IL-6, TNF$\alpha$, and epiregulin) promote tumor cell’s survival in blood circulation for micrometastasis and extravasation. Inflammatory extracellular matrix component: versican leads to M$\mathrm{\Phi }$ activation and induces TNF production in M$\mathrm{\Phi }$s, ensuring adhesion and metastatic cell attachment in a new landscape. Furthermore, inflammation derived from IL-1/6 and TNF$\alpha$ followed by NF$\kappa$B and STAT3 activations promotes MMP expression for invasion. In addition, chemokine: CCL-9 induces MMP2/9 secretion [176, 177] that contributes to metastasis, angiogenesis, migration, and beyond.

Cancer treatments remain most focused basic and clinical research. Classical cancer treatments include chemotherapies, radiation/surgery, and immunotherapies [178]. In addition to target/precision oncotherapies, many developing innovations include combinations of oral chemo- prevention/therapeutic agents with DC/DNA/mRNA vaccines, significantly enhancing immune responses (e.g., Th1 enrichment, CD8+ T infiltration, etc.) for arresting tumor growth. Small molecules (e.g., CA 170) are also developed for immune checkpoint blockade in addition to mAbs against PD-1/PDL-1 or CTLA-4. (a) Metformin, bexarotene, zoledronic acid and other bisphosphonates, COX inhibitors, aromatase inhibitors, and retinoid ATRA are of cancer chemoprevention. For instance, aspirin is known CRC chemoprevention, while aromatase inhibitors are breast cancer chemoprevention agents. (i) Metformin increases effector CD8+ T cell populations and resulting memory cells, but also increases MHC-I expression on tumor cells, increasing visibility to effector CD8+ T cells. (ii) Bexarotene inhibits apoptosis in T cells by increasing expression of BCL2. (iii) Zoledronic acid and other bisphosphonates increase phosphoantigens in peripheral blood mononuclear cells and on cancer cells, resulting in activation of anti-tumor $\gamma$$\delta$ T cells. Zoledronic acid readily decreases populations of M2 M$\mathrm{\Phi }$s and may re-polarize them to the anti-tumor M1 M$\mathrm{\Phi }$s. (iv) COX inhibitors (aspirin, celecoxib, naproxen, and meloxicam) can reverse PGE${}_2$ effects on increasing immunosuppressive Treg, MDSC, M2 M$\mathrm{\Phi }$s, and even Th2. The inhibition also blocks the PGE2 effect on Wnt/$\beta$ catenin signaling assembly for CRC development. (v) Aromatase inhibitors (letrozole) reduce Treg populations and increased Th1-cytokine release; estrogen is known to promote a Th2 cytokine profile and expand Tregs. (vi) Retinoid (all trans retinoic acid; ATRA) can differentiate MDSCs into immature DCs, which may account for its ability to enhance proliferation of both effector and memory CD8+ T cells. (vi) Preventive vaccines (e.g., HPV vaccine) receives clinical efficicay. (b) Common chemotherapies, mentioning a few, have been practiced across different types of cancers. Chemotherapy-induced oxidative stress reduces the rates of both the proliferation and the survival of cancer cells, resulting in response and shrinkage of tumor volume. Chemotherapy leads to senescent cells undergoing a permanent cell cycle arrest (antiproliferation). Some resistance to chemotherapies including MDR-efflux and toxicities have been reported. It is noted that combined chemotherapies with cancer vaccines achieve better outcomes and survival rates. (i) Inhibitors of the Wnt signaling FRP (Frizzled-Related Protein), Cer (cerberus), WIF1 (Wnt-inhibitory factor-1), and Dkk1 (Dickkopf-1) could downregulate Wnt signaling. (ii) Small molecule kinase inhibitors including ATP-competitive vs. non-ATP competitive and covalent vs. non-covalent inhibitors suppress kinase activities by differential fashions, providing some specificity and reversibility for inhibitory actions. For instance, non-Type I ATP-competivitive erlotinib (quinazoline analog), dasatinib (pyrimidine analog), suninib (urea analog), gefitinib (quinazoline analog) target VEGFR, EGFR, FGFR, PDGFR, KIT, FLT3, ABL1/2, SRC, RET, and CSFR; Type II ATP-competivitive imatinib (pyridine/pyrimidine analog), nilotinib (pyridine/pyrimidine analog), sorafenib (pyridine analog), vatalinib, lapatinib (quinazoline analog) could inhibit ABL-1/2, PDGFR, TIE2, MET, EGFR, VEGFR, PDGFR, BRAF, ABL-2, KIT, FLT3, PDGFR, Raf kinase, and ErbB2; non-ATP-competitive rapamycin analogs (everolimus and temsirolimus) apparently are able to suppress mTOR, CHK1, ABL, IKK, CDK2, and AkT. (iii) EGFR antagonists (e.g., Cetuximab & Panitumumab) are used as passive immunotherapy. (iv) Antagonism against AR and ER signaling includes inhibitions of steriodogenesis, AR/ER ligand-binding, DNA binding, coactivator binding, and AR/ER breakdown, thereby attenuating estrogen and androgen effects. For instance, aromatase inhibitor (anastrozole, letrozole), faslodex fulvestrant, tamoxifen, pyrrole imidazole polyamide, pyrimidines, guanylhydrazone, etc. attack ER signaling. Ketoconazole, abiraterone, finasteride, dutasteride, hydroxyflutamide, bicaltamide, pyrvinium maoate, polyamide, T3, flufenamic acid, T3 acetate, HDAC inhibitor, HSP90 inhibitor, etc. target AR signaling. (v) Bortezomib inhibits NF-$\kappa$B, a central oncogene associated with tumor