Natural Products: A Dependable Source of Therapeutic Alternatives for Inflammatory Bowel Disease through Regulation of Tight Junctions
Abstract
:1. Introduction
2. The Pathogenesis of IBD
3. Natural Products for the Treatment of IBD
Classes of Single Bioactive Components | Monomers | Major Plants Present |
---|---|---|
Flavonoids | Kaempferol | Fruits, vegetables, and herbs [23] |
Quercetin | Flowers, leaves, and fruits of plant [24] | |
Puerarin | Pueraria lobata [25] | |
Naringin | Grapes and citrus fruits [26] | |
Icariin | Epimedium [27] | |
Alpinetin | Alpinia katsumadai Hayata [28] | |
Baicalin | Scutellaria baicalensis Georgi [29] | |
Rhein | Rheum rhabarbarum [30] | |
Terpenoids | Ginsenosides | Ginseng [31] |
Astragaloside IV | Astragalus membranaceus [32] | |
Geniposide | Gardenia jasminoides Ellis [33] | |
Patchouli alcohol | P. cablin [34] | |
Atractylodes A | Atractylodes macrocephala [35] | |
Clematichinenoside | Clematis chinensis Osbeck [36] | |
Oridonin | Rabdosia rubescens [37] | |
Alkaloids | Berberine | ranunculaceae, rutaceae and berberidaceae [38] |
Koumine | Gelsemium [39] | |
Non-flavonoid polyphenols | Curcumin | Turmeric (Zingiberaceae) [40] |
Resveratrol | Red wine and grape skin [41] | |
Other classes | Emodin | Rheum palmatum [42] |
Arctigenin | Fructus Arctii [43] | |
Sodium houttuyfonate | Houttuynia cordata Thunb [44] | |
Artemisinin | Artemisia annua L. [45] |
4. Flavonoids for the Treatment of IBD (Table 2)
4.1. Kaempferol
4.2. Quercetin
4.3. Puerarin
4.4. Naringin
4.5. Icariin
4.6. Alpinetin
4.7. Baicalin
4.8. Rhein
Monomers | Objects (Model Induces) | Effects | Signaling Pathway |
---|---|---|---|
Kaempferol | 1. A model of colitis mice induced by dextran sulfate sodium 2. Epithelial-endothelial cells co-culture model 3. Caco-2 cell caused by Deoxynivalenol | 1. ZO-1, occludin, and claudin-1 ↑, IL-1β, IL-6, and TNF-a ↓, IL-10 ↑ 2. TEER ↑, FITC ↓, ZO-1, occludin, and claudin-2 ↑, NF-κB and I-κB ↓ 3. Claudin-3, claudin-4, and occludin ↑, PKA ↑ | 1. Inhibiting the LPS-TLR4-NF-κB pathway [49] 2. Inhibiting NF-κB signaling pathway activation [50] 3. Activating the PKA pathway and deactivation of the MAPK/ERK pathway [51] |
Quercetin | 1. IEC-6 cell injured by indomethacin 2. A rat intestinal epithelial (IEC-6) cells 3. In a rat model of acute necrotizing pancreatitis (ANP) 4. IPEC-1 incubated with vehicle or diquat | 1. ZO-1, occludin, and claudin-1 ↑ 2. ZO-1, occludin, and claudin-1 ↑ 3. ZO-1, claudin-1, occludin ↑, IL-1β, TNF-α, and IL-17A ↓ 4. ROS ↓, GSH ↑, ZO-1, ZO-2, ZO-3, occludin, and claudin-4 ↑ | 1. Attenuating calcium-mediated JNK/Src activation [52] 2. Inhibiting the RhoA/ROCK signal pathway [53] 3. Inhibiting TLR4/MyD88/p38MAPK and ERS [54] 4. Activating Nrf2 [55] |
Puerarin | 1. Ethanol-induced Caco-2 monolayer 2. DSS-induced colitis mice | 1. ZO-1, occludin, claudin-1 ↑, NF-κB ↓, MLCK, ERK1 and ERK2 ↑ 2. TNF-α, IL-1β, IL-6 ↓, Nrf2, HO-1, and NQO1 ↑, MDA ↓, CAT, GSH, and SOD ↑, ZO-1, occludin, and claudin-1 ↑ | 1. Activation of the MAPK (ERK1 and ERK2) signal pathway and inhibition of the NF-κB signal pathway [35] 2. Inhibition of NF-κB and activation of the Nrf2 signaling pathway [25] |
