Polyphyllin I induces rapid ferroptosis in acute myeloid leukemia through simultaneous targeting PI3K/SREBP-1/SCD1 axis and triggering of lipid peroxidation.

Acute myeloid leukemia (AML) is a malignant disease that is difficult to completely cure. Polyphyllin I (PPI), a steroidal saponin isolated from Paris polyphylla, has exhibited multiple biological activities. Here, we discovered the superior cytotoxicity of PPI on AML cells MOLM-13 with an IC50 values of 0.44 ± 0.09 µM. Mechanically, PPI could cause ferroptosis via the accumulation of intracellular iron concentration and triggering lipid peroxidation. Interestingly, PPI could induced stronger ferroptosis in a short time of about 6 h compared to erastin. Furthermore, we demonstrate that PPI-induced rapid ferroptosis is due to the simultaneous targeting PI3K/SREBP-1/SCD1 axis and triggering lipid peroxidation, and PI3K inhibitor Alpelisib can enhance the activity of erastin-induced ferroptosis. Molecular docking simulations and kinase inhibition assays demonstrated that PPI is a PI3K inhibitor. In addition, PPI significantly inhibited tumor progression and prolonged mouse survival at 4 mg/kg with well tolerance. In summary, our study highlights the therapeutic potential of PPI for AML and shows its unique dual mechanism.

Myricetin exhibit selective anti-lymphoma activity by targeting BTK and is effective via oral administration in vivo.

BACKGROUND: Myricetin (MYR) is a polyhydroxy flavone originally isolated from Myrica rubra, and is widely distributed in a variety of medicinal plants and delicious food. MYR has been proven to have inhibitory effects against various types of cancer. However, the exact role of MYR in lymphoma development is still unclear. METHODS: In vitro, the MTT assay was performed to evaluate the activity of human diffuse large B lymphoma cell TMD-8 and other tumor cells. Homogeneous time-resolved fluorescence (HTRF) and molecular docking were used to detect the target of MYR inhibiting TMD-8 cells. In addition, flow cytometry, Annexin V-FITC/PI assays, Hoechst 33258, and mondansylcadaverine (MDC) fluorescent standing were used to detect the cell cycle, apoptosis, and autophagy, respectively. Moreover, Western blot analysis was conducted to analyze related signaling pathways. In TMD-8 cell xenotransplanted mice, immunohistochemistry, histopathology, and blood biochemical tests were used to evaluate the effectiveness and safety of oral administration of MYR. RESULTS: Here, we found that MYR is more sensitive to TMD-8 cells than other tumor cells by targeting bruton tyrosine kinase (BTK). BTK is an attractive target for the treatment of B-cell malignancies. The HTRF assay showed that MYR inhibited BTK kinase with an IC50 of 1.82 µM. Furthermore, the HTRF assay and Western blot analysis demonstrated that MYR could bind to key residues (Ala478, Leu408, Thr474) in the BTK active pocket, inhibit the autophosphorylation on tyrosine 223, and block BTK/ERK and BTK/AKT signal transduction cascades (including downstream substrates GSK-3ß, IKK, STAT3, and NF-κb). The results of cell cycle, apoptosis, and autophagy showed that MYR could induce G1/G0 cycle arrest by regulating cyclinB1/D1 expression, induce apoptosis by increasing the Bax/Bcl-2 ratio, and trigger autophagy by inhibiting mTOR activation. In vivo, oral administration of MYR significantly inhibited the growth of TMD-8 xenograft tumora without toxic side effects. Furthermore, Ki67 and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) analysis showed that MYR could inhibit proliferation and induce apoptosis of tissue lymphoma cells. CONCLUSION: Taken together, MYR is an oral available natural BTK inhibitor that effectively inhibits the growth of lymphoma TMD-8 cells both in vitro and in vivo. In addition, our findings support that the use of MYR is a novel and promising therapeutic strategy for the treatment of lymphoma.

Specific recognition, intracellular assay and detoxification of fluorescent curcumin derivative for copper ions.

Recognition and excretion of metal ions play an important role in the diagnosis and treatment of various diseases and poisoning. Although copper (Cu) is a cofactor of many key enzymes in the human body, its accumulation caused by genetic ATP7B mutation or environmental pollution can lead to hepatotoxicity, renal failure, Wilson's disease, inflammation, and even Parkinson's disease (PD) and Alzheimer's disease (AD). Therefore, in this work, a difluoroboron curcumin derivative (DF-Cur) was used for the specific recognition of copper ions (Cu2+). DF-Cur could be further used to as a rapid diagnostic agent for the copper detection in cells and zebrafish at the nanomolar level. DF-Cur could significantly reduce the toxic damage caused by high Cu2+ dose. Inductively coupled plasma-mass spectrometry (ICP-MS) analysis indicated that DF-Cur could promote the excretion of copper ions in the urine and bile and reduce the accumulation of copper ions in vivo. In addition, DF-Cur could selectively detect cholesterol in the blood and adipose tissue in vivo by fluorescent staining. These results demonstrated that this molecule might represent a new and promising diagnostic and therapeutic agent to combat diseases related to copper ions accumulation.

Myricetin: A review of the most recent research.

Myricetin(MYR) is a flavonoid compound widely found in many natural plants including bayberry. So far, MYR has been proven to have multiple biological functions and it is a natural compound with promising research and development prospects. This review comprehensively retrieved and collected the latest pharmacological abstracts on MYR, and discussed the potential molecular mechanisms of its effects. The results of our review indicated that MYR has a therapeutic effect on many diseases, including tumors of different types, inflammatory diseases, atherosclerosis, thrombosis, cerebral ischemia, diabetes, Alzheimer's disease and pathogenic microbial infections. Furthermore, it regulates the expression of Hippo, MAPK, GSK-3ß, PI3K/AKT/mTOR, STAT3, TLR, IκB/NF-κB, Nrf2/HO-1, ACE, eNOS / NO, AChE and BrdU/NeuN. MYR also enhances the immunomodulatory functions, suppresses cytokine storms, improves cardiac dysfunction, possesses an antiviral potential, can be used as an adjuvant treatment against cancer, cardiovascular injury and nervous system diseases, and it may be a potