Bioactive chemical constitutes from the root of Salvia miltiorrhiza classified in two major groups, viz., liposoluble tanshinones and water-soluble phenolics. Tanshinone IIA is a major lipid-soluble compound having promising health benefits. The in vivo and in vitro studies showed that the tanshinone IIA and salvianolate have a wide range of cardiovascular and other pharmacological effects, including antioxidative, anti-inflammatory, endothelial protective, myocardial protective, anticoagulation, vasodilation, and anti-atherosclerosis, as well as significantly help to reduce proliferation and migration of vascular smooth muscle cells. In addition, some of the clinical studies reported that the S. miltiorrhiza preparations in combination with Western medicine were more effective for treatment of various cardiovascular diseases including angina pectoris, myocardial infarction, hypertension, hyperlipidemia, and pulmonary heart diseases. In this review, we demonstrated the potential applications of S. miltiorrhiza, including pharmacological effects of salvianolate, tanshinone IIA, and its water-soluble derivative, like sodium tanshinone IIA sulfonate. Moreover, we also provided details about the clinical applications of S. miltiorrhiza preparations in controlling the cardiovascular diseases.

/pdf/salvia-miltiorrhiza-in-treating-cardiovascular-diseases-a-3fotqdw0rb.pdf

Salvia miltiorrhiza in Treating Cardiovascular Diseases: A Review on Its Pharmacological and Clinical Applications.

B88 A class of synthetic triterpenoids have been developed which are potent inducers of cytoprotective enzymes and inhibitors of inflammation, greatly improving upon the weak activity of naturally occurring triterpenoids. An imidazolide triterpenoid derivative, 1-[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole (CDDO-Im or TP235), has been previously shown to potently protect against hepatic tumorigenesis, acting in part by inducing cytoprotective genes through Keap1-Nrf2-ARE signaling. In these studies, the pharmacodynamic activity of CDDO-Im is characterized in two distinct lines of ARE reporter mice and by measuring increases in Nqo1 transcript levels as a marker of cytoprotective gene induction. Oral administration of CDDO-Im induces ARE-regulated cytoprotective genes in many tissues in the mouse including liver, lung, kidney, intestines, brain, heart, thymus, and salivary gland. CDDO-Im induces Nqo1 RNA transcripts in some organs at doses as low as 0.3 µmol/kg body weight, p.o. A structure activity evaluation of 15 additional triterpenoids a) confirmed the importance of Michael acceptor groups on both the A and C rings, b) demonstrated the requirement for a nitrile group at C-2 of the A ring, and c) indicated that substituents at C-17 dramatically affected pharmacodynamic action in vivo. In addition to CDDO-Im, other triterpenoids, particularly the methyl ester, CDDO-Me (TP155) and the dinitrile (TP225), are extremely potent inducers of cytoprotective genes in mouse liver, lung, small intestine mucosa, and cerebral cortex. This pharmacodynamic characterization highlights the chemopreventive promise of several synthetic triterpenoids in multiple target organs. This work was supported by NIH grants CA94076 (T.W. Kensler), CA78814 (M.B. Sporn), the National Foundation for Cancer Research (M.B. Sporn), Reata Pharmaceuticals (M.B. Sporn) and ERATO-JST (M. Yamamoto). M.S. Yates was supported by T32 GM08763.

Pharmacodynamic characterization of chemopreventive triterpenoids as exceptionally potent inducers of Nrf2-regulated genes.

Natural products in licorice for the therapy of liver diseases: Progress and future opportunities.