proliferation/growth/migration, angiogenesis, EMT, and metastasis. (xvii) Fascin inhibits cell adhension. NF$\kappa$B inactivation by IKK$\beta$ inhibitor (BMS-345541) could rescue resistance to tyrosine kinase inhibitors (erlotinib) in addition to its anti-metastasis. (vi) Doxorubicin, all-trans retinoid acid, TNF, and bisphosphonates reduce telomerase activity by suppressing the expression of the catalytic RNA component. Antisense olgionucleotides to such telomerase RNA component suppress the expression and activity. AZT accelerates both apoptosis and telomere loss. (vii) Growth inhibition include apoptotic inducer, promoted phagocytosis by M$\mathrm{\Phi }$s, antagonism against inhibitor of apoptosis proteins (IAP), and inhibition of anti-apoptotic GAS6 (ligand)/AXL (receptor) pathway. (viii) Synthetic MMP inhibitors (doxycycline and chemically modified tetracyclines) inhibit the activity of MMPs, bevacizumab or VEGF inhibitors (sunitinib, pazopanib, and axitinib) targets VEGF and VEGFR, tyrosine kinase inhibitors (e.g., sorafenib or motesanib) supprerss VEGFR intracellular kinase activity, and AMG 386 targets Ang/Tie2 pathway all for anti- angiogenesis, invasion, tumorgenesis, and metastasis. (ix) For anti-hypoxia, aminoflavone inhibits HIF1$\alpha$ mRNA expression for the protein synthesis; mTOR inhibitors, cardiac glycosides, microtubule targeting agents, topoisomerase inhibitors, synthetic oligonucleotides, and PX-478 inhibit HIF1$\alpha$ translation and protein synthesis; HSP90 inhibitors, HDAC inhibitors, antioxidants, oligonucleotides, berberine, PX-12, and mTOR inhibitor/guanylate cyclase activator destabilize HIF1$\alpha$ protein; acriflavine blocks HIF-1$\alpha$/$\beta$ dimerization; anthracyclines, echinomycin, and doxorubicin block HIF1 DNA binding; and borterzomib inhibits HIF1 transactivation. (x) 5-FU (pro-drug capecitabine) inhibits thymidine synthase, presenting diverse impacts on pyrimidine, pruine, and one carbon metabolism along with elevated serum deoxyuridine/uridine represents overflow of nucleotide metabolism along with many other metabolic effects including decreased ATP/ADP and GSH/GSSG ratios and increased NADH/NAD${}^{+}$ ratio in cancer cells. In addition, 5-FU attenuates glycolysis and decreases FA oxidation, favoring anti-cancer. (xi) For restoring/enhancing immune responses, anti-CD47 Ab (CD47, a “don’t eat me signal”) is as effective as anti-PD-1/PDL1, anti-soluble NKG2D ligand mAB facilitates NK cell function in eliminating tumors, and IDO inhibitors (epacadostat) deactivates DMSC suppression. (xii) Small molecule THZ1 inhibits CDK7 for cell cycle proceeding. (xiii) High doses of vitamin C inhibits DNA demethylation; (xiv) PARP inhibitors (olaparib, AZD2281, ABT-888, BSI-201, KU-0058948, and AG-014699) promote DNA repair (cell cycle arrest). (xv) Small molecule antagonists inhibit oncogenic pathways (PI3K/AkT/mTORC1, Ras/Raf/Mek/Erk, etc.). (xvi) For autophagy inhibition, 3-MA, BafA, LC3-RNAi, ATG5/7RNAi, ATG 3/4C/5/12-RNAi result in autophagy inhibition for treating glioma, myeloma, cervical, breast, colon, and prostate cancer treatments. Chloroquine and hydroxychloroquine blocking lysosomal acidification and indirectly inhibiting autophagy are under clinical trials of glioma, myeloma, cervical, breast, colon, lung (small cell or non-small cell), leukemia, multiple myeloma, and prostate cancer. (xvii) Trastuzumab and pertuzumab are the 2 current FDA-approved mAbs that inhibit the signaling of HER2 as target therapies. (xviii) Classical platinum-based (cisplatin, carboplatin, and oxaliplatin) treatment since 1978 basically restores DNA repair pathways. (xix) Taxol (paclitaxel) kills tumors by mitotic arrest across cancer types. Others such as sunitinib, temozolomide, gemcitabin, bortezomib, gefitinib, erlotinib, tamoxifen, etc. are also included in this chemotherapy category. (c) Immunotherapies include active/passive immune modulations, adoptive T cells (ATC), CAR-T, CD8+ T activation, therapeutic DC/DNA/RNA vaccines, etc. (i) High dose IL-2 promotes T proliferation. (ii) PD-1/PDL-1 checkpoint blockade rescues T exhaustion, while CLTA-4 Ab/inhibitor facilitates CD8+ T infiltration. (iii) CAR-T enhances cancer infiltrating T. (d) Radiation therapy achieves efficacies in cancers such as prostate, brain, breast, lung, etc. Radiation therapy activates ATM that triggers p53 DNA repair mechanism and ROS production for killing tumors. (i) Radiation via ATM/ATR sensor induces p53 upregulation that elicits expression of CDK inhibitors to arrest cell cycle. (ii) ATM per se inhibits MDM2 (an E3 ligase) that degrades p53. (iii) ATM also phosphorylates Ser15 at N-terminus of p53, which facilitates dissociation with MDM2 resulting in p53 nuclear translocation. The resulting p53 effects favor apoptosis and suppresses cell proliferation. p53 inhibits Bcl-2 while enhancing the intrinsic apoptotic pathway including elevated cytoplasmic proapototic proteins (PIDD, Bid) and mitochondrial proapoptotic proteins: Bax, Bak, Puma, and Noxa. p53 also promotes the extrinsic pathway by elevating death receptors (Fas/Apo1, DR 5, etc.). (e) Surgery is often highly recommended at earlier stage of the treatment plan/sequence.

