Corinne Vanucci-Bacqué

Florence Bedos-Belval

Anti-inflammatory Activity of Naturally Occuring Diarylheptanoids -A Review

Keywords: anti-inflammatory activity, natural diarylheptanoids, inflammatory mediator, macrocycles AA: ascorbic acid, ABTS: 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid, Akt: Protein kinase B, Api :-D-apiofuranosyl, BMDC: bone marrow derived cell, COX: cyclooxygenase, DPPH : 2,2-diphenyl-1-picrylhydrazyl, EGFR: epidermal growth factor receptor, ERK: extracellular signal-regulated kinase, Glc

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Introduction

Inflammation is a combination of reactions generated by the body due to an aggression which can be external, such as an injury, infection or trauma, or internal, such as those observed in autoimmune diseases. [START_REF] Liu | Biomarkers of chronic inflammation in disease development and prevention: challenges and opportunities[END_REF] The inflammation process is complex and divided mainly into acute and chronic inflammation. Acute inflammation is the immediate response to an aggressive agent and is essential to maintain the organism integrity. To the opposite, chronic inflammation does not heal spontaneously, persists over several months or even years and sustains many pathologies such as rheumatoid arthritis, 2 inflammatory bowel disease, [START_REF] Yeshi | Revisiting Inflammatory Bowel Disease: Pathology, Treatments, Challenges and Emerging Therapeutics Including Drug Leads from Natural Products[END_REF] atherosclerosis, [START_REF] Bäck | Inflammation and its resolution in atherosclerosis: mediators and therapeutic opportunities[END_REF] diabetes, [START_REF] Berbudi | Type 2 Diabetes and its Impact on the Immune System[END_REF] cancers [START_REF] Piotrowski | Interplay between inflammation and cancer[END_REF] and Alzheimer's disease. [START_REF] Maccioni | Inflammation: A Major Target for Compounds to Control Alzheimer's Disease[END_REF] These inflammatory diseases are self-induced by excessive secretion of numerous pro-inflammatory mediators such as cytokines, reactive oxygen species (ROS) and nitric oxide (NO) radicals.

The therapy of inflammation mainly focuses on steroid and non-steroid anti-inflammatory drugs (NSAIDs). Corticosteroid is one of the most commonly used medications and can regulate the fat and protein metabolisms. However, corticosteroid therapy has side-effects such as sepsis and gastrointestinal hemorrhage, making their long-term consumption controversial and representing an important limitation to the use of these drugs. NSAIDs, a group of different chemical classes without any steroidal structure, display also diverse adverse-effects (mainly digestive, renal and cutaneous) making their long-term use inappropriate. [START_REF] Ghlichloo | Nonsteroidal Anti-inflammatory Drugs (NSAIDs)[END_REF] Although continuous efforts have been made to discover molecules with anti-inflammatory therapeutic value in organic and medicinal chemistry, finding potentially non-toxic and effective substances for inhibiting inflammation is always urgently required.

Toward this aim, diarylheptanoids, a class of secondary plant metabolites with a wide range of biological activities including anti-inflammatory [see ref cited in this review], pro-apoptotic, [START_REF] Tian | Cytotoxic diarylheptanoid induces cell cycle arrest and apoptosis via increasing ATF3 and stabilizing p53 in SH-SY5Y cells[END_REF] antiinfluenza, [START_REF] Sawamura | In Vitro and in Vivo Anti-Influenza Virus Activity of Diarylheptanoids Isolated from Alpinia Officinarum[END_REF] anti-emetic [START_REF] Yang | Structure-antiemetic-activity of some diarylheptanoids and their analogues[END_REF] and anti-cancer activities [START_REF] Uto | Antiproliferative and Pro-Apoptotic Activity of Diarylheptanoids Isolated from the Bark of Alnus japonica in Human Leukemia Cell Lines[END_REF] have been attracting growing interest over the last few decades. Diarylheptanoids consist of a 1,7-diphenylheptane skeleton. They can be subdivided into linear and macrocyclic compounds (Fig. 1). The latter can be further distributed into biaryl and diarylether structures, depending whether the aromatic rings are connected to form [7.0]-meta,metaor [7.1]-meta,para-cyclophanes respectively. The aromatic rings of diarylheptanoids are often hydroxylated or methoxylated. The C7-chain essentially incorporates ketone, alkene and alcohol functionalities, but also 1,5-or 3,6-oxy bridges (pyran or furan ring), flavonoid (e.g. chalcone, flavanone) and glycosyl moieties. Historically, the yellow pigment curcumin has been characterized as the first diarylheptanoid and the extensive research on naturally occurring analogues is still ongoing. Approaching 500 diarylheptanoids have been isolated and characterized so far. [START_REF] Alberti | Characterization of diarylheptanoids: An emerging class of bioactive natural products[END_REF]

Fig. 1. Representative diarylheptanoid skeletons

This review provides a comprehensive overview of 182 naturally occurring diarylheptanoids displaying anti-inflammatory activity. Most of them have been isolated from plant genus including Curcuma, Zingiber, Alpinia (Zingiberaceae), Alnus, Corylus, Betula, Carpinus (Betulaceae), Myrica (Myricaceae), Acer (Aceraceae) and Juglans (Juglandaceae), which roots, leaves and barks are often used in traditional Asian medicine. Figure 2 illustrates the distribution of the 182 diarylheptanoids between the different genus.

Fig. 2. Sources of anti-inflammatory diarylheptanoids

Materials and methods

Sources, search and selection modes

This review compiled extensive literature (from 1982 to June 2020) of the anti-inflammatory activity of natural diarylheptanoids evidenced by in vitro and in vivo studies with quantified data. All articles without any mention of anti-inflammatory assay were excluded. All values in the present review are rounding values. Positive control values are mentioned as reference point whenever they were cited in the referenced article. Most of positive references used in this review are acid ascorbic (AA), indomethacin, N-monomethyl-L-arginine (L-NMMA). AA acts as anti-inflammatory drugs through its strong antioxidant properties. [START_REF] Sorice | Ascorbic Acid: Its Role in Immune System and Chronic Inflammation Diseases[END_REF] Indomethacin is a non-steroid anti-inflammatory drug (NSAID) acting as non-selective inhibitor of the isoenzymes cyclooxygenases 1/2 (COX-1/COX-2). [START_REF] Lucas | The Pharmacology of Indomethacin[END_REF] L-NMMA is an inhibitor of inducible nitric oxide synthase (iNOS). [START_REF] Ianaro | A nitric oxide synthase inhibitor reduces inflammation, down-regulates inflammatory cytokines and enhances interleukin-10 production in carrageenin-induced oedema in mice[END_REF] Curcumin and its better known derivatives demethoxycurcumin and bis-demethoxycurcumin, major constituents of Curcuma longa rhizomes, have been deliberately excluded from this review. Curcumin is low-soluble, unstable in aqueous media, poorly bioavailable, non-selective [START_REF] Nelson | The Essential Medicinal Chemistry of Curcumin: Miniperspective[END_REF] and has already been widely reviewed for its pleiotropic activity. [START_REF] Salehi | The therapeutic potential of curcumin: A review of clinical trials[END_REF][START_REF] Hewlings | Curcumin: A Review of Its' Effects on Human Health[END_REF] Only accessible online articles in English available via classic databases such as Pubmed and Scifinder were considered. Patents, proceedings, conferences abstracts and theses were rejected.

Studies descriptions

In the pathological inflammatory process, immune cells such as macrophages are first activated, then recruited to the injury site, resulting in the generation of ROS that damage macromolecules including DNA. At the same time, these inflammatory cells produce also large amounts of inflammatory mediators which further activate multiple signal transduction cascades and transcription factors associated with inflammation. The nuclear factor kappa-B (NF-κB), mitogen-activated protein kinase (MAPK), and janus kinase (JAK), signal transducers and activators of transcription (STAT) signaling pathways are involved in the development of the classical pathway of inflammation. Thus, the NF-κB transactivation will increase the production of pro-inflammatory cytokines such as tumor necrosis factor- (TNF-, interleukin-1 (IL-1and interleukin-6 (IL-6), and the activity of important proinflammatory enzymes such as inducible nitric oxide synthase (iNOS) and cyclooxygenases-2 (COX-2) and their derived production NO and prostaglandin E2 (PGE2), respectively. [START_REF] Chen | Inflammatory responses and inflammation-associated diseases in organs[END_REF] The anti-inflammatory activity of a compound is thus usually highlighted by evaluating its potency to inhibit the proinflammatory cytokines/mediators production and the inflammatory protein and enzyme expression. Among the mentioned articles in this review, 182 diarylheptanoids were selected for their reported anti-inflammatory activity. Their toxicity was evaluated by measuring cell viability with the 3-(4,5dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, and their antioxidant potency was essentially estimated using 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical, nitro-blue tetrazolium (NBT) superoxide or 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid (ABTS) radical scavenging assays. Their in vitro and/or in vivo anti-inflammatory activities were measured through different assays. Among the examined methods for in vitro evaluation, cell stimulation (mostly by lipopolysaccharides (LPS)) to induce inflammation followed by quantification of production/inhibition and RNA expression of inflammatory mediators such as NO, TNF-, IL-1, IL-6 or PGE2, of transcription factor such as NF-B, or inflammatory enzymes such as iNOS or COX-2, were applied in the majority of the studies. Most of the assays were conducted using RAW 264.7 or J774.1 murine macrophage cell lines, mouse peritoneal macrophages, HepG2 cells, N-11 or BV-2 microglia cells and activated bone marrow derived (BMD) macrophages. In vivo studies were performed essentially using the carrageenan-induced hind paw edema test in rats and 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced ear inflammatory edema assay in mice. All these assays are relevant for inflammation studies.

The reported data will be subdivided into two structure types, including linear (Tables 1 and2) and macrocyclic diarylheptanoids (Tables 3 and4).

Linear natural diarylheptanoids

The structures of the selected linear diarylheptanoids are compiled in Table 1 (compounds 1-133) for compounds with a linear heptanoid chain and in Table 2 (compounds 134-150) for derivatives including 1,5-oxo bridge in the seven-carbon chain skeleton. Compound 151 with a 3,6-oxo bridge in the C7chain is depicted in Fig. 3. Stereochemistry is reported as mentioned in the original articles. Alnus sibirica [START_REF] Le | Anti-inflammatory and anti-oxidative activities of phenolic compounds from alnus sibirica stems fermented by lactobacillus plantarum subsp. argentoratensis[END_REF][START_REF] Yin | Inhibitory activity of allergic contact dermatitis and atopic dermatitis-like skin in BALB/c mouse through oral administration of fermented barks of Alnus sibirica[END_REF][START_REF] Wang | Inhibitory Effects on NO Production and DPPH Radicals and NBT Superoxide Activities of Diarylheptanoid Isolated from Enzymatically Hydrolyzed Ehthanolic Extract of Alnus sibirica[END_REF] Alnus formosana 27 Alnus japonica [START_REF] Kim | Nitric oxide and prostaglandin E2 synthesis inhibitory activities of diarylheptanoids from the barks of Alnus japonica steudel[END_REF][START_REF] Lee | Diarylheptanoid hirsutenone prevents tumor necrosis factor-α-stimulated production of inflammatory mediators in human keratinocytes through NF-κB inhibition[END_REF][START_REF] Lee | Hirsutenone inhibits lipopolysaccharideactivated NF-κB-induced inflammatory mediator production by suppressing Toll-like receptor 4 and ERK activation[END_REF][START_REF] Jeong | Atopic dermatitis-like skin lesions reduced by topical application and intraperitoneal injection of hirsutenone in NC/Nga mice[END_REF][START_REF] Seo | Hirsutenone reduces deterioration of tight junction proteins through EGFR/Akt and ERK1/2 pathway both converging to HO-1 induction[END_REF] Alnus hirsuta [START_REF] Cai | Diarylheptanoids from Alnus hirsuta inhibit the NF-kB activation and NO and TNF-alpha production[END_REF] Alnus tinctoria [START_REF] Ko | Modulation effect of diarylheptanoids on interleukin 1β-related immune responses of bone-marrow macrophage[END_REF] -

