Open Access

MicroRNAs as crucial mediators in the pharmacological activities of triptolide (Review)

  • Authors:
    • Kun Zhou
    • Yinxia Chang
    • Bo Han
    • Rui Li
    • Yanming Wei
  • View Affiliations

  • Published online on: March 17, 2021     https://doi.org/10.3892/etm.2021.9930
  • Article Number: 499
  • Copyright: © Zhou et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Triptolide is the main bioactive constituent isolated from the Chinese herb Tripterygium wilfordii Hook F., which possesses a variety of pharmacological properties. MicroRNAs (miRNAs/miRs) are short non‑coding RNAs that regulate gene expression post‑transcriptionally. miRNAs are implicated in several intracellular processes, whereby their dysregulation contributes to pathogenesis of various diseases. Thus, miRNAs have great potential as biomarkers and therapeutic targets for diseases, and are implicated in drug treatment. Previous studies have reported that specific miRNAs are targeted, and their expression levels can be altered following exposure to triptolide. Thus, miRNAs are emerging as crucial mediators in the pharmacological activities of triptolide. The present review summarizes current literature on miRNAs as target molecules in the pharmacological activities of triptolide, including antitumor, anti‑inflammatory, immunosuppressive, renal protective, cardioprotective, antiangiogenesis activities and multiorgan toxicity effects. In addition, the diverse signaling pathways involved are discussed to provide a comprehensive understanding of the underlying molecular mechanisms of triptolide in the regulation of target miRNAs.

1. Introduction

Traditional Chinese medicine is attracting great interest due to the high efficacy of its biological components for the treatment of several diseases. For example, Astragalus membranaceus is commonly used in various herbal formulations to cure inflammatory diseases and cancers (1), and Forsythia suspense-based treatments have provided notable protection against bacterial infections, allergies, neurodegeneration and cancers (2). Triptolide, a diterpenoid triepoxide, is one of the main active ingredients extracted from the traditional Chinese herb, Tripterygium wilfordii Hook F., which possesses several pharmacological activities. In preclinical in vitro and in vivo models, triptolide has exhibited a broad spectrum of potent antitumor activity (3,4). Triptolide can induce cell cycle arrest, interfere with tumor cell proliferation, suppress cell migration, invasion and metastasis, prevent angiogenesis, enhance caspase-dependent and -independent cell death, and produce a synergistic effect in combination with antitumor drugs (3,5). In addition, triptolide significantly inhibits the expression of pro-inflammatory cytokines and chemokines, and is considered a promising anti-inflammatory agent for the treatment of diseases, including rheumatoid arthritis (6). Triptolide exhibits profound immunosuppressive activity by regulating the proportion of immune cells and inhibiting the release of immune factors (7). Triptolide also alleviates renal and myocardial pathological injuries, and exerts protective roles in kidney and cardiovascular diseases (8,9). However, despite its desirable clinical applications, treatment with triptolide is restricted due to its potential multiorgan toxicity, including hepatic, cardiac and reproductive toxicity (10).

Currently, the molecular mechanisms underlying the pharmacological activities of triptolide have been extensively investigated (11,12), which have revealed various cellular targets and the involvement of different signaling pathways, including the heat shock protein 70 (Hsp70), vascular endothelial growth factor (VEGF), c-Jun and protein kinase B (AKT) pathways (13). MicroRNAs (miRNAs/miRs) are highly conserved endogenous small non-coding RNA molecules that negatively regulate gene expression. The phylogenetic conservation of several miRNAs across mammals highlights the importance of the miRNAs regulatory network (14). Consistently, extensive studies of miRNA knockout and overexpression models have suggested that miRNAs participate in various essential cellular processes, including cell differentiation, organ development, metabolism and apoptosis (15,16). In addition, several diseases are associated with aberrant expression of miRNAs, and miRNAs exhibit potential as biomarkers and therapeutic targets for diseases, and are highly implicated in drug treatment (17). Increasing evidence suggest that miRNAs also serve as key regulatory elements for triptolide-mediated activity (18-22). Some studies assessing the effect of triptolide on miRNAs have demonstrated that the expression levels of specific miRNAs change several folds in different cell lines and tissues (23-25).

The present review summarizes miRNAs targeted by triptolide and discusses the underlying molecular mechanisms defining the association between the expression of miRNAs and triptolide to outline the critical roles these miRNAs play in the pharmacological activities of triptolide.

2. An overview of miRNAs

miRNAs are single-stranded RNA molecules that are 22 nucleotides in length, and their genes mostly reside in either introns or exons of non-coding transcripts, while others are located within introns of neighboring protein-coding pre-mRNAs and dispersed across the genome (26). miRNA genes are transcribed in the nucleus by RNA polymerase II or III into long primary transcripts called pri-miRNA, which are folded into double-stranded RNA hairpin. The pri-miRNA is cleaved by a microprocessor to release the miRNA precursor named pre-miRNA, containing a stem-loop of ~60 nucleotides, which is subsequently exported to the cytoplasm by exportin 5 and Ran-GTP (15,27). In the cytoplasm, the pre-miRNA is further processed by the endonuclease, Dicer, to generate the small double-stranded miRNA duplex (28). Once formed, the miRNA duplex recruits argonaute protein (AGO) for unwinding (29). A strand of the duplex, namely mature miRNA, associates with the RNA induced silencing complex and mediates mRNA degradation or translational repression by binding to the partially complementary sequences of the 3'-untranslated region of specific mRNAs (30).

Similar to protein-coding genes, miRNAs are subjected to stringent regulation, and transcriptional regulation is a major contributor to the tissue- or development-specific gene expression of miRNAs (31). Furthermore, during the maturation steps, specific RNA binding proteins intricately interact with the processing machineries of a range of miRNAs through functional interactions, which subsequently modulates the expression of their target mRNAs (32). In addition, single nucleotide polymorphisms, RNA editing and methylation are considered important mechanisms that control the expression levels and functions of miRNAs (33).

3. Triptolide modulates the expression of miRNAs

Recent studies have demonstrated that miRNAs are involved in antitumor, anti-inflammatory and immunosuppressive activities of triptolide (18,20,21,34-37). In addition, triptolide exerts renal protective, cardioprotective and antiangiogenesis functions by regulating the expression of miRNAs (38-42). Furthermore, miRNAs are closely associated with the multiorgan toxicity of triptolide (23,43). Tables I and II list evidence supporting miRNAs as pivotal mediators in the pharmacological properties of triptolide.

Table I

Triptolide modulates the expression of miRNAs in vitro.

Table I

Triptolide modulates the expression of miRNAs in vitro.

