Figures (6)  Tables (4)

    • Figure 1. 

      Plant morphology of A. macrocephala.

    • Figure 2. 

      Current progress of A. macrocephala.

    • Figure 3. 

      Origin, distribution and processing of A. macrocephala.

    • Figure 4. 

      Structure of small molecule compounds with bioactivities from AMR. Atractylenolide I (1); Atractylenolide II (2); Atractylenolide III (3); 3β-acetoxyl atractylenolide I (4); 4R,5R,8S,9S-diepoxylatractylenolide II (5); 8S,9S-epoxyla-tractylenolide II (6); Atractylmacrols A (7); Atractylmacrols B (8); Atractylmacrols C (9); Atractylmacrols D (10); Atractylmacrols E (11); 2-[(2E)-3,7-dimethyl-2,6-octadienyl]-6-methyl-2,5-cyclohexadiene-1,4-dione (12); 8-epiasterolid (13); (3S,4E,6E,12E)-1-acetoxy-tetradeca-4,6,12-triene-8,10-diyne-3,14-diol (14); (4E,6E,12E)-tetradeca-4,6,12-triene-8,10-diyne-13,14-triol (15); 1-acetoxy-tetradeca-6E,12E-diene-8, 10-diyne-3-ol (16); 1,3-diacetoxy-tetradeca-6E, 12E-diene-8,10-diyne (17); Biatractylenolide II (18); Biepiasterolid (19); Biatractylolide (20).

    • Figure 5. 

      Schematic diagram for the anti-tumor mechanism of atractylenolides.

    • Figure 6. 

      Biosynthetic pathways for bioactive compounds of A. macrocephala.

