Pharmacotherapy against Oxidative Stress in Chronic Kidney Disease: Promising Small Molecule Natural Products Targeting Nrf2-HO-1 Signaling
Abstract
:1. Introduction
2. Oxidative Stress in Chronic Kidney Disease
2.1. Diabetic Kidney Disease (DKD)
2.2. Glomerulosclerosis and Glomerulonephritis
2.3. Lupus Nephritis (LN) and Systemic Lupus Erythematosus (SLE)
2.4. Tubulointerstitial Fibrosis
2.5. Chronic Renal Allograft Dysfunction (CRAD)
2.6. The Role of Oxidative Stress in Kidney Cells
3. Role of Nrf2 and HO-1 against Oxidative Stress
4. Functional Link between Nrf2 and HO-1
5. Small Molecule Natural Products Activating Nrf2-HO-1 Signaling
5.1. Phenolic Compounds
5.2. Non-Phenolic Compounds
6. Conclusions and Future Perspectives
Author Contributions
Funding
Conflicts of Interest
References
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No. | Modulator | Chemical Class and Natural Sources | Experimental Model | Disease Model | Pathobiology Involved | Major Research Outcomes | Molecular Markers | Ref. |
---|---|---|---|---|---|---|---|---|
Phenolic compounds | ||||||||
1 | Ampelopsin | Flavonoid; Ampelopsis grossedentata | HG-stimulated hGMCs | OS | OS, ECM accumulation | Amelioration of OS and ECM accumulation | ↓ROS, ↓MDA, ↑SOD, ↓Nox2, ↓Nox4, ↓NADPH, ↓FN, ↓Col IV, ↑n-Nrf2, ↑HO-1, | [109] |
2 | Apigenin | Flavonoid; common fruits and vegetables | HG-treated HK-2 cells | Oxidative damage | Oxidative damage | Decrease in apoptosis, inhibition of OS, and inflammatory response | ↓LDH, ↓MDA, ↑SOD, ↑CAT, ↓TNFα, ↓IL-1β, ↓IL-6, ↑Nrf2, ↑HO-1 | [110] |
3 | Astaxanthin | Xanthophyll carotenoid; algae, shrimp, lobster, crab, salmon, and other organisms | STZ-injected rat | DKD | ECM accumulation | Amelioration of kidney injury | ↓FN, ↓TGFβ1, ↓ICAM-1 | [111] |
HG-treated GMCs | Kidney fibrosis | OS | Increase in antioxidative capacity | ↓FN, ↓TGFβ1, ↓ICAM-1, ↑SOD, ↓MDA, ↓ROS, ↓DHE, ↑n-Nrf2, ↓keap1, ↓SOD-1, ↓Nqo1, ↓HO-1 | ||||
Adriamycin-treated BALB/c mice | FSGS | OS, inflammation | Anti-inflammation, antioxidation | ↓TGFβ1, ↓collagen1, ↓α-SMA, ↓MDA, ↑GSH, ↑SOD, ↑CAT, (serum: ↓IL-1 β, IL-18), ↑Nrf2, ↓NLRP3 | [112] | |||
4 | Baicalein | Flavonoid; roots of Scutellaria baicalensis Georgi | Pristine -injected BALB/c mice | LN | OS, inflammation | Attenuation of kidney dysfunction, antioxidation, anti-inflammation, inhibition of MDSC expansion | ↓IL-1b, ↓IL-18, ↓O2¯˙, ↑ GPx, ↑Nrf2, ↑HO-1, ↓ NLRP3, ↓Casp-1, ↓mIL-1 β, ↓p-NF-kB | [113] |