Tripterygium wilfordii Hook F (TwHF)-based therapy is among the most efficient and crucial therapeutics for the treatment of rheumatoid arthritis (RA), which indicates that TwHF is a potential source of novel anti-RA drugs. However, accumulating studies have observed that TwHF-based therapy induces multi-organ toxicity, which prevents the wide use of this herb in clinical practice, although several recent studies have attempted to reduce the toxicity of TwHF. Notably, our research group developed a "Clinical Practice Guideline for Tripterygium Glycosides/Tripterygium wilfordii Tablets in the Treatment of Rheumatoid Arthritis" (No. T/CACM 1337-2020) approved by the China Association of Chinese Medicine to standardize the clinical application of TwHF-based therapy and thus avoid adverse effects. Although great strides have been made toward the characterization of TwHF-based therapy and revealing its underlying pharmacological and toxicological mechanisms, several crucial gaps in knowledge remain as potential barriers to enhance its therapeutic effects on the premise of safety assurance. This review offers a global view of TwHF, ranging from its chemical constituents, quality control, clinical observations, and underlying pharmacological mechanisms to toxic manifestations and mechanisms. We focus on the important and emerging aspects of this field and highlight the major challenges and strategies for using novel techniques and approaches to gain new insights into unresolved questions. We hope that this review will improve the understanding of TwHF application and draw increasing interdisciplinary attention from clinicians that practice both Chinese and Western medicine, basic researchers, and computer scientists.

Tripterygium wilfordii: An inspiring resource for rheumatoid arthritis treatment

Nrf2 and NF-κB are important regulators of the response to oxidative stress and inflammation in the body. Previous pharmacological and genetic studies have confirmed crosstalk between the two. The deficiency of Nrf2 elevates the expression of NF-κB, leading to increased production of inflammatory factors, while NF-κB can affect the expression of downstream target genes by regulating the transcription and activity of Nrf2. At the same time, many therapeutic drug-induced organ toxicities, including hepatotoxicity, nephrotoxicity, cardiotoxicity, pulmonary toxicity, dermal toxicity, and neurotoxicity, have received increasing attention from researchers in clinical practice. Drug-induced organ injury can destroy body function, reduce the patients’ quality of life, and even threaten the lives of patients. Therefore, it is urgent to find protective drugs to ameliorate drug-induced injury. There is substantial evidence that protective medications can alleviate drug-induced organ toxicity by modulating both Nrf2 and NF-κB signaling pathways. Thus, it has become increasingly important to explore the crosstalk mechanism between Nrf2 and NF-κB in drug-induced toxicity. In this review, we summarize the potential molecular mechanisms of Nrf2 and NF-κB pathways and the important effects on adverse effects including toxic reactions and look forward to finding protective drugs that can target the crosstalk between the two.

/pdf/dissecting-the-crosstalk-between-nrf2-and-nf-kb-response-1wtc8k16.pdf

Dissecting the Crosstalk Between Nrf2 and NF-κB Response Pathways in Drug-Induced Toxicity

Doxorubicin (DOX), a potent and widely used anticancer agent, can give rise to severe cardiotoxicity that limits its clinical use by inducing oxidative stress. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is the central regulator of cellular responses to electrophilic/oxidative stress, which serves a critical role in maintenance of normal cardiac function. Tanshinone IIA (Tan IIA) has previously been reported to protect against DOX-induced cardiotoxicity. The aim of the present study was to elucidate whether Nrf2 signaling serves a role in the underlying mechanism. In the animal model, DOX induced acute cardiotoxicity, whereas Tan IIA pretreatment reduced the activity of myocardial enzymes, and increased activity of the antioxidant enzymes superoxide dismutase, catalase and glutathione (GSH). Furthermore, Tan IIA pretreatment (3-10 µM) significantly increased the cell viability and markedly restored morphological changes in DOX-injured H9c2 cells, decreased the generation of reactive oxygen species, and increased the level of intracellular GSH. Additionally, Tan IIA pretreatment also induced the nuclear accumulation of Nrf2 and its downstream genes heme oxygenase-1, NAD(P)H dehydrogenase (quinone) 1, and glutamate-cysteine ligase catalytic subunit in both the mice cardiac tissues and H9c2 cells. Nrf2 knockdown by small interfering RNA downregulated Tan IIA-induced Nrf2 activation and reversed the effect of Tan IIA on the DOX-induced inhibition of cell viability. These results suggest that the Nrf2-dependent antioxidant response mediates the protective effect of Tan IIA on DOX-induced cardiotoxicity.