    • Pharmacological activitiesDetailed functionPolysaccharides informationModelDoseTest indexResultsRef.
      Immunomodulatory effectsRestore immune
      function      		/Chicken models
      (HS-induced)      		200 mg/kgOxidative index;
      Activities of mitochondrial complexes and ATPases;
      Ultrastructure in chicken spleens;
      Expression levels of cytokines, Mitochondrial dynamics- and apoptosis-related genes      		Alleviated
      the expression of
      IL-1 ↑,TNF-α ↑, IL-2 ↓, IFN- γ ↓; mitochondrial dynamics- and anti-apoptosis-related genes ↓; pro-apoptosis-related genes ↑;
      the activities of mitochondrial complexes and ATPases ↓ caused by HS      		[35]
      Regulate the immune function/Chicken models
      (HS-induced)      		200 mg/kgiNOS–NO activities;
      ER stress-related genes;
      Apoptosis-related genes;
      Apoptosis levels      		Alleviated NO content ↑; activity of iNOS ↑ in the chicken spleen; GRP78, GRP94, ATF4, ATF6, IRE ↑; caspase3 ↑; Bcl-2 ↓ caused by HS[36]
      Relieve immunosuppressionCommercial AMR powder (purity 70%)Geese models
      (CTX-induced)      		400 mg/kgSpleen development;
      Percentages of leukocytes in peripheral blood      		Alleviated the spleen damage;
      T and B cell proliferation ↓; imbalance of leukocytes; disturbances of humoral; cellular immunity caused by CTX      		[37]
      Active the lymphocytesCommercial AMR powder (purity 95%)Geese models
      (CTX-induced)      		400 mg/kgThymus morphology;
      The level of serum GMC-SF, IL-1b, IL-3, IL-5;
      mRNA expression of CD25, novel_mir2, CTLA4 and CD28 signal pathway      		Maintain normal cell morphology of thymus;
      Alleviated GMC-SF ↓, IL-1b ↓, IL-5↓, IL-6↓, TGF-b↓; IL-4 ↑, IL-10 ↑; novel_mir2 ↓, CD25↓, CD28↓ in thymus and lymphocytes caused by CTX      		[38]
      Alleviate immunosuppressionCommercial AMR powder (purity 70%)Geese models
      (CTX-induced)      		400 mg/kgThymus development;
      T cell proliferation rate;
      The level of CD28, CD96, MHC-II;
      IL-2 levels in serum;
      differentially expressed miRNAs      		Alleviated thymus damage;
      T lymphocyte proliferation rate ↓; T cell activation ↓; IL-2 levels ↓ caused by CTX;
      Promoted novel_mir2 ↑; CTLA4 ↓; TCR-NFAT signaling pathway      		[39]
      Alleviates T cell activation declineCommercial AMR powder (purity 95%)BALB/c female mice (CTX-induced)200 mg/kgSpleen index;
      Morphology, death, cytokine concentration of splenocytes;
      Th1/Th2 ratio, activating factors of lymphocytes;
      T cell activating factors;
      mRNA expression level in CD28 signal pathway      		Improved the spleen index;
      Alleviated abnormal splenocytes morphology and death; Balance Th1/Th2 ratio; IL-2 ↑, IL-6 ↑, TNF-α ↑, IFN-γ ↑; mRNA levels of CD28, PLCγ-1, IP3R, NFAT, AP-1 ↑      		[40]
      Immunoregulation and ImmunopotentiationCommercial AMR powder (purity 80%)BMDCs (LPS-induced);
      Female BALB/c mice (ovalbumin as a model antigen)      		/Surface molecule expression of BMDCs;
      Cytokines secreted by dendritic cell supernatants;
      OVA-specific antibodies in serum;
      Cytokines in serum;
      Lymphocyte immunophenotype      		Expression of CD80 and CD86 ↑; IL-1β ↑, IL-12 ↑, TNF-α↑ and IFN-γ ↑; OVA-specific antibodies in serum ↑; Secretion of cytokines ↑; Proliferation rate of spleen lymphocytes ↑; Activation of CD3+CD4+ and CD3+CD8+ lymphocytes[46]
      Increase immune-response capacity of the spleen in miceCommercial AMR powder (purity 70%)BALB/c female mice100, 200, 400 mg/kgSpleen index;
      Concentrations of cytokines;
      mRNA and protein expression levels in TLR4 signaling      		In the medium-PAMK group:
      IL-2, IL-4, IFN-c, TNF-a ↑; mRNA and protein expression of TLR4, MyD88, TRAF6, TRAF3, NF-κB in the spleen ↑      		[41]
      Immunological activityCommercial AMR powder (purity 80%)Murine splenic lymphocytes (LPS or PHA-induced)13, 26, 52, 104, 208 μg/mLT lymphocyte surface markersLymphocyte proliferation ↑;