In addition to the antioxidation and anti-inflammatory mechanisms by polyphenols, targeting specific tumorigenic signaling pathways/components certainly contributes to anticancer activities (Fig. 2), which has been generally demonstrated by (a) antioxidant activity scavenging free radicals (please refer to 3.1 (1)) and reducing oxidative stress, (b) inhibition of cell proliferation (e.g., NF$\kappa$B inactivation, PKC inhibition, mTORC1 inhibition) (please refer to 3.3 (26), (33), (36)), (c) inhibition of cell differentiation (e.g., NF$\kappa$B inactivation, PKC inhibition, etc.) (please refer to 3.2 (11) & 3.3 (36)), (d) inhibition of oncogene (e.g., cMyC) expression (please refer to 3.3 (26)), (e) induction of tumor suppressor gene expression (e.g., p53, FOXO1, etc.) (please refer to 3.2 (9), (12), etc.), (f) induction of cell-cycle arrest, (g) induction of apoptosis (PKC inhibition (please refer to 3.3 (36)), (h) inhibition of oncogenic signaling pathways (IP3K/AkT/mTOR, JAK/STAT, etc.) (please refer to 3.3 (22), (28), etc.), (i) enzyme induction and enhancing detoxification: (e.g., Phase II enzyme: glutathione peroxidase, catalase, SOD), (j) enzyme inhibition (e.g., Phase I enzyme (blocked activation of carcinogens): COX-2, iNOS, xanthine oxidase) (please refer to 3.2 (7) & (11), 3.1 (5)), (k) enhancement of immune functions (please refer to 3.4 (47)) and surveillance (M2/Treg downregulation) (please refer to 3.1 (7), 4.2, etc.), (l) anti-angiogenesis (VEGF, TGF$\beta$, NF$\kappa$B inactivation, etc.) (please refer to 3.2 (7), 4.6.2 (b), etc.), (m) inhibition of cell adhesion and invasion (e.g., P-selectin), (n) suppressed metastasis (EMT, NF$\kappa$B inactivation, etc.) (please refer to 3.2 (11) & 4.6.2, etc.), (o) reduced stemness (NF$\kappa$B inactivation) (please refer to 3.2 (11)), (p) inhibition of nitrosation and nitration (please refer to 4.1 & 4.2 (c)), (q) prevention of DNA binding, (r) downregulation of steroid hormone metabolism and signaling, (s) downregulation of estrogen metabolism, (t) a target for attenuating cancers, $\beta$-catenin inactivation (please refer to 3.3 (23); curcumin blocking axin/APC/GSK3$\beta$/$\beta$-catenin complex disassembly for $\beta$-catenin degradation) by directly inhibiting GSK3$\beta$ for quenching $\beta$-catenin release and nuclear translocation [28, 29, 30], also resulting in transcription factors: PPAR$\gamma$ and C/EBP$\alpha$ being downregulated (please refer to 3.2 (17)), (u) as epigenetic modifiers (please refer to 3.4 (45)), flavonoids, EGCG, genistein, resveratrol, and quercetin downregulating pro-cancer oncogene (e.g., DNMT, HAT, HDAC, MECP2, etc.) while upregulating acetylation and tumor-suppressor gene (e.g., p53, SCUBE2, BRCA1/2, ERa/b, EZH2, p300, ATP2A3, etc.) expression, and (v) anti-viral potentials (please refer to 4.8 (c)) reducing pathogenic risk.

Moreover, resveratrol and other dietary polyphenols are inhibitors of estrogen metabolism in human breast cancer cells. JAK/STAT1 inhibition by resveratrol [55] extends its benefit to IDO suppression for cancer immunoprotection; IDO plays roles in tumor immunosuppressive microenvironment. Resveratrol and other dietary polyphenols are inhibitors of estrogen metabolism in human breast cancer cells. Polyphenols also target HDAC 6-related pathways. Curcumin induces Nrf2 and increases the target gene HO-1 expression, favoring apoptosis with anti-tumor action. Polyphenols even target cell senescence or sphingolipid (ceramide)-mediated mechanisms, presenting novel cancer preventions and therapeutic strategies.

Antagonisms against the progression (please refer to 4.6.2 (a) (b), 4.6.4) and pathophysiology (please refer to 4.6.1) of cancers by polyphenols offer broad coverages compatible to current pharmacological approaches (please refer to 4.6.3 & Table 1) including chemoprevention (e.g., AMPK-dependent metformin & aspirin), target therapies (inhibiting PI3K/AkT/mTOR/ ERK/IKK/HIF/NF$\kappa$B/AP1, suppressing JAK/STAT signaling, autophagy inducers, Th1 activation, Treg/Th17 downregulation, etc.), etc.