- O  4 (E) - - OH OH - OH OH H Hirsutanonol (3)
Alnus sibirica [START_REF] Le | Anti-inflammatory and anti-oxidative activities of phenolic compounds from alnus sibirica stems fermented by lactobacillus plantarum subsp. argentoratensis[END_REF][START_REF] Wang | Inhibitory Effects on NO Production and DPPH Radicals and NBT Superoxide Activities of Diarylheptanoid Isolated from Enzymatically Hydrolyzed Ehthanolic Extract of Alnus sibirica[END_REF] Alnus formosana [START_REF] Lai | A comprehensive investigation of anti-inflammatory diarylheptanoids from the leaves of Alnus formosana[END_REF] Alnus japonica 28 Alnus hirsuta [START_REF] Cai | Diarylheptanoids from Alnus hirsuta inhibit the NF-kB activation and NO and TNF-alpha production[END_REF][START_REF] Lee | Diarylheptanoids with In Vitro Inducible Nitric Oxide Synthesis Inhibitory Activity from Alnus hirsuta[END_REF][START_REF] Lee | Inhibition of Cyclooxygenase-2 Expression by Diarylheptanoids from the Bark of Alnus hirsuta var. sibirica[END_REF] Alnus sibirica 23 Alnus formosana [START_REF] Lai | A comprehensive investigation of anti-inflammatory diarylheptanoids from the leaves of Alnus formosana[END_REF][START_REF] Choi | Inhibition of activated responses in dendritic cells exposed to lipopolysaccharide and lipoteichoic acid by diarylheptanoid oregonin[END_REF][START_REF] Lee | Oregonin inhibits lipopolysaccharide-induced iNOS gene transcription and upregulates HO-1 expression in macrophages and microglia[END_REF] Alnus japonica [START_REF] Kim | Nitric oxide and prostaglandin E2 synthesis inhibitory activities of diarylheptanoids from the barks of Alnus japonica steudel[END_REF][START_REF] Han | Effects of diarylheptanoids on the tumor necrosis factor-α-induced expression of adhesion molecules in human umbilical vein endothelial cells[END_REF][START_REF] Choi | Inhibition of activated responses in dendritic cells exposed to lipopolysaccharide and lipoteichoic acid by diarylheptanoid oregonin[END_REF][START_REF] Chi | Oregonin inhibits inflammation and protects against barrier disruption in intestinal epithelial cells[END_REF] Alnus hirsuta [START_REF] Lee | Diarylheptanoids with In Vitro Inducible Nitric Oxide Synthesis Inhibitory Activity from Alnus hirsuta[END_REF][START_REF] Lee | Inhibition of Cyclooxygenase-2 Expression by Diarylheptanoids from the Bark of Alnus hirsuta var. sibirica[END_REF][START_REF] Hu | Antioxidative activity and anti-inflammatory effects of diarylheptanoids isolated from Alnus hirsuta[END_REF] Alnus nepalensis [START_REF] Saxena | Diarylheptanoids from Alnus nepalensis attenuates LPS-induced inflammation in macrophages and endotoxic shock in mice[END_REF] Alnus tinctoria [START_REF] Ko | Modulation effect of diarylheptanoids on interleukin 1β-related immune responses of bone-marrow macrophage[END_REF] Alnus incana Alnus sibirica [START_REF] Le | Anti-inflammatory and anti-oxidative activities of phenolic compounds from alnus sibirica stems fermented by lactobacillus plantarum subsp. argentoratensis[END_REF][START_REF] Wang | Inhibitory Effects on NO Production and DPPH Radicals and NBT Superoxide Activities of Diarylheptanoid Isolated from Enzymatically Hydrolyzed Ehthanolic Extract of Alnus sibirica[END_REF] Alnus formosana [START_REF] Lai | A comprehensive investigation of anti-inflammatory diarylheptanoids from the leaves of Alnus formosana[END_REF] Alnus japonica [START_REF] Kim | Nitric oxide and prostaglandin E2 synthesis inhibitory activities of diarylheptanoids from the barks of Alnus japonica steudel[END_REF] -

- (R)-OH - - - - OH OH - OH OH H Rubranoside A (8)
Alnus sibirica [START_REF] Le | Anti-inflammatory and anti-oxidative activities of phenolic compounds from alnus sibirica stems fermented by lactobacillus plantarum subsp. argentoratensis[END_REF] Alnus formosana [START_REF] Lai | A comprehensive investigation of anti-inflammatory diarylheptanoids from the leaves of Alnus formosana[END_REF] Alnus japonica [START_REF] Kim | Nitric oxide and prostaglandin E2 synthesis inhibitory activities of diarylheptanoids from the barks of Alnus japonica steudel[END_REF] -

- (R)-O-GLc - - - - OH OH H OH OH H Rubranoside B (9)
Alnus sibirica [START_REF] Le | Anti-inflammatory and anti-oxidative activities of phenolic compounds from alnus sibirica stems fermented by lactobacillus plantarum subsp. argentoratensis[END_REF] Alnus formosana [START_REF] Lai | A comprehensive investigation of anti-inflammatory diarylheptanoids from the leaves of Alnus formosana[END_REF] Alnus hirsuta [START_REF] Hu | Antioxidative activity and anti-inflammatory effects of diarylheptanoids isolated from Alnus hirsuta[END_REF] - [START_REF] Jang | Diarylheptanoids from Curcuma phaeocaulis Suppress IL-6-Induced STAT3 Activation[END_REF] -

- (R)-O-Xyl - - - - OH OH H OH OH H 10 Alnus japonica 28 - - (R)-O-Xyl(3→1)-GLc - - - - OH OH H OH OH H 11 Alnus japonica 28 - - (R)-O-GLc(6→1
- (R)-OH - (R)-OH - - OCH3 OCH3 H OCH3 OCH3 H Curcuma phaeocaulis 81   1 (E) (R)-OH - (S)-OH - - OCH3 OCH3 OCH3 OCH3 OCH3 H Curcuma phaeocaulis 81   1 (E) (R)-OH - (S)-OH - - OCH3 OCH3 H OCH3 OCH3 H Curcuma phaeocaulis 81   1 (E) (R)-OCH3 - (S)-OH - - OCH3 OCH3 H OCH3 OCH3 H Curcuma phaeocaulis 81   1 (E) OCH3 - (R)-OH - - OCH3 OCH3 H OCH3 OCH3 H Curcuma phaeocaulis 81   1 (E) O     6 (E) H OH H H OH H Curcuma phaeocaulis 81 OH O - O  6 (E) OCH3 OH H OCH3 OH H Plantegineoside A (115) Tacca plantaginea 82 - - O - - - - OH O-GLc H OH O-GLc H Plantegineoside B (116) Tacca plantaginea 82 - - (R)-OH - - - - OH O-GLc H OH O-GLc H Tacca plantaginea 82 - - (R)-O-GLc - (R)-OH - - H OH H H OH H Tacca plantaginea 82 - - (R)-O-GLc - (R)-OH - - OH OH H H OH H Tacca plantaginea 82 - - (R)-O-GLc - (R)-OH - -
(R) ─ (R)-OH ─ (R) ─ ─ OH H 144 Kampferia galanga 74 (R) ─ (R)-O-Glc ─ (R) ─ ─ OH H 145 Kampferia galanga 74 (S) ─ (R)-OH ─ (S) ─ ─ OH H 146 Kampferia galanga 74 (S) (S)-OH (R)-OH ─ (S) (S)-OH ─ OCH3 H Kravanol D (147) Amomum kravanh 89 (R) (R )-Y (R)-OH ─ (S) (R)-OH ─ OCH3 OCH3 Kravanol G (148) Amomum kravanh 89 (R) (R)-OH (S)-OH ─ (S) ─ ─ OCH3 OCH3 Kravanol H (149) Amomum kravanh 89 (R) ─ (R)-OH ─ (S) ─ O OCH3 OCH3 Kravanol B (150) Amomum kravanh 89 (R) ─ ─ ─ (S) (S)-OH ─ OCH3 OCH3
Fig. 3. Structure of renealtin A (151) [START_REF] Raju | Diarylheptanoids with anti-inflammatory activity from the rhizomes of Pleuranthodium racemigerum (Zingiberaceae)[END_REF][START_REF] Zhang | Diarylheptanoids with NO production inhibitory activity from Amomum kravanh[END_REF] Diarylheptanoids are the dominant constituents within the genus Alnus plants which are well known for their traditional uses in the treatment of various diseases like cancer, hepatitis, inflammation etc… Some of these diarylheptanoids exhibiting potent antioxidant and anti-inflammatory effects are discussed in the review. [START_REF] Sati | Bioactive constituents and medicinal importance of genus Alnus[END_REF] In particular, a series of tetraphenolic linear compounds have attracted much interest and been subjected of numerous biological evaluations.

Among them, muricarpon B (1), initially characterized in 2006 from Amomum muricarpum (Zingiberaceae), [START_REF] Giang | New Diarylheptanoids from Amomum muricarpum Elmer[END_REF] was isolated by Korean Min-Won Lee's team from fermented barks of Alnus sibirica (Betulaceae) and reported intensive biological studies to evaluate its anti-inflammatory activity. According to the various reported studies, it showed potent antioxidant activities in DPPH radical scavenging assays with IC50 values of 20.1 M, [START_REF] Le | Anti-inflammatory and anti-oxidative activities of phenolic compounds from alnus sibirica stems fermented by lactobacillus plantarum subsp. argentoratensis[END_REF] 24.1 M 24 and 38.7 M 25 (compared to AA: IC50 = 46.0, [START_REF] Le | Anti-inflammatory and anti-oxidative activities of phenolic compounds from alnus sibirica stems fermented by lactobacillus plantarum subsp. argentoratensis[END_REF] 24.8 [START_REF] Yin | Inhibitory activity of allergic contact dermatitis and atopic dermatitis-like skin in BALB/c mouse through oral administration of fermented barks of Alnus sibirica[END_REF] and 44.7 [START_REF] Wang | Inhibitory Effects on NO Production and DPPH Radicals and NBT Superoxide Activities of Diarylheptanoid Isolated from Enzymatically Hydrolyzed Ehthanolic Extract of Alnus sibirica[END_REF] M respectively), NBT superoxide radical scavenging effect with IC50 values of 30.1 M 24 and 12.7 M 25 (compared to allopurinol as positive control, IC50 = 8 24 and 3.9 [START_REF] Wang | Inhibitory Effects on NO Production and DPPH Radicals and NBT Superoxide Activities of Diarylheptanoid Isolated from Enzymatically Hydrolyzed Ehthanolic Extract of Alnus sibirica[END_REF] M respectively) and strong NO production inhibitory activity with IC50 values of 6.6 M, [START_REF] Le | Anti-inflammatory and anti-oxidative activities of phenolic compounds from alnus sibirica stems fermented by lactobacillus plantarum subsp. argentoratensis[END_REF] 22.7 M 24 and 2.6 M 25 in LPS-stimulated RAW 264.7 macrophages (compared to N-monomethyl-L-arginine (L-NMMA) : IC50 = 41.9, [START_REF] Le | Anti-inflammatory and anti-oxidative activities of phenolic compounds from alnus sibirica stems fermented by lactobacillus plantarum subsp. argentoratensis[END_REF] 37.1 [START_REF] Yin | Inhibitory activity of allergic contact dermatitis and atopic dermatitis-like skin in BALB/c mouse through oral administration of fermented barks of Alnus sibirica[END_REF] and 33.9 [START_REF] Wang | Inhibitory Effects on NO Production and DPPH Radicals and NBT Superoxide Activities of Diarylheptanoid Isolated from Enzymatically Hydrolyzed Ehthanolic Extract of Alnus sibirica[END_REF] M respectively). No cytotoxicity activities on RAW264.7 cells was displayed up to 100 µM. Muricarpone B (1) was also isolated from the unusual source Nidus vespae (nest of the paper wasp Polistes) and showed to inhibit NO production with IC50 value of 16.8 M (compared to proteasome inhibitor MG132 (carbobenzoxy-Leu-Leu-leucinal) as positive control : IC50 = 0.1 M) in LPS-stimulated RAW 264.7 macrophages. [START_REF] He | Sesquiterpenoids and Diarylheptanoids from Nidus Vespae and Their Inhibitory Effects on Nitric Oxide Production[END_REF] M-W Lee's team equally isolated and similarly biologically evaluated hirsutenone (2), displaying an additional conjugated double bond compared to muricarpon B. In a similar way, according to the reported studies, it showed antioxidant activities in DPPH radical scavenging assays with IC50 values of 29 M, [START_REF] Le | Anti-inflammatory and anti-oxidative activities of phenolic compounds from alnus sibirica stems fermented by lactobacillus plantarum subsp. argentoratensis[END_REF] 14.1 M 24 and 13.4 M 25 (compared to AA), NBT superoxide radical scavenging effect with IC50 values of 17.6 M 24 and 16.8 M 25 (compared to allopurinol) and NO production inhibitory activity with IC50 values of 5.8 M, [START_REF] Le | Anti-inflammatory and anti-oxidative activities of phenolic compounds from alnus sibirica stems fermented by lactobacillus plantarum subsp. argentoratensis[END_REF] 14.1 M 24 and 0.8 M 25 in LPS-stimulated RAW 264.7 macrophages (compared to L-NMMA). These results are in agreement with those previously obtained on LPSstimulated NO production inhibitory activity of hirsutenone (2) isolated from Alnus formosana (Betulaceae) a species of alder endemic to Taiwan, with IC50 value of 5 M in RAW 264.7 macrophages.

A slight cytotoxicity was mentioned (IC50 value of 39.0 µM with MTT assay on RAW 264.7 macrophages) which could be explained by non-specific Michael addition reactions. [START_REF] Lai | A comprehensive investigation of anti-inflammatory diarylheptanoids from the leaves of Alnus formosana[END_REF] Hirsutenone (2) was also widely evaluated against cytokines production and proteins expression. Isolated from the barks of Alnus japonica (Betulaceae), it was evaluated for its inhibitory activities on NO and prostaglandin E2 production via COX-2 inhibition in interferon- (INF-)-and LPS-activated RAW 264.7 cells. It dosedependently inhibited NO production with an IC50 value of 27.2 g/mL (compared to L-NMMA: IC50 =22.8 g /mL) and reduced the COX-2 level with an IC50 value of 25.0 g/mL (compared to indomethacin : IC50 = 26.2 g /mL). [START_REF] Kim | Nitric oxide and prostaglandin E2 synthesis inhibitory activities of diarylheptanoids from the barks of Alnus japonica steudel[END_REF] Alnus hirsuta (Betulaceae) also provided hirsutenone (2) which was further evaluated for its inhibitory activity against LPS-induced NO and TNF- production and NF-B activation in RAW 264.7 cells. However, it showed very weak activity with IC50 values above 100 M. [START_REF] Cai | Diarylheptanoids from Alnus hirsuta inhibit the NF-kB activation and NO and TNF-alpha production[END_REF] A comprehensive study was conducted by Chung Soo Lee et al. [START_REF] Lee | Diarylheptanoid hirsutenone prevents tumor necrosis factor-α-stimulated production of inflammatory mediators in human keratinocytes through NF-κB inhibition[END_REF] to evaluate the anti-inflammatory activity of hirsutenone on TNF--stimulated human keratinocytes (HEK001). It revealed that this diarylheptanoid attenuated the TNFα-elicited formation of IL-8, PGE2 and chemokine CCL27 in a dose-dependent manner and the TNF-induced production of NO, with inhibitory rates of 33%, 46%, 43% and 37% respectively at 7.5 M.