      Ratio of CD4+/CD8+ T cells ↑      		[47]
      Immunomodulatory activityTotal carbohydrates content 95.66 %Mouse splenocytes
      (Con A or LPS-induced)      		25, 50, 100 μg/mLSplenocyte proliferation;
      NK cytotoxicity;
      Productions of NO and cytokines;
      Transcription factor activity;
      Signal pathways and receptor      		Promoted splenocyte proliferation; Cells enter S and G2/M phases; Ratios of T/B cells ↑; NK cytotoxicity ↑; Transcriptional activities of NFAT ↑; NF-κB, AP-1 ↑; NO, IgG, IL-1α, IL-1β, IL-2, IL-3, IL-4, IL-6, IL-10, IL-12p40, IL-12p70, IL-13, IFN-γ, TNF-α, G-CSF, GM-CSF, KC, MIP-1α, MIP-1β, RANTES, Eotaxin ↑[42]
      Promote the proliferation of thymic epithelial cellsContents of fucrhaara, galactose, glucose, fructose,
      and xylitol: 0.98%, 0.40%, 88.67%, 4.47%, and 5.47%      		MTEC1 cells50 μg/mLCell viability and proliferation;
      lncRNAs, miRNAs, and mRNAs expression profiles in MTEC1 cells      		The differential genes were 225 lncRNAs, 29 miRNAs, and 800 mRNAs; Genes enriched in cell cycle, cell division, NF-κB signaling, apoptotic process, and MAPK signaling pathway[44]
      Immunomodulatory activityMW: 4.354 × 103 Da;
      Composed of mannose, galacturonic acid, glucose, galactose and arabinose;
      The main linkages are →3-β-glcp-(1→, →3,6-β-glcp-(1→, →6-β-glcp-(1→, T-β-glcp-(1→,
      →4-α-galpA-(1→, →4-α-galpA-6-OMe-(1→, →5-α-araf-(1→, →4,6-β-manp-(1→ and →4-β-galp-(1→      		CD4+ T cell50, 100, 200 μg/mLMolecular weight;
      Monosaccharide composition;
      Secondary structure;
      Surface topography;
      Effect on Treg cells      		Treg cells percentage ↑; mRNA expressions of Foxp3, IL-10 and IL-2 ↑; STAT5 phosphorylation levels ↑; IL-2/STAT5 pathway[28]
      Immunostimulatory activityMW of AMAP-1, AMAP-2, and AMAP-3 were 13.8×104 Da, 16.2×104 Da and 8.5×104 Da;
      HG region consists of α-(1→4)-linked GalpA residues      		RAW264.7 cells (LPS-induced)80, 40, 200 μg/mLMolecular weight;
      Total carbohydrate;
      Uronic acid contents;
      Secondary structure;
      Monosaccharide composition;
      Immunostimulatory activity      		RG-I-rich AMAP-1 and AMAP-2 improved the release of NO[29]
      Immunomodulatory effectMW: 1.867×103 Da;
      Contents of glucose, mannose, rhamnose,
      arabinose and galactose: 60.67%, 14.99%, 10.61%, 8.83% and 4.90%      		SMLN lymphocytes25
      μg/ml      		Molecular weight;
      Monosaccharide composition;
      Ultrastructure;
      Intracellular Ca2+concentration;
      Target genes;
      Cell cycle distribution      		[Ca2+]i ↑; More cells in S and G2/M phases; IFN-γ ↑, IL-17A ↑; mRNA expressions of IL-4 ↓[30]
      Macrophage activationTotal carbohydrates content 95.66 %RAW264.7 macrophages (LPS-induced)25, 50, 100 μg/mLPinocytic activity;
      Phagocytic uptake;
      Phenotypic characterization;
      Cytokine production;
      Bioinformatics analysis;
      Transcription factor inhibition      		IL-6, IL-10 and TNF-α ↑; CCL2 and CCL5 ↑; Pinocytic and phagocytic activity ↑; CD40, CD80, CD86, MHC-I, MHC-II ↑; NF-κB and Jak-STAT pathway[43]
      Immunomodulatory effectTotal carbohydrates content 95.66 %SMLN lymphocytes25, 50, 100 μg/mLCytokine production;
      CD4+ and CD8+ lymphocytes;
      Target genes;
      Bioinformatics analysis;
      T and B lymphocyte proliferation;
      Receptor binding and blocking      		IFN-γ, IL-1α, IL-21, IFN-α, CCL4, CXCL9, CXCL10 ↑; CD4+ and CD8+subpopulations proportions ↑;
      c-JUN, NFAT4, STAT1, STAT3 ↑;
      67 differentially expressed miRNAs (55 ↑ and
      12 ↓), associated with immune system pathways; Affect T and B lymphocytes      		[45]
      Improving gastrointestinal functionRelieve enteritis and improve intestinal
      flora disorder      		Commercial AMR powder (purity 70%);