(a) Considering the role of oxidative stress in triggering neurodegeneration, largely deriving from activated microglia (resident M$\mathrm{\Phi }$s) and astrocytes through NOX, ROS targets cholinergic or dopaminergic neurons and poses risks. (i) AD brain shows a decreased electron transport chain, especially decreased complex IV, thereby releasing ROS from mitochondria. AD is also reported with increased brain content of Fe2${}^{+}$ and Cu2${}^{+}$, both of which are capable of stimulating free radical formation. ONOO${}^{-}$ induces tau protein hyperphosphorylation, nitration, and accumulation. Oxidative damage of lipids generates toxic aldehydes (4-HNE and MDA), leading to cholinergic neuron death. Interestingly, AGE per se could trigger ROS production from activated microglia, accounting for the risk by diabetes. (ii) Similarly, oxidative stress leads to PD pathogenesis. Mitochondrial damage has been associated with some PD incidence with deficit/impairment in mitochondrial complex I, resulting in reduced ATP production and enhanced free radical formation. Furthermore, there are reduced GSH and elevated iron in substantia nigra of PD patients. As a result, dopaminergic neuron apoptosis could occur. Environmental insults such as pesticides or insecticides are proposed to damage mitochrondria [179]. For instance, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine known as MPTP inhibits the complex I; the impaired/inhibited mitochondrial complex I leads to oxidative stress. Among which, particularly increase in 3,4-dihydroxyphenylacetaldehyde (DOPAL) is the critical endogenous toxin triggering dopaminergic neuron loss in PD. DOPAL reacts with H${}_2$O${}_2$ to generate OH• radicals triggering aggregation of toxic olgiomeric $\alpha$-synuclein protein. The small acidic protein $\alpha$-synuclein binds loosely to the surface of vesicles, possibly playing a role in synaptic dynamics and initiating dopaminergic neuron death. (iii) Concerning HD, ROS worsens the expansion of the CAG triplet repeat tract in postmitotic neurons, resulting in a longer and more toxic polyglutamine expansion in huntingtin, with possible consequences on disease onset and progression. Interestingly, there is a positive feedback loop refueling ROS production. The mutant huntingtin protein suppresses activity of several enzymes involved in oxidative phosphorylation such as the complex I, II, III, and IV, leading to energy metabolism defects and enhanced ROS production. In addition, up-regulated uncoupling protein 2 mRNA ensures inefficient coupling of electron transport to ATP production. (iv) Oxidative stress is also generally proposed to play a relevant pathogenic role in depression [180]. ROS and RNS have been demonstrated to modulate levels and activity of noradrenaline (norepinephrine), serotonin, dopamine and glutamate, all of which are principal neurotransmitters involved in the neurobiology of depression. Moreover, major depression has been associated with an impairment of the total antioxidant status with lowered endogenous antioxidants (vitamin E, zinc, and coenzyme Q10), or antioxidant enzymes (e.g., GSH-Px). (b) CNS inflammation as a risk factor, enormous amounts of cytokines (e.g., TNF$\alpha$, IL-1$\beta$, and IL-6) are produced by activated microglia and astrocytes target cholinergic neurons. In addition, AGE is proinflamatory to activate microglia. Apoptotic or necrotic neuron death secreting ATP further activates microglia. Such a positive feedback loop of inflammation ensures AD pathogenesis [181]. There are elevated TNF$\alpha$, IL-1$\beta$, and IL-6 in PD patients, which accompanies with caspase-3/8 activation consistent with neuronal apoptosis for the pathogenesis. Apart from elevated cytokines (e.g., IL-6 and TNF$\alpha$), there are increased COX-2 expression and PGE2 level in PD patients. PGE2 diffuses into the brain parenchyma and activates catecholaminergic and serotonergic brainstem nuclei that innervate the paraventricular hypothalamus (PVH), bed nucleus of the stria terminalis (BNST), and central nucleus of the amygdala (CeA). IL1$\beta$ activates the vagus nerve that in turn stimulates primary and secondary projection areas including the dorsal motor complex, PVH, BNST and CeA.

(a) $\gamma$-Secretase inhibitors prevent amyloid precursor protein (APP) cleavage into pathological A$\beta$42. (b) Anti-A$\beta$ mAb decreases A$\beta$ oligomer/aggregation. (c) Acetylcholine (Ach) facilitates neurotransmission, while (d) Ach esterase inhibitor (e.g., donepezil, galantamine, rivastigmine) brings up Ach level for neurotransmission. (e) L-DOPA supplies dopamine bioavailability. (f) Monoamine reuptake inhibitors maintain neurotransmitter level in synaptic cleft for continuous transmission. (g) Catechol-O-methyltransferase inhibitors (tolcapone and entacapone), and monoamine oxidase B inhibitors (rasagiline, selegiline) reduce dopamine metabolism to improve dopamine bioavailability. (h) Pramipexole and talipexole (D2-receptor agonists) inhibit the in vitro $\alpha$-synuclein aggregation and cytochrome C release or Lewy body formation, limiting DOPAL toxicity and neuron death. (i) Tetrabenazine, a specific inhibitor of vesicular monoamine transporter, decreases dopaminergic neurotransmission. (j) TREM-2 antibody activates TREM2 receptor; TREM-2 is responsible for A$\beta$42 internalization/trafficking and ApoE reception, preventing A$\beta$ deposition and delaying A$\beta$ pathology and neurofibrillary tangle formation. (k) Deep brain stimulation involves inhibiting cells and exciting fibers, changing firing rate of basal ganglia, electrical current acting on synapses to trigger neighboring astrocytes to release neurotransmitters (adenosine and glutamate), increasing cerebral blood flow, and stimulating neurogenesis.