Hirsutenone decreased inflammatory mediators' production in keratinocytes by inhibiting the activation of nuclear factor NF-κB. The same authors [START_REF] Lee | Hirsutenone inhibits lipopolysaccharideactivated NF-κB-induced inflammatory mediator production by suppressing Toll-like receptor 4 and ERK activation[END_REF] completed this study by evaluating the activity on LPS-stimulated human keratinocytes. IL-1, IL-8 and CCL17 release were inhibited with 39 %, 40% and 51% rates respectively at 7.5 µM in HEK001 keratinocytes. In primary foreskin keratinocytes, IL-1 and CCL17 inhibition rates were 39% and 49% at 7.5 M. Moreover, at this concentration, hirsutenone was shown to inhibit NF-B DNA binding (29.5%) and LPS -induced extracellular signal-regulated kinase (ERK) expression (37%) which suggested that it could prevent LPS-induced inflammatory skin diseases by inhibition of ERK pathway-mediated by NF-B activation. In vivo assays were then conducted by Chung Soo Lee collaborators [START_REF] Jeong | Atopic dermatitis-like skin lesions reduced by topical application and intraperitoneal injection of hirsutenone in NC/Nga mice[END_REF] to evaluate the hirsutenone efficacy on atopic dermatitis-like skin lesions in NC/Nga mice. Intraperitoneal injection of 0.1% of hirsutenone resulted in 51 and 37% inhibition of the IL-4 and IL-5 cytokines levels production respectively. These values increased up to 60 and 74%, after injection of 1% of the active compound. COX-2 and iNOS expressions were equally reduced by 57 and 61 % at a dose of 0.1%, and rise up to 62 and 73% at a dose of 1%. Topical application of hirsutenone at 1% also evaluated was equally effective.

In another study, Sung Hee Lee and co-workers [START_REF] Seo | Hirsutenone reduces deterioration of tight junction proteins through EGFR/Akt and ERK1/2 pathway both converging to HO-1 induction[END_REF] investigated the protective effect of hirsutenone against disruption of the intestinal barrier in vitro and in a mouse model of colitis. Hirsutenone significantly suppressed mRNA expression of TNF-, IL-1 and IL-6, and decreased oxidative stressinduced intestinal epithelial barrier dysfunction by activating both the EGFR/Akt and ERK1/2 pathways, which are involved in the regulation of heme oxygenase 1 (HO-1) expression. Moreover, administration of hirsutenone significantly improved 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced experimental colitis in mice. Hirsutenone stemming from Alnus tinctoria Sarg. (Betulaceae) exhibited IL-1β secretion inhibition in a concentration dependent manner with a reduction rate of 73.4 % at 5 μM in LPSactivated bone marrow derived (BMD) macrophages. [START_REF] Ko | Modulation effect of diarylheptanoids on interleukin 1β-related immune responses of bone-marrow macrophage[END_REF] As shown in this different studies, hirsutenone, demonstrated interesting and applicable antiinflammatory activities for various pathologies where chronic inflammation plays a major role.

Hirsutanonol (3), the hydration product of hirsutenone, was isolated from leaves of Alnus hirsuta, and found by M-W Lee et al. [START_REF] Lee | Diarylheptanoids with In Vitro Inducible Nitric Oxide Synthesis Inhibitory Activity from Alnus hirsuta[END_REF] to inhibit NO production in IFN- and LPS-activated RAW 264.7 cells in a dose dependent manner with an IC50 value of 3.8 M and to suppress the expression of iNOS mRNA. Moreover, the same researcher showed that hirsutanonol dose-dependently inhibited the 12-Otetradecanoylphorbol-13-acetate (TPA)-induced expression of COX-2 protein in immortalized human mammary epithelial MCF-10A cells with inhibitory rates of 27 to 70% in the range 12.5-100 M. [START_REF] Lee | Inhibition of Cyclooxygenase-2 Expression by Diarylheptanoids from the Bark of Alnus hirsuta var. sibirica[END_REF] [START_REF] Wang | Inhibitory Effects on NO Production and DPPH Radicals and NBT Superoxide Activities of Diarylheptanoid Isolated from Enzymatically Hydrolyzed Ehthanolic Extract of Alnus sibirica[END_REF] Hirsutanonol is always extracted from the Alnus genus sources and its anti-inflammatory effects are well documented. However, assays conditions are always different, making comparisons difficult.

Nevertheless, it appears that hirsutanonol is a diarylheptanoid with antioxidant properties and capable of inhibiting the production of various mediators and proteins involved in inflammation.

5-O-Methylhirsutanonol (4), isolated from Alnus japonica leaves, was comprehensively investigated by Jeong et al. [START_REF] Han | Effects of diarylheptanoids on the tumor necrosis factor-α-induced expression of adhesion molecules in human umbilical vein endothelial cells[END_REF] for its anti-inflammatory and related anti-atherosclerotic activities. In particular, diarylheptanoid 4 was efficient against TNF- induced vascular cell adhesion protein 1 (VCAM-1) and intercellular adhesion molecule 1 (ICAM-1) expression with 77 and 21 % inhibition rates respectively at 20 M in human umbilical vein endothelial cells (HUVEC) making it potentially useful in the prevention and treatment of atherosclerosis. Moreover, 5-O-Methylhirsutanonol inhibited ROS production with 37 to 87 % rates in the range 5-50 M, NO release in a dose-dependent manner with IC50 value of 14.5 M, LPS-induced iNOS protein expression at 50 M, TNF- mRNA level with 60 % rates at 50 M and NF-B expression in LPS-activated RAW 264.7 macrophages. In addition, pretreatment with 4 (at 20 and 50 μM) suppressed the induced mRNA expressions of COX-2 and IL-1 but not IL-6. By comparing these results with anti-inflammatory activity of two others diarylheptanoids such as oregonin (mentioned later in this review) and curcumin, the authors considered that diarylheptanoids displaying a ketone and an alcohol function or a 5-O-substituted group as well as diarylheptanoids with two ketones functions on their C7-chain were the most effective in reducing the activation of NF-B. [START_REF] Han | Effect of 5-O-Methylhirsutanonol on Nuclear Factor-κB-Dependent Production of NO and Expression of iNOS in Lipopolysaccharide-Induced RAW264.7 Cells[END_REF] In 2017, M-W Lee et al. [START_REF] Le | Anti-inflammatory and anti-oxidative activities of phenolic compounds from alnus sibirica stems fermented by lactobacillus plantarum subsp. argentoratensis[END_REF] Hirsutanonol 5-O--D-glucopyranoside (5), was isolated from the barks of Alnus japonica [START_REF] Kim | Nitric oxide and prostaglandin E2 synthesis inhibitory activities of diarylheptanoids from the barks of Alnus japonica steudel[END_REF] and stems of Alnus formosana [START_REF] Lai | A comprehensive investigation of anti-inflammatory diarylheptanoids from the leaves of Alnus formosana[END_REF] and Alnus nepalensis. [START_REF] Saxena | Diarylheptanoids from Alnus nepalensis attenuates LPS-induced inflammation in macrophages and endotoxic shock in mice[END_REF] It displayed moderate NO production inhibition and COX-2 level reduction with an IC50 values of 29.4 g/mL and 33.7 g /mL respectively (compared to L-NMMA: IC50 (NO) = 22.8 g /mL and indomethacin: IC50 (COX-2) = 26.2 g /mL) in INF- and LPSactivated RAW 264.7 cells. [START_REF] Kim | Nitric oxide and prostaglandin E2 synthesis inhibitory activities of diarylheptanoids from the barks of Alnus japonica steudel[END_REF] Likewise, LPS-induced NO production was inhibited with IC50 value of 10

M in RAW 264.7 macrophages. [START_REF] Lai | A comprehensive investigation of anti-inflammatory diarylheptanoids from the leaves of Alnus formosana[END_REF] Moreover, 5 was able to reduce the production of cytokines TNF- and IL-6 with 51 and 75 % inhibition rates respectively at 10 µg/mL by inhibiting the expression of NF-B protein in LPS-activated mouse peritoneal macrophages J774A.1. [START_REF] Saxena | Diarylheptanoids from Alnus nepalensis attenuates LPS-induced inflammation in macrophages and endotoxic shock in mice[END_REF] Hirsutanonol 5-O--D-xylopyranoside called oregonin (6), initially isolated in 1974 from Alnus rubra, [START_REF] Karchesy | Structure of oregonin, a natural diarylheptanoid xyloside[END_REF] and found in many Alnus genus sources such as japonica, sibirica, hisuta, formosana and nepalensis, has been widely documented for its biological activities including antioxidant and anti-inflammatory ones. In particular M-W Lee et al. [START_REF] Lee | Diarylheptanoids with In Vitro Inducible Nitric Oxide Synthesis Inhibitory Activity from Alnus hirsuta[END_REF] showed in 2000 that oregonin inhibited NO production in a dosedependent manner with an IC50 value of 14.3 M in INF- and LPS-activated RAW 2647.7 cells and suppressed the iNOS mRNA expression. The same team further highlighted that diarylheptanoid 6 dose-dependently inhibited the TPA-induced expression of COX-2 protein in MCF-10A cells with inhibitory rates of 31.5 to 58 % in the range 12.5-100 M. [START_REF] Lee | Inhibition of Cyclooxygenase-2 Expression by Diarylheptanoids from the Bark of Alnus hirsuta var. sibirica[END_REF] Five years later, they confirmed its activity against LPS, INF--induced production of NO and COX-2 in a dose-dependent manner with IC50 values of 16.7 and 20.7 µg/mL respectively in RAW 264.1 macrophages (compared to L-NMMA: IC50(NO) = 22.8 g /mL and indomethacin: IC50 (COX-2) = 26.2 g /mL). [START_REF] Kim | Nitric oxide and prostaglandin E2 synthesis inhibitory activities of diarylheptanoids from the barks of Alnus japonica steudel[END_REF] In 2017, they reported that oregonin displayed DPPH radical scavenging activity with an IC50 values of 32.1 M and NO production inhibition capacity with an IC50 value of 9.7 M against in LPS-activated RAW 264.1 macrophages (compared to AA : IC50(DPPH) = 46 M and L-NMMA: IC50(NO) = 42 M ). [START_REF] Le | Anti-inflammatory and anti-oxidative activities of phenolic compounds from alnus sibirica stems fermented by lactobacillus plantarum subsp. argentoratensis[END_REF] In a devoted study to oregonin, the same Korean team showed that this compound significantly inhibited the production of NO and cytokines (IL-12p 70, TNF-), the formation of ROS and the change of intracellular Ca 2+ levels in LPS or IL-1stimulated bone marrow dendritic cells in a dose dependent manner. [START_REF] Choi | Inhibition of activated responses in dendritic cells exposed to lipopolysaccharide and lipoteichoic acid by diarylheptanoid oregonin[END_REF] In 2012, they furthermore evaluated the NO inhibitory activity of oregonin with an IC50 value of 21.1 M in LPS-activated RAW 264.1 macrophages. [START_REF] Lai | A comprehensive investigation of anti-inflammatory diarylheptanoids from the leaves of Alnus formosana[END_REF] In a study conducted by Jeong et al. in 2007 already mentioned about 5-Omethylhirsutanonol (4), [START_REF] Han | Effects of diarylheptanoids on the tumor necrosis factor-α-induced expression of adhesion molecules in human umbilical vein endothelial cells[END_REF] oregonin was shown to efficiently reduce in a similar way the expression of VCAM-1 and ICAM-1 with 76.6 and 20.8 % inhibition rates respectively at 20 M in TNF- stimulated HUVECs.

In a complete study, Lin et al. [START_REF] Lee | Oregonin inhibits lipopolysaccharide-induced iNOS gene transcription and upregulates HO-1 expression in macrophages and microglia[END_REF] In a comprehensive study on inflammatory factors promoting atherosclerosis, a Sweden team [START_REF] Lundqvist | Oregonin reduces lipid accumulation and proinflammatory responses in primary human macrophages[END_REF] demonstrated that oregonin decreased cellular lipid accumulation, ROS production and proinflammatory cytokines secretion, with 48.6, 18.9, 31.4, 37.9, 33.3, 75 and 40.6 % inhibition rates against TNF-, IL-1, IL-2, IL-6, IL-10, IFNand IL-8 respectively at 50 M in LPS-stimulated primary human macrophages. The same year, a IL-1secretion inhibition rate of 42% at 5 M in LPS-activated BMD macrophages was moreover reported by Choi and co-workers. [START_REF] Ko | Modulation effect of diarylheptanoids on interleukin 1β-related immune responses of bone-marrow macrophage[END_REF] In 2016, Bawankule et al. [START_REF] Saxena | Diarylheptanoids from Alnus nepalensis attenuates LPS-induced inflammation in macrophages and endotoxic shock in mice[END_REF] further reported that oregonin acted on TNF- and IL-6 secretion with 43 and 76 % inhibition rates at 10 g/mL in LPS-activated peritoneal macrophages (J774A.1) by inhibiting of the expression of NF-B protein. In 2018, SH Lee's team [START_REF] Chi | Oregonin inhibits inflammation and protects against barrier disruption in intestinal epithelial cells[END_REF] carried out a comprehensive study on the oregonin effects on intestinal inflammation as well as they did on hirsutenone (2) in 2014. [START_REF] Seo | Hirsutenone reduces deterioration of tight junction proteins through EGFR/Akt and ERK1/2 pathway both converging to HO-1 induction[END_REF] Oregonin did not affect the viability of HT-29 cells even at 100 µM and suppressed the expression of COX-2, ICAM-1, IL-8 and IL-1β mRNA, inhibited the activation of NF-κB and increased HO-1 expression in TNF-α stimulated intestinal epithelial HT-29 cells used as cellular model. Moreover, oregonin attenuated tert-butyl hydroperoxideinduced intestinal epithelial barrier dysfunction by induction of HO-1 expression. The authors concluded that oregonin can be a potential candidate to prevent mucosal inflammation and barrier disruption As shown here, oregonin (6) was extensively studied as a part of the efforts against chronic inflammation. Although the results of the different studies are difficult to compare because of the disparity of the experimental conditions, taken together, all these results clearly highlight its antiinflammatory actions.