      Contents of fucrhaara, galactose, glucose, xylitol, and fructose: 0.98%, 0.40%, 88.67%, 4.47%, and 5.47%      		Goslings (LPS-induced)400 mg/kgSerum CRP, IL-1β, IL-6, and TNF-α levels;
      Positive rate of IgA;
      TLR4, occludin, ZO-1, cytokines, and immunoglobulin mRNA expression;
      Intestinal flora of gosling excrement      		Relieved IL-1β, IL-6, TNF-α levels in serum ↑; the number of IgA-secreting cells ↑; TLR4 ↑; tight junction occludin and ZO-1 ↓; IL-1β mRNA expression in the small intestine ↑; Romboutsia ↓ caused by LPS[48]
      Ameliorate ulcerative colitisMW: 2.391 × 104 Da;
      Composed of mannose, glucuronic acid, glucose and arabinose in a molar ratio of 12.05:6.02:72.29:9.64      		Male C57BL/6J mice (DDS-induced)10, 20, 40 mg/kg bwHistopathological evaluation;
      Inflammatory mediator;
      Composition of gut microbiota;
      Feces and plasma for global metabolites profiling      		Butyricicoccus, Lactobacillus ↑;
      Actinobacteria, Akkermansia, Anaeroplasma, Bifidobacterium, Erysipelatoclostridium, Faecalibaculum, Parasutterella,
      Parvibacter, Tenericutes, Verrucomicrobia ↓;
      Changed 23 metabolites in fecal content; 21 metabolites in plasma content      		[49]
      Attenuate ulcerative colitis/Male SD rats (TNBS-induced);
      Co-culture BMSCs and IEC-6 cells      		540 mg/kg
      (for rats);
      400 μg/mL (for cell)      		Histopathological analysis;
      Cell migration;
      Levels of cytokines
      		Potentiated BMSCs’ effect on preventing colitis and homing the injured tissue, regulated cytokines;
      BMSCs and AMP promoted the migration of IEC      		[52]
      Against intestinal mucosal injuryMW: 3.714 × 103 Da;
      Composed of glucose, arabinose, galactose, galacturonic acid, rhamnose
      and mannose with molar ratios of 59.09:23.22:9.32:4.70:2.07:1.59      		Male C57BL/6 mice (DDS-induced)100 mg/kgIntestinal morphology;
      IL-6, TNF-α and IL-1β in serum;
      mRNA expression;
      Intestinal microbiota      		Alleviated body weight ↓; colon length ↓; colonic damage caused by DSS;
      Over-expression of TNF-α, IL-1β, IL-6 ↓; Infiltration of neutrophils in colon ↓; Mucin 2 ↑;
      Tight junction protein Claudin-1 ↑;
      Harmful bacteria content ↓;
      Beneficial bacteria content ↑      		[50]
      Against intestinal injuryTotal carbohydrates 95.66 %IECs (DDS-induced)5, 25, 50 μg/mLCell proliferation and apoptosis;
      Expression levels of intercellular TJ proteins;
      lncRNA screening      		Proliferation and survival of IECs ↑;
      Novel lncRNA ITSN1-OT1 ↑;
      Blocked the nuclear import of phosphorylated STAT2      		[51]
      Anti-tumor activityInduce apoptosis in transplanted H22 cells in miceMW: 4.1× 103 Da;
      Neutral heteropolysaccharide composed of galactose, arabinose, and glucose with α-configuration (molar ratio, 1:1.5:5)      		Female Kunming mice100 and 200 mg/kg (for rats)Secondary structure;
      Molecular weight;
      Molecular weight;
      Thymus index and Spleen index;
      Lymphocyte Subpopulation in peripheral blood;
      Cell cycle distribution      		In tumor-bearing mice CD3+, CD4+, CD8+ ↓;
      B cells ↑      		[31]
      Regulate the innate immunity of colorectal cancer cellsCommercial AMR powder (purity 70%)C57BL/6J mice (MC38 cells xenograft model)500 mg/kgExpression of pro-inflammatory cytokines and secretionIL-6, IFN-λ, TNF-α, NO ↑ through MyD88/TLR4-dependent signaling pathway;
      Survival duration of mice with tumors ↑;
      Prevent tumorigenesis in mice      		[54]
      Induce apoptosis of Eca-109 cellsMW: 2.1× 103 Da;
      Neutral hetero polysaccharide composed
      of arabinose and glucose (molar ratio, 1:4.57) with pyranose rings and α-type and β-type glycosidic linkages      		Eca-109 cells0.25, 0.5, 1, 1.5, 2.00 mg/mLCell morphology;
      Cell cycle arrest;
      Induction of apoptosis      		Accelerate the apoptosis of Eca109 cells[53]
      '/' denotes no useful information found in the study.