(a) Curcumin and EGCG phosphorylate CREBP that in turn activates BDNF that is required for long term potential and cognition process in hippocampus [31, 32]. (b) Curcumin inactivates $\alpha$/$\beta$/$\gamma$ secretases that otherwise cleave APP into A$\beta$, thereby suppressing of AD progression along with intracellular neurofibrillary tangle formation [28, 29, 30, 31, 70]. (c) Resveratrol, curcumin, and quercetin directly inhibit monoamine oxidase that otherwise catabolizes neurotransmitters (e.g., 5-HT, epinephrine, DOPA, dopamine, etc.), therefore exhibiting antidepressive property and cognitive improvement [31, 70]. (d) The ability to inactivate p38 MAPK (e.g., NF-$\kappa$B inactivation, reduced glutamate excitotoxicity, and recovering synaptic plasticity, anti-apoptosis, etc.) (please refer to 3.3 (27)) by polyphenols in part contributes to neuroprotection in easing AD patholgy and A$\beta$ toxicity [182]. (e) In the context of antioxidation (please refer to 4.1) in terms of both chemical structures and cellular functions, polyphenols could target the pathogenesis of neurodegeneration for full protection. (f) In view of anti-inflammatory effects by polyphenols, SirT1 activation (please refer to 3.2 (8)), NF$\kappa$B inactivation (please refer to 3.2 (11)), NLRP3 inactivation (please refer to 3.2 (20)) (autophagy upregulation), TLR suppression (please refer to 3.4 (40)), and many others readily antagonize against CNS inflammation. (g) Resveratrol markedly reduces CSF, MMP9, IL-12p40, IL12p70, and RANTES while increasing macrophage-derived chemokine (IL-4), FGF-2, and plasma MMP10, showing induced adaptive immunity.

In summary, fighting against the pathophysiology (please refer to 4.7.1 (a) & (b) of neurodegeneration by polyphenols offer broad coverages compatible to current pharmacological approaches (please refer to 4.7.2 and Table 1) including AMPK-dependent & mTOR-inhibiting rapamycin, $\gamma$-secretase inhibitors, monoamine reuptake inhibitors, etc. Thus far, clinical trials have echoed protection of neurodegeneration by polyphenols [183, 184, 185, 186, 187, 188, 189, 190, 191].

In view of the ability to inhibit mitochondrial ATPase (please refer to 3.1 (4)) and activate AMPK (please refer to 3.2 (7)) and its downstream SirT1 (please refer to 3.2 (8)), polyphenols could be in line with calorie restriction for longevity. Moreover, the polyphenolic action on mTOR inhibition (please refer to 3.2 (15), 3.3 (33)) readily supports metabolic downregulation for anti-aging approach.

NAFLD is generally characterized with inflammation, insulin resistance, hepatic TG/VLDL-TG overload/accumulation (obesity), and oxidative stress. The anti-oxidative (please refer to 3.1 (1) to (6) & 4.1), anti-inflammatory (please refer to 4.2.3), anti-diabetic (please refer to 4.4.3), and hypolipidemic (anti-obesity; please refer to 4.5.3) capacities could certainly afford and make polyphenols beneficial to NAFLD that could progress to nonalcoholic steatohepatitis, liver fibrosis, or even hepatocellular carcinoma.

IBD is a chronic inflammatory disorder caused by deregulated immune responses in a genetically predisposed individual. This is a complex process mediated by cytokines, chemokines, adhesion molecules, cytoplasm nuclear receptors, among others. IBD pathogenesis presents disrupted intestinal homeostasis, including gut microbiota population, barrier function, epithelial restitution, microbial defense, innate immune regulation (ROS generation, ER stress, autophagy, TLRs, NOD2, etc.), adaptive immunity (T/B imbalances), and cellular signaling. Genetic mutations also contribute to IBD pathogenesis. Genetic susceptibility, barrier defects, infection, sustained innate immunity, and their defective regulations/coordination in concert ensure the development of IBD. As a consequence of enhanced luminal bacterial invasion, the production of TNF-$\alpha$ and IL-1$\beta$/6/12/23 increases, triggering imbalanced T cells differentiation and further increased cytokine and chemokines for proinflammation. Consistent with the notion of elevated Th17 cells, IL-23 and its signaling on JAK-STAT activation mediate IBD. In these regards, it is plausible that IBD could share some genetic association with certain autoimmune disease.

Polyphenolic (quercetin, isoflavones, flavones, anthocyanins, etc.) benefits could readily extend to IBD that features gut inflammation and microbiota leakage. (a) The anti-inflammatory effects (e.g., NF$\kappa$B inactivation, iNOS/COX2 downregulation, LOX-12 inhibition, suppressed cytokine TNF$\alpha$, IL-1$\beta$/6/8, and IFN$\gamma$ expression, upregulated IL-10, favored Th1/2 balance, etc.) [194, 195, 196] naturally contribute to anti-IBD. (b) Immunomodulation by polyphenols could ease IBD episodes as well as prevent its progression. Polyphenols reduce inflammation by suppressing the proinflammatory cytokines in IBD by inducing Treg cells in the intestine, inhibition of TNF-$\alpha$, induction of apoptosis, and decreasing DNA damage. (c) As prebiotics and a consequence of altered microbiota with decreased species (Bacteroides acidifaciens) but increased species (Ruminococcus gnavus and Akkermansia mucinphilia), polyphenols induce Tregs while suppressing inflammatory Th1/Th17 cells, thereby preventing murine colitis development [196].

The capabilities of polyphenols in anti-oxidation (please refer to 3.1 (1) to (6) & 4.1), antiinflammation (please refer to 4.2.3), and anti-infection (please refer to 4.8) are certainly responsible for fighting against iron deficiency anemia, a common form of anemia. Polyphenolic hypolipidemic actions in anti-obesity (please refer to 4.5.3) also lower the risk for such iron deficiency anemia.