Naringin | 1. CLP mice and lipopolysaccharide (LPS)-stimulated MODE-K cells | 1. TNF-α and IL-6 ↓, IL-10 ↑, ZO-1, and claudin-1 ↑, p65 and IκB-α ↓, P-MLC and MLCK ↓, GTP-RhoA ↓ | 1. Inhibiting the RhoA/ROCK/NF-kappaB/MLCK/MLC signaling pathway [47] |
Icariin | 1. Bisphenol A(BPA)-exposed mice and MODE-K cells 2. Piglets and IPEC-J2 cell with ETEC K88 | 1. ZO-1, occludin, and claudin-1 ↑, ROS, RNS, MDA, andH2O2 ↓, SOD, GPx, CAT, and T-AOC) ↑ 2. ZO-1 and occludin ↑, IL-1β, IL-6, IL-8, and TNF-α ↓, ROS, MDA, and H2O2 ↓, p38 MAPK ↓ | 1. Inhibiting p38 MAPK [42] 2. Regulating the expression of p38 MAPK [60] |
Alpinetin | 1. A mouse model of (DSS)-induced ulcerative colitis 2. A mouse model of DSS-induced UC and in TNF-α-stimulated Caco-2 and NCM460 cells | 1. DAI and SOD ↑, MDA ↓, occludin and ZO-1 ↑, claudin-2 ↓ 2. TEER ↑, claudin-7 and occludin ↑ | 1. Activation of the Nrf2/HO-1 signal pathway [62] 2. Regulating the AhR/SUV39H1/TSC2/mTORC1/ autophagy pathway [63] |
Baicalin | 1. A mouse model of pediatric RV-DH diarrhea | 1. Occludin, claudin-1, and ZO-1↑, IL-1β, IL-2, IL-6, and IL-8 ↓, SIgA ↓ | 1. Inhibiting STAT1 and activating the STAT3 signaling pathways [66] |
Rhein | 1. An IEC-6 cell model with LPS stimulation 2. A rat model induced by intraperitoneal injection of lipopolysaccharide (LPS) | 1. ZO-1 ↑, p-MLC, MLCK, NF-κB ↓, IL-1β, and IL-6 ↓, TLR4, NLRP3, and cleaved caspase1 ↓, NF-κB ↓ 2. DAO, ZO-1, and occludin ↑, TNF-α, IL-1β, IL-6, and NO ↓, CAT, GSH-Px, and HO-1 ↑, MDA ↓ | 1. Inhibition of the NF-κB/MLCK/p-MLC pathway, TLR4/NF-κB pathway, andNLRP3 inflammasome [68] 2. Inhibiting the MAPKs (p38MAPK and JNK) signaling pathways, activating Nrf2 pathway [69] |
5. Terpenoids for the Treatment of IBD (Table 3)
5.1. Ginsenosides
5.2. Astragaloside IV
5.3. Geniposide
5.4. Patchouli Alcohol
5.5. Atractylodes A
5.6. Atractylodes Clematichinenoside
5.7. Oridonin
Monomers | Objects (Model Induces) | Effects | Signaling Pathway |
---|---|---|---|
Ginsenoside Rg1 | A mouse model of colitis induced by sodium glucan sulfate (DSS) | IL-1β and TNF-α ↓ | Interfering with TLR4-NLRP12-NF-κB [72] |
Ginsenoside Rk3 | A mouse model of colitis induced by DSS | TNF-α, IL-1β, IL-6, NLRP3, ASC, and Caspase-1 ↓, ZO-1, occludin, and claudin-1 ↑ | Blockading of the NLRP3 inflammasome pathway [73] |
Astragaloside IV | Septic mice modeled by cecal ligation and puncture (CLP) operation and LPS-challenged Caco-2 monolayer barrier model | Occludin and ZO-1 ↑, Caspase-1, IL-1β, and IL-18 ↓ | Suppressing RhoA/NLRP3 inflammasome signaling [76] |
Geniposide | Rats with TNBS-induced colitis and Caco-2 cells-induced LPS | TNF-α, IL-1β, and IL-6 ↓, NF-κB, COX-2, iNOS, and MLCK ↓, occludin and ZO-1 ↑, p-AMPK ↑ | Activating the AMPK signaling pathway, inhibiting the MLCK pathway [78] |