LPS-primed spleen-derived MDSCs | OS, inflammation | ↓ROS, ↓IL-1β, ↓IL-18, ↑Nrf2, ↑HO-1, ↓NLRP3, ↓mIL-1β/pro-IL-1β, ↓Casp-1-p20/pro-casp-1-p45, ↓p-NF-kB/NF-kB, ↓Ang-1, ↓p47phox, ↓GP91phox, ↓iNOS | ||||||
5 | Calycosin | Isoflavone; root of Astragalus membranaceus | HFD-fed/ STZ-injected SD rat | DKD | Inflammation, OS, fibrosis | Inhibition of inflammatory, oxidative, and fibrotic events | ↓IL-33, ↓ST2, ↓NF-kB p65, ↓TNFα, ↓IL-1 β, ↓IL-6, ↑Nrf2, ↓MDA, ↓TGFβ | [114] |
6 | Chlorogenic acid | Cinnamate ester; coffee, fruits, and vegetables | STZ-injected and HFD-fed SD rat | DKD | OS, inflammation | Relieve kidney injury, mitigation of OS, inflammation | ↓MDA, ↑SOD, ↑GSH-Px, ↑n-Nrf2, ↑HO-1, ↓IL-6, ↓TNFα, ↓IL-1 β, ↑c-NF-kB, ↓n-NF-kB, ↑IkBα, ↓p-IkBα, | [115] |
HG-treated rat mesangial cell line (HBZY-1) | Mitigation of OS, inflammation, increase in cell proliferation | ↑n-Nrf2, ↑HO-1, ↑c-NF-kB, ↓n-NF-kB, ↑IkBα, ↓p-IkBα, ↓IL-6, ↓TNFα, ↓IL-1 β | ||||||
7 | Cryptotanshinone | Quinoid diterpene; Salvia miotiorrhiza bunge | UUO-operated mice | Kidney fibrosis | OS, inflammation | Attenuation of OS and inflammation | ↓collagen-1, ↓FN, ↓CD68, ↓CD3, ↑IkBα, ↓NF-kB p65, ↑SOD2, ↑CAT, ↑GSH, ↓MDA, ↑Nuclear Nrf2, ↓cytosolic Nrf2, ↑HO-1 | [116] |
8 | Curcumin | Curcuminoid; turmeric (Curcuma longa) | 5/6 nephrectomy Wistar rat | CKD | OS, inflammation | Protection of kidney function, antioxidant, anti-inflammation | ↓Nox4, ↑eNOS, ↓nitrotyrosine, ↓MCP-1, ↓Keap-1, ↑Nrf2, ↑GPx-1, ↑CAT, ↑SOD-1, ↓phospho serine D1R | [117] |
0.25% Adenine -diet rat | CKD | OS, inflammation | Amelioration of kidney function and OS | ↓IL-1 β, ↓IL-6, ↓TNFα, ↑cycstatin C, ↓adiponecitn, ↑sclerostin, ↑SOD, ↑Nrf2, ↑GSH reductase. ↓ caspase3 | [118] | |||
HG-treated NRK-52E cells | OS | OS | Increase in cell viability, inhibition of EMT | ↑E-cadherin, ↓α-SMA, ↑Nrf2, ↑HO-1 | [119] | |||
9 | Epigallocatechin-3 -Gallate | Polyphenol; Dried leaves of tea plant (Camellia sinensis) | STZ-injected mice | DKD | Oxidative damage, inflammation, | Anti-OS | ↓TGFβ1, ↓PAI-1, ↓ICAM-1, ↓VCAM-1, ↓MDA, ↓iNOS, ↓3-NT, ↑Nqo1, ↑HO-1, ↑t-Nrf2, ↑c-Nrf2, ↑n-Nrf2, ↑n-Nrf2/t-Nrf2 | [120] |
HG-cultured MMC | ↑t-Nrf2, ↑c-Nrf2, ↑n-Nrf2, ↑Nqo1, ↑HO-1, ↓MDA, ↓iNOS, ↓VCAM-1, ↓ICAM-1, ↓COL4, ↓FN | |||||||