Iron is the only micronutrient known to have a regulatory hormone (hepcidin) that responds to both nutrient status and infection [197]. Hepcidin, an antimicrobial peptide made in the liver, is a negative regulator of iron trafficking; hepcidin binds iron exporter (ferroportin; FPN) to cause FPN internalization and degradation for consequent blocking not only iron release from cellular stores but also GI absorption of dietary iron [198, 199]. Upregulated hepcidin dictates low plasma iron and its reduced bioavailability for heme/hemoglobin syntheses and effective erythropoiosis for red blood cell production, major characteristics of anemia. (a) ROS readily drives iron deficiency; sustained endogenous H${}_2$O${}_2$ induces hepcidin expression. Similar to IL-6 signaling (see below section on anemia of chronic inflammation), endogenous H${}_2$O${}_2$ mediates its positive action on upregulation of hepcidin expression by JAK1/STAT3 signaling pathway. Such activation mediated by H${}_2$O${}_2$ on hepcidin upregulation could provide mechanism by which infection or inflammation induces hepcidin expression. Interestingly, H${}_2$O${}_2$ shows synergistic positive effects on hepcidin expression with IL-6 and BMP6 [200]. (b) Inflammation upregulates hepcidin expression, resulting in so-called anemia of chronic inflammation. IL-6, IL-22, and type I IFN stimulate hepcidin transcription through STAT3 signaling [103]. Several microbial-derived TLR ligands can induce hepcidin expression, likely via induction of IL-6. SMAD and STAT3 signaling, which together also play a role in Th17 responses. (c) Infection also upregulates hepcidin expression [201]. Except HCV, infection or stimuli in general that invoke a systemic inflammatory response are likely to induce liver hepcidin expression, reduce serum iron, and increase iron accumulation in reticuloendothelial cells. (i) In bacterial infection, local neutrophils and M$\mathrm{\Phi }$s also synthesize hepcidin in response to Gram-positive (group A Streptococcus) and Gram-negative (e.g., Pseudomonas aeruginosa or Salmonella typhimurium) bacteria in a TLR4-dependent fashion. Similarly in systemically, P. aeruginosa increases liver hepcidin mRNA levels. (ii) During parasitic infection, increased systemic hepcidin levels are observed during the blood stage of Plasmodium infection. Thus, lower serum iron levels and anemia are common in malaria. (iii) During viral infection, influenza A and Candida albicans increase liver hepcidin with concomitant reduction of transferrin saturation in animal models in which pathogens likely increase hepcidin via an inflammatory STAT3-mediated response [201].

The antioxidative property (please refer to 3.1 (1) to (6) & 4.1) of polyphenols could protect against antiphospholipid syndrome (APS), a prothrombotic autoimmune disease being characterized by elevated auto-antibodies against phospholipid (cardiolipin), $\beta$2-glycoprotein I ($\beta$2 GPI), and/or prothrombin. Oxidative stress plays a key contributory role in APS pathogenicity of thrombosis, preeclampsia, and inflammation. (a) These antibodies activate neutrophil NOX and impair mitochondrial respiration, both of which promote ROS production [202]. (b) Oxidized $\beta$2GPI has a disulfide bridge between C32 and C60 within domain I near B-cell epitope in the N-terminus, while another disulfide bridge is formed between C326 and C288 in the domain V near T-cell epitope in the C-terminus. The oxidized $\beta$2GPI immune complex causes EC damage/injury and activates protease disulfide isomerase; as a result, tissue factor is decrypted and activated, while FXI disulfide bridge is cleaved to become FXIa. Thus, APS manifests as thrombosis, inflammation, and preeclampsia [202, 203]. The $\beta$2GPI immune complex also activates the classical pathway of complement, which leads to not only thrombosis but preeclampsia.

Age-related macular degeneration (AMD) is a multifactorial disease of the retina (e.g., changes in retinal vasculature), featuring degeneration and loss of photoreceptors and retinal pigment epithelium (RPE) cells. AMD pathogenesis includes oxidative stress for degeneration and death of retinal cells, which are mainly associated with aging, ROS overproduction, reduced antioxidants and antioxidant enzymes, and accumulation of damages to mitochondrial DNA. The macula concentrates light and displays high metabolic activity and high oxygen consumption associated with intense blood flow. In addition, inflammation in RPE, mutations in the complement factor H, epigenetic dysregulation, angiogenesis (e.g., upregulated TGFBR1, VEGF-A), HDL-C pathway (e.g., ApoE, CETP, and LIPC upregulation), immune dysregulation, etc. are also involved. Current treatments involve VEGF inhibitors and diet supplementation with vitamins C and E, zinc, copper lutein, n-3 FAs, and zeaxanthin.

Polyphenols with anti-oxidantive (please refer to 3.1 (1) to (6) & 4.1), anti-inflammatory (please refer to 4.2.3), anti-angiogenic (please refer to 3.3 (23)), and anti- aging/senescence (please refer to 3.2 (8) & (15), 3.3 (33)) activities contribute to AMD relief. (a) The anti-oxidative stress is mainly achieved by induced Nrf2 activation (please refer to 3.1 (6)), reduced A2E photooxidation, and suppressed mitochondrial dysfunction (please refer to 3.2 (7)). (b) The anti-inflammatory action in RPE cells is associated with downregulation of various IL signaling pathways, including IL-6/JAK2 (Janus kinase 2)/STAT3 (please refer to 3.3 (28)) as well as suppressed expressions of iNOS, COX2, TNF (please refer to 3.2 (11)), and complement factor B. (c) The ability to inhibit IP3K/AkT (please refer to 3.3 (22)) leads to BcL2 upregulation and Bax and caspase-3,9 inactivation for anti-apoptosis. (d) The upregulation on phagocytosis contributes to improve impaired cellular waste clearance, including AMD-specific deficient phagocytosis of the A$\beta$42 peptide and autophagy. (e) The anti-angiogenesis (please refer to 3.3(22) PI3K/AkT/mTOR inhibition and ref. [36]) is accomplished by suppressed EMT and VEGF.