Another hirsutanonol derivative, the deoxohirsutanonol or rubranol (7) isolated from different Alnus sources was evaluated for its antioxidant activity through DPPH scavenging assay with IC50 values of 34.9 M (compared to AA : IC50= 46.1 M) [START_REF] Le | Anti-inflammatory and anti-oxidative activities of phenolic compounds from alnus sibirica stems fermented by lactobacillus plantarum subsp. argentoratensis[END_REF] or 23.3 M (compared to AA : IC50 = 44.7 M) [START_REF] Wang | Inhibitory Effects on NO Production and DPPH Radicals and NBT Superoxide Activities of Diarylheptanoid Isolated from Enzymatically Hydrolyzed Ehthanolic Extract of Alnus sibirica[END_REF] and NBT superoxide scavenging assay with IC50 value of 11.6 M (compared to allopurinol : IC50 = 3.9 M). [START_REF] Wang | Inhibitory Effects on NO Production and DPPH Radicals and NBT Superoxide Activities of Diarylheptanoid Isolated from Enzymatically Hydrolyzed Ehthanolic Extract of Alnus sibirica[END_REF] According to the assays, rubranol showed a potent NO production inhibitory activity in LPS-activated RAW 264.7 macrophages with IC50 values of 28.4 g/mL (compared to L-NMMA : 22.8 g/mL), [START_REF] Kim | Nitric oxide and prostaglandin E2 synthesis inhibitory activities of diarylheptanoids from the barks of Alnus japonica steudel[END_REF] 20.0

M [START_REF] Lai | A comprehensive investigation of anti-inflammatory diarylheptanoids from the leaves of Alnus formosana[END_REF] (no reported reference) , 10.2 M (compared to L-NMMA : 41.9 M) [START_REF] Le | Anti-inflammatory and anti-oxidative activities of phenolic compounds from alnus sibirica stems fermented by lactobacillus plantarum subsp. argentoratensis[END_REF] and 5.2 M (compared to L-NMMA : 33.9 M). [START_REF] Wang | Inhibitory Effects on NO Production and DPPH Radicals and NBT Superoxide Activities of Diarylheptanoid Isolated from Enzymatically Hydrolyzed Ehthanolic Extract of Alnus sibirica[END_REF] Moreover, a moderate inhibitory activity of COX-2 expression with an IC50 value of 45.3 g/mL (compared to indomethacin: IC50 = 26.2 g/mL) in LPS-activated RAW 264.7 macrophages was reported. [START_REF] Kim | Nitric oxide and prostaglandin E2 synthesis inhibitory activities of diarylheptanoids from the barks of Alnus japonica steudel[END_REF] It should be noted that the same authors (M-W Lee et al.) published different IC50 values for the same DPPH assay in 2017 [START_REF] Le | Anti-inflammatory and anti-oxidative activities of phenolic compounds from alnus sibirica stems fermented by lactobacillus plantarum subsp. argentoratensis[END_REF] and 2019 [START_REF] Wang | Inhibitory Effects on NO Production and DPPH Radicals and NBT Superoxide Activities of Diarylheptanoid Isolated from Enzymatically Hydrolyzed Ehthanolic Extract of Alnus sibirica[END_REF] and for NO production inhibition assay (in 2005 [START_REF] Kim | Nitric oxide and prostaglandin E2 synthesis inhibitory activities of diarylheptanoids from the barks of Alnus japonica steudel[END_REF] and 2017 [START_REF] Le | Anti-inflammatory and anti-oxidative activities of phenolic compounds from alnus sibirica stems fermented by lactobacillus plantarum subsp. argentoratensis[END_REF] ) illustrating that the comparison between different series of tests is very tricky even when they were conducted by the same team. Nevertheless, a trend emerges to conclude to the real interest of hirsutanonol derivatives as anti-inflammatory agent.

Rubranosides A (8) (rubranol 5--O-D-glucoside), isolated along with rubranol from Alnus japonica, [START_REF] Kim | Nitric oxide and prostaglandin E2 synthesis inhibitory activities of diarylheptanoids from the barks of Alnus japonica steudel[END_REF] Alnus formosana [START_REF] Lai | A comprehensive investigation of anti-inflammatory diarylheptanoids from the leaves of Alnus formosana[END_REF] and fermentation of Alnus sibirica, [START_REF] Le | Anti-inflammatory and anti-oxidative activities of phenolic compounds from alnus sibirica stems fermented by lactobacillus plantarum subsp. argentoratensis[END_REF] displayed antioxidant activity with IC50 values of 45.1 M (compared to AA : IC50 = 46.1 µM) in DPPH assay, [START_REF] Le | Anti-inflammatory and anti-oxidative activities of phenolic compounds from alnus sibirica stems fermented by lactobacillus plantarum subsp. argentoratensis[END_REF] NO release inhibitory activity with IC50 values 32.5 g/mL (compared to L-NMMA : IC50 = 22.8 µg/mL) [START_REF] Kim | Nitric oxide and prostaglandin E2 synthesis inhibitory activities of diarylheptanoids from the barks of Alnus japonica steudel[END_REF] or 81.9 M (compared to L-NMMA : IC50 = 41.9 µM) [START_REF] Le | Anti-inflammatory and anti-oxidative activities of phenolic compounds from alnus sibirica stems fermented by lactobacillus plantarum subsp. argentoratensis[END_REF] and COX-2 expression inhibition with IC50 value of 32.2 g/mL (compared to indomethacin : IC50 = 26.2 µg/mL) [START_REF] Kim | Nitric oxide and prostaglandin E2 synthesis inhibitory activities of diarylheptanoids from the barks of Alnus japonica steudel[END_REF] in LPS-activated RAW 264.7 macrophages.

The antioxidant and anti-inflammatory activities of the 5--O-D-xylopyranoside rubranoside B (9), the xyloside analogue of rubranoside A were tested in 2011 by assessing its DPPH scavenging activity (IC50 = 8.7 M (compared to gallic acid : IC50 = 10.4 µM) [START_REF] Hu | Antioxidative activity and anti-inflammatory effects of diarylheptanoids isolated from Alnus hirsuta[END_REF] or IC50 = 31.1 M (compared to AA : IC50 = 3.1 µM) [START_REF] Le | Anti-inflammatory and anti-oxidative activities of phenolic compounds from alnus sibirica stems fermented by lactobacillus plantarum subsp. argentoratensis[END_REF] ) and its efficiency against NO production with 20.8 to 83.3 % inhibition rates, intracellular ROS production with 4.2 to 71 % inhibition rates, iNOS expression with 12.5 to 29.1 % inhibition rates and COX-2 expression with 7.7 to 25.6 % inhibition rates in the range 10-100 M in LPS-activated RAW 264.7 macrophages. [START_REF] Hu | Antioxidative activity and anti-inflammatory effects of diarylheptanoids isolated from Alnus hirsuta[END_REF] It was latter reported to inhibited NO production in 28 % rate at 30 M [START_REF] Lai | A comprehensive investigation of anti-inflammatory diarylheptanoids from the leaves of Alnus formosana[END_REF] or with an IC50 value of 38.9 M (compared to L-NMMA : IC50 = 41.9 µM) [START_REF] Le | Anti-inflammatory and anti-oxidative activities of phenolic compounds from alnus sibirica stems fermented by lactobacillus plantarum subsp. argentoratensis[END_REF] [START_REF] Kim | Nitric oxide and prostaglandin E2 synthesis inhibitory activities of diarylheptanoids from the barks of Alnus japonica steudel[END_REF] In 2016, platyphylloside 12 was further tested after isolation from Alnus nepalensis for its activity against TNF- and IL-6 expression with 52 and 80 % inhibition at 10 µg/mL in LPS-activated peritoneal macrophages. [START_REF] Saxena | Diarylheptanoids from Alnus nepalensis attenuates LPS-induced inflammation in macrophages and endotoxic shock in mice[END_REF] Among tetraphenolic linear diarylheptanoids 8-11, the presence of any glycoside moiety in 5-position on the heptanoid chain does not seem to significantly improve the desired activity, compared to rubranol (7).

In 2012, SS Lee et al. performed a comprehensive study on a series of 28 diarylheptanoids isolated from leaves of Alnus formosana to assess the IC50 values of NO production inhibition in LPS-stimulated RAW macrophages 264.7. [START_REF] Lai | A comprehensive investigation of anti-inflammatory diarylheptanoids from the leaves of Alnus formosana[END_REF] Along with derivatives 2, 3, 5-9 already mentioned, alluside A ( 13 M) were found the most potent but the most cytotoxic from the MTT assay with IC50 values of 9, 30.7 and 36.4 µM respectively. [START_REF] Lai | A comprehensive investigation of anti-inflammatory diarylheptanoids from the leaves of Alnus formosana[END_REF] The authors concluded that compounds 13-16 and 20 were more effective than oregonin without consideration of their significant toxicity. Diarylheptanoids 24 (11% inhibition rate at 30 M), 25 (37% inhibition rate at 30 M), aceroside VII (26) (24% inhibition rate at 30 M) and (-)-centrolobol ( 27) (29% inhibition rate at 30 M) were found less active as NO production inhibitors. Nevertheless no toxicity for 24-26 while a noticeable one for 27 (52 % cell viability at 30 µM) were observed. The absence of known positive control value in the NO assay is regrettable. [START_REF] Lai | A comprehensive investigation of anti-inflammatory diarylheptanoids from the leaves of Alnus formosana[END_REF] Independently, in 2013, H Morita collaborators studied also aceroside VII ( 26) isolated from barks of Acer nikoense (Aceraceae) used in Japanese folk medicine for hepatic disorders and eye diseases. They confirmed that 26 displayed no toxicity at 50 µM and poor effect on LPS-induced NO production with an IC50 value above 100 M in J774.1 macrophages. [START_REF] Deguchi | Cyclic diarylheptanoids as inhibitors of NO production from Acer nikoense[END_REF] In 2017, platyphyllenone (23), equally isolated from Alnus sibirica, was again tested against NO production in LPS-activated RAW 264.7 macrophages with IC50 value of 15.9 M (compared to AA : IC50 = 12.3 µM) and for antioxidant activity through DPPH assay with IC50 values of 101.2 M (compared to AA : IC50 = 3.1 µM). [START_REF] Le | Anti-inflammatory and anti-oxidative activities of phenolic compounds from alnus sibirica stems fermented by lactobacillus plantarum subsp. argentoratensis[END_REF] The same year, further studies on (-)-centrolobol (27) reported an IC50 values of 27.8 M for NO production inhibition in LPS-activated RAW 264.7 macrophages (compared to L-NMMA : IC50 = 41.9 µM), and 44.4 M for DPPH radical scavenging activity (compared to AA : IC50 = 46.1 µM). [START_REF] Le | Anti-inflammatory and anti-oxidative activities of phenolic compounds from alnus sibirica stems fermented by lactobacillus plantarum subsp. argentoratensis[END_REF] 27 was equally tested in vivo for its anti-inflammatory effect against TPA-induced inflammation in mice (1 mg/ear) with an ID50 value of 0.66 mg/ear, compared to those of quercetin (ID50 = 1.6 mg/ear). [START_REF] Akihisa | Acerogenin M, a Cyclic Diarylheptanoid, and Other Phenolic Compounds from Acer nikoense and Their Antiinflammatory and Anti-tumor-Promoting Effects[END_REF] Its enantiomer (+)-centrolobol (28) isolated from Nidus vespae was tested against NO release with an IC50 value above 25 M compared to the positive control MG132 with IC50 value = 0.1 M in LPSactivated RAW 264.7 macrophages. [START_REF] He | Sesquiterpenoids and Diarylheptanoids from Nidus Vespae and Their Inhibitory Effects on Nitric Oxide Production[END_REF] The same study reported the isolation from Nidus vespae of diarylheptanoids 29 and 30. Their NO production inhibitory effect was evaluated with IC50 values of 13.8 and 13.2 M respectively in LPS-activated RAW 264.7 macrophages [START_REF] He | Sesquiterpenoids and Diarylheptanoids from Nidus Vespae and Their Inhibitory Effects on Nitric Oxide Production[END_REF] The presence of a ketone or alcohol function in position 3 and the number of phenol functionalities (2 or 3) do not influence the NO production inhibitory activity.

In 2013, Kang Ro Lee and coworkers [START_REF] Woo | Antineuroinflammatory diarylheptanoids from the rhizomes of Dioscorea nipponica[END_REF] The genus Alpinia is an important member of Zingiberaceae family widely distributed in Asia from which 143 diarylheptanoids were isolated in 2017. [START_REF] Ma | An overview of chemical constituents from Alpinia species in the last six decades[END_REF] From the 1980's, anti-inflammatory activities of yakuchinone A (36) and yakuchinone B (37), isolated from Alpinia oxyphylla (Zingiberaceae) used for centuries in traditional medicine for inflammatory disorders, have attracted interest. They initially were identified by Sankawa et al. [START_REF] Kiuchi | Inhibitors of prostaglandin biosynthesis from Alpinia officinarum[END_REF] as strong PG biosynthesis inhibitors with IC50 values of 0.5 and 2.3 µM respectively (compared to indomethacin: IC50 = 4.9 µM). 36 and 37 were reported to inhibit 5-hydroxyeicosatetraenoic acid (5-HETE) production with IC50 values of 5.4 and 4.0 µM respectively from intact human neutrophils and PGE2 formation by bovine seminal vesicles (BVS) cycloxgenase with IC50 values of 16 and 23 µM respectively (compared to BW-756C : IC50 = 32.0 µM and phenidone: IC50 = 11.8 µM as references). [START_REF] Flynn | Inhibition of 5-hydroxy-eicosatetraenoicacid (5-HETE) formation in intact human neutrophils by naturally-occurring diarylheptanoids: inhibitory activities of curcuminoids and yakuchinones[END_REF] They were further shown to inhibit the TNF- production with 43 and 52 % rates respectively at 20 µM in TPA-treated mouse skin and the COX-2 expression in TPA-stimulated mouse skin. [START_REF] Chun | Inhibition of mouse skin tumor promotion by antiinflammatory diarylheptanoids derived from Alpinia oxyphylla Miquel (Zingiberaceae)[END_REF] Yamazaki et al. [START_REF] Yamazaki | Diarylheptanoids suppress expression of leukocyte adhesion molecules on human vascular endothelial cells[END_REF] also assayed yakuchinone B (37) against TNF- and IL-1-induced VCAM-1 expression with 0 to 95 % and 0 to 100 % inhibition respectively, and against TNF- and IL-1-induced ICAM-1 expression with 0 to 51 % and 0 to 85 % inhibition respectively the range 1-50 µM in HUVECs cells (indomethacin used as positive control had no effect up to 100µM).