NZB/W F1 lupus-prone mice | LN | OS | Antioxidant and anti-inflammation | ↑Nrf2, ↓p47phox, ↑Nqo1, ↑HO-1, ↑GPx, ↓CD3, ↓F4/80, ↓NF-kB, ↓NLRP3, ↓IL-1 β, ↓IL-18, ↓casp1-p20, | [56] | |||
UUO mice | CKD | OS, inflammation | Kidney function improvement, prevention of OS and inflammation | ↑SOD, ↑CAT, ↑GSH-Px, ↓MPO, ↓TNFα, ↓IL-6, ↓IL-1 β, ↑IkBα, ↓p-IkBα, ↓NF-kB, ↑n-Nrf2, ↑HO-1, ↑t-bilirubin | [121] | |||
10 | Ethyl acetate extract of Saliva miltiorrhiza | Diterpenoids, phenolic compounds, flavonoids, triterpenoids; dried root of Salvia miltiorrhiza Bunge | STZ-injected mice | DKD | Oxidative stress | Antioxidation, attenuation of kidney dysfunction | ↑Nrf2, ↑HO-1, ↑Nqo1, ↓Keap1 | [122] |
HG-treated SV40-MES-13 MMCs | hyperglycemia | Antioxidation | ↓ROS, ↑Nrf2, ↑HO-1, ↑Nqo1, ↓Keap1 | |||||
11 | Isoliquiritin | Flavonoid glycoside; Chinese licorice (Glycyrrhiza uralensis) | Cationic BSA-injected SD rat | MGN | Inflammation and OS | Antioxidative, anti-inflammatory activities | ↓Keap1, ↑Nrf2, ↓n-Nrf2, ↑c-Nrf2, ↑HO-1, ↑Nqo1, ↓MDA, ↓NO, ↑SOD, ↑CAT, ↑GPx, ↑GSH, ↓NF-kB p65, ↓nuclear NF-kB p65, ↑cyclic NF-kB, ↓IKKb, ↓p-IKKb, ↓TNFα, ↓IL-1 β, ↓COX2, ↓iNOS, ↓p38 MAPK, ↓p-p38 MAPK | [54] |
12 | Oleuropein, peracetylatedoleuropein | Secoiridoid; olive leaves, roots, and unprocessed olive drupes | Pristine -injected BALB/c mice | LN | Inflammation and OS | Amelioration of kidney abnormalities, inhibition of proinflammation, antioxidation | ↓MMP-3, ↓iNOS, ↓mPGEs-1, ↓PGE2, ↑Nrf2, ↑HO-1, ↓pSTAT3, ↓NF-kB-p65, ↑IkBα, ↓pp38, ↓pJNK, ↓pERK1/2 ↓NLRP3, ↓ASC, ↓IL-18, ↓ IL-1β, ↓cleaved caspase-1, ↓cleaved caspase 11 | [123] |
13 | Osthole | Coumarin; Fructus Cnidii | 2% adenine suspension -received rat | CKD | Inflammation | Protection of kidney function, antiinflammation | ↓TNFα, ↓IL-6, ↓IL-8, ↓NF-kB/p65, ↓TGFβ1, ↓MCP-1, ↑p-Akt/Akt, ↑Nrf2 | [124] |
14 | Polydatin | Stilbenoid glucoside; Polygonum cuspidatum Sieb.et Zucc | STZ-injected diabetic mice | DKD | OS | Improvement of antioxidative effect and kidney dysfunction | ↑CKIP-1, ↑Nrf2, ↑HO-1, ↑SOD1, ↓FN, ↓ICAM-1, ↓MDA, ↑t-SOD | |
HG-treated rat GMCs | ↑Nrf2, ↓Keap1, ↑n-Nrf2, ↓n-CKIP-1, ↑ARE binding activity, ↑HO-1, ↑SOD1, ↓DHE, ↓H2O2, ↓FN, ↓ICAM-1 | |||||||
15 | Resveratrol | Phytoalexin; red grapes (Vitis vinifera L.), peanuts (Arachis spp.), berries (Vaccinium spp.) | STZ-induced Wistar rat | DKD | OS | Anti-inflammation, Anti-OS | ↓iNOS, ↓NF-kB, ↓Nrf2, ↓NGAL, ↓IL-1β, ↓IL-6, ↓IL-8, ↓TNFα | [125] |