In addition to in vitro cellular actions [204, 205], clinical potentials of polyphenols (e.g., curcumin, resveratrol, EGCG, flavonoids, etc.) in treating autoimmune diseases (RA, psoriasis, MS, etc.) have recently been reported and reviewed [206, 207, 208, 209, 210, 211, 212, 213, 214, 215]. (a) Concerning immunomodulation of Th17 downregulation, (i) EGCG reduces Th1 differentiation and numbers of Th17 and Th9 cells [204]. (ii) Grape seed pro-anthocyanidin extract exhibits anti-arthritic properties by upregulating the number of Tregs that contribute to the maintenance of immune tolerance and, therefore, the inhibition of autoimmunity [205] and by maintaining the balance between Th17/Treg for attenuating autoimmunity. Green tea polyphenol EGCG also induces Tregs, which similarly easing autoimmunity [207]. (iii) Rresveratrol decreases Th17 cell numbers; inhibited Th17 cell differentiation through the downregulation of phospho-STAT3/ROR$\gamma$t, whereas it promoted Treg differentiation by upregulating phospho-STAT5/Foxp3 [216]. Th17 readily marks autoimmunity [217]. (iv) Curcumin inhibits IL-17 production, easing autoimmune encephalomyelitis, epidermal hyperproliferation, abnormal keratinocyte differentiation, angiogenesis with blood vessel dilatation, and excess Th-1 and Th-17 cell infiltration, main histopathological features of psoriasis [218]. (b) In view of autoimmunity often leading to chronic inflammation, vice versa [102], diverse polyphenolic anti-inflammatory effects naturally ease autoimmunity. For instance, downregulation on TLR expression, NF$\kappa$B, and proinflammatory cytokines (TNF$\alpha$, IL-1$\beta$/6) by curcumin in part contributes to antiinflammation and ease autoimmunity. By downregulating inflammatory cytokines such as IL-1$\beta$, IL-6, IL-12, TNF-$\alpha$ and IFN-$\gamma$ and associated JAK-STAT, AP-1, and NF-$\kappa$B signaling pathways in immune cells, curcumin inhibits autoimmune diseases [209]. (c) In conjunction with oxidative stress leading to autoimmunity (e.g., RA), the anti-oxidative stress (please refer to 3.1 (1) to (6) & 4.1) by polyphenols could ease RA [219].

The immuomodulation by polyphenols has been reported as translational studies [220, 221, 222, 223, 224, 225]. (a) In response to the immunomodulation (please refer to 3.4 (46)), for instance, shifting Th1/Th2 balance, (i) polyphenols (e.g., flavonoids, caffeic acid, etc.) could affect allergic sensitization and re-exposure to the allergen, which is largely mediated by binding to allergic protein, suppressed MHC II expression or co-stimulatory molecules (CD80, CD86), decreased Th2 cytokines, T inactivation, etc.; (ii) polyphenols could also regulate the Th1/Th2 balance and inhibit antigen-specific IgE antibody formation, showing asthma relieving; (iii) curcumin inhibits experimental allergic encephalomyelitis by blocking IL-12 signaling through JAK/STAT pathway; (iv) polyphenols also improve allergic contact hypersensitivity by regulating the balance of Th1/Th2/Th17/Treg cell subsets; (v) by activation of Th1 and inhibition of Th2 and Th17 in a mouse model, gallic acid alleviates nasal inflammation of allergic rhinitis; and (vi) quercetin inhibits histamine production and proinflammatory mediators and regulates the Th1/Th2 stability/balance with the potential effect on allergic diseases. (b) Polyphenols increase the growth of probiotics: Bifidobacterium and Lactobacillus, known to have beneficial impacts in food allergies. (c) By targeting the pathogenesis of allergy [226, 227, 228, 229, 230, 231, 232, 233], the effective polyphenolic anti-oxidative stress (please refer to 3.1 (1) to (6) & 4.1) readily eases allergic asthma, atopic dermatitis, and beyond.