Among linear diarylheptanoids, the natural compounds 38 to 51 were isolated from Alpinia officinarum (Zingiberaceae) originally from China, widely cultivated in south-east Asia and employed as flavoring agent. [START_REF] Abubakar | A review on the ethnomedicinal uses, phytochemistry and pharmacology of Alpinia officinarum Hance[END_REF] Diarylheptanoid 38 was proved efficiently active against mice TPA-induced ear inflammatory edema with ID50 value of 0.8 µmol/ear, compared to indomethacin (ID50 = 0.9 µmol/ear). [START_REF] Yasukawa | Inhibitory effect of the rhizomes of Alpinia officinarum on TPA-induced inflammation and tumor promotion in two-stage carcinogenesis in mouse skin[END_REF] A comprehensive study devoted on the anti-inflammatory potential of this compound showed its inhibitory activity against NO release with IC50 value of 5 µg/mL, against IL-1, TNF-, COX-2, NF-B and iNOS expression with 70, 71, 69, 50 and 69% inhibition rates respectively at 5 µg/mL in LPSstimulated RAW 264.7 macrophages without any toxic effect. [START_REF] Rajaganapathy | Molecular basis of the anti-inflammatory potential of a diarylheptanoid in murine macrophage RAW 264.7 cells[END_REF] In 1982, Sankawa et al. [START_REF] Kiuchi | Inhibitors of prostaglandin biosynthesis from Alpinia officinarum[END_REF] identified 39 as a PG biosynthesis inhibitor with IC50 value of 50 µM which is 10 folder higher than the one of indomethacin used as positive control. It was latter shown that, at 25 µM, 39 inhibited NO release in LPS-activated RAW 264.7 macrophages with 50% rate, IL-1, TNF- production in LPS-induced human peripheral blood mononuclear (PBM) cells with 85 and 43% rates respectively, and iNOS and COX-2 gene expression by 75.5 and 54.6% in LPS-activated RAW 264.7 macrophages by inhibiting NF-B activation and phosphorylation of p44/42 MAPK. [START_REF] Yadav | A diarylheptanoid from lesser galangal (Alpinia officinarum) inhibits proinflammatory mediators via inhibition of mitogen-activated protein kinase, p44/42, and transcription factor nuclear factor-κB[END_REF] An IC50 value of 0.6 µM for NO release in LPS-activated macrophages [START_REF] Lee | Suppression of inducible nitric oxide synthase expression by diarylheptanoids from Alpinia officinarum[END_REF] and an ID50 value of 2.2 µmol/ear against mice TPA-induced ear inflammatory edema [START_REF] Yasukawa | Inhibitory effect of the rhizomes of Alpinia officinarum on TPA-induced inflammation and tumor promotion in two-stage carcinogenesis in mouse skin[END_REF] were further reported. Recently, in silico studies suggested that 39 interacted with P38 MAPK. It was shown to reduce IL-1, IL-6 and TNF- expression with 86, 52 and 85% inhibition rates respectively at 10 g/mL in LPS-induced HepG2 cells. [START_REF] Elgazar | Isolates from Alpinia officinarum Hance attenuate LPS-induced inflammation in HepG2: Evidence from in silico and in vitro studies[END_REF] Moreover, 39 displayed significant inhibitory activity against TNF-α production with 54% rate at 0.02 mg/mL (concentration for which cell viability of diarylheptanoid 39 was more than 80 % by MTT assay) in Kdo2lipid (KL) A-stimulated RAW 264.7 macrophages. [START_REF] Zhang | Anti-inflammatory activities and glycerophospholipids metabolism in KLA-stimulated RAW 264.7 macrophage cells by diarylheptanoids from the rhizomes of Alpinia officinarum[END_REF] In 1982, diarylheptanoids 40 and 41 were proved to inhibit PG biosynthesis with IC50 values of 2.0 and 4.4 M respectively in the same range than indomethacin. [START_REF] Kiuchi | Inhibitors of prostaglandin biosynthesis from Alpinia officinarum[END_REF] Hydroxyketone 41 was thereafter comprehensively evaluated for its anti-inflammatory activity. In 2008, (R )-41 was assayed in vivo against mice TPA-induced ear inflammatory edema with ID50 value of 1.8 µmol/ear compared to indomethacin (ID50 = 0.9 µmol/ear). [START_REF] Yasukawa | Inhibitory effect of the rhizomes of Alpinia officinarum on TPA-induced inflammation and tumor promotion in two-stage carcinogenesis in mouse skin[END_REF] 41 was moreover reported by Ryu et al. [START_REF] Lee | Suppression of inducible nitric oxide synthase expression by diarylheptanoids from Alpinia officinarum[END_REF] to inhibit NO production with 40% rate at 10 µg/mL (IC50 >30 µM) in LPS-activated macrophages. In 2016, Bodhankar, Rojatkar, Natu and co-workers [START_REF] Honmore | Isolates of Alpinia officinarum Hance as COX-2 inhibitors: Evidence from antiinflammatory, antioxidant and molecular docking studies[END_REF] showed that 41 displayed antioxidant properties in a concentration-dependent manner with DPPH scavenging activity with an IC50 value of 93.5 µg/mL (compared to AA : IC50 = 58 µg/mL), hydroxyl radical HO • scavenging assay with an IC50 value of 77 µg/mL (compared to AA : IC50 = 47 µg/mL) and in vivo antiinflammatory one against carrageenan induced hind paw edema in rats with 1.53% (after 1h), 33.1% (after 3h) and 42 % (after 5h) inhibition rates at a dose of 10 mg/kg. The molecular docking study revealed affinity towards COX-2 active site of which 41 could be a selective inhibitor.

The same authors [START_REF] Honmore | Diarylheptanoid, a constituent isolated from methanol extract of Alpinia officinarum attenuates TNF-α level in Freund's complete adjuvant-induced arthritis in rats[END_REF] recently showed that oral administration of this diarylheptanoid reduced the serum levels of TNF-, IL-1 and IL-6 levels with 0 to 18%, 3 to 5% and 0 to 2.5% inhibition rates at doses ranging from 5 mg/ kg to 20 mg/kg in Freund' complete adjuvant (FCA)-induced arthritis in rats on day 28 (compared to diclofenac: 47%, 7% and 2.5% inhibition rates respectively at 5 mg/kg). More interestingly, diarylheptanoid 41 significantly inhibited the increase in paw volume of Freund' complete adjuvant (FCA)-induced arthritic rats with 20.1 and 21.3% rates at 10 mg/kg and 20 mg/kg respectively on day 28 (compared to diclofenac with 28.3% rate at 5 mg/kg). Docking study indicated good in-silico binding with active site of TNF-Another comprehensive study on anti-inflammatory activity of 41 in LPS-induced RAW 264.7 macrophages was conducted by Wu and Feng's team. [START_REF] She | An analysis on the suppression of NO and PGE2 by diphenylheptane A and its effect on glycerophospholipids of lipopolysaccharide-induced RAW264.7 cells with UPLC/ESI-QTOF-MS[END_REF] Cytotoxicity assays revealed that up to 20 µg/mL the cell viability was above 80%. Thus, 41 was evaluated for its potency to reduce NO production, PGE2, TNF- and IL-1 expression level with 12 to 44%, 57 to 85%, 10 to 87% and 4 to 64% inhibition rates respectively in the range 5-20 µg/mL. 41 was further shown to inhibit the expression of iNOS and COX-2 and to reduce the phosphorylation of NF-B p65 in a dose dependent manner. The same team reported latter that 41 acted against TNF- expression with 43% inhibition rate at 0.05 mg/mL (cell viability >80%) in KLA-stimulated RAW 264.7 macrophages. [START_REF] Zhang | Anti-inflammatory activities and glycerophospholipids metabolism in KLA-stimulated RAW 264.7 macrophage cells by diarylheptanoids from the rhizomes of Alpinia officinarum[END_REF] Following preliminary molecular docking studies, 41 was also proved by Elgazar's team [START_REF] Elgazar | Isolates from Alpinia officinarum Hance attenuate LPS-induced inflammation in HepG2: Evidence from in silico and in vitro studies[END_REF] to exhibit cytotoxicity with an IC50 value 26.6 µg/mL and anti-inflammatory activities against IL-1, IL-6 and TNF- expression with 83, 65 and 89 % inhibition rates respectively at 10 µg/mL in LPSinduced HepG2 cells. Investigations on -methoxyketone 42 according to the same experiments than hydroxyketone 41 showed better anti-inflammatory activity with PG biosynthesis inhibition IC50 value of 2.3 µM [START_REF] Kiuchi | Inhibitors of prostaglandin biosynthesis from Alpinia officinarum[END_REF] and reduction of mice TPA-induced ear inflammatory edema with ID50 value of 0.9 µmol/ear (compared to indomethacin : ID50 = 0.9 µmol/ear). [START_REF] Yasukawa | Inhibitory effect of the rhizomes of Alpinia officinarum on TPA-induced inflammation and tumor promotion in two-stage carcinogenesis in mouse skin[END_REF] In 2006, low to moderate NO release inhibitory activities were reported for diarylheptanoids 43-45 in LPS-activated RAW 264.7 macrophages as for 41. [START_REF] Lee | Suppression of inducible nitric oxide synthase expression by diarylheptanoids from Alpinia officinarum[END_REF] Derivatives 43 and 44 only induced 32 and 27 % inhibitory rates at 10 µg/mL respectively (IC50>30 µM). An IC50 value of 22.8 µM was evaluated for 45 which reduced iNOS expression level with 32% inhibition rate at 25 µM (no reported reference).

Five non phenolic diarylheptanoids 46-50, also isolated form Alpinia officinarum, were equally found to display anti-inflammatory activities. In 2007, Fan et al. [START_REF] Fan | Platelet-activating factor (PAF) receptor binding antagonists from Alpinia officinarum[END_REF] proved that compounds 46-47-48 exhibited potent platelet-activating factor (PAF) receptor biding activities with IC50 values of 1.3, 1.6 and 5.0 µM respectively and concluded that diarylheptanoid represented a new class of potent PAF receptor binding inhibitory compounds. Moreover, in vivo assays on TPA-induced mice inflammation showed that compounds 47, 48 and 49 inhibit edema with ID50 value of 2.7, 2.1 and 2.7 µmol/ear respectively (compared to indomethacin : ID50 = 0.9 µmol/ear). [START_REF] Yasukawa | Inhibitory effect of the rhizomes of Alpinia officinarum on TPA-induced inflammation and tumor promotion in two-stage carcinogenesis in mouse skin[END_REF] Further studies showed that 48 inhibited NO release with an IC50 value of 6.8 µM and reduced iNOS expression level with 71% inhibition rate at 25 µM in LPS-activated RAW 264.7 macrophages. [START_REF] Lee | Suppression of inducible nitric oxide synthase expression by diarylheptanoids from Alpinia officinarum[END_REF] In another report, 48 and 49 were evaluated in vivo as for 41 against carrageenan induced hind paw edema in rats. They showed no significant inhibition in the increase of paw edema from 1h to 5h after injection of carrageenan at 10 mg/kg (6.9 % and 4.7 % inhibition respectively after 5h compared to for 39.5 % diclorofenac). [START_REF] Honmore | Isolates of Alpinia officinarum Hance as COX-2 inhibitors: Evidence from antiinflammatory, antioxidant and molecular docking studies[END_REF] 49 was also noted to exhibit weak effect against PG biosynthesis with IC50 value of 170 µM. [START_REF] Kiuchi | Inhibitors of prostaglandin biosynthesis from Alpinia officinarum[END_REF] Moreover 48, 50 and 51 displayed moderate inhibitory activity against TNF-α production with 38, 35 and 37% rates respectively at 0.06 mg/mL in Kdo2-lipid (KL) A-stimulated RAW 264.7 macrophages. [START_REF] Zhang | Anti-inflammatory activities and glycerophospholipids metabolism in KLA-stimulated RAW 264.7 macrophage cells by diarylheptanoids from the rhizomes of Alpinia officinarum[END_REF] The numerous studies cited here show that Alpinia officinarum is an important source of diarylheptanoids with proven anti-inflammatory properties.