4-hydroxy-2-hexenal-treated mouse cortical collecting duct cells (M1) | OS | ↓nuclear p65, ↑cytosol IkB, ↑SIRT1, ↓Nox4, ↓COX2, ↑AQP2, ↓pERK/ERK, ↓pJNK/JNK, ↓pP38/P38, ↓Nrf2, ↑Keap1 | [126] | |||||
16 | Rotenone | Isoflavonone; seeds and stems of jicama vine plant, the roots of Fabaceae, etc. | UUO-operated mice | Kidney fibrosis | Mitochondrial abnormality | Anti-OS, anti-inflammation, anti-fibrosis | ↓TBARS, ↓HO-1, ↓TNFα, ↓IL-1β, ↓ICAM1, ↓collagen I, ↓FN, ↓α-SMA, ↓PAI-1, ↓collagen III, ↓TGFβ, ↑mtDNA, ↑mtNd1 | [127] |
17 | Salidroside | phenylpropanoid glycoside; plant Rhodiola rosea | HG-treated mouse podocytes | Apoptosis | Apoptosis | Improvement of cell viability | ↓Caspase-9, ↓caspase-3, ↑HO-1, ↑p-ILK/ILK, ↑p-Akt/Akt, ↑p-ERK/ERK, ↑p-JNK/JNK, ↓p-p38/p38, ↑Nrf2 | [128] |
18 | Salvianolic acid A | Polyphenol derivative; root of Salvia miltiorrhiza | STZ-injected mice | DKD | OS | Anti-OS | ↓VCAM-1, ↑HO-1, ↓α-SMA, ↓NT, ↓DHE, ↑GPx-1 | [129] |
HG-treated HK-2 cells | ↑HO-1, ↓α-SMA, ↓p65, ↓ROS | |||||||
5/6 nephrectomized SD rats | CKD | OS | OS attenuation, | ↑t-SOD, ↑GPx, ↑CAT, ↓MDA, ↓ROS, ↓Nox4, ↑p-Akt/Akt, ↑p-GSK3β/GSK3β, ↑p-Nrf2/Nrf2, ↑HO-1 | [130] | |||
H2O2-treated/LPS-treated HK-2 cells | Cell viability improvement, decrease in OS | ↑t-SOD, ↑GPx, ↑CAT, ↓MDA, ↓ROS, ↓Nox4, ↑p-Akt/Akt, ↑p-GSK3β/GSK3β, ↑n-Nrf2, ↑HO-1, ↓p-NF-kB p65/NF-kB p65, ↓ICAM-1, ↓p-NF-kB p65, ↓ICAM-1, ↑n-Nrf2, ↑HO-1 | ||||||
19 | Silibinin | Flavonoliganas: milk thistle seeds | Arsenic -induced rat | CKD | Inflammation | Attenuation of OS, inflammation, and apoptosis | ↓TNFα, ↓iNOS, ↓NO, ↓NF-kB, ↓Caspase-3, ↓NADPH oxidase, ↑Nrf2 | [131] |
20 | Sinapnic acid | Hydroxycinnamic acid; wine, vinegar | STZ-injected rat | DKD | OS, inflammation | Amelioration of OS and inflammation | ↑CAT, ↑GPx, ↑SOD, ↓TNFα, ↓IL-6, ↓NO2, ↓MDA, ↓TFGβ, ↑HO-1, ↑Nrf2, ↓NF-kB, ↑IkBα, ↑Bcl2, ↓Caspase3, ↓Bax | [132] |
No. | Modulator | Chemical Class and Natural Sources | Experimental Model | Disease Model | Pathobiology Involved | Major Research Outcomes | Molecular Markers | Ref. |
---|---|---|---|---|---|---|---|---|
Non-phenolic compounds | ||||||||
1 | Akebia Saponin D | triterpenoid saponin; Dipsaci Radix | STZ-injected mice | DKD | OS, inflammation | Amelioration of kidney damage, inflammation, OS, and apoptosis | ↓TNFα, ↓IL-1β, ↓IL-6, ↓MCP-1, ↓ROS, ↓MDA, ↓LDH, ↑SOD, ↑Bcl2, ↓Bax, ↓cleaved caspase3/caspase3, ↓cleaved caspase9/caspase9, ↑n-Nrf2, ↓p-NF-kB/t-NF-kB, ↑HO-1, ↑Nqo1, ↓p-IkBα/t-IkBα | [133] |