      Table 1. 

      Components and bioactivity of polysaccharides from Atractylodes macrocephala Koidz. Rhizome.

    • TypesSubstancesModelIndexDoseSignal pathwayResultsRef.
      Human colorectal cancerAT-IIIHCT-116 cell;
      HCT-116 tumor xenografts bearing in nude mice      		Cell viability;
      Cell apoptotic;
      mRNAs and protein
      expressions of Bax, Bcl-2, caspase-9 and caspase-3      		25, 50, 100, 200 μM (for cell);
      50, 100,
      200 mg/kg (for rats)      		Bax/Bcl-2 signaling pathwayPromoting the expression of proapoptotic related gene/proteins; Inhibiting the expression of antiapoptotic related gene/protein; Bax↑; Caspase-3↓; p53↓; Bcl-2↓[55]
      Human gastric carcinomaAT-IIHGC-27 and AGS cell
      		Cell viability;
      Morphological changes;
      Flow cytometry;
      Wound healing;
      Cell proliferation, apoptosis, and motility      		50, 100, 200, 400 μMAkt/ERK signaling pathwayCell proliferation, motility↓; Cell apoptosis↑; Bax↑;
      Bcl-2↓; p-Akt↓; p-ERK↓      		[56]
      Mammary
      tumorigenesis      		AT-IIMCF 10A cell;
      Female SD rats (NMU-induced)
      		Nrf2 expression and nuclear accumulation;
      Cytoprotective effects;
      Tumor progression;
      mRNA and protein levels of Nrf2;
      Downstream detoxifying enzymes      		20, 50, 100 μM (for cell);
      100 and 200 mg/kg (for rats)      		JNK/ERK-Nrf2-ARE signaling pathway;
      Nrf2-ARE signaling pathway      		Nrf2 expressing↑; Nuclear translocation↑; Downstream detoxifying enzymes↓; 17β-Estradiol↓; Induced malignant transformation[57]
      Human colon adenocarcinomaAT-IHT-29 cellCell viability;
      TUNEL and Annexin V-FITC/PI double stain;
      Detection of initiator and
      executioner caspases level      		10, 20, 40, 80, 100 μMMitochondria-dependent pathwayPro-survival Bcl-2↓; Bax↑; Bak↑; Bad↑; Bim↑; Bid↑; Puma↑[58]
      Sensitize triple-negative
      TNBC cells to paclitaxel      		AT-IMDA-MB-231 cell;
      HS578T cell;
      Balb/c mice (MDA-MB-231 cells-implanted)      		Cell viability
      Transwell migration
      CTGF expression      		25, 50, 100 μM (for cell);
      50 mg/kg (for rats)      		/Expression and secretion of CTGF↓; CAF markers↓; Blocking CTGF expression and fibroblast activation[59]
      Human ovarian cancerAT-IA2780 cellCell cycle;
      Cell apoptosis;
      Cyclin B1 and CDK1 level
      		12.5, 25, 50, 100 and 200 μMPI3K/Akt/mTOR
      signaling pathway      		Cyclin B1, CDK1↓; Bax↑;
      Caspase-9↓; Cleaved caspase-3↓; Cytochrome c↑; AIF↑; Bcl-2↓; Phosphorylation level of PI3K, Akt, mTOR↓      		[60]
      Impaired metastatic properties transfer of CSCsAT-ILoVo-CSCs; HT29-CSCsCell migration
      and invasion;
      miR-200c expression;
      Cell apoptosis      		200 μMPI3K/Akt/mTOR signaling pathwaySuppressing miR-200c activity; Disrupting EV uptake by non-CSCs[61]
      Colorectal cancerAT-IHCT116 cell;
      SW480 cell;
      male BALB/c nude mice (HCT116-implanted)      		Cell viability;
      Cell apoptosis;
      Glucose uptake;
      Lactate Production;
      STAT3 expression;
      Immunohistological analysis      		25, 50, 100, 150, 200 μM (for cell);
      50 mg/kg (for rats)      		JAK2/STAT3 signalingCaspase-3↑; PARP-1↓;
      Bax↑; Bcl-2↓; Rate-limiting glycolytic
      enzyme HK2↓; STAT3 phosphorylation↓      		[62]
      Human lung cancerAT-INSCLC cells (A549 and H1299);
      female nude mice (A549-Luc cells- implanted)      		Cell viability;
      Cell cycle;
      Phosphorylation and protein expression of
      ERK1/2, Stat3,
      PDK1, transcription factor SP1;
      mRNA levels of PDK1 gene      		12.5, 25, 50, 100, 150 μM (for cell);
      25 and 75 mg/kg (for rats)      		/ERK1/2↑; Stat3↓; SP1↓;
      PDK1↓      		[63]
      '/' denotes no useful information found in the study.

      Table 2. 

      Anti-tumor activity of atractylenolides.