In Note that in 1997, the same team initially reported that compounds 54-59 inhibited the production of NO in activated murine macrophages J774.1 at a range of 90-94% at 100 µg/mL with a cell viability of 85-90% at this concentration. [START_REF] Kumar Prasain | Six novel diarylheptanoids bearing chalcone or flavanone moiety from the seeds of Alpinia blepharocalyx[END_REF] Curcuma, a genus of flowering plants of the Zingiberaceae family, contains about forty species of tropical origin well known for containing various polyphenolic compounds with used as medicines and food ingredients. In 2017, 97 diarylheptanoids were extracted from curcuma genus. [START_REF] Sun | Chemical constituents and biological research on plants in the genus Curcuma[END_REF] In 1993, three non-phenolic diarylheptanoids, alnustone (63), 64 and 65 isolated from rhizomes of Curcuma xanthorrhiza (Zingiberaceae), by Taylor et al. [START_REF] Claeson | Three Non-Phenolic Diarylheptanoids with Anti-Inflammatory Activity from Curcuma xanthorrhiza[END_REF] were shown to exhibit significant antiinflammatory activity in the in vivo assay of carrageenan-induced hind paw edema in rats with 44, 30 and 39% inhibition rates 3h after injection at 100 mg/kg, compared to aspirin (80% inhibition).

In 1996, the same team tested diarylheptanoids 63-65 against ethyl phenylpropiolate-induced rat ear edema. Alnustone (63) showed an ID50 value of 63 µg/ear and 67 µg/ear, 30min and 1h after edema induction respectively, compared to oxyphenbutazone : ID50 = 12 µg/ear and 46 µg/ear, 30 min and 1h after edema induction respectively as positive reference drug. Compound 64 exhibited ID30 values of 35 µg/ear and 28 µg/ear, 30 min and 1h after edema induction (compared to oxyphenbutazone : ID30 = 0.2 µg/ear and 0.3 µg/ear, 30 min and 1h after edema induction respectively), while 65 displayed ID50 values of 129 µg/ear and 312 µg/ear, 30 min and 1h after edema induction respectively. Thus, alnustone (63) was thus identified as the most potent in the series with an activity in the same doserange than the reference compound at 1h after induction. [START_REF] Claeson | Non-phenolic linear diarylheptanoids from Curcuma xanthorrhiza. A novel type of topical antiinflammatory agents. Structure-activity relationship[END_REF] Very recently, (R)-65, isolated from Curcuma comosa (Zingiberaceae), was further evaluated in vivo in thioacetamide-induced mice hepatotoxicity assay and its protective effect highlighted by Piyachaturawat's team. [START_REF] Chuaicharoen | Non-Phenolic Diarylheptanoid from Curcuma comosa Protects Against Thioacetamide-Induced Acute Hepatotoxicity in Mice[END_REF] In particular pretreatment with 65 significantly attenuated TNF- expression (53% rate at dose of 1 mg/ kg). This data could be related to an anti-inflammatory potential.

Comprehensive studies were conducted by Qiu's Chinese team [START_REF] Li | Diarylheptanoids from the Rhizomes of Curcuma kwangsiensis[END_REF] aiming at isolating, identifying and evaluating extracts from rhizomes of Curcuma kwangsiensis (Zingiberaceae), which are one then most important crude drugs used in traditional Chinese medicine. In 2010, these authors evaluated 12 new and 6 known diarylheptanoids 66-83. They made efforts to separate enantiomers by chiral HPLC and determined the absolute configuration using the modified Mosher's method. Their inhibitory effect on NO production in LPS-stimulated RAW 264.7 macrophages was evaluated compared to indomethacin (IC50 = 12.9 µM) and hydrocortisone (IC50 = 40. It should be pointed out an IC50 value of 32.1 µM for NO release inhibition of 3-platyphyllone (82) in LPS-activated RAW 264.7 macrophages was later found by other authors (compared to L-NMMA : IC50 = 41.9 µM). [START_REF] Le | Anti-inflammatory and anti-oxidative activities of phenolic compounds from alnus sibirica stems fermented by lactobacillus plantarum subsp. argentoratensis[END_REF] Moreover, 83 was widely tested by He and Lu's team [START_REF] Liu | Diarylheptanoid from rhizomes of Curcuma kwangsiensis (DCK) inhibited imiquimod-induced dendritic cells activation and Th1/Th17 differentiation[END_REF] against imiquimod-stimulated production of IL-1, IL-6 and IL-12 with 86, 61 and 69% inhibition rates respectively in mRNA level and with 56, 58 and 31% inhibition rates respectively in protein level at 10 µM in BMDCs.

In their continuing search for bioactive constituents from Curcuma kwangsiensis, Qiu et al. [START_REF] Li | Diarylheptanoids from Curcuma kwangsiensis and their inhibitory activity on nitric oxide production in lipopolysaccharide-activated macrophages[END_REF] [START_REF] Woo | Antineuroinflammatory diarylheptanoids from the rhizomes of Dioscorea nipponica[END_REF] and for 99 an IC50 value of 30 µM (in LPS-activated RAW 264.7 macrophages compared to L-NMMA : IC50 = 41.9 µM). [START_REF] Le | Anti-inflammatory and anti-oxidative activities of phenolic compounds from alnus sibirica stems fermented by lactobacillus plantarum subsp. argentoratensis[END_REF] Derivatives 87 and 88 showed weak activity with IC50 values of 75.7 and 82.8 µM respectively, while IC50 values of meso-hanokinol (100) and (+)-hanokinol (101) were found above 100 µM. [START_REF] Li | Diarylheptanoids from Curcuma kwangsiensis and their inhibitory activity on nitric oxide production in lipopolysaccharide-activated macrophages[END_REF] Note that 84 was tested in 2018 against NO production with an IC50 value of 27.0 µM compared to indomethacin (IC50 = 32.3 µM) in LPS-activated RAW 264.7 macrophages. [START_REF] Yao | Anti-inflammatory diarylheptanoids and phenolics from the rhizomes of kencur (Kaempferia galanga L.)[END_REF] Diarylheptanoids 99, 100, 101 and 102 were furthermore isolated from the fruits of Amomun tsao-ko (Zingiberaceae) and showed to attenuate NO production in LPS-activated BV2 microglial cells with respectively 66.3, 65.2, 51.3 and 76.7% inhibition rates at 10 µM (compared to 70.5% inhibition rate for ω-nitro-L-arginine methyl ester used as a positive control). [START_REF] Lee | Inhibitory Constituents of Lipopolysaccharide-Induced Nitric Oxide Production in BV2 Microglia isolated from Amomum tsao-ko[END_REF] Compounds 103-106 were isolated from Curcuma comosa rhizomes, cultivated and used in traditional Thai medicine, and studied by many teams. Thus, 103 and 104 were found to dose-dependently strongly inhibit the NO release in LPS-treated RAW 264.7 macrophages with IC50 values of 0.66 and 0.42 µM respectively by Suksamrarn and coworkers. [START_REF] Sornkaew | Diarylheptanoids of Curcuma comosa with Inhibitory Effects on Nitric Oxide Production in Macrophage RAW 264.7 Cells[END_REF] No numerical data was mentioned for BAY 11-7082 used as positive control. In 2016, a comprehensive study was conducted on 104 to evaluate its potency as therapeutic agent against osteoporosis tightly linked to inflammation. It exhibited both anti-inflammatory activity with an IC50 value of 1.1 µM for NO inhibition in LPS-activated RAW 264.7 macrophages with no cytotoxicity. An anti-osteoclastogenic activity was displayed by strongly inhibiting RANKL-mediated osteoclast differentiation in BMDCs (IC50 = 325 nM), which may be due, at least in part, to inhibition of the MAPK pathway. [START_REF] Chawalitpong | Diarylheptanoid from Curcuma comosa Roxb. suppresses RANKL-induced osteoclast differentiation by decreasing NFATc1 and c-Fos expression via MAPK pathway[END_REF] In the search of new treatment against neurodegenerative diseases, 104 was further shown at 5 µM (no toxic concentration) to inhibit NO production with 91 % rate, suppress iNOS expression with 85% rate, attenuate the activation of NF-B with 52% rate and lower ROS production with 90% rate and p38 MAPK activation with 44% rate in LPSactivated aggressive proliferating immortalized (HAPI) microglial cells. [START_REF] Jiamvoraphong | Concurrent suppression of NF-κB, p38 MAPK and reactive oxygen species formation underlies the effect of a novel compound isolated from Curcuma comosa Roxb. in LPSactivated microglia[END_REF] Evaluation of 105 and 106 revealed that these compounds decreased secretion of cytokines TNF- with 19 and 44% inhibition rates respectively and IL-1 with 20 and 30 % inhibition rates respectively, reduced TNF- protein expression with 58 and 64% inhibition rates respectively at 1 µg/mL and suppressed IKKexpression and NF-B activation in phorbol-12-myristate-13-acetate (PMA)-stimulated human monocytes U937 cells. [START_REF] Sodsai | Suppression by Curcuma comosa Roxb. of pro-inflammatory cytokine secretion in phorbol-12-myristate-13acetate stimulated human mononuclear cells[END_REF] In 2018, tetrahydroxy compound 107 was isolated from Curcuma zedoaroides A. (Zingiberaceae) rhizomes as a new diarylheptanoid by Tewtrakul et al. [START_REF] Tungcharoen | Antiinflammation constituents from Curcuma zedoaroides[END_REF] Its anti-inflammation activity was investigated on NO production with an IC50 value of 32.6 µM compared to indomethacin (IC50 = 26.3 µM) in LPS activated RAW 264.7 macrophages. 107 did not inhibit TNF-production (IC50 >100 µM), and suppressed iNOS and COX-2 mRNA expressions in dose-dependent manner.

In a search for new inhibitors of STAT3 (a major actor of inflammation activated by the pleiotropic cytokine IL-6), extracts of Curcuma phaeocaulis (Zingiberaceae) recently provided five non-phenolic compounds 108-112 along with two phenolic diarylheptanoids 113 and 114. These compounds were evaluated for their inhibitory effect on IL-6-stimulated STAT3 expression in Hep3B cells. Whereas 108 was found inefficient with an IC50 value above 50 µM, 109-114 gave IC50 values of 37.6, 19.9, 12.9, 11.1, 4.1 and 21.5 µM respectively (compared to stattic as positive control: IC50 = 0.67 µM). Particular attention was paid for compound 112 as the more potent. Therefore, derivative 112 was evaluated for its effect on ICAM-1, C-reactive protein (CRP), IL-1and suppressor of cytokine signaling 3 (SOCS3) mRNA expression with 76, 91, 91 and 91% inhibition rates respectively at 30 µM. [START_REF] Jang | Diarylheptanoids from Curcuma phaeocaulis Suppress IL-6-Induced STAT3 Activation[END_REF] In 2012, three new diarylheptanoid glycosides plantagineoside A (115), plantagineoside B (116) and unusual cyclic plantagineoside C (141) were characterized by Kim's team [START_REF] Quang | Diarylheptanoid glycosides from Tacca plantaginea and their effects on NF-κB activation and PPAR transcriptional activity[END_REF] along with three known ones 117-118-119 after isolation from Tacca plantaginea (Taccaceae), whose rhizomes have been widely used in traditional medicine. Compounds 115 and 116 were found inactive (IC50 > 10 µM) to inhibit TNF--induced NF-B transcriptional activity in HepG2 cells, whereas derivatives 117-119 and 141 proved significantly active with IC50 values of 6.2, 0.9, 9.4 and 8.0 µM respectively compared to sulfasalazine (IC50 = 0.9 µM) as positive control. Moreover all compounds 115-119 and 141 significantly activated the transcriptional activity of peroxisome proliferator-activated receptors (PPARs) in a dose-dependent with IC50 values of 7.0, 10.4, 1.2, 0.3, 9.9 and 5.2 µM respectively, compared to benzafibrate (IC50 = 1.0 µM) as positive control. Evaluation on three individual PPAR subtypes, including PPAR, , and () was equally performed and showed that these compounds essentially enhanced the transcriptional activity of PPAR(which is particularly important for inflammation regulation with IC50 values of 11.0, 13. Seeds from Aframomum melegueta (Zingiberaceae), a commonly used African spice, allowed isolation of diarylheptanoids 126 and 127 which were tested for their hepatoprotective effect against CCl4induced liver toxicity. They significantly decreased the levels of serum alanine amino transferase (ALT) which is an enzyme associated to liver diseases and considered as pertinent marker of inflammation, [START_REF] Wiener | Association of Alanine Aminotransferase and Periodontitis: A Cross-Sectional Analysis-NHANES 2009-2012[END_REF] Recently extraction from the fruits of Amomum kravanh (Zingiberaceae) allowed the isolation and identification of new diarylheptanoids which were evaluated for their NO inhibitory effect in LPSactivated RAW 264.7 macrophages. In particular, new kravanol D (147), G (148) and H (149), embedding a tetrahydropyran ring in the seven carbon chain, and known renealtin A (151) with a tetrahydrofuran ring (Fig. 3), with IC50 values 23.6, 21.8 , 17.4 and 26.5 µM respectively (compared to dexamethasone: IC50 = 32.5 µM as reference) showed moderate activity. [START_REF] Zhang | Diarylheptanoids with NO production inhibitory activity from Amomum kravanh[END_REF] In 2013, kravanol B (150) and renealtin A (151) had been previously evaluated with IC50 values of 38.9 µM and above 100 µM respectively (compared to L-NMMA: IC50 = 40.4 µM) in LPS-induced RAW 264.7 macrophages). 90

Macrocyclic natural diarylheptanoids

The structures of the selected macrocyclic diarylheptanoids are compiled in [START_REF] Ibrahim | Alnuheptanoid B: a new cyclic diarylheptanoid from Alnus japonica stem bark[END_REF] These compounds were tested for their antioxidant activity, they showed a moderate DPPH inhibitory activity in the range 41-70% at 50 M, compared to 97% inhibition for propyl gallate as positive control. Their anti-inflammatory activity was evaluated using carrageenan induced rat paw edema model at a dose 10 mg/kg. They displayed potent activity with 49.6, 51.5, 46.3, 46.9 and 47.1% inhibition after 4 hours, compared to indomethacin as reference (55.2% inhibition). The authors noticed that glucosidation of phenolic groups led to reduced activities.