Patchouli alcohol | Rat intestinal mucositis model established by intraperitoneal injection of 5-fluorouracil (5-FU) | TLR2 and MyD88 ↓, NF-κB p-IκBα and p65 ↓, TNF-α, IL-1β, IL-6, and MPO ↓, IL-10 ↑, MLC, ZO-1, occludin, claudin-1, and mucin-2 ↑ | Inhibiting the TLR2/MyD88/NF-κB pathway [79] |
Atractylodes A | A rat model of spleen deficiency syndrome (SDS) | ZO-1 and occludin ↑, p-p38MAPK and p-MLC ↓ | Inhibition of the p38 MAPK pathway [81] |
Clematichinenoside AR | In a spontaneous colitis mice model by in interleukin-10 gene knockout (IL-10−/−) | Occludin and ZO-1 ↑, IL-17A+CD4+T cells Bcl-2, caspase-3, and Bax ↓ | Inhibiting the PI3K/Akt signal pathway [84] |
Oridonin | In a PI-IBS rat model and Caco-2 cell lines | Claudin-1, occludin, and ZO-1 ↑, p-NF-κB, and p65 ↓, iNOS, COX-2, IL-1β, and IL-6 ↓ | Inhibiting PxR/NF-κB signaling [86] |
Saikosaponin-d | Dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) mice | TNF-α, IL-6, and IL-1β ↓, IL-10 ↑, Muc1 and Muc2 ↑, ZO-1 and Claudin-1 ↑ | Inhibiting NF-κB activation [87] |
Morroniside and loganin | DSS-induced murine model of colitis and an LPS-induced colorectal cancer (CRC) cell inflammation model | ZO-1, occludin, claudin-3, Ecadherin, and Muc2 ↑, IL-1β, IL-6, TNF-α, and IFN-γ ↓, p-STAT3 and p-p65 ↓ | Blocking of the STAT3/NF-κB pathway [88] |
6. Alkaloids for the Treatment of IBD (Table 4)
6.1. Berberine
6.2. Koumine
Monomers | Objects (Model Induces) | Effects | Signaling Pathway |
---|---|---|---|
Berberine | 1. A model of colitis mice induced with DSS 2. In a mice model of IBS-D established by using 4% acetic acid 3. A rat model of acute endotoxemia induced by injection of lipopolysaccharide (LPS) 4. DSS-induced colitis mice | 1. ZO-1, occludin, and epithelial cadherin ↑, IL-1β, IL-6, and TNF-α ↓, P-STAT3 ↓, MPO ↓, and SOD, CAT ↑ 2. Occludin, claudin-1, ZO-1, and F-actin ↑, TNF-α, NF-kB p65, MLCK, MLC, TRAF6, and RIP1 ↓ 3. Ileal insulin-like growth factor I (IGF-I) and binding protein 3 (IGFBP-3) ↑, occludin and claudin-1 ↑ 4. ZO-1, ZO-2, JAM-A, claudin-1, and occludin ↑, TLR4 and MyD88 ↓, P-IκBα and NF-κB p65 ↓ | 1. Inhibiting the STAT3 signaling pathway [90] 2. Inhibiting the activation of the NF-κB-MLCK pathway [91] 3. Modulation of the Wnt/beta-catenin signaling pathway [93] 4. Blocking the TLR4-MyD88-NF-κB signaling pathway [94] |
Koumine | 1. IPEC-J2 cells induced by lipopolysaccharide | 1. TNF-α, IL-6, IL-1β, NO, iNOS, and COX-2 ↓, p-IκBα and NF-κB p-p65 ↓, Nrf2 and HO-1 by KEAP-1 ↑, SOD and CAT ↑ | 1. Inhibition of the NF-κB pathway, activating the Nrf2 pathway [96] |
7. Non-Flavonoid Polyphenols for the Treatment of IBD (Table 5)
7.1. Curcumin
7.2. Resveratrol
Monomers | Objects (Model Induces) | Effects | Signaling Pathway |
---|---|---|---|
Curcumin | 1. The human IEC lines Caco-2 and HT-29 induced with LPS 2. H2O2 induced oxidative stress in IPEC-J2 cell and in a piglet’s intestinal oxidative stress model by challenging with diquat 3. BALB/c mice were fed with 3% DSS | 1. MLCK ↓, IL-10 ↑, and IL-1β ↓, p38MAPK ↓, ZO-1, claudin-1, claudin-7, and actin filaments ↑ 2. SOD, CAT, Cu/Zn-SOD, Mn-SOD, GPX-1, and GPX-4 ↑, MDA and ROS ↓, FD4 flux ↓, TER ↑, occludin, ZO-1, and claudin-1, PINK-1 and Parkin ↑ 3. CD4+ Foxp3+regulatory T cells and CD103+CD8α ↑, TNF-α, IL-1β, IL-6, CXCL1, and CXCL2 ↓ | 1. Inhibition p38MAPK [98] 2. Activation of the AMPK-TFEB signal pathway [99] 3. Suppressing NF-κB [100] |