    • ActivitiesSubstancesModelIndexDoseSignal pathwayResultsRef.
      Establish a PD modelAT-II; AT-I;
      Biepiasterolid;
      Isoatractylenolide I;
      AT-III; 3β-acetoxyl atractylenolide I;
      (4E,6E,12E)- tetradeca-4,6,12-triene-8,10-diyne-13,14-triol;
      (3S,4E,6E,12E)-1-acetoxy-tetradeca-4,6,12-triene-8,10-diyne-3,14-diol      		SH-SY5Y cell (MPP+-induced)Cell viability10, 1, 0.1 μM/All compounds have inhibitory activity on MPP+-
      induced SH-SY5Y cell      		[64]
      /4R,5R,8S,9S-diepoxylatractylenolide II;
      8S,9S-epoxyla-tractylenolide II      		BV-2 microglia cells (LPS-induced)Cell viability;
      NO synthase
      inhibitor;
      IL-6 levels      		6.25, 12.5, 25, 50, 100 μMNF-κB signaling
      pathway      		NO inhibition with IC50 values
      of 15.8, and 17.8 μМ, respectively;
      IL-6 ↓      		[65]
      Protecting Alzheimer’s diseaseBiatractylolidePC12 cell (Aβ25-35-induced);
      Healthy male Wistar rats (Aβ25-35-induced)      		Cell viability;
      Morris water maze model;
      TNF-α, IL-6, and IL-1β      		20, 40, 80 μM (for cells);
      0.1, 0.3, 0.9 mg/kg (for rats)      		NF-κB signaling
      pathway      		Reduce apoptosis; Prevent cognitive decline; Reduce the activation of NF-κB signal pathway[66]
      /BiatractylolidePC12 and SH-SY5Y cell (glutamate-induced)Cell viability;
      Cell apoptosis;
      LDA;
      Protein expression      		10, 15, 20 μMPI3K-Akt-GSK3β-Dependent
      Pathways      		GSK3β protein expression ↓;
      p-Akt protein expression ↑      		[67]
      Parkinson's DiseaseAT-IBV-2 cells (LPS-induced);
      Male C57BL6/J mice (MPTP-intoxicated)      		mRNA and protein levels;
      Immunocytochemistry; Immunohistochemistry;      		25, 50, 100 μM (for cells);
      3, 10, 30 mg/kg/mL (for rats)      		/NF-κB ↓; HO-1 ↑; MnSOD ↑; TH-immunoreactive neurons ↑; Microglial activation ↓[68]
      Anti depressant like effectAT-IMale ICR mice (CUMS induced depressive like behaviors)Hippocampal neurotransmitter levels;
      Hippocampal pro inflammatory cytokine levels;
      NLRP3 inflammasome in the hippocampi      		5, 10, 20 mg/kg/Serotonin ↓;
      Norepinephrine ↓; NLRP3 inflammasome ↓; (IL)-1β ↓      		[69]
      Alzheimer's diseaseBiatractylenolide II/AChE inhibitory activities;
      Molecular docking      		//Biatractylenolide II can interact with PAS and CAS of AChE[70]
      Cerebral ischemic injury and
      neuroinflammation      		AT-IIIMale C57BL/6J mice (MCAO- induced);
      Primary microglia (OGDR
      stimulation)      		Brain infarct size;
      Cerebral blood flow;
      Brain edema;
      Neurological deficits;
      Protein expressions of proinflammatory;
      Anti-inflammatory
      cytokines      		0.01, 0.1, 1, 10, 100 μM (for cells);
      0.1–10 mg/kg
      (for rats)      		JAK2/STAT3/Drp1-dependent mitochondrial fissionBrain infarct size ↓;
      Restored CBF;
      ameliorated brain edema; Improved neurological deficits;
      IL-1β ↓; TNF-α ↓; IL-6 ↓;
      Drp1 phosphorylation ↓      		[71]
      Reduces depressive- and anxiogenic-like behaviorsAT-IIIMale SD rats (LPS-induced and CUMS rat model)Forced swimming test;
      Open field test;
      Sucrose preference test;
      Novelty-suppressed feeding test;
      Proinflammatory cytokines levels
      		3, 10, 30 mg/kg/30 mg/kg AT-III produced an anxiolytic-like effect; Prevented depressive- and anxiety-like behaviors; Proinflammatory cytokines levels ↓[72]
      Alleviates
      injury in rat
      hippocampal neurons      		AT-IIIMale SD rats (isoflurane-induced)Apoptosis and autophagy in the hippocampal neurons;
      Inflammatory factors;
      Levels of p-PI3K,
      p-Akt, p-mTOR      		1.2, 2.4, 4.8 mg/kgPI3K/Akt/mTOR signaling pathwayTNF-α ↓; IL-1β ↓; IL-6 ↓; p-PI3K ↑; p-Akt ↑; p-mTOR ↑[73]
      ''/' denotes no useful information found in the study.