HG-treated HK-2 cells | ↓TNFα, ↓IL-1β, ↓IL-6, ↓MCP-1, ↓ROS, ↓MDA, ↓LDH, ↑SOD, ↑Bcl2, ↓Bax, ↓cleaved caspase3/caspase3, ↓cleaved caspase9/caspase9, ↑Nrf2, ↓p-NF-kB/t-NF-kB, ↑HO-1, ↑Nqo1, ↓p-IkBα/t-IkBα | |||||||
2 | Allicin | Diallyl thiosulfinate; garlic (Allium sativum L.) | 5/6 nephrectomy Wistar rat | CKD | Fibrosis, OS | Antihypertensive and antioxidant effects | ↑AT1R, ↑AT2R, ↑Nrf2, ↓Keap1, ↑CAT, ↑SOD, ↓HO-1, ↑eNOS | [134] |
3 | Antroquinonol | Enone; mushroom (Antrodia camphorate) | Adriamycin -injected BALB/c mice | FSGS | OS | Decrease in kidney dysfunction, anti-OS, anti-inflammation | ↓desmin, ↓O2●−, (serum, urine ↓ O2●−, ↓NO), ↓DHE, ↓p47phox, ↑Nrf2, ↑GPx, ↓NF-kB p65, ↓MCP-1, ↓IL-6, ↓CD3, ↓F4/80, ↓Col I, ↓Col III, ↓Col IV, ↓TGFβ1 | [135] |
4 | Artemisinin | sesquiterpene lactones; Asteraceae Artemisia annua | STZ-injected rat | DKD | OS | Amelioration of kidney dysfunction and OS | ↓MDA, ↑t-SOD, ↑GPx, ↓TGFβ1, ↑t-Nrf2, ↑n-Nrf2, ↑HO-1, ↑Nqo1 | [136] |
5 | Aucubin | iridoid glycoside; leaf of Eucommia ulmoides | HFD-fed and STZ-injected mice | DKD | OS, inflammation | Amelioration of kidney dysfunction, anti-inflammation, anti-OS | ↓FN, ↓collagen IV, ↓MDA, ↑SOD, ↑CAT, ↑GSH/T-GSH, ↓TNFα, ↓IL-6, ↓IL-1β, ↓p65, ↓IkBα, ↑Nrf2, ↑HO-1, ↑Nqo1, ↑FOXO3α, ↓p-FOXO3α/FOXO3α, ↑SIRT1, ↑SIRT3, ↓Ac-FOXO3α/FOXO3α | [137] |
6 | Berberine | isoquinoline alkaloid; Coptidis Rhizoma and Cortex Phellodendri | STZ-injected mice | DKD | OS | Anti-fibrosis | ↓α-SMA, ↓collagen-1, ↑Nrf2, ↑NQO1, ↑HO-1 | [138] |
HG-treated NRK 52E cells | EMT | ↓E-cadherin, ↓α-SMA, ↑n-Nrf2, ↑Nqo1, ↑HO-1, ↓p-Smad2, ↓p-Smad3 | ||||||
7 | Betulinic acid | pentacyclic triterpenoid; from the outer bark of white birch trees (Betula alba) | STZ-injected SD rat | DKD | OS | Anti-OS | ↓IL-1 β, ↓IL-6, ↓MDA, ↑SOD, ↑CAT, ↑p-AMPK/AMPK, ↓p-IkBα/IkBα, ↓p-NF-kB/NF-kB, ↑Nrf2, ↑HO-1 | [139] |
8 | Citral | Terpeonids; Litsea cubeba | Adriamycin -injected BALB/c mice | FSGS | OS | Amelioration of kidney dysfunction, anti-OS, anti-inflammation, anti-apoptosis | ↓O2¯˙, (serum, urine ↓O2¯˙, ↓NO), ↓DHE, ↓p47phox, ↑Nrf2, ↑Nqo1, ↑HO-1, ↓desmin, ↓TUNEL, ↓Casp-3p17, ↓Casp-9p37, ↓Bax/Bcl2, ↓pNF-kB p65, ↓MCP-1, ↓ CD3, ↓F4/80 | [140] |