Resveratrol | 1. IPEC-J2 cell induced by Deoxynivalenol 2. Oxidative stress induced by H2O2 in IPEC-J2 cells | 1. TEER ↑, promoting the assembly of claudin-4, IL-6, and IL-8 ↓, reduced DON-induced phosphorylation of p38, ERK, and JNK 2. claudin-1, occludin, and ZO-1 ↑, superoxide dismutase-1 SOD-1, CAT, and GSH-Px ↑, ROS and apoptosis ↓, p-Akt, p-Nrf2, and HO-1, SOD-1, and CAT ↑ | 1. Suppressing MAPK signaling [101] 2. Inhibiting the PI3K/Akt-mediated Nrf2 signaling pathway [102] |
8. Other Classes of Single Bioactive Components from Herbs for the Treatment of IBD (Table 6)
8.1. Emodin
8.2. Arctigenin
8.3. Sodium Houttuyfonate
8.4. Artemisinin
Monomers | Objects (Model Induces) | Effects | Signaling Pathway |
---|---|---|---|
Emodin | 1. Caco-2 cells induced by LPS/hypoxia-reoxygenation 2. Rat intestinal epithelial cell-6, pancreatitis model rats induced by Taurocholate | 1. ZO-1 ↑, HIF-1α, IκB-α, NF-κB, and COX-2 ↓ 2. Fas, FasL, Bax, caspase-9, and caspase-3 ↓, occludin, ZO-1, and E-cadherin ↑ | 1. Inhibiting the HIF-1α and NF-κB signaling pathways [104] 2. Regulate the activity of the RhoA/ROCK and NOTCH signaling pathways [105] |
Arctigenin | Colitis mice induced by DSS, TNBS, (Caco-2 and HT-29 cell lines), TNF-α, and IL-1β | Occludin, ZO-1, and F-actin ↑, TEER ↑ | Inhibiting the ERβ-MLCK/MLC pathway [107] |
Sodium houttuyfonate (SH) | A mouse model of diarrhea induced by Salmonella typhimurium (ST) | TNF-α, IL-1β, and IL-6 ↓, iNOS, COX-2 ↓, p-NF-κBp65, and IκB ↓, the localization and distribution of tight junction proteins ↑ | Inhibiting the NF-κB signaling pathway [108] |
Artemisinin | A mouse model of ulcerative colitis induced by DSS | Muc2 and claudin-1 ↑, Bcl-2/Bax ↓, cleaved-caspase-3 ↓, p-IκBα and NF-κBp65 ↓, IL-1β, I L-6, and TNF-α ↓, IL-10 ↑ | Inhibiting the NF-κB signaling pathway [111] |
9. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Sample Availability
References
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Peng, J.; Li, H.; Olaolu, O.A.; Ibrahim, S.; Ibrahim, S.; Wang, S. Natural Products: A Dependable Source of Therapeutic Alternatives for Inflammatory Bowel Disease through Regulation of Tight Junctions. Molecules 2023, 28, 6293. https://doi.org/10.3390/molecules28176293
Peng J, Li H, Olaolu OA, Ibrahim S, Ibrahim S, Wang S. Natural Products: A Dependable Source of Therapeutic Alternatives for Inflammatory Bowel Disease through Regulation of Tight Junctions. Molecules. 2023; 28(17):6293. https://doi.org/10.3390/molecules28176293
Chicago/Turabian StylePeng, Jing, Hao Li, Oladejo Ayodele Olaolu, Saber Ibrahim, Sally Ibrahim, and Shengyi Wang. 2023. "Natural Products: A Dependable Source of Therapeutic Alternatives for Inflammatory Bowel Disease through Regulation of Tight Junctions" Molecules 28, no. 17: 6293. https://doi.org/10.3390/molecules28176293