/pdf/nrf2-dependent-antioxidant-response-mediated-the-protective-4fbkmaev6t.pdf

Nrf2‑dependent antioxidant response mediated the protective effect of tanshinone IIA on doxorubicin‑induced cardiotoxicity

Triptolide (TP), the main bioactive component of Tripterygium wilfordii Hook F, can cause severe hepatotoxicity. Isoliquiritigenin (ISL) has been reported to be able to protect against TP-induced liver injury, but the mechanisms are not fully elucidated. This study aims to explore the role of nuclear transcription factor E2-related factor 2 (Nrf2) and hepatic transporters in TP-induced hepatotoxicity and the reversal protective effect of ISL. TP treatment caused both cytotoxicity in L02 hepatocytes and acute liver injury in mice. Particularly, TP led to the disorder of bile acid (BA) profiles in mice livers. Combined treatment of TP with ISL effectively alleviated TP-induced hepatotoxicity. Furthermore, ISL pretreatment enhanced Nrf2 expressions and nuclear accumulations and its downstream NAD(P)H: quinine oxidoreductase 1 (NQO1) expression. Expressions of hepatic P-gp, MRP2, MRP4, bile salt export pump, and OATP2 were also induced. In addition, in vitro transport assays identified that neither was TP exported by MRP2, OATP1B1, or OATP1B3, nor did TP influence the transport activities of P-gp or MRP2. All these results indicate that ISL may reduce the hepatic oxidative stress and hepatic accumulations of both endogenous BAs and exogenous TP as well as its metabolites by enhancing the expressions of Nrf2, NQO1, and hepatic influx and efflux transporters. Effects of TP on hepatic transporters are mainly at the transcriptional levels, and changes of hepatic BA profiles are very important in the mechanisms of TP-induced hepatotoxicity.

/pdf/mechanisms-of-triptolide-induced-hepatotoxicity-and-12ujt1h7nx.pdf

Mechanisms of Triptolide-Induced Hepatotoxicity and Protective Effect of Combined Use of Isoliquiritigenin: Possible Roles of Nrf2 and Hepatic Transporters.

Background: CircRNA has appeared as a critical molecular in the development of various cancers. However, the cellular function of circRNAs and exosomal circRNAs has not been well explored in Chronic myeloid leukemia (CML). Methods: Differentially expressed circRNAs were identified by a human circRNA microarray analysis. The expression of hsa_circ_0058493 in peripheral blood mononuclear cells (PBMCs) and exosomes was verified using quantitative real-time PCR. Short hairpin RNAs against hsa_circ_0058493 were constructed to silence the expression of circ_0058493. CCK8, flow cytometry and EdU assay were performed to investigate the biological functions of circ_0058493. Results: Hsa_circ_0058493 was significantly overexpressed in the PBMCs of CML patients and high level of circ_0058493 was associated with the poor clinical efficacy of imatinib. Silencing the expression of circ_0058493 significantly inhibited the development of imatinib-resistant CML cells. miR-548b-3p was overexpressed in circ_0058493-downregulated CML cells. Bioinformatic analysis revealed that circ_0058493 might exert its regulatory function acting as a "sponge" of miR-548b-3p. Moreover, hsa_circ_0058493 was significantly enriched in the exosomes derived from imatinib-resistant CML cells. Conclusion: Hsa_circ_0058493 in PBMCs could be a promising prognostic biomarker and might provide a therapeutic target for CML treatment.

/pdf/circrna-microarray-profiling-reveals-hsa-circ-0058493-as-a-20rrej6e28.pdf

CircRNA Microarray Profiling Reveals hsa_circ_0058493 as a Novel Biomarker for Imatinib-Resistant CML.

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Nrf2‑dependent antioxidant response mediated the protective effect of tanshinone IIA on doxorubicin‑induced cardiotoxicity

Mechanisms of Triptolide-Induced Hepatotoxicity and Protective Effect of Combined Use of Isoliquiritigenin: Possible Roles of Nrf2 and Hepatic Transporters.

CircRNA Microarray Profiling Reveals hsa_circ_0058493 as a Novel Biomarker for Imatinib-Resistant CML.