LPS-treated RAW 264.7 macrophages | OS | ↓NO, ↓NF-kB, ↓IL-6, ↓TNFα, ↓IL-1β, ↓p-ERK1/2(10min), ↓p-JNK1/2(15,30min) | ||||||
9 | Dioscin | Steroid saponin; Dioscoreae rhizoma | 10% fructose -fed mice | CKD | Oxidative damage, lipid metabolism, fibrosis | Inhibition of inflammation, lipid metabolism, OS, kidney fibrosis | ↓MDA, ↑SOD, ↑GSH-Px, ↓α-SMA, ↑SIRT3, ↑SOD2, ↓IL-1β, ↓IL6, ↓TNFα, ↓NF-kB, ↓HMGB1, ↓COX2, ↓c-Jun, ↓c-Fos, ↓SREBP-1c, ↓SCD-1, ↓FASn, ↓p-Akt, ↓p-FoxO1A, ↓ACC, ↑CPT1, ↑Nrf2, ↓Keap1, ↑GST, ↓TGFβ1, ↓p-Smad3, ↑Smad7 | [141] |
10 | Ergone (alisol B 23-acetate, pachymic acid B) | steroid; Polyporus umbellatus, surface layer of Poria cocos, Alisma orientale | AngII- treated HK-2 and conditionally immortalized MPC5 cells | CKD | OS, inflammation, impaired Nrf 2 activation | inhibition of the RAS/Wnt/b-catenin signaling cascade | (HK-2) ↓Snail1, ↓MMP-7, ↓Twist, ↓FSP-1, ↓Col I, ↓Col III, ↓α-SMA, ↓vimentin, ↑E-cadherin, ↓NF-kB, ↓MCP-1, ↓COX2, ↑Nrf2, ↑HO-1 (podocyte) ↓Snail1, ↓MMP-7, ↓Twist, ↓FSP-1, ↑podocin, ↑nephrin, ↑podocalyxin, ↑synaptopodin, ↓desmin, ↑WT1, ↓Akt2, ↓NF-kB, ↓MCP-1, ↓COX2, ↑Nrf2, ↑HO-1 | [142] |
11 | L-mimosine | Amino acid; Mimosa pudica | Rats with remnant kidneys after subtotal nephrectomy (5/6 nephrectomy) | CKD | Fibrosis | Improvement of kidney function, inhibition of fibrosis | ↑HIF-1α, ↑HIF-2α, ↑VEGF, ↑HO-1, ↑GLUT-1, ↓α-SMA, ↓collagen III | [143] |
12 | Melatonin | Endogenous indoleamine, coffee, walnut, etc. | Pristine -injected BALB/c mice | LN | OS, inflammation | Attenuation of OS, inflammation | ↑SIRT1, ↑Nrf2, ↓TNFα, ↓NF-kB, ↓iNOS, ↓NLRP3, ↑CD31 | [144] |
13 | Notoginsenoside R1 | Saponin; Panax notoginseng | db/db mice | DKD | OS | Anti-OS, decrease in apoptosis | ↓Collagen I, ↓TGFβ1, ↑Nrf2, ↑HO-1, ↓Bax/Bcl2, ↓Caspase-3, ↓Caspase-9 | [145] |
AGEs-treated HK-2 cells | Mitochondria injury | ↓LDH, ↓ROS, ↑n-Nrf2, ↑HO-1, ↓Bax/Bcl2, ↓Cspase-3, ↓Caspase-9, ↓TGFβ1, ↓collagen I | ||||||
14 | Obacunone | Triterpenoid limonoid; citrus and other plants of the Rutaceae family | HG-treated NRK-52E cells | OS | OS | Inhibition of OS, mitochondrial injury, and apoptosis | ↑SOD, ↑GSH, ↑CAT, ↓ROS, ↓JC-1 monomer/aggregate, ↑p-GSK3β/GSK3β, ↓n-Fyn, ↑n-Nrf2, ↑Nqo1, ↑HO-1, ↑SOD, ↑GSH, ↑CAT, ↓c-CytC/m-CytC, ↓cleaved caspase3 | [146] |