The diarylheptanoids macrocycles carpinontriol A (165) and B (166) first identified by Y-S Lee and al. [START_REF] Lee | New Diarylheptanoids from the Stems of Carpinus cordata[END_REF] from the stem of Carpinus cordata (Betulaceae) did not show any significant antioxidant activity in DPPH assay (IC50 >100 and 80.2 µg/mL respectively, compared to epigallocathechin gallate : IC50 = 2.7 µg/mL as positive control). Later, N-H Lee 97 also isolated macrocycles 165 and 166 from Carpinus turczaniwii branches and evaluated their anti-inflammatory activity in LPS-stimulated RAW 264.7 macrophages. 165 and 166 reduced the NO release with high IC50 values of 396 and 199.4 µM respectively and IL-6 production in a dose dependent manner from 6.3 to 76.6% and 19 to 55.3% respectively in the range 50-500 µM. No cell toxicity was observed during the experiments.

Juglanin B (167) initially identified from walnut husks Juglans regia L. (Juglandaceae) [START_REF] Liu | Cytotoxic Diarylheptanoids from the Pericarps of Walnuts (Juglans regia)[END_REF] and its O-sulfate derivative 168 found in leaves of Myrica rubra (Myricaceae) were evaluated against LPS-induced cytokines production in macrophage RAW 264.7 cells. Juglanin B (167) inhibiting TNF-α, IL-1β and IL-6 production with IC50 values of 19.5, 17.9 and 20.3 M respectively was slightly more potent than its sulfate counterpart with IC50 values of 20.1, 22.9 and 22.7 M respectively, compared to quercetin as positive control with IC50 values of 13.6, 16.9 and 16.8 M respectively. Moreover, these compounds dose-dependently reduced significantly the LPS-expression of iNOS and COX-2 proteins. [START_REF] Kim | Anti-inflammatory activity of sulfate-containing phenolic compounds isolated from the leaves of Myrica rubra[END_REF] In 2019, diarylheptanoid 169 isolated from leaves of Micromelum integerrimum (Rutaceae) was studied in the context of retinitis pigmentosa, in which inflammation plays a key role by Zheng's team. 100 169 treatment (daily intraperitoneal injection at 5mg/kg) decreased NO production (21%) and IL-1β, (22%), IL-6 (12%), IL-12 (12%), TNF-α (16%) levels in the retinas of Rd10 mice model. Macrocycle 169 also decreased gene expression of IL-1β (41%), IL-6 (31%), IL-12 (38%), TNF-α (49%) and protein expression of NF-κB (50%) in the retinas of Rd10 mice. The authors concluded that a treatment with the diarylheptanoid 169 protected photoreceptor cells against degeneration in the Rd10 mouse model of retinitis pigmentosa.

The biphenyl macrocycles acerogenin E (170) and K (171) isolated from the stem bark Acer nikoense (Acereaceae), a tree indigenous to Japan, were shown to inhibit NO production with IC50 values of 24 and 25 M respectively in LPS-activated mouse peritoneal macrophages, equivalent to that of L-NMMA (IC50 = 28 M) as positive control. When compared to the inhibitory activities of diarylethers acerogenin A (172) and B (173) (IC50 values of 74 and 88 M respectively), equally isolated, Yoshikawa and coworkers suggested that biphenyl-type structures display stronger NO production inhibitory activity than biphenyl-ether type ones. 101 The two latter derivatives 172 and 173 were further assayed for their NO production inhibitory activity in LPS-activated J774.1 macrophages and showed only weak to no-activity with IC50 values of 162.3 and above 200 M respectively (compared to L-NMMA : IC50 = 73 M). In the same report, acerogenin C (174) was shown to exhibit moderate activity (IC50 = 66.1 M), whereas acerogenin L (175) was inefficient (IC50 >100 M). No cell cytotoxicity was observed at 50 µM. [START_REF] Deguchi | Cyclic diarylheptanoids as inhibitors of NO production from Acer nikoense[END_REF] In vivo assays were conducted by Akihisa et al. [START_REF] Akihisa | Acerogenin M, a Cyclic Diarylheptanoid, and Other Phenolic Compounds from Acer nikoense and Their Antiinflammatory and Anti-tumor-Promoting Effects[END_REF] on acerogenin A (172) and B (173), glycosides aceroside III (176), IV (177) and B1 (178) still isolated from Acer nikoense. These compounds were evaluated for their anti-inflammatory effects against TPA-induced inflammation in mice (1 mg/ear) showing marked activity with ID50 values of 0.32, 0.26, 0.81, 0.49 and 0.32 mg/ear, compared to those of quercetin (ID50 = 1.6 mg/ear) and indomethacin (ID50 = 0.30 mg/ear).

Myricatomentogenin (179) and alcohol 180 extracted from stem bark of Alnus hirsuta were investigated for their inhibitory activity against LPS-induced NF-B activation and NO and TNF- production in LPS-activated RAW 264.7 macrophages. They showed similar potent inhibitory activity of NF-B gene expression with IC50 values of 9.4 and 9.2 M respectively, on NO production with IC50 values of 18.5 and 18.2 M, and TNF- production with IC50 values of 22.9 and 22.3 M respectively, in comparison with parthenolide, a known NF-B inhibitor (IC50 = 3.4, 2.4 and 2.6 M respectively for NF-B, NO and TNF-). [START_REF] Cai | Diarylheptanoids from Alnus hirsuta inhibit the NF-kB activation and NO and TNF-alpha production[END_REF] An unique cyclic diaryl heptadienoid tedarene A (181) was isolated from the unusual source marine sponge Tedania ignis (Tedaniidae) and showed 68% inhibition of NO production at 30 M in LPSactivated J774.1 cells. 102 Moreover, it was proved by F Bedos-Belval et al. 103 to inhibit 65% of NO release, and respectively 40% and 75% of IL-1 and IL-6 cytokines production at 30M in LPSstimulated RAW 264.1 macrophages. However, the authors noticed the self-toxicity of this compound with only 40% cell viability at 30 M.

Macrocycle 182 was recently isolated from the roots of Juglans mandshurica and showed antiinflammatory activity in a dose-dependent manner in LPS-stimulated RAW264.7 cells. It is active against NO production with 32.7 to 91.3% inhibition, TNF-α and IL-6 production with 44.1 to 95.7% and 29.2 to 95.6% inhibition respectively in the range 3-100 M. No significant cytotoxicity in RAW 264.7 cells at 100 μM was observed. 83

Conclusion

This review summarizes the findings from 1982 to 2020 concerning the anti-inflammatory activities of a total of 182 diarylheptanoids, mainly isolated as secondary metabolites from plants used in traditional medicine. In our opinion, all natural diarylheptanoids with quantified anti-inflammatory properties have been considered. However, some works may not have been retrieved by the literature method used herein. This review suggests the potential of the diarylheptanoid scaffold for the treatment of chronic inflammatory diseases even if structure-activity outcomes are difficult to highlight due to the complexity of inflammation process and the data variability of in vitro and/or in vivo studies. Diarylheptanoids may act as anti-inflammatory agents affecting the arachidonic metabolism, the cytokines production or the modulation of pro-inflammatory gene expression. Thus, the diarylheptanoid scaffold represents an important basis for the development of new, safe, effective and side effect-free anti-inflammatory drug candidates.

  supported the interest of 4 as anti-inflammatory agent by reporting potent antioxidant activity in DPPH assay (IC50 = 28.3 M compared to AA: IC50 = 46.0 µM) and NO production inhibition with IC50 value of 11.4 M in LPS-stimulated RAW 264.7 macrophages (compared to L-NMMA: IC50 = 42 µM).

) (IC50 = 8 . 1

 81 M), alluside B (14) (IC50 = 15.2 M), 15 (IC50 = 15.2 M), 17 (IC50 = 22.1 M), 18 (IC50 = 30 M), 19 (IC50 = 22 M), 20 (IC50 = 15.4 M), 21 (IC50 = 30 M), 22 (IC50 = 10.5 M) were found efficient. Conjugated diarylheptanoids 16 (IC50 = 2.9 M), platyphyllenone (23) (IC50 = 6.9 M) and 33 (IC50 = 8.6

Compounds 123 -

 123 124-125 were isolated as new diarylheptanoids from hemiparasitic shrub Viscum album L. (Santalaceae) and tested for their inhibitory effects on the LPS-stimulated production of TNF-, IL-6 and IL-12p40 in BMDCs. With IC50 values of 0.32, 0.68 and 0.09 µM respectively, 123 revealed potent efficiency, compared to SB203580 (IC50 = 7.53, 3.45 and 5.21 µM respectively) used as positive control. 124 showed moderate activity with IC50 values above 50 µM for TNF- , IL-6 and 11.8 µM for IL-12p40, whereas 125 proved inefficient (all IC50 > 50 µM).[START_REF] Nhiem | Diarylheptanoids and flavonoids from Viscum album inhibit LPS-stimulated production of proinflammatory cytokines in bone marrow-derived dendritic cells[END_REF]

Table 1 .

 1 Structures and sources of natural anti-inflammatory linear 1,7-diaylheptanoids.

	Diarylheptanoids	Sources of evaluated diarylheptanoids	1	2	3	4	5	6	7	R1	R2	R3	R4	R5	R6
	Muricarpone B (1)	Alnus sibirica 23-25 Nidus vepae 26	-	-	O	-	-	-	-	OH	OH	-	OH	OH	H
	Hirsutenone (2)

Table 2 .

 2 Structures and sources of natural anti-inflammatory 1,7-diaylheptanoids embedding a 1,5-oxo bridge in the 7-carbon chain.

	Diarylheptanoids	diarylheptanoids Sources of evaluated	1	2	3	4	5	6	7	R1	R2
	Diosniponol A (134)	Dioscorea nipponica 48	(S)	─	(R)-OH	─	(S)	─	─	OCH3	OCH3
	Diosniponol B (135)	Dioscorea nipponica 48	(S)	─	(S)-OH	─	(S)	─	─	OCH3	OCH3
	136	Dioscorea nipponica 48	(S)	─	(R)-OH	─	(S)	─	─	H	H
	137	Dioscorea nipponica 48	(S)	─	(S)-OH	─	(S)	─	─	H	H
	138	Dioscorea nipponica 48	(S)	─	(S)-OH	─	(R)	 6 (E)		H	H
	Calyxin F (139)	Alpinia blepharocalyx 66	(R)	─	(R)-X	─	(S)	─	─	H	H
	6-Hydroxycalyxin F (140) Alpinia blepharocalyx 66	(S)	(S)-OH	(R)-X	─	(S)	─	─	H	H
	Plantagineoside C (141)	Tacca plantaginea 81	(R)	─	(S)-O-Glc	─	(R)	─	─	OH	OH
	Rhoiptelol B (142)	Alnus hirsuta 29 Juglans mandshurica 83	(R)	─	(S)-OH	─	(S)	(S)-OH	─	OCH3	H
	143	Kampferia galanga 74

  IC50 = 26.2 g /mL) in INF- and LPS-activated RAW 264.7 cells.[START_REF] Kim | Nitric oxide and prostaglandin E2 synthesis inhibitory activities of diarylheptanoids from the barks of Alnus japonica steudel[END_REF] Hirsutanonol (3) was further evaluated for its potent inhibitory activity against LPS-induced NO and TNF- production and NF-B activation in RAW 264.7 macrophages with IC50 values of 19.3, 23.7 and 9.9 M respectively (compared to the IC50 values of parthenolide as positive control: 2.4, 2.6 and 3.4 M respectively).[START_REF] Cai | Diarylheptanoids from Alnus hirsuta inhibit the NF-kB activation and NO and TNF-alpha production[END_REF] Alnus formosana and Alnus sibirica were also hirsutanonol sources. According to the reported studies, the evaluation of its NO production inhibitory activity led to IC50 values of 30 M,[START_REF] Lai | A comprehensive investigation of anti-inflammatory diarylheptanoids from the leaves of Alnus formosana[END_REF] 21.3 M 23 and 17.8 M 25 in LPSstimulated RAW 264.7 macrophages. It also demonstrated potent antioxidant activity in DPPH and NBT superoxide scavenging radicals assays with IC50 values of 26.0 and 19.0 M respectively (compared to

They isolated diarylheptanoid 3 from the barks of Alnus japonica and reported moderate NO production inhibition with an IC50 value of 44.3 g/mL (compared to L-NMMA : IC50 =22.8 g/mL) and potent COX-2 level reduction in a dose dependent manner with an IC50 of 25.7 g/mL (compared to indomethacin: AA IC50(DPPH) = 44.7 M and allopurinol IC50 (NBT) = 3.92 M as positive controls).

  demonstrated that oregonin dose-dependently (from 10 to 100 µM) reduced LPS-stimulated NO production (48 to 95% inhibition rates in RAW 264.7 cells, vs 19 to 81% inhibition rates in BV-2 microglia). Oregonin further inhibited the LPS-induced iNOS protein production in RAW264.7 macrophages (48 to 95% inhibition rates from 10 to 100 µM) and BV-2 microglial cells (22 to 79% inhibition rates from 10 to 100 µM) notably by acting on HO-1 induction. Oregonin also displayed dose-dependent inhibition (from 10 to 100 µM) of LPS-mediated NF-B promoter activity (35 to 84% inhibition rates in RAW 264.7 cells, vs 26 to 72% inhibition rates in BV-2 microglia) and DNAbinding ability, as well as p65 nuclear translocation and phosphorylation. Oregonin attenuated activator protein (AP)-1 transactivation (which participates in the upregulation of iNOS gene transcription) via p38 MAPK inhibition. The antioxidant and anti-inflammatory efficiency of oregonin was further reported by Hu and Wang[START_REF] Hu | Antioxidative activity and anti-inflammatory effects of diarylheptanoids isolated from Alnus hirsuta[END_REF] with an IC50 value of 8.4 µM in DPPH assay and inhibition rates of NO production from 31.2 to 77.3 %, inhibition of intracellular ROS formation from 6.7 to 71.6 %, reduction of iNOS expression from 16.7 to 75 % and reduction of COX-2 expression from 7.7 to 71.8% in the range 10-100 M in LPS activated RAW 264.7 macrophages.

  in LPS-activated RAW 264.1 macrophages. No cell toxicity was observed up to 100 µM. Barks of Alnus japonica also provided others rubranol glycosides 10, 11, and platyphylloside 12 which proved a moderate efficiency compared to the control assays against NO production (IC50 values of 48.6, 49.4 and 53.1 g/mL respectively compared to 22.8 g/mL for L-NMMA) and COX-2 expression (IC50 values of 45.2, 34.2 and 32.7 g/mL respectively compared to 26.2 g/mL for indomethacin) in LPS-activated RAW 264.7 macrophages.