miRNAsTriptolide dosage and treatment timeCell linesmiRNA statusDownstream targetsRelated biological effectsRefs.
miR-16-180 nmol/l, 3, 6 or 12 h; 20, 40 or 80 nmol/l, 8 hHuman T-cell lymphocytic leukemia cell line, Molt-4Not mentionedApoptosis↑(46)
miR-16-120, 40 or 80 nmol/l, 8 hHuman T-cell lymphocytic leukemia cell line, JurkatNot mentionedNot mentioned(46)
miR-138-280 nmol/l, 3, 6 or 12 h; 20, 40 or 80 nmol/l, 8 hHuman T-cell lymphocytic leukemia cell line, Molt-4Not mentionedNot mentioned(46)
miR-138-220, 40 or 80 nmol/l, 8 hHuman T-cell lymphocytic leukemia cell line, JurkatNot mentionedNot mentioned(46)
miR-17-92, miR-106b-25 clusters200 nmol/l, 24 hHuman liver cancer cell line, HepG2PTEN and BIMBIM and PTEN↑; apoptosis↑(24)
miR-204100 nmol/l, 24 hHuman pancreatic cancer cell line, MIA PaCa-2Mcl-1Mcl-1↓; apoptosis↑(48)
miR-204100 nmol/l, 24 hHuman pancreatic cancer cell line, S2-VP10Mcl-1Mcl-1↓; autophagic cell death↑(48)
miR-142-3p100 nmol/l, 24 hHuman pancreatic cancer cells lines, MIA PaCa-2, Capan-1 and S2-013Hsp70Hsp70↓; cell proliferation↓(50)
miR-19150 or 100 nmol/l, 24 hHuman colorectal cancer cell lines, HT-29 and SW480Not mentionedEMT↓; NF-κB and Wnt/β-catenin pathways↓; cell proliferation↓; migration↓; apoptosis↑(34)
miR-146a15 ng/ml, 24 hHuman breast cancer cell line, MDA-MB-231Rac1; RhoARhoA and Rac1↓; cell invasion and metastasis↓(18)
miR-14440 nmol/l, 36 hHuman nasopharyngeal carcinoma cell lines, NPC-TW039 and NPC-TW076PTENPTEN↑; p85α–PTEN complex↑; p-CDK2↓; S phase arrest(35)
miR-193b-3p25 nmol/l, 72 hHuman malignant rhabdoid kidney tumor cell line, G-401KLF4KLF4↓; PI3K/AKT and ERK signaling pathways↓; cell viability↓; cell migration↓; apoptosis↑(51)
miR-193b-3p10, 25 or 50 nmol/l, 72 hHuman malignant rhabdoid kidney tumor cell line, WiT49Not mentionedNot mentioned(51)
miR-138100 nmol/l, 24 hHuman medulloblastoma cell line, DaoyCDK6CDK6↓; PI3K/AKT and Notch signaling pathways↓; cell proliferation↓; cell migration↓; apoptosis↑(52)
miR-218100 nmol/l, 24 hHuman benign prostatic hypertrophy epithelial cell line, BPH-1SurvivinSurvivin↓; mTOR signaling pathway↓; apoptosis↑(53)
miR-215, miR-146a, miR-199b, miR-449a, miR-190b10 nmol/l, 48 hHuman non-small cell lung cancer cell line, H460Not mentionedFAK↓; p-FAK, p-Src, p-p130Cas↓; p-ERK1/2, MMP14↑; cell migration, invasion and metastasis↓(25)
miR-92a, miR-222, miR-23b, miR-27a, miR-25, miR-29610 nmol/l, 48 hHuman non-small cell lung cancer cell line, H460Not mentionedFAK↓; p-FAK, p-Src, p-p130Cas↓; p-ERK1/2, MMP14↑; cell migration, invasion and metastasis↓(25)
miR-204-5p50 or 100 nmol/l, 20 hHuman non-small cell lung cancer cell line, A549Sirt-1Sirt-1↓, Cav-1↓; apoptosis↑(58)
miR-2125 or 50 nmol/l, 48 hHuman non-small cell lung cancer cell line, PC-9PTENPTEN↑; cell viability↓(62)
miR-215 nmol/l, 72 hHuman multidrug-resistant chronic myeloid leukemia cell line, K562/A02PTENPTEN↑; adriamycin resistance↓(63)
miR-6751100 nmol/l, 24 hCisplatin-resistant human ovarian cancer cell line, A2780/CP70HK2HK2↓; apoptosis↑; cisplatin resistance↓(64)
miR-142-5p and miR-181a10 ng/ml, 24 h Dexamethasone-treated human multiple myeloma cell line, MM.1SGRGR↑; dexamethasone resistance↓(65)
miR-181a150 nmol/l, 24 hHuman osteosarcoma cell lines, SAOS2 and U2OSPTENPTEN↑; cell proliferation↓; apoptosis↑; cell invasion↓(66)
miR-181a20 nmol/l, 24 hHuman neuroblastoma cell line, SH-SY5YNot mentionedMAPK and NF-kB signaling pathways↑; cell proliferation↓; apoptosis↑; cell migration↓(67)
miR-1550.05, 0.1 or 0.5 µmol/l, 0.5 hLPS-stimulated murine macrophage cell line, RAW264.7Not mentionedProinflammatory cytokines (TNF-α, IL1β, and IL-6) ↓(70)
miR-15515 nmol/l, 24 hLPS-stimulated monocytes of patients with rheumatoid arthritisSHIP-1SHIP-1↑; proinflammatory cytokines (TNF-α, IL-6)↓(19)
miR-15540 nmol/l, 12 hHuman wild-type αSyn preformed fibrils-treated mouse primary microgliaSHIP-1SHIP-1↑; PI3K/AKT signaling pathway↓; NF-κB activity↓; proinflammatory cytokines (TNFα and IL-1β)↓(20)
miR-16-120 ng/ml, 24 hHuman primary intestinal fibroblasts from strictured anastomosis tissueHsp70Hsp70↑; cell migration↓; cell proliferation↓; extracellular matrix-associated proteins (Col-I, Col-III and α-SMA)↓(36)
miR-20b20 ng/ml, 1 hLPS- and ATP-treated human monocytic cell line, THP-1NLRP3NLRP3↑; cleaved caspase-1↓; proinflammatory cytokines (IL-1β and TNF-α)↓(37)
miR-9612.5 nmol/l, 24 hLPS-treated murine microglial cell line, BV2IKKβIKKβ↓; Iba-1↓; proinflammatory cytokines (TNF-α and IL-1β)↓(100)
miR-9610 nmol/l, 0.5 hLPS-treated rat primary microgliaNot mentionedIba-1↓; NF-κB signaling pathway↓; proinflammatory cytokines (TNF-α and IL-1β)↓(100)
miR-125a-5p10 nmol/l, 3 daysSplenocytes of B6 miceNot mentionedFoxp3↑; Treg proportion↑(21)
miR-125a-5p0.2 mg/kg/day, 91 daysSplenocytes of MRL/lpr miceNot mentionedFoxp3↑; Treg proportion↑(21)
miR-3010 ng/ml, 24 hTGF-β-treated immortalized human podocyte cell lineNot mentionedCell injury mediators (MAPK, NF-κB and NFATC3)↓(22)
miR-188-5p5 ng/ml, 48 hHigh glucose-treated human proximal tubular epithelial cell line, HK-2PTENPTEN↑; PI3K/AKT signaling pathway↓; renal EMT↓(38)
miR-141-3p10 µmol/l, 48 hHigh glucose-treated human mesangial cellPTENPTEN↓; autophagy↑; AKT/mTOR signaling pathway↓; diabetic renal fibrosis↓(75)
miR-13710 µg/l, 48 hHigh glucose-treated human renal mesangial cellNotch1Notch1 signaling pathway↓; extracellular matrix proteins (Col IV and FN)↓(39)
miR-2110 ng/ml, 24 hRat myocardial cell line, H9C2TLR4TLR4↓; MAPK/NF-κB signaling pathway↓; proinflammatory cytokines (TNF-α, IL-6, and IL-17)↓(40)
miR-92a3 µmol/l, 12 hHuman dermal microvascular endothelial cell line, HMEC-1Integrin subunit alpha 5 (ITGA5)Angiogenic mediators (eNOS, VEGFR2 and VEGF)↓; ITGA5↓; ERK and PI3K/AKT signaling pathways↓(42)
miR-26a120 nmol/l, 24 hMouse Leydig cell line MLTC-1GSK3βGSK3β↓; apoptosis↑(43)

[i] miRNA/miR, microRNA; ↑, upregulation; ↓, downregulation; PTEN, phosphatase and tensin homolog; Mcl-1, myeloid cell leukemia-1; Hsp70, heat shock protein 70; EMT, epithelial-to-mesenchymal transition; NF-κB, nuclear factor kappa-B; CDK2, cyclin-dependent kinase 2; KLF4, Kruppel-like factor; PI3K, phosphatidylinositol 3 kinase; AKT, protein kinase B; ERK, extracellular regulated protein kinase; mTOR, mammalian target of rapamycin; FAK, focal adhesion kinase; MMP14, matrix metalloprotease 14; Cav-1, caveolin-1; HK2, hexokinase 2; GR, glucocorticoid receptor; MAPK, mitogen-activated protein kinase; SHIP-1, Src homology 2-containing inositol phosphatase-1; Col I, collagen I; α-SMA, α-smooth muscle actin; LPS, lipopolysaccharide; NLRP3, nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing protein 3; IKKβ, inhibitor of nuclear factor kappa B kinase subunit β; Treg, regulatory T cells; FN, fibronectin; TLR4, Toll-like receptor 4; eNOS, endothelial nitric oxide synthase; VEGFR2, vascular endothelial growth factor receptor-2; ITGA5, integrin subunit α 5; GSK3β, glycogen synthase kinase-3β.

Table II

Triptolide modulates the expression of miRNAs in vivo.

Table II

Triptolide modulates the expression of miRNAs in vivo.

miRNAsTriptolide dosage and treatment timeTissue typemiRNA statusDownstream targetsRelated biological effectsRefs.
miR-17-92; miR-106b-25 clusters0.2 mg/kg/day, 14 daysXenografted hepatocellular carcinoma from BALB/c nude miceNot mentionedTumor volume↓; apoptosis↑(24)
miR-2040.42 mg/kg/day, 7 daysXenografted human pancreatic ductal adenocarcinoma from SCID miceMcl-1Mcl-1↓; tumor volume↓(48)
miR-142-3p0.42 mg/kg/day, 7 daysXenografted human pancreatic ductal adenocarcinoma from SCID miceHsp70Hsp70↓(50)
miR-1910.1, 0.3 or 1 mg/kg/day, 28 daysXenografted human colon carcinoma from BALB/c nude miceNot mentionedTumor volume and weight↓(34)
miR-1550.07 mg/kg every 2 days, 56 daysSmall intestinal of IL-10 deficient mice performed ileocecal resectionSHIP-1SHIP-1↑; anastomosis inflammation score↓; MPO and calprotectin↓; inflammatory cytokines TGF-β ↑, IFN-γ and IL-4, IL-17 ↓(72)
miR-16-10.07 mg/kg every 2 days, 56 daysSmall intestinal of IL-10 deficient mice performed ileocecal resectionHsp70Hsp70↑; anastomosis inflammation score↓; CD4+ cell infiltration area↓; fibrosis score↓; extracellular matrix-associated proteins (collagen, procollagen I and III)↓; inflammatory cytokines (TGF-β1, IL-6 and TNF-α)↓(73)
miR-960.1 mg/kg/day, 10 daysSpinal cord of spinal cord injury ratNot mentionedIba-1↓; NF-κB pathway↓; inflammatory cytokines (TNF-α and IL-1β)↓(100)
miR-344b-3p; miR-30b-3p200 µg/kg/day, 56 daysRat renal cortex with adriamycin- induced nephropathyNot mentionedNephrin↑; proteinuria↓; renal pathological lesions↓(76)
miR-30a10 ng/ml, 24 hTGF-β1-treated isolated glomeruli of mouse or ratsNot mentionedNot mentioned(22)
miR-188-5p200 µg/kg/day, 84 daysDiabetic rat kidneyPTENPTEN↑; renal EMT↓; PI3K/AKT signaling pathway↓(38)
miR-137100 µg/kg/day, 84 daysDiabetic rat kidneyNot mentionedExtracellular matrix proteins (Col IV and FN)↓; Notch1 signaling pathway↓(39)
miR-210.4 mg/kg every 7 days, 28 daysAdjuvant arthritis rat cardiac tissueTLR4TLR4↓; apoptosis↓; proinflammatory cytokines (TNF-a, IL-6, and IL-17)↓; MAPK/NF-κB signaling pathway↓(41)
miR-546, miR-343, 108 miRNAs0.1 mg/kg, single oral dose, 14 daysLeft ventricular tissue from ratsNot mentionedRegulation of cell adhesion, cell cycling, action potential, cell-cell communication, and DNA binding(23)
miR-384-3p, miR-384-5p, 8 miRNAs0.1 mg/kg, single oral dose, 14 daysLeft ventricular tissue from ratsNot mentionedRegulation of calmodulin activity, heterodimerization activity, and signal transduction(23)
miR-483-3p0.1 mg/kg, single oral dose, 14 daysLeft ventricular tissue from ratsAhRAhR↓; CYP1A1↓(23)
miR-15a-3p, miR-615, miR-4833p, miR-127-5p0.1 mg/kg, single oral dose, 14 daysPlasma from ratsNot mentionedNot mentioned(23)
miR-1220.2, 0.4 or 0.8 µmol/l, 48 hZebrafish larvaeNot mentionedHistology score of hepatocyte vacuolation, hepatocyte disarray and oncotic necrosis↑; liver volume↓(83)

[i] miRNA/miR, microRNA; ↑, upregulation; ↓, downregulation; Mcl-1, myeloid cell leukemia-1; Hsp70, heat shock protein 70; SHIP-1, Src homology 2-containing inositol phosphatase-1; MPO, myeloperoxidase; NF-κB, nuclear factor kappa-B; PTEN, phosphatase and tensin homolog; EMT, epithelial-to-mesenchymal transition; Col IV, collagen IV; FN, fibronectin; TLR4, Toll-like receptor 4; MAPK, mitogen-activated protein kinase; AhR, aryl hydrocarbon receptor.

miRNAs involved in the antitumor activity of triptolide

Several miRNAs act as tumor-suppressor genes or oncogenes, and increasing evidence suggest that the suppressive function of triptolide on multiple tumors is mediated by regulating miRNAs (44,45). In human T-cell lymphocytic leukemia cells, triptolide significantly increases miR-16-1 expression and decreases miR-138-2 expression, and downregulation of miR-16-1 expression contributes to triptolide-induced apoptosis (46). Triptolide-induced hepatocellular carcinoma cell death is associated with the suppression of two oncogenic miRNA clusters, miR-17-92 and miR-106b-25(24). In pancreatic cancer cells, treatment with triptolide increases miR-204 expression, which directly binds to myeloid cell leukemia-1 (Mcl-1), an antiapoptotic gene essential for cell survival (47), thereby inhibiting Mcl-1 protein expression and inducing cell-type dependent apoptosis or autophagic cell death (48). In addition, triptolide decreases miR-142-3p expression, which negatively regulates Hsp70 expression, a stress protein recognized as an apoptosis inhibitor (49), and suppresses pancreatic cancer cell proliferation (50). In vivo studies have confirmed that triptolide abrogates human pancreatic tumors xenografts by concurrent upregulation of miR-204 and miR-142-3p expression and downregulation of Mcl-1 or Hsp70 expression, respectively (48,50). In colon carcinoma cells, treatment with triptolide downregulates miR-191 expression, which in turn suppresses cell proliferation and migration, induces apoptosis and activates the nuclear factor kappa-B (NF-κB) and Wnt/β-catenin signaling pathways (34). Notably, these effects were reversed following transfection with miR-191 mimics, suggesting that the anti-colorectal cancer activities of triptolide are associated with the downregulation of miR-191 expression (34). Through upregulation of miR-146a expression, triptolide markedly decreases the expression levels of the RhoA and Rac1 genes in breast cancer cells, which are both key members of the Rho GTPase family involved in tumor invasion and metastasis, and thus act as metastasis suppressors (18). Triptolide also induces S phase cell cycle arrest of human nasopharyngeal carcinoma cells by enhancing p85α-phosphatase and tensin homolog (PTEN) complex formation and inactivating AKT-mediated cyclin-dependent kinase 2 phosphorylation, which requires downregulation of miR-144 expression (35). Triptolide also inhibits the proliferation of nephroblastoma and medulloblastoma cells, and benign prostatic epithelial cells. In addition, triptolide inhibits the migratory ability of these cells but promotes apoptosis by upregulating the expression levels of miR-193b-3p, miR-138 and miR-218 (51-53). The latter activities involving miRNAs corresponded to inactivation of the phosphatidylinositol 3 kinase (PI3K)/AKT and extracellular regulated protein kinase (ERK) signaling pathways by downregulating Kruppel-like factor, inactivating the Notch signaling pathway, as well as suppressing CDK6 expression, or negatively regulating survivin and inactivating the mammalian target of rapamycin (mTOR) signaling pathway, respectively (51-53).

Sequencing data indicate that triptolide markedly alters the expression profiles of miRNAs in human non-small cell lung cancer cells. miRNAs associated with cell motility, such as miR-146a, miR-23b and miR-199b (54-56), are significantly upregulated or downregulated, and subsequent studies have validated that triptolide notably decreases lung cancer cell migration, invasion and metastasis by suppressing focal adhesion kinase expression and disrupting its downstream signaling pathways (25). Furthermore, treatment with triptolide causes a dose-dependent upregulation of miR-204-5p expression, along with decreased expression of its target, SIRT-1, a member of the class III histone deacetylase family required for caveolin-1 (Cav-1) expression (57), thereby coupling Cav-1 downregulation with activation of classical AKT/Bax-mediated apoptosis in non-small cell lung cancer cells (58).

Drug resistance is one of the main reasons for therapy failure in cancer treatment (59). miRNAs are critical regulators of molecular pathways implicated in cancer drug resistance (60). miR-21 is highly expressed and associated with disease progression and multidrug-resistance in different types of cancer (61). Triptolide notably decreases miR-21 expression in non-small cell lung cancer cells, and increases PTEN protein expression, which acts as a tumor suppressor and participates in tumor occurrence and development, and decreases cell proliferation and enhances apoptosis (62). However, ectopic miR-21 expression rescues the effect of triptolide on PTEN protein expression and cell viability, suggesting that triptolide mediates the decrease in miR-21 expression, which in turn promotes cell death by upregulating PTEN expression (62). Furthermore, triptolide significantly enhances adriamycin-induced cytotoxicity by decreasing miR-21 expression and increasing PTEN expression, and reverses drug resistance to human chronic myeloid leukemia cells (63).

In cisplatin-resistant human ovarian cancer cells, upregulation of miR-6751 expression via triptolide decreases hexokinase 2 protein expression, which confers resistance to cisplatin by enhancing autophagic activity, and sensitizes cells to the proapoptotic effect of cisplatin (64). A similar synergistic proapoptotic effect was detected following combined treatment with triptolide and dexamethasone in human multiple myeloma cells, which has the ability to overcome the glucocorticoid resistance of these cells by enhancing glucocorticoid receptor expression by inhibiting miR-142-5p and miR-181a expression (65). Furthermore, miR-181a expression is notably attenuated in osteosarcoma cells following treatment with triptolide, which directly upregulates PTEN expression, whereas transfection with miR-181a mimics restores PTEN expression, and decreases the inhibitory effect of triptolide on osteosarcoma cell proliferation and invasion, suggesting the anti-osteosarcoma properties of triptolide depended on the regulation of miR-181a and its targeting of the PTEN gene (66). Conversely, upregulated miR-181a expression participates in the suppressive effect of triptolide against human neuroblastoma cell proliferation and migration, and via activation of the mitogen-activated protein kinase (MAPK) and NF-κB signaling pathways (67). Thus, triptolide can upregulate or downregulate the expression of specific miRNAs, influence downstream targeting signaling pathways, and thus exert antitumor activities (Fig. 1).

miRNAs involved in the anti-inflammatory and immunosuppressive activities of triptolide

Several miRNAs are substantially activated by inflammatory stimuli, such as the Toll-like receptor (TLR), ligand lipopolysaccharide (LPS) and components of the inflammatory processes by post-transcriptional regulation of either signal transduction proteins of inflammatory pathways or specific inflammatory cytokines (68). For example, miR-155, which is implicated in the pathogenesis of inflammatory diseases (69), has prompted investigation on the association between triptolide and miR-155 in these inflammatory diseases. cDNA array and northern blot analysis have demonstrated that the expression of inflammatory cytokine, as well as miR-155 are markedly upregulated in macrophages following LPS stimulation, whereas triptolide attenuates the induction of these genes in a dose-dependent manner (70).

Similar observations were obtained in monocytes from patients with rheumatoid arthritis (19), whereby overexpression of miR-155 reverses the inhibitory effect of triptolide on LPS-induced interleukin (IL)-6 and tumor necrosis factor-α production, and antagonizes the effect of triptolide on Src homology 2-containing inositol phosphatase-1 (SHIP-1), which is a target of miR-155 and functions as a potent inhibitor of several inflammatory pathways (71). Thus, it has been proposed that triptolide inhibits miR-155 expression, which negatively affects its downstream target, SHIP-1, and suppresses the inflammatory response stimulated by LPS.

The miR-155/SHIP-1 axis plays a critical role in triptolide-induced improvement on the symptoms of other inflammatory diseases. Inhibiting the miR-155/SHIP-1 axis via triptolide suppresses NF-κB activity via the PI3K/AKT pathway, which significantly inhibits microglial activation and stimulates inflammatory cytokines stimulated by prion-like preformed fibril (20).

Triptolide has also been reported to suppress miR-155 expression and simultaneously promote SHIP-1 expression in the small intestine, particularly in the anastomosis of IL-10 deficient mice subjected to ileocecal resection (72). These effects are also associated with decreased levels of inflammatory cytokines, and eventually exert therapeutic effects on Crohn's disease, an inflammatory bowel disease (72). Studies on Crohn's disease have reported that triptolide effectively reverses upregulated miR-16-1 expression and downregulated Hsp70 expression at the anastomosis sites in IL-10 deficient mice, as well as in patients with Crohn's disease, which represents a protective mechanism against postsurgical inflammation and anastomotic fibrosis (37,73).

With regards to the effects on osteoarthritis, downregulation of miR-20b expression following treatment with triptolide notably upregulates its target inflammasome-related gene, nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing protein 3, which limits the activation of caspase-1 and subsequently inhibits the maturation of inflammatory cytokines, thus preventing the development of osteoarthritis (41). In the treatment of spinal cord injury (SCI), the anti-inflammatory activity of triptolide is mediated by upregulated miR-96 expression, which inactivates NF-κB by negatively regulating the inhibitor of NF-κB kinase subunit β expression, and decreases inflammatory cytokine levels in LPS-induced primary microglia and spinal cord tissues of SCI rats (42).

Triptolide is frequently used as an immunosuppressive compound in the treatment of chronic autoimmune diseases, including systemic lupus erythematosus (SLE) (12). Recently, a novel miRNA target was identified following treatment of SLE by triptolide. Triptolide was demonstrated to markedly increase miR-125a-5p expression, as well as the percentage of regulatory T cells (Treg), which are important in modulating self-tolerance and autoimmunity (74). Conversely, miR-125a-5p inhibitor significantly abrogates the effects of triptolide on Treg, suggesting that triptolide stimulates Treg activation via miR-125a-5p, and thereby alleviates the clinical and histological symptoms observed in the SLE mouse model (21). Taken together, these findings suggest that changes in the expression levels of specific miRNAs contribute to the anti-inflammatory and immunosuppressive properties of triptolide.

miRNAs involved in the renal protective and cardioprotective activities of triptolide

Increasing evidence suggest that triptolide exhibits renal protective effects by regulating the expression of miRNAs (22,38,39,75,76). In adriamycin-induced nephropathy rat models, elevated expression levels of miR-344b-3p and miR-30b-3p were observed, the effects of which were reversed following treatment with triptolide. Triptolide also increases the levels of nephrin protein, which is involved in the maintenance of the glomerular filtration barrier structure in the kidney cortex, thereby attenuating podocyte damage and partially improving renal function (76). Thus, it has been speculated that miR-344b-3p and miR-30b-3p are involved in the protective effect of triptolide towards podocytes from adriamycin-induced nephropathy (76). In the transforming growth factor-β (TGF-β)-induced podocyte injury model, the presence of triptolide completely reversed TGF-β-induced miR-30 downregulation, suppressed TGF-β-stimulated activation of downstream damaging pathways, including MAPK, NF-κB and calcineurin/NFATC3, and alleviated podocyte injury in vitro and ex vivo (22).

During the development of diabetic kidney disease (DKD), miRNAs are closely associated with multiple pathological modifications (77). Triptolide notably mitigates the impaired renal function by exerting a therapeutic effect on DKD through the regulation of miRNA-mediated signaling pathways (38,75). For example, triptolide significantly reverses the increase in miR-188-5p expression induced by high glucose in human proximal tubular epithelial cells and diabetic kidneys, which enhances the expression of action target PTEN, and inactivates the downstream PI3K/AKT signaling pathway and inhibits renal epithelial-to-mesenchymal transition in DKD (38). Similarly, downregulation of miR-141-3p expression via triptolide affects the target PTEN protein in human renal mesangial cells, under high glucose, with an opposite tendency. In addition, triptolide-induced autophagic activation and fibrosis alleviation in association with the activation of the PTEN/AKT/mTOR pathway is blocked following overexpression of miR-141-3p (75).

The miR-137/Notch1 pathway prevents glomerulosclerosis under diabetic conditions (39). Unlike miR-188-5p and miR-141-3p, miR-137 expression significantly decreases in high glucose-incubated renal mesangial cells and in diabetic rat kidney tissues, but returns to normal levels following treatment with triptolide (39). Triptolide inactivates the Notch1 pathway reliance on miR-137, which suppresses extracellular matrix protein accumulation of collagen IV and fibronectin, thus improving DKD by protecting against glomerulosclerosis (39).

The cardioprotective activity of triptolide has been attributed to the changes in miR-21 expression. Treatment with triptolide markedly decreases miR-21 expression, inactivates the TLR4/MAPK/NF-κB signaling pathway and prevents cell apoptosis in LPS-treated myocardial cells, as well as in cardiac tissues from adjuvant arthritis rat models (40,41). Collectively, these findings confirm the regulatory role of miRNAs in the renal protective and cardioprotective activities of triptolide.

miRNAs involved in the antiangiogenesis activity of triptolide

A key feature of atherosclerosis is the dysregulated progression of endothelial cell angiogenesis within the plaques, a process that is regulated by several miRNAs, particularly miR-92a (78). miR-92a blocks angiogenesis both in vitro and in vivo (79), and participates in the inhibitory effect of triptolide in atherosclerosis. In human dermal microvascular endothelial cells, triptolide effectively induces miR-92a expression in a dose-dependent manner, and impedes the production of integrin subunit α 5 (ITGA5), which is a direct target of miR-92a (42). Overexpression of ITGA5 inactivates the ERK and PI3K/AKT signaling pathways, as well as the accumulation of a number of angiogenesis-related factors, such as endothelial nitric oxide synthase, VEGF receptor-2 and VEGF, which inhibits angiogenesis (42). These effects are reversed following ITGA5 knockdown (42). Thus, miR-92a acts as a crucial mediator in the antiangiogenesis activity of triptolide by inactivating the ERK and PI3K/AKT signaling pathways following downregulation of ITGA5 expression.

miRNAs involved in the multiorgan toxicity of triptolide

Several miRNAs, such as miR-122 and miR-26a, are involved in the multiorgan toxicity observed following treatment with triptolide, and are considered sensitive early warning indicators (80). Oral administration of triptolide in male rats led to cardiac dysfunction and myocardial cell death. These effects were associated with at least a 2-fold increase in the expression levels of 108 miRNAs, as well as a 2-fold decrease in the expression levels of eight miRNAs in heart tissue samples. Furthermore, changes in plasma miRNAs were also detected (81). Among these, 28 miRNAs were predicted to simultaneously regulate the expression of aryl hydrocarbon receptor (AhR), which is a transcription factor that is closely associated with cardiac pathophysiology (81). Another study confirmed that triptolide significantly decreases myocardial and plasma AhR levels, as well as its downstream gene, CYP1A1 (23).

miR-122 expression is significantly upregulated in adult zebrafish or mice livers following treatment with liver toxicants, including acetaminophen or tamoxifen (82). A similar trend has been observed in zebrafish larvae following treatment with triptolide, which causes hepatic injury (83), which is considered to be a crucial event resulting from deregulated hepatic function caused by altered miR-122 expression (84). Taken together, these findings suggest that miR-122 may be used as a diagnostic predictor and an attractive therapeutic target for the hepatotoxicity activity of triptolide.

miR-26a expression is upregulated in triptolide-induced reproductive toxicity in mouse Leydig cells (43). This results in cytotoxicity via inhibition of its downstream target, glycogen synthase kinase-3β, which possesses antiapoptotic effects (43). Collectively, these findings indicate the association between miRNAs and the multiorgan toxicity of triptolide.

4. Molecular mechanisms underlying regulation of miRNAs by triptolide

The regulation of the expression of miRNAs by triptolide is partly mediated by specific transcription factors. Triptolide has been reported to interfere with TGF-β-induced Smad2/3 phosphorylation and activation, and prevents phosphorylated protein binding to Smad4 and their subsequent translocation to nuclei where they are known to regulate gene expression as transcription factors, and thereby completely restore miR-30 downregulation in podocytes (22). As a multifunctional transcription factor, NF-κB positively and negatively regulates the expression of miRNAs (85). Treatment with triptolide decreases the expression and nuclear accumulation of NF-κB in a dose-dependent manner, accompanied by the differential expression of 23 miRNA genes in lymphocytic leukemic cell lines, suggesting that triptolide-induced cytotoxic effects may occur by inhibiting NF-κB transcriptional activity, and consequently influencing the expression of miRNAs (46). c-Myc also plays a critical role in repressing two oncogenic miRNA clusters by triptolide in hepatocellular carcinoma cells (24). Through direct binding to the E-box element in the promoter region of MCM7, c-Myc transactivates both miR-7-92 and miR-106b-25, which function as oncogenes in cancer initiation and progression (86). Triptolide significantly antagonizes the transcription of these two miRNA clusters by targeting c-Myc, and XPB (also known as ERCC3) is involved in this process (24). XPB is a subunit of general transcription factor TFIIH, which is essential for RNA polymerase II-dependent transcription initiation and nucleotide excision repair (87). It has been reported that triptolide covalently binds to the Cys342 residue of XPB, the largest subunit of the general transcription factor TFIIH (88), and impedes its ATPase activity, inhibiting RNA polymerase II mediated transcription (89). Triptolide also acts as an inhibitor of RNA polymerase II by selectively activating CDK7, and subsequently by triggering proteasome-dependent degradation of hyperphosphorylated Rpb1, which is the largest RNA polymerase II subunit (90). On the other hand, triptolide directly suppresses the recruitment of B-related factor 1 to TFIIIB complex, an essential transcription initiation factor of RNA polymerase III (91), and significantly inhibits RNA polymerase III transcription (92). Based on these observations and the fact that miRNA genes are transcribed by RNA polymerase II or III, it is reasonable to speculate that the inhibition of RNA polymerase II and III mediated general transcription underlies miRNAs regulation by triptolide.

Triptolide may also regulate the expression of miRNAs via an enhancer of zeste homolog 2 (EZH2)-involved mechanism. EZH2, a well-known histone methyltransferase (93), is capable of binding to the promoter regions of miRNAs genes and catalyzing histone H3 trimethylation, resulting in the transcriptional silencing of miRNAs genes (94). It has been proven that EZH2 is a target for triptolide in prostate cancer and multiple myeloma cells (95), and a recent study demonstrated that treatment with triptolide significantly downregulates miR-191 expression in colon carcinoma cells in an EZH2-dependent manner, suggesting a modulatory activity of triptolide on the expression of miRNAs at the epigenetic level (34).

The regulation of miRNAs by triptolide may be ascribed to the autophagy pathway. Autophagy can be modulated by triptolide through multiple machineries and signaling pathways, such as oxidative stress, cytoplasmic calcium and the AKT/mTOR/p70S6K pathway (13). miRNAs also play vital roles in autophagy as they can target autophagy-related genes or other related regulators, and participate in regulating the dynamic process of autophagy (96). Triptolide has been reported to significantly decrease miR-141-3p expression, which directly acts on PTEN, and thereby reverses the induced autophagy in high glucose treated human mesangial cells and in DKD rats (75). Conversely, autophagy selectively regulates miRNA homeostasis, which is activated by promoting autophagy receptor-mediated degradation of miRNA pathway components, including DICER and AGO2, further proving an association between autophagy and miRNAs (97). Although the molecular mechanisms involved in the role of autophagy in triptolide regulation of miRNAs remain unclear, it is possible that autophagy may play a functional role, and the precise molecular targets and regulatory networks remain to be elucidated. Collectively, these findings suggest that the expression of triptolide-regulated miRNAs is mediated by multiple intracellular components and molecular mechanisms.

5. Conclusions and future perspective

Traditional Chinese medicines have been effectively used to cure various diseases. Thus, investigating the molecular mechanisms underlying their activities is highly warranted. As a biologically active ingredient derived from the Chinese herb, Tripterygium wilfordii Hook F., recent studies have demonstrated that triptolide exerts effects on the expression of a series of endogenous miRNAs, which in turn employ several downstream cellular factors to achieve its multiple pharmacological activities, highlighting miRNAs as critical mediators for triptolide-induced effects (18,20,21,23,34-43). However, determining the exact role of these miRNAs is limited by the in vitro models offered by these studies. Haploid cells are effective tools to study gene function due to having one set of chromosomes (98,99). Thus, prospective studies will aim to use haploid cells to screen novel miRNAs for specific functions following treatment with triptolide, and additional evidence from in vivo experiments will validate the conclusions. In addition, regulation of miRNA expression is usually cell- or tissue-specific, and as precise base pairing between miRNA and their corresponding mRNA targets is not required. A single miRNA may simultaneously target several mRNAs, whereas one mRNA can be regulated by different miRNAs (28,30,33). Triptolide may affect PTEN expression by regulating the expression of several miRNAs, including miR-21 (62,63), miR-181a (66), miR-188-5p (38), miR-144(35), miR-141-3p (75), miR-17-92 and miR-106b-25 clusters (24). miR-21 is a common target when triptolide controls the expression of both TLR4 and PTEN (40,41,62,63). Thus, the intricate complexity and integration of the activity of miRNAs present challenges in identifying their function and regulatory pathways. Supplementary bioinformatics tools may provide integrated analyses of these complicated networks that participate in the pharmacological activities of triptolide. Prospective studies are required to investigate whether miRNAs play roles in other pharmacological activities of triptolide.

In conclusion, specific miRNAs have been identified as primary targets when triptolide displays multiple pharmacological effects. These findings also suggest that triptolide can serve as a novel molecular probe for studying miRNAs. A comprehensive understanding of the regulatory pathways and specific functions of these miRNAs will help determine the underlying molecular mechanisms of triptolide and provide more effective strategies for drug development and disease treatment.

Acknowledgements

Not applicable.

Availability of data and materials

Not applicable.

Authors' contributions

YW conceived and supervised the present study. KZ drafted the initial manuscript. YC, BH, RL and YW reviewed the manuscript for important intellectual content. All authors have read and approved the final manuscript.

Ethics approval and consent to participate

Not applicable.

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

References

1 

Auyeung KK, Han QB and Ko JK: Astragalus membranaceus: A review of its protection against inflammation and gastrointestinal cancers. Am J Chin Med. 44:1–22. 2016.PubMed/NCBI View Article : Google Scholar

2 

Wang Z, Xia Q, Liu X, Liu W, Huang W, Mei X, Luo J, Shan M, Lin R, Zou D and Ma Z: Phytochemistry, pharmacology, quality control and future research of Forsythia suspensa (Thunb.) Vahl: A review. J Ethnopharmacol. 210:318–339. 2018.PubMed/NCBI View Article : Google Scholar

3 

Shi JF, Luo YY, Li JX, Luo RF, Chen L, Li J, Zhang JM and Fu CM: Research progress on anti-tumor effects and mechanisms of triptolide and its combined application. China J Chin Mater Med. 44:3391–3398. 2019.PubMed/NCBI View Article : Google Scholar

4 

Noel P, Von Hoff DD, Saluja AK, Velagapudi M, Borazanci E and Han M: Triptolide and its derivatives as cancer therapies. Trends Pharmacol Sci. 40:327–341. 2019.PubMed/NCBI View Article : Google Scholar

5 

Yan P and Sun X: Triptolide: A new star for treating human malignancies. J Cancer Res Ther. 14 (Suppl):S271–S275. 2018.PubMed/NCBI View Article : Google Scholar

6 

Huang G, Yuan K, Zhu Q, Zhang S, Lu Q, Zhu M, Sheng H, Yu R, Luo G and Xu A: Triptolide inhibits the inflammatory activities of neutrophils to ameliorate chronic arthritis. Mol Immunol. 101:210–220. 2018.PubMed/NCBI View Article : Google Scholar

7 

Huang SH, Lin GJ, Chu CH, Yu JC, Chen TW, Chen YW, Chien MW, Chu CC and Sytwu HK: Triptolide ameliorates autoimmune diabetes and prolongs islet graft survival in nonobese diabetic mice. Pancreas. 42:442–451. 2013.PubMed/NCBI View Article : Google Scholar

8 

Zheng CX, Chen ZH, Zeng CH, Qin WS, Li LS and Liu ZH: Triptolide protects podocytes from puromycin aminonucleoside induced injury in vivo and in vitro. Kidney Int. 74:596–612. 2008.PubMed/NCBI View Article : Google Scholar

9 

Yu H, Shi L, Zhao S, Sun Y, Gao Y, Sun Y and Qi G: Triptolide attenuates myocardial ischemia/reperfusion injuries in rats by inducing the activation of Nrf2/HO-1 defense pathway. Cardiovasc Toxicol. 16:325–335. 2016.PubMed/NCBI View Article : Google Scholar

10 

Xi C, Peng S, Wu Z, Zhou Q and Zhou J: Toxicity of triptolide and the molecular mechanisms involved. Biomed Pharmacother. 90:531–541. 2017.PubMed/NCBI View Article : Google Scholar

11 

Chen SR, Dai Y, Zhao J, Lin L and Wang Y and Wang Y: A mechanistic overview of triptolide and celestrol, natural products from Tripterygium wilfordii Hook F. Front Pharmacol. 9(104)2018.PubMed/NCBI View Article : Google Scholar

12 

Yuan K, Li X, Lu Q, Zhu Q, Jiang H, Wang T, Huang G and Xu A: Application and mechanisms of triptolide in the treatment of inflammatory diseases-a review. Front Pharmacol. 10(1469)2019.PubMed/NCBI View Article : Google Scholar

13 

Wei YM, Wang YH, Xue HQ, Luan ZH, Liu BW and Ren JH: Triptolide, A potential autophagy modulator. Chin J Integr Med. 25:233–240. 2019.PubMed/NCBI View Article : Google Scholar

14 

Jin W, Wang J, Liu CP, Wang HW and Xu RM: Structural basis for pri-miRNA recognition by Drosha. Mol Cell. 78:423–433. 2020.PubMed/NCBI View Article : Google Scholar

15 

Olejniczak M, Kotowska-Zimmer A and Krzyzosiak W: Stress-induced changes in miRNA biogenesis and functioning. Cell Mol Life Sci. 75:177–191. 2018.PubMed/NCBI View Article : Google Scholar

16 

Dexheimer PJ and Cochella L: MicroRNAs: From mechanism to organism. Front Cell Dev Biol. 8(409)2020.PubMed/NCBI View Article : Google Scholar

17 

Rupaimoole R and Slack FJ: MicroRNA therapeutics: Towards a new era for the management of cancer and other diseases. Nat Rev Drug Discov. 16:203–222. 2017.PubMed/NCBI View Article : Google Scholar

18 

Liu Q, Wang W, Li F, Yu D, Xu C and Hu H: Triptolide inhibits breast cancer cell metastasis through inducing the expression of miR-146a, a negative regulator of Rho GTPase. Oncol Res. 27:1043–1050. 2019.PubMed/NCBI View Article : Google Scholar

19 

Peng A, Huang X, Liu R, Wang X and Zhuang J: Triptolide inhibits the inflammatory response of monocytes from rheumatoid arthritis patients by regulating miR-155. Chin J Cell Mol Immunol. 30:635–638. 2014.PubMed/NCBI

20 

Feng Y, Zheng C, Zhang Y, Xing C, Cai W, Li R, Chen J and Duan Y: Triptolide inhibits preformed fibril-induced microglial activation by targeting the microRNA155-5p/SHIP1 pathway. Oxid Med Cell Longev. 2019(6527638)2019.PubMed/NCBI View Article : Google Scholar

21 

Zhao X, Tang X, Yan Q, Song H, Li Z, Wang D, Chen H and Sun L: Triptolide ameliorates lupus via the induction of miR-125a-5p mediating Treg upregulation. Int Immunopharmacol. 71:14–21. 2019.PubMed/NCBI View Article : Google Scholar

22 

Yang Q, Sun M, Chen Y, Lu Y, Ye Y, Song H, Xu X, Shi S and Wang J: Triptolide protects podocytes from TGF-β-induced injury by preventing miR-30 downregulation. Am J Transl Res. 9:5150–5159. 2017.PubMed/NCBI

23 

Wang SR, Chen X, Ling S, Ni RZ, Guo H and Xu JW: MicroRNA expression, targeting, release dynamics and early-warning biomarkers in acute cardiotoxicity induced by triptolide in rats. Biomed Pharmacother. 111:1467–1477. 2019.PubMed/NCBI View Article : Google Scholar

24 

Li SG, Shi QW, Yuan LY, Qin LP, Wang Y, Miao YQ, Chen Z, Ling CQ and Qin WX: C-Myc-dependent repression of two oncogenic miRNA clusters contributes to triptolide-induced cell death in hepatocellular carcinoma cells. J Exp Clin Cancer Res. 37(51)2018.PubMed/NCBI View Article : Google Scholar

25 

Reno TA, Kim JY and Raz DJ: Triptolide inhibits lung cancer cell migration, invasion, and metastasis. Ann Thorac Surg. 100:1817–1825. 2015.PubMed/NCBI View Article : Google Scholar

26 

Kalla R, Ventham NT, Kennedy NA, Quintana JF, Nimmo ER, Buck AH and Satsangi J: MicroRNAs: New players in IBD. Gut. 64:504–517. 2015.PubMed/NCBI View Article : Google Scholar

27 

Michlewski G and Caceres JF: Post-transcriptional control of miRNA biogenesis. RNA. 25:1–16. 2019.PubMed/NCBI View Article : Google Scholar

28 

Saliminejad K, Khorram Khorshid HR, Soleymani Fard S and Ghaffari SH: An overview of microRNAs: Biology, functions, therapeutics, and analysis methods. J Cell Physiol. 234:5451–5465. 2019.PubMed/NCBI View Article : Google Scholar

29 

Vishnoi A and Rani S: miRNA biogenesis and regulation of diseases: An overview. Methods Mol Biol. 1509:1–10. 2017.PubMed/NCBI View Article : Google Scholar

30 

Yates LA, Norbury CJ and Gilbert RJ: The long and short of microRNA. Cell. 153:516–519. 2013.PubMed/NCBI View Article : Google Scholar

31 

Turner MJ and Slack FJ: Transcriptional control of microRNA expression in C elegans: Promoting better understanding. RNA Biol. 6:49–53. 2009.PubMed/NCBI View Article : Google Scholar

32 

Kedde M, Strasser MJ, Boldajipour B, Oude Vrielink JA, Slanchev K, le Sage C, Nagel R, Voorhoeve PM, van Duijse J, Orom UA, et al: RNA-binding protein Dnd1 inhibits microRNA access to target mRNA. Cell. 131:1273–1286. 2007.PubMed/NCBI View Article : Google Scholar

33 

Krol J, Loedige I and Filipowicz W: The widespread regulation of microRNA biogenesis, function and decay. Nat Rev Genet. 11:597–610. 2010.PubMed/NCBI View Article : Google Scholar

34 

Qi Y and Li J: Triptolide inhibits the growth and migration of colon carcinoma cells by down-regulation of miR-191. Exp Mol Pathol. 107:23–31. 2019.PubMed/NCBI View Article : Google Scholar

35 

Wu CW, Wang SG, Lin ML and Chen SS: Downregulation of miR-144 by triptolide enhanced p85α-PTEN complex formation causing S phase arrest of human nasopharyngeal carcinoma cells. Eur J Pharmacol. 855:137–148. 2019.PubMed/NCBI View Article : Google Scholar

36 

Chen M, Wang JM, Wang D, Wu R and Hou HW: Triptolide inhibits migration and proliferation of fibroblasts from ileocolonic anastomosis of patients with Crohn's disease via regulating the miR161/HSP70 pathway. Mol Med Rep. 19:4841–4851. 2019.PubMed/NCBI View Article : Google Scholar

37 

Qian K, Zhang L and Shi K: Triptolide prevents osteoarthritis via inhibiting hsa-miR-20b. Inflammopharmacology. 27:109–119. 2019.PubMed/NCBI View Article : Google Scholar

38 

Xue M, Cheng Y, Han F, Chang Y, Yang Y, Li X and Chen L, Lu Y, Sun B and Chen L: Triptolide attenuates renal tubular epithelial-mesenchymal transition via the miR-188-5p-mediated PI3K/AKT pathway in diabetic kidney disease. Int J Biol Sci. 14:1545–1557. 2018.PubMed/NCBI View Article : Google Scholar

39 

Han F, Wang S, Chang Y, Li C, Yang J, Han Z, Chang B, Sun B and Chen L: Triptolide prevents extracellular matrix accumulation in experimental diabetic kidney disease by targeting microRNA-137/Notch1 pathway. J Cell Physiol. 233:2225–2237. 2018.PubMed/NCBI View Article : Google Scholar

40 

Cao Y, Guo Y, Wang Y, Cao Y, Zong R, Huang C and Liu J: Drug-containing serum of Xinfeng capsules protect against H9C2 from death by enhancing miRNA-21 and inhibiting toll-like receptor 4/phosphorylated p-38 (p-p38)/p-p65 signaling pathway and proinflammatory cytokines expression. J Tradit Chin Med. 38:359–365. 2018.PubMed/NCBI

41 

Cao YX, Huang D, Liu J, Zong RK, Wan L, Huang CB, Zhang WD and Wang Y: A novel chinese medicine, xinfeng capsule, modulates proinflammatory cytokines via regulating the toll-like receptor 4 (TLR4)/Mitogen-activated protein kinase (MAPK)/Nuclear Kappa B (NF-κB) signaling pathway in an adjuvant arthritis rat model. Med Sci Monit. 25:6767–6774. 2019.PubMed/NCBI View Article : Google Scholar

42 

Xu X, Tian L and Zhang Z: Triptolide inhibits angiogenesis in microvascular endothelial cells through regulation of miR-92a. J Physiol Biochem. 75:573–583. 2019.PubMed/NCBI View Article : Google Scholar

43 

Liang H, Zhang S and Li Z: Ginsenoside Rg3 protects mouse leydig cells against triptolide by downregulation of miR-26a. Drug Des Devel Ther. 13:2057–2066. 2019.PubMed/NCBI View Article : Google Scholar

44 

Mamoori A, Gopalan V and Lam AK: Role of miR-193a in cancer: Complexity and factors control the patterns of its expression. Curr Cancer Drug Targets. 18:618–628. 2018.PubMed/NCBI View Article : Google Scholar

45 

Svoronos AA, Engelman DM and Slack FJ: OncomiR or tumor suppressor? The duplicity of microRNAs in cancer. Cancer Res. 76:3666–3670. 2016.PubMed/NCBI View Article : Google Scholar

46 

Meng HT, Zhu L, Ni WM, You LS, Jin J and Qian WB: Triptolide inhibits the proliferation of cells from lymphocytic leukemic cell lines in association with downregulation of NF-kappaB activity and miR-16-1*. Acta Pharmacol Sin. 32:503–511. 2011.PubMed/NCBI View Article : Google Scholar

47 

Xiang W, Yang CY and Bai L: Mcl-1 inhibiton in cancer treatment. Onco Targets Ther. 11:7301–7314. 2018.PubMed/NCBI View Article : Google Scholar

48 

Chen Z, Sangwan V, Banerjee S, Mackenzie T, Dudeja V, Li X, Wang H, Vickers SM and Saluja AK: miR-204 mediated loss of Myeloid cell leukemia-1 results in pancreatic cancer cell death. Mol Cancer. 12(105)2013.PubMed/NCBI View Article : Google Scholar

49 

Roufayel R and Kadry S: Molecular chaperone HSP70 and key regulators of apoptosis - a review. Curr Mol Med. 19:315–325. 2019.PubMed/NCBI View Article : Google Scholar

50 

MacKenzie TN, Mujumdar N, Banerjee S, Sangwan V, Sarver A, Vickers S, Subramanian S and Saluja AK: Triptolide induces the expression of miR-142-3p: A negative regulator of heat shock protein 70 and pancreatic cancer cell proliferation. Mol Cancer Ther. 12:1266–1275. 2013.PubMed/NCBI View Article : Google Scholar

51 

Hang S, Wang X and Li H: Triptolide inhibits viability and migration while promotes apoptosis in nephroblastoma cells by regulation of miR-193b-3p. Exp Mol Pathol. 108:80–88. 2019.PubMed/NCBI View Article : Google Scholar

52 

Zhang H, Li H, Liu Z, Ge A, Guo E, Liu S and Chen Z: Triptolide inhibits the proliferation and migration of medulloblastoma Daoy cells by upregulation of microRNA-138. J Cell Biochem. 119:9866–9877. 2018.PubMed/NCBI View Article : Google Scholar

53 

Yao C, Li H and Zhang W: Triptolide inhibits benign prostatic epithelium viability and migration and induces apoptosis via upregulation of microRNA-218. Int J Immunopathol Pharmacol. 32(2058738418812349)2018.PubMed/NCBI View Article : Google Scholar

54 

Liu Q, Wang W, Yang X, Zhao D, Li F and Wang H: miRNA-146a inhibits cell migration and invasion by targeting RhoA in breast cancer. Oncol Rep. 36:189–196. 2016.PubMed/NCBI View Article : Google Scholar

55 

Hu H, Tang J, Liu C and Cen Y: miR-23b promotes the migration of keratinocytes through downregulating TIMP3. J Surg Res. 254:102–109. 2020.PubMed/NCBI View Article : Google Scholar

56 

Wang J, Zhou F, Yin L, Zhao L, Zhang Y and Wang J: MicroRNA-199b targets the regulation of ZEB1 expression to inhibit cell proliferation, migration and invasion in non-small cell lung cancer. Mol Med Rep. 16:5007–5014. 2017.PubMed/NCBI View Article : Google Scholar

57 

Charles S, Raj V, Arokiaraj J and Mala K: Caveolin1/protein arginine methyltransferase1/sirtuin1 axis as a potential target against endothelial dysfunction. Pharmacol Res. 119:1–11. 2017.PubMed/NCBI View Article : Google Scholar

58 

Philips BJ, Kumar A, Burki S, Ryan JP, Noda K and D'Cunha J: Triptolide-induced apoptosis in non-small cell lung cancer via a novel miR204-5p/Caveolin-1/Akt-mediated pathway. Oncotarget. 11:2793–2806. 2020.PubMed/NCBI View Article : Google Scholar

59 

Cao Y: Adipocyte and lipid metabolism in cancer drug resistance. J Clin Invest. 129:3006–3017. 2019.PubMed/NCBI View Article : Google Scholar

60 

Gomes BC, Rueff J and Rodrigues AS: MicroRNAs and cancer drug resistance. Methods Mol Biol. 1395:137–162. 2016.PubMed/NCBI View Article : Google Scholar

61 

Pfeffer SR, Yang CH and Preffer LM: The role of miR-21 in cancer. Drug Dev Res. 76:270–277. 2015.PubMed/NCBI View Article : Google Scholar

62 

Li X, Zang A, Jia Y, Zhang J, Fan W, Feng J, Duan M, Zhang L, Huo R, Jiao J and Zhu X: Triptolide reduces proliferation and enhances apoptosis of human non-small cell lung cancer cells through PTEN by targeting miR-21. Mol Med Rep. 13:2763–2768. 2016.PubMed/NCBI View Article : Google Scholar

63 

Li H, Hui L, Xu W, Shen H, Chen Q, Long L and Zhu X: Triptolide modulates the sensitivity of K562/A02 cells to adriamycin by regulating miR-21 expression. Pharm Biol. 50:1233–1240. 2012.PubMed/NCBI View Article : Google Scholar

64 

Wang R, Ma X, Su S and Liu Y: Triptolide antagonized the cisplatin resistance in human ovarian cancer cell line A2780/CP70 via hsa-mir-6751. Future Med Chem. 10:1947–1955. 2018.PubMed/NCBI View Article : Google Scholar

65 

Huang X, Yang M and Jin J: Triptolide enhances the sensitivity of multiple myeloma cells to dexamethasone via microRNAs. Leuk Lymphoma. 53:1188–1195. 2012.PubMed/NCBI View Article : Google Scholar

66 

Jiang C, Fang X, Zhang H, Wang X, Li M, Jiang W, Tian F, Zhu L and Bian Z: Triptolide inhibits the growth of osteosarcoma by regulating microRNA-181a via targeting PTEN gene in vivo and vitro. Tumour Biol. 39(1010428317697556)2017.PubMed/NCBI View Article : Google Scholar

67 

Jiang J, Song X, Yang J, Lei K, Ni Y, Zhou F and Sun L: Triptolide inhibits proliferation and migration of human neuroblastoma SH-SY5Y cells by upregulating MicroRNA-181a. Oncol Res. 26:1235–1243. 2018.PubMed/NCBI View Article : Google Scholar

68 

O'Connell RM, Rao DS and Baltimore D: microRNA regulation of inflammatory responses. Annu Rev Immunol. 30:295–312. 2012.PubMed/NCBI View Article : Google Scholar

69 

Mahesh G and Biswas R: miRNA-155: A master regulator of inflammation. J Interferon Cytokine Res. 39:321–330. 2019.PubMed/NCBI View Article : Google Scholar

70 

Matta R, Wang X, Ge H, Ray W, Nelin LD and Liu Y: Triptolide induces anti-inflammatory cellular responses. Am J Transl Res. 1:267–282. 2009.PubMed/NCBI

71 

Tang H, Mao J, Ye X, Zhang F, Kerr WG, Zheng T and Zhu Z: SHIP-1, a target of miR-155, regulates endothelial cell responses in lung fibrosis. FASEB J. 34:2011–2023. 2020.PubMed/NCBI View Article : Google Scholar

72 

Wu R, Li Y, Guo Z, Gong J, Zhu W, Li N and Li J: Triptolide ameliorates ileocolonic anastomosis inflammation in IL-10 deficient mice by mechanism involving suppression of miR-155/SHIP-1 signaling pathway. Mol Immunol. 56:340–346. 2013.PubMed/NCBI View Article : Google Scholar

73 

Hou HW, Wang JM, Wang D, Wu R and Ji ZL: Triptolide exerts protective effects against fibrosis following ileocolonic anastomosis by mechanisms involving the miR-16-1/HSP70 pathway in IL-10-deficient mice. Int J Mol Med. 40:337–346. 2017.PubMed/NCBI View Article : Google Scholar