15 | Oleanolic acid | Triterpenoid; olive oil, Phytolacca Americana, Syzygium spp, garlic, etc. | Cyclosporine -treated ICR mice | Chronic nephropathy | Inflammation, fibrosis | Antioxidation, anti-inflammation | ↓α-SMA, ↑HO-1, ↑nuclear/total Nrf2, ↑SOD1, ↓MDA, ↓urinary 8-iso-PGF2α, ↓urine 8-oxo-dG, ↓Bax/Bcl2, ↓active caspase-3 | [147] |
16 | Pyrroloquinoline quinone | In soil and foods such as kiwifruit and human breast milk | HG-treated HK-2 cells | OS | OS | Decrease in OS, inflammation and cellular senescence | ↓IL-1β, ↓TNFα, ↓NF-kB, ↓p16, ↓p21, ↓ROS, ↑SOD2, ↑CAT, ↓keap1, ↑Nrf2, ↑HO-1, ↑Nqo1, ↑GST, ↑GPx3, | [148] |
17 | Sinomenine | Alkaloid; Sinomenium acutum | UUO-operated ICR mice | CKD | Fibrosis, OS | Anti-fibrosis, antioxidation | ↑E-cadherin, ↓α-SMA, ↓FN, ↑HO-1, ↑Nqo1, ↑Nrf2, ↑SOD, ↑GPx, ↑CAT, ↑SOD2, ↓p-Smad3, ↓β-catenin | [149] |
TGFβ-treated/H2O2-treated HEK293 cells, TGFβ-treated RAW264.7 cells | ↑E-cadherin, ↓α-SMA, ↓FN, ↑HO-1, ↑Nqo1, ↑Nrf2, ↑SOD, ↑GPx, ↑CAT, ↑SOD2, ↓p-Smad3, ↓β-catenin | |||||||
18 | Sulforaphane | Isothiocyanate (organosulfur compound); Cruciferous vegetables such as broccoli, brussels sprouts, and cabbages | STZ-injected and meglumine diatrizoate-injected Wistar rats | DKD, CIN | OS | Renoprotective | ↓MDA, ↓8-oxo-dG, ↑Nrf2, ↑HO-1, ↓IL6, ↑Caspase3 | [150,151] |
Meglumine diatrizoate-treated NRK-52E cells | Cell viability | ↑Nrf2, ↑HO-1, ↓IL6 | ||||||
F344 rat kidneys transplanted Lewis rat | CRAD | OS | OS alleviation, kidney functional and morphological improvements | ↓MDA, ↓8-isoprostane, ↓ox-LDL, ↓8-oxo-dG, ↑SOD, ↑CAT, ↑GPx, ↑GR, ↑ γ-GCS, ↑Nrf2, ↑HO-1, ↑Nqo-1 | [151] | |||
19 | Trigonelline | Alkaloid; traditional herbs (especially fenugreek), coffee bean, soybean, and other edible food plants | Oxalate-induced MDCK cells | EMT | Fibrosis | Attenuation of EMT, prevention of cell migration and ROS overproduction, | ↓FN, ↓vimentin, ↓α-SMA, ↑ E-cadherin, ↑ZO-1, ↓MMP9, ↓ROS, ↑Nrf2 | [152] |
Compound | Conditions or Disease | Phase of Clinical Trials | Outcome Measures | Clinical trials.gov Identifier or Ref. | |
---|---|---|---|---|---|
Curcumin | Curcumin (320 mg/day, for 8 weeks) | CKD | Phase III (2013.2-2014. 4, 101 participants) | Oxidative stress markers (MDA, GSH, GSSG), antioxidants (GPx, SOD, CAT, Nrf2 activity. | NCT01831193 [154] |
Curcumin supplementation (500 mg of curcumin and 5 mg of piperine/day, for 12 weeks) | CKD | Not applicable (2018.2–2021.12, 31 participants) | Antioxidants (Nrf2, GPx, HO-1) and inflammatory biomarkers (NF-kB, IL-6, TNFα) in blood samples | NCT03475017 [155] | |