  2003, a series of new original diarylheptanoids were isolated from seeds of Alpinia blepharocalyx (Zingiberaceae), one of the most important Chinese medicinal plants and their structures elucidated. In particular in vitro NO inhibitory activity of linear compounds 52-62 and tetrahydropyran enclosing diarylheptanoids 139 and 140 was evaluated in LPS-activated J774.1 macrophages byKadota et al.

	moiety
	inhibited NO release with IC50 values of 84, 95, 103, 83 and 76 µM respectively. 6-Hydroxycalixin F
	(140) showed 37.6% inhibition rate at 10 µg/mL. Stronger activity was found for dimeric
	diarylheptanoids blepharocalyxin A (61) and B (62) with IC50 values of 39 and 36 µM without any
	cytotoxicity.

[START_REF] Kadota | Novel Diarylheptanoids of Alpinia blepharocalyx[END_REF]

All the tested compounds inhibited the NO release in a dose dependent manner more efficiently than curcumin (IC50 = 190 µM) as positive control. Diarylheptanoid 52 showed a moderate activity with an IC50 value of 181 µM. More potent were hydroperoxide calyxin A (53), calyxin B (54), epicalyxin B (55) and calyxin F (139) bearing a chalcone moiety displaying IC50 values of 49, 39, 84 and 51 µM respectively. calyxin C (56), epicalyxin C (57) (stereoisomeric to each other at C9"), calyxin D (58), epicalyxin D (59) (stereoisomeric to each other at C9") and calyxin E (60) bearing a flavanone

, 71, 72, 77, 78, 80 and

  6 µM) as positive controls. Compounds 7081 displayed moderate activities close to that of reference compounds with IC50 values of 16.1, 42.0, 20.6, 49.5, 28.5, 15.6 and 10.6 µM respectively. Derivatives 66

, 67, 68, 69, 73, 74, 75, 76, 79, 3

  -platyphyllone(82) and 83 showed strong inhibition with IC50 values of 2.7, 7.0, 8.9, 9.8, 3.9, 7.3, 9.7, 5.8, 6.5, 5.6 and 4.8 µM respectively. Noteworthy, for each pair of enantiomers, the inhibitory effects of each enantiomer are not significantly different.

93-94, 95, 96, and 97 exhibited

  activity close to the reference compound with IC50 values of 10.7, 9.5, 9.4, 11.5 and 8 µM. Diarylheptanoid

identified in 2011 a series of 11 new diarylheptanoids 84-94 and 7 known ones 95-101 which were examined for their inhibitory activity on NO production in LPS-activated RAW 264.7 macrophages. Diols 84, 85 and 86 showed strong activity with IC50 values of 3.1, 2.8 and 2.4 µM respectively, compared to indomethacin (IC50 = 12.9 µM). Derivatives 92, enantiomeric mixture of

89, 90, 91, 98 and

  hanokinin (99) displayed moderate activity with IC50 values of 37.5, 32, 35.5, 25.8 and 46.4 µM respectively. Moreover, other studies described for 98 an IC50 value of 89.7 µM (in LPS-activated BV2 microglial cells compared to L-NMMA : IC50 = 18.3 µM)

  It inhibited NO production with 43 to 88 %, 39 to 89 %, 39 to 87 %, 34 to 85% rates respectively, TNF-production with 39 and 77 %, 36 to 95 %, 34 to 78 % and 41 to 94% rates respectively and IL-6 expression with and 57 to 89 %, 43 to 90 % , 43 to 95 % and 40 to 95% rates in the range 10-100 µM.[START_REF] Diao | A new diarylheptanoid and a new diarylheptanoid glycoside isolated from the roots of Juglans mandshurica and their antiinflammatory activities[END_REF] Cell viability determined by MTT assay, showed that compounds 120-122 and 142 had no significant cytotoxicity. Rhoiptelol B (142) had also been evaluated in 2007 after isolation from Alnus hirsuta for its inhibitory activity against LPS-induced NO and TNF- production and NF-B activation in RAW 264.7 cells. However, it showed very weak activity with IC50 values above 100 M.[START_REF] Cai | Diarylheptanoids from Alnus hirsuta inhibit the NF-kB activation and NO and TNF-alpha production[END_REF]

	1, 29.3, 15.6, 23.1 and 30.1 µM respectively, compared to L-165041 (IC50 = 0.65
	µM) as positive control. No significant toxicity was noticed at the tested concentration.
	Many other plant genus have been explored for diarylheptanoids with anti-inflammatory properties.
	Linear compounds 120-121-122 and cyclic rhoiptelol B (142) isolated from roots of Juglans
	mandshurica (Juglandaceae), an important medicinal plant primarily distributed throughout
	Northeastern Asia, showed anti-inflammatory activities in a dose-dependent manner in LPS-stimulated
	RAW264.7 cells.

  TBARS, TNF- and IL-1, with 61.1, 67.1, 38.6 and 63.6% inhibition rates respectively for 126, and 56.3, 60.4, 43.8 and 58.8% inhibition rates respectively for 127 at 1 µM in rats liver hepatocytes 180 min after CCl4 addition (compared to curcumin : 57.6%, 39.2%, 37.1% and 63.3% inhibition rates respectively).[START_REF] El-Halawany | Protective Effect of Aframomum melegueta phenolics Against CCl4-Induced Rat Hepatocytes Damage; Role of Apoptosis and Proinflammatory Cytokines inhibition[END_REF] Moreover, the experimental results did not show any toxicity for the hepatocytes. 126 and 127 showed same range of anti-inflammatory efficiency as curcumin. Recently, He and co-workers[START_REF] Yao | Anti-inflammatory diarylheptanoids and phenolics from the rhizomes of kencur (Kaempferia galanga L.)[END_REF] characterized new pentaol 128, cyclic diarylheptanoids 143-146 fromIn the course of investigation on the therapeutic effect of ginger on cardiovascular diseases, it was shown that gingerenone A (129) efficiently inhibited TNF- and LPS-induced VCAM-1 expression with 26 to 89 % and 17 to 94 % rates respectively and attenuated TNF- and LPS-induced NF-B transactivation with 7 to 46 % and 8 to 40 % rates respectively in the range 5-20 µM in HUVECs, showing its potential in prevention for atherosclerosis.[START_REF] Kim | Gingerenone A Attenuates Monocyte-Endothelial Adhesion via Suppression of I Kappa B Kinase Phosphorylation[END_REF] Phenolic 130, 131 and non-phenolic 132, 133 diarylheptanoids isolated from rhizomes of Pleuranthodium racemigerum (Zingiberaceae), an endemic plant of New Guinea, were tested for their anti-inflammatory activity against NO production and TNF- downregulation in LPS-activated RAW 264.7 macrophages and N-11 microglial cells. These compounds inhibited the NO release with IC50 values of 47, 25.1, 28.3 and 47.0 µM respectively in RAW 264.7 macrophages (compared to curcumin : IC50 = 12.3 µM as reference) and IC50 values of 63.2, 41.3, 12.7 and 44.2 µM respectively in activated N-11 microglial cells (compared to apigenin : IC50 = 15 µM as positive control). Concerning the TNF-level, these derivatives showed IC50 values of 29.6 , 15.9, 5.3 and 9.9 µM respectively in RAW 264.7 macrophages (compared to curcumin : IC50 = 11.2 µM) and IC50 values of 29.6, 23.3, 4.3 and 29.6 µM respectively in N-11 microglial cells (compared to apigenin : IC50 = 20 µM) were found. Yet, they proved some degree of cytotoxicity, however lower than that of curcumin in RAW 264.7 cells for the same range of efficacy.[START_REF] Raju | Diarylheptanoids with anti-inflammatory activity from the rhizomes of Pleuranthodium racemigerum (Zingiberaceae)[END_REF]

	Kaempferia galanga L. (Zingiberaceae) rhizomes and evaluated their inhibitory effect against LPS-
	induced NO production in RAW 264.7 macrophages. 143 and 145 proved particularly efficient with IC50
	values 27.9 and 17.3 µM respectively, compared to indomethacin (IC50 = 32.3 µM). 128 (IC50 = 46.7 µM)
	and 144 (IC50 = 79.9 µM) exhibited moderate activity, while 146 proved inefficient (IC50>100µM).

Table 3 (compounds 152- 171) for

 3

meta-meta bridged biphenyl diarylheptanoids and Table

4

(compounds 172-182) for metapara bridged diphenyl ether diarylheptanoids. Macrocyclic diarylheptanoids are mainly found in genus Myrica (Myricaceae),

[START_REF] Silva | Recent Breakthroughs in the Antioxidant and Anti-Inflammatory Effects of Morella and Myrica Species[END_REF]

Alnus, Carpinus (Betulaceae) and Acer (Acereaceae).

[START_REF] Bi | Traditional uses, phytochemistry, and pharmacology of the genus Acer (maple): A review[END_REF]

Table 3 .

 3 Structures and sources of natural anti-inflammatory macrocyclic meta-meta-bridge biphenyl heptanoids.

	Diarylheptanoids	Sources of evaluated diarylheptanoids	1	2	3	4	5	6	7 R1	R2	R3	R4	R5
	Myricananin A (152)	Myrica nana 93	-	(S)-OH	(R)-OH	-	-	-		OH	OH	OH	OCH3	H
	Myricananin C (153)	Myrica nana 93 Myrica adenophora 94	-	-	O	-	-	-	-	H	OH	OH	OCH3	H
	Myricananin D (154)	Myrica nana 93		 1 (E)	O	-	-	-	-OH	OH	OCH3 OCH3	OH
	Myricananin E (155)	Myrica nana 93	-	OH	O	-	-	-	-OH	OH	OCH3 OCH3	OH
	12-Hydroxymyricanone (156)	Myrica nana 93	-	OH	O	-		-	-	H	OH	OCH3 OCH3	OH
	Alnusonol (157)	Myrica nana 93	-	-	O	-OH -	-	H	OH	OH	H	H
	(R)-Myricanol (158)	Myrica adenophora 94	-	-	(R)-OH	-	-	-		H	OH	OCH3 OCH3	OH
	Porson (159)	Myrica adenophora 94	-	OH	O	-		-	-	H	OH	OCH3 OCH3 OCH3
	Myricanone (160)	Myrica adenophora 94 Alnus japonica 95	-	-	O	-	-	-	-	H	OH	OCH3 OCH3	OH
	(S)-Myricanol (161)	Alnus japonica 95	-	-	(S)-OH	-	-	-	-	H	OH	OCH3 OCH3	OH
	Halnuheptanoid B (162)	Alnus japonica 95	-	-	O	-	-	-	-	H	OAc	OCH3	OH	O-Glc
	163	Alnus japonica 95	-	-	O	-	-	-	-	H	OH	OCH3 OCH3 O-Glc
	164	Alnus japonica 95	-	-	(S)-OH	-	-	-	-	H	OH	OCH3 OCH3 O-Glc
	Carpinontriol A (165)	Carpinus cordata 96 Carpinus turczaninowii 97	-	OH	O	OH OH OH		H	OH	OH	H	H

Table 4 .

 4 Structures and sources of natural anti-inflammatory macrocyclic meta-para-bridge diphenylether heptanoid.

	Diarylheptanoids	Sources of evaluated diarylheptanoids	1	2	3	4	5	6	7	R1	R2	R3
	Acerogenin A (172)	Acer nikoense 46, 47, 101	-	-	-	-	(R)-OH	-	-	OH	H	H
	Acerogenin B (173)	Acer nikoense 46, 47, 101	-	-	(R)-OH	-	-	-	-	OH	H	H
	Acerogenin C (174)	Acer nikoense 46	-	-	-	-	O	-	-	OH	H	H
	Acerogenin L (175)	Acer nikoense 46	-	-	O	-	-	-	-	OH	H	H
	Aceroside III (176)	Acer nikoense 46	-	-	-	-	(R)-O-Api(1→6)-Glc -	-	OH	H	H
	Aceroside IV (177)	Acer nikoense 46	-	-	(R)-O-Glc	-	O	-	-	OH	H	H
	Aceroside B1 (178)	Acer nikoense 47	-	-	-	-	(R)-OH	-	-O-Glc	H	H
	Myricatomentogenin (179)	Alnus hirsuta 29	-	-	O	-	-	-	-	OH	OCH3 OH
	180	Alnus hirsuta 29	-	-	(R)-OH	-	-	-	-OCH3 OCH3 OH
	Tedarene A (181)	Tedania ignis 102, 103	-		 2 (E)		 4 (Z)	-	-	OH	H	H
	182	Juglans mandshurica 83	-	-	(S)-OGlc	-	O	-	-	OH	OCH3 H

[START_REF] Ting | Biological evaluation of secondary metabolites from the roots of Myrica adenophora[END_REF]

Myricanone (160) was also isolated from Alnus japonica stem bark, along with (S)-myricanol (161), glucopyranosides halnuheptanoid B (162), O--D-glucoside macrocycles 163 and 164 by Ibrahim et al.

Acknowledgments

We thank CNRS and University Toulouse 3 for financial support.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.