      Table 3. 

      Neuroprotective effects of esters and sesquiterpenoids.

    • ActivitiesSubstanceModelIndexDoseSignal pathwayResultRef.
      Against LPS-induced NO productionAtractylmacrols A-ERAW264.7 macrophages (LPS-induced)Isolation;
      Structural identification;
      Inhibition activity of
      NO production      		25 μM/Have effects on LPS-induced NO production[74]
      Anti-inflammatory2-[(2E)-3,7-dimethyl-2,6-octadienyl]-6-methyl-2,5-cyclohexadiene-1,
      4-dione;
      1-acetoxy-tetradeca-6E,12E-diene-8, 10-diyne-3-ol;
      1,3-diacetoxy-tetradeca-6E, 12E-diene-8,
      10-diyne      		RAW 264.7
      macrophages (LPS-induced)      		Level of NO and PGE2;
      Level of iNOS, COX-2;
      Levels of pro-inflammatory cytokines;
      Phosphorylation of MAPK(p38, JNK, and ERK1/2)      		2 and 10 μMNF-κB signaling pathwayIL-1β ↓; IL-6 ↓; TNF-α ↓;
      p38 ↓; JNK ↓; ERK1/2 ↓      		[75]
      Anti-inflammatoryAT-I; AT-II;
      8-epiasterolid      		RAW264.7 macrophages;
      BV2 microglial cells (LPS-
      induced)      		Structure identification;
      NO, PGE2 production;
      Protein expression of iNOS, COX-2, and cytokines      		40 and 80 μMNF-κB signaling pathway.NO ↓; PGE2 ↓; iNOS ↓;
      COX-2 ↓; IL-1β ↓; IL-6 ↓; TNF-α ↓      		[76]
      Intestinal inflammationAT-IIIMale C57BL/6 mice (TNBS-induced)Levels of myeloperoxidase;
      Inflammatory factors;
      Levels of the prooxidant markers, reactive oxygen species, and malondialdehyde;
      Antioxidant-related enzymes;
      Intestinal flora      		5, 10, 20 mg/kgFPR1 and Nrf2 pathwaysDisease activity index score ↓; Myeloperoxidase ↓; Inflammatory factors interleukin-1β ↓; Tumor necrosis factor-α ↓; Antioxidant enzymes catalase ↓; Superoxide dismutase ↓; Glutathione peroxidase ↓; FPR1 and Nrf2 ↑; Lactobacilli ↓[77]
      Anti-inflammatoryAT-IIIMG6 cells (LPS-
      induced)      		mRNA and protein levels of TLR4,
      TNF-α, IL-1β, IL-6, iNOS, COX-2;
      Phosphorylation of p38 MAPK and JNK      		100 μMp38 MAPK and JNK signaling pathwaysTNF-α ↓; IL-1β ↓; IL-6 ↓;
      iNOS ↓; COX-2 ↓      		[78]
      Ameliorates spinal cord injuryAT-IIIBV2 microglial (LPS-
      induced);
      Female SD rats (Infinite Horizon impactor)      		Spinal cord lesion area;
      Myelin integrity;
      Surviving neurons;
      Locomotor function;
      Microglia/macrophages;
      Inflammatory factors      		1, 10, 100 μM (for cell);
      5 mg/kg (for rats)      		NF-κB,
      JNK MAPK, p38 MAPK, and Akt pathways      		Active microglia/macrophages;
      Inflammatory mediators ↓      		[79]
      Ulcerative colitisAT-IIIIEC-6 (LPS-induced);
      C57BL/6J male mice (DSS-induced)      		MDA,GSH content;
      SOD activity;
      Intestinal permeability;
      Mitochondrial membrane potential;
      Complex I and complex IV activity      		40 and 80 μM (for cell);
      5 and 10 mg/kg (for rats)      		AMPK/
      SIRT1/PGC-1α signaling pathway      		Disease activity index ↓;
      p-AMPK ↑; SIRT1 ↑;
      PGC-1α ↑;
      Acetylated PGC-1α ↑      		[80]
      '/' denotes no useful information found in the study.

      Table 4. 

      Immunomodulatory and anti-inflammatory activities of esters and sesquiterpenoids.