Curcumin supplementation (500 mg of curcumin and 5 mg of piperine/day, for 12 weeks) | CKD, Peritoneal dialysis, hemodialysis | Not applicable (2020.10–2021.10, 30 participants) | Antioxidants (Nrf2, GPx, HO-1) and inflammatory biomarkers (NF-kB, IL-6, TNFα, CRP, IL-18, TBARS, inflammasome) in blood samples | NCT04413266 | |
Curcumin, NFE2L2 A > G (400 mg/2 times/day, for up to 24 weeks) | CKD, Type 2 diabetes mellitus, Polymorphism | Phase II/III (2018.8–2019.4, 176 participants) | Antioxidants (Nrf2, SOD, HO-1, GPx) | NCT03262363 | |
Resveratrol | Resveratrol (500 mg/day, for 4 weeks) | CKD | Phase III (2013.01–2014.12, 20 participants) | Antioxidants (Nrf2, GPx, HO-1) and inflammatory biomarkers (NF-kB, IL-6, TNFα) in blood samples | NCT02433925 |
Resveratrol 200 mg/2 times/day, for 6 weeks) | CKD, Endothelial dysfunction | Not applicable (2019.1–2021. 8, 25 participants) | Oxidative stress | NCT03597568 | |
Sulforaphane | Sulforaphane (4 g L-sulforaphane/day, for 2 months + 4 g corn starch colored with chlorophyll /day, for 2 months) | CKD | Not applicable (2021.1–2022.12, 122 participants) | Antioxidants (Nrf2, GPx, HO-1) and inflammatory biomarkers (NF-kB, IL-6, TNFα) in blood samples | NCT04608903 |
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Uddin, M.J.; Kim, E.H.; Hannan, M.A.; Ha, H. Pharmacotherapy against Oxidative Stress in Chronic Kidney Disease: Promising Small Molecule Natural Products Targeting Nrf2-HO-1 Signaling. Antioxidants 2021, 10, 258. https://doi.org/10.3390/antiox10020258
Uddin MJ, Kim EH, Hannan MA, Ha H. Pharmacotherapy against Oxidative Stress in Chronic Kidney Disease: Promising Small Molecule Natural Products Targeting Nrf2-HO-1 Signaling. Antioxidants. 2021; 10(2):258. https://doi.org/10.3390/antiox10020258
Chicago/Turabian StyleUddin, Md Jamal, Ee Hyun Kim, Md. Abdul Hannan, and Hunjoo Ha. 2021. "Pharmacotherapy against Oxidative Stress in Chronic Kidney Disease: Promising Small Molecule Natural Products Targeting Nrf2-HO-1 Signaling" Antioxidants 10, no. 2: 258. https://doi.org/10.3390/antiox10020258
APA StyleUddin, M. J., Kim, E. H., Hannan, M. A., & Ha, H. (2021). Pharmacotherapy against Oxidative Stress in Chronic Kidney Disease: Promising Small Molecule Natural Products Targeting Nrf2-HO-1 Signaling. Antioxidants, 10(2), 258. https://doi.org/10.3390/antiox10020258