(a) Till now, phytochemical aspirin [234] remains mostly recommended for cardioprotection; the American Heart Association strongly advocates low dose NSAID aspirin (e.g., 80 mg) daily for healthy hearts. (i) Its classical COX1 inhibition arrests PGE2 and TxA2 production; PGE2 is proinflammatory, while TxA2 is responsible for vasoconstriction and platelet aggregation. (ii) Such common blood-thinner aspirin essentially activates AMPK and promotes resolvin (Rv) formation from n-3 PUFAs [108, 123], which presents a wide range of antiinflammation. (iii) In transcellular metabolisms, COX-2 acetylation by aspirin undergoing conformational changes leads to 18R-HpEPA or 17R-HpDHA formation [235]. The R form derivatives are continually metabolized by 5-LOX and epoxide hydrolase in neutrophils; thus, RvE1 and at-RvD1 are formed from EPA and DHA, respectively. In a close relation to cardioprotection, RvE1 reduces ADP-stimulated platelet aggregation, TxA2 generation, P-selectin mobilization, and actin polymerization in a calcium-independent manner; RvE1 counter-regulation of ADP activation is ChemR23-dependent [123]. (iv) Furthermore, acetylated COX-2 catalyzes AA conversion to 15(R)-HETE that then through 5-LOX reaction followed by hydrolysis results in epi-LXA4 and epi-LXB4 derivatives, two potent anti-inflammatory mediators. Beyond cardioprotection, aspirin, a “wonder drug”, has also been used for diabetes, colorectal cancer, inflammation, Alzheimer’s, and many other medical applications. (b) Ever since compactin or mevastatin being extracted from fungi by Endo group in 1976 [236], statin family compounds have been identified to competitively inhibit HMG-CoAR, a regulatory enzyme in the pathway, for effectively blocking cholesterol de novo biosynthesis in lowering blood cholesterol and offering cardioprotection. Beyond hypocholesterolemic action, statins also exhibit anti-oxidation (NOX inhibition, HO-1 activation, and Nrf2 activation), antiinflammation (CRP suppression [116], AMPK activation [113], eNOS activation, FOXO upregulation, IKK inhibition, NF$\kappa$B inactivation, JAK/STAT inhibition [114, 115], PI3K/AkT/mTOR inhibition, NLPR3 inactivation, increased IL-10, attenuated proinflammatory biomarkers, etc.), anti-thrombosis (platelet aggregation, tPA induction, downregulation of PAI-1 and TF expression, etc.), and anti-hypertension (decreased ET-1 expression, upregulated eNOS and NO bioavailability, and downregulated AT${}_1$R expression). (c) Metformin (e.g., galegine or isoamylene guanidine) originating from herb Galega officinalis has been developed into anti-diabetes therapy, decreasing blood glucose inputs (hepatic gluconeogenesis and intestinal glucose absorption) and improving insulin sensitivity (increased peripheral glucose uptake and utilization). In addition, the ability to activate AMPK readily shows anti-oxidative stress and anti-inflammatory effects, being referred to as another “wonder drug” including cancer chemoprevention. (d) Terpenoid paclitaxel, also known as taxol from bark of pacific yew tree (Taxus brevifolia), is used for treating lung, ovarian, and breast cancer, as well as Kaposi sarcoma, gastroesophageal, endometrial, cervical, prostate, and head and neck cancers, in addition to sarcoma, lymphoma, and leukemia, killing tumors by mitotic arrest. In principle, paclitaxel stabilizes the microtubule polymer and protects it from disassembly; chromosomes are unable to achieve a metaphase spindle configuration, thus blocking the progression of mitosis and prolonging activation of the mitotic checkpoint for triggering apoptosis or reversion to the G0-phase of the cell cycle without cell division. The mitotic checkpoint delays separation of the chromosomes, which enter mitosis as replicated pairs of sister chromatids, until each pair has made stable attachments to both poles of the mitotic spindle. The presence of a small number of unattached kinetochores arrests cells in mitosis (e.g., metaphase and contain near-normal, bipolar spindles) by inhibiting the anaphase-promoting complex/cyclosome. Thus, such mitotic arrest results in either cell death during mitosis or an abnormal exit from mitosis to form a tetraploid G1 cell without chromosome segregation or cytokinesis. In addition, it is proposed that taxol might directly cause cell death in interphase without having an affected earlier phase in the mitosis. (e) Potent immunosuppressive and anti-proliferative rapamycin disrupts cytokine signaling that promotes lymphocyte growth and differentiation. (i) Rapamycin impedes progression through the G1/S transition of the proliferation cycle, resulting in a mid-to-late G1 arrest. Initially, rapamycin binds to intracellular proteins (FKBP), thereby forming a unique effector molecular complex. The FKBP-rapamycin complex specifically targets mTOR, a Ser/Thr kinase on the upstream of (p70s6K) and cdk2-cyclin E. Thus, rapamycin leads to p70s6k inhibition or p27-induced cdk2-cyclin E inhibition, downregulating cell growth and proliferation by cell cycle arrest. (ii) Its inhibition on mTORC1 naturally suppresses purine/pyrimidine biosynthesis, reducing protein expression and cell proliferation. (iii) Its function in autophagy induction also exhibits anti-infections by decreased proliferation and growth for pathogen clearance and death. The clinical application of rapamycin includes inflammatory (e.g., obesity) and aging related pathological conditions such as cognition decline, Alzheimer’s, cancer, and kidney, heart, and autoimmune diseases [34, 35, 36, 37, 38, 39, 237]. (f) Named after mould Penicillium notatum, penicillins, a family of broad spectrum $\beta$-lactam antibiotics, are effective against staphylococcal and pseudomonal bacterial infection by blocking peptidoglycan biosynthesis (transpeptidases inhibition) and glycosylation in membrane/cell wall synthesis.

The well-known modes of actions could build polyphenols suitable candidates for therapeutic drug development. Concerning drug biochemical actions, (a) polyphenol-induced AMPK activation is analogous to anti-inflammatory (e.g., aspirin, methotrexate, pemetrexed, acadesine, and salicylate) [238] and anti-diabetes (e.g., metformin, phenformin, and A769662) agents [239]. It is noted that AMPK activation is a key metabolic regulator for metabolic symptoms; (b) its direct and indirect mTORC1 inhibition could make polyphenols compatible to rapamycin benefits in clinical practices. Such mTORC1 inhibition could also lead to longevity benefits along with polyphenol-induced AMPK/SirT1 activation similar to caloric restriction; (c) polyphenol-mediated signaling enzyme/pathway inhibition such as IP3K/AkT/mTOR, PKC, MAPK/ERK, NF$\kappa$B, etc. readily confer anti-proliferation and pro-apoptosis in anti-cancer strategies, neuroprotection, and beyond; and (d) in addition to powerful autophagic consequence of antioxidation and antiinflammation, autophagy upregulation per se by polyphenols could play a unique role in combating a host of diseases such as inflammation, cancer, neurodegeneration, infection, etc.