74 

Lee GR: The balance of Th17 versus Treg cells in autoimmunity. Int J Mol Sci. 19(730)2018.PubMed/NCBI View Article : Google Scholar

75 

Li XY, Wang SS, Han Z, Han F, Chang YP, Yang Y, Xue M, Sun B and Chen LM: Triptolide restores autophagy to alleviate diabetic renal fibrosis through the miR-141-3p/PTEN/Akt/mTOR pathway. Mol Ther Nucleic Acids. 9:48–56. 2017.PubMed/NCBI View Article : Google Scholar

76 

Jiang CB, Wei MG, Tu Y, Zhu H, Li CQ, Jing WM and Sun W: Triptolide attenuates podocyte injury by regulating expression of miRNA-344b-3p and miRNA-30b-3p in rats with adriamycin-induced nephropathy. Evid Based Complement Alternat Med. 2015(107814)2015.PubMed/NCBI View Article : Google Scholar

77 

Ignarski M, Islam R and Muller RU: Long non-coding RNAs in kidney disease. Int J Mol Sci. 20(3276)2019.PubMed/NCBI View Article : Google Scholar

78 

Bonauer A, Carmona G, Iwasaki M, Mione M, Koyanagi M, Fischer A, Burchfield J, Fox H, Doebele C, Ohtani K, et al: MicroRNA-92a controls angiogenesis and functional recovery of ischemic tissues in mice. Science. 324:1710–1713. 2009.PubMed/NCBI View Article : Google Scholar

79 

Zhang L, Zhou M, Qin G, Weintraub NL and Tang Y: miR-92a regulates viability and angiogenesis of endothelial cells under oxidative stress. Biochem Biophys Res Commun. 446:952–958. 2014.PubMed/NCBI View Article : Google Scholar

80 

Marrone AK, Beland FA and Pogribny IP: The role for microRNAs in drug toxicity and in safety assessment. Expert Opin Drug Metab Toxicol. 11:601–611. 2015.PubMed/NCBI View Article : Google Scholar

81 

Ichihara S, Li P, Mise N, Suzuki Y, Izuoka K, Nakajima T, Gonzalez F and Ichihara G: Ablation of aryl hydrocarbon receptor promotes angiotensin II-induced cardiac fibrosis through enhanced c-Jun/HIF-1α signaling. Arch Toxicol. 93:1543–1553. 2019.PubMed/NCBI View Article : Google Scholar

82 

Nam HS, Hwang KS, Jeong YM, Ryu JI, Choi TY, Bae MA, Son WC, You KH, Son HY and Kim CH: Expression of miRNA-122 induced by liver toxicants in Zebrafish. Biomed Res Int. 2016(1473578)2016.PubMed/NCBI View Article : Google Scholar

83 

Vliegenthart ADB, Wei C, Buckley C, Berends C, de Potter CMJ, Schneemann S, Del Pozo J, Tucker C, Mullins JJ, Webb DJ and Dear JW: Characterization of triptolide-induced hepatotoxicity by imaging and transcriptomics in a novel Zebrafish model. Toxicol Sci. 159:380–391. 2017.PubMed/NCBI View Article : Google Scholar

84 

Cheng B, Zhu Q, Lin W and Wang L: MicroRNA-122 inhibits epithelial-mesenchymal transition of hepatic stellate cells induced by the TGF-β1/Smad signaling pathway. Exp Ther Med. 17:284–290. 2019.PubMed/NCBI View Article : Google Scholar

85 

Yuan Y, Tong L and Wu S: microRNA and NF-kappa B. Adv Exp Med Biol. 887:157–170. 2015.PubMed/NCBI View Article : Google Scholar

86 

Ichikawa D, Komatsu S, Konishi H and Otsuji E: Circulating microRNA in digestive tract cancers. Gastroenterology. 1421074–1078. (e1071)2012.PubMed/NCBI View Article : Google Scholar

87 

Titov DV, Gilman B, He QL, Bhat S, Low WK, Dang Y, Smeaton M, Demain AL, Miller PS, Kugel JF, et al: XPB, a subunit of TFIIH, is a target of the natural product triptolide. Nat Chem Biol. 7:182–188. 2011.PubMed/NCBI View Article : Google Scholar

88 

Chauhan AK, Li P, Sun Y, Wani G, Zhu Q and Wani AA: Spironolactone-induced XPB degradtion requires TFIIH integrity and ubiquitin-selective segregase VCP/p97. Cell Cycle. 20:81–95. 2021.PubMed/NCBI View Article : Google Scholar

89 

He QL, Titov DV, Li J, Tan M, Ye Z, Zhao Y, Romo D and Liu JO: Covalent modification of a cysteine residue in the XPB subunit of the general transcription factor TFIIH through single epoxide cleavage of the transcription inhibitor triptolide. Angew Chem Int Ed Engl. 54:1859–1863. 2015.PubMed/NCBI View Article : Google Scholar

90 

Manzo SG, Zhou ZL, Wang YQ, Marinello J, He JX, Li YC, Ding J, Capranico G and Miao ZH: Natural product triptolide mediates cancer cell death by triggering CDK7-dependent degradation of RNA polymerase II. Cancer Res. 72:5363–5373. 2012.PubMed/NCBI View Article : Google Scholar

91 

Abascal-Palacios G, Ramsay EP, Beuron F, Morris E and Vannini A: Structural basis of RNA polymerase III transcription initiation. Nature. 553:301–306. 2018.PubMed/NCBI View Article : Google Scholar

92 

Liang X, Xie R, Su J, Ye B, Wei S, Liang Z, Bai R, Chen Z, Li Z and Gao X: Inhibition of RNA polymerase III transcription by Triptolide attenuates colorectal tumorigenesis. J Exp Clin Cancer Res. 38(217)2019.PubMed/NCBI View Article : Google Scholar

93 

Yamagishi M and Uchimaru K: Targeting EZH2 in cancer therapy. Curr Opin Oncol. 29:375–381. 2017.PubMed/NCBI View Article : Google Scholar

94 

Ihira K, Dong P, Xiong Y, Watari H, Konno Y, Hanley SJ, Noguchi M, Hirata N, Suizu F, Yamada T, et al: EZH2 inhibition suppresses endometrial cancer progression via miR-361/Twist axis. Oncotarget. 8:13509–13520. 2017.PubMed/NCBI View Article : Google Scholar

95 

Tamgue O, Chai CS, Hao L, Zambe JC, Huang WW, Zhang B, Lei M and Wei YM: Triptolide inhibits histone methyltransferase EZH2 and modulates the expression of its target genes in prostate cancer cells. Asian Pac J Cancer Prev. 14:5663–5669. 2013.PubMed/NCBI View Article : Google Scholar

96 

Akkoc Y and Gozuacik D: MicroRNAs as major regulators of the autophagy pathway. Biochim Biophys Acta Mol Cell Res 1867: Kappa B, 2020.

97 

Gibbings D, Mostowy S, Jay F, Schwab Y, Cossart P and Voinnet O: Selective autophagy degrades DICER and AGO2 and regulates miRNA activity. Nat Cell Biol. 14:1314–1321. 2012.PubMed/NCBI View Article : Google Scholar

98 

Peng K, Li X, Wu C, Wang Y, Yu J, Zhang J, Gao Q, Zhang W, Zhang Q, Fan Y, et al: Derivation of haploid trophoblast stem cells via conversion in vitro. iScience. 11:508–518. 2019.PubMed/NCBI View Article : Google Scholar

99 

Wang H, Zhang W, Yu J, Wu C, Gao Q, Li X, Li Y, Zhang J, Tian Y, Tan T, et al: Genetic screening and multipotency in rhesus monkey haploid neural progenitor cells. Development. 145(dev160531)2018.PubMed/NCBI View Article : Google Scholar

100 

Huang Y, Zhu N, Chen T, Chen W, Kong J, Zheng W and Ruan J: Triptolide suppressed the microglia activation to improve spinal cord injury through miR-96/IKKβ/NF-κB pathway. Spine (Phila Pa 1976). 44:E707–E714. 2019.PubMed/NCBI View Article : Google Scholar

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May-2021
Volume 21 Issue 5

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Spandidos Publications style
Zhou K, Chang Y, Han B, Li R and Wei Y: MicroRNAs as crucial mediators in the pharmacological activities of triptolide (Review). Exp Ther Med 21: 499, 2021
APA
Zhou, K., Chang, Y., Han, B., Li, R., & Wei, Y. (2021). MicroRNAs as crucial mediators in the pharmacological activities of triptolide (Review). Experimental and Therapeutic Medicine, 21, 499. https://doi.org/10.3892/etm.2021.9930
MLA
Zhou, K., Chang, Y., Han, B., Li, R., Wei, Y."MicroRNAs as crucial mediators in the pharmacological activities of triptolide (Review)". Experimental and Therapeutic Medicine 21.5 (2021): 499.
Chicago
Zhou, K., Chang, Y., Han, B., Li, R., Wei, Y."MicroRNAs as crucial mediators in the pharmacological activities of triptolide (Review)". Experimental and Therapeutic Medicine 21, no. 5 (2021): 499. https://doi.org/10.3892/etm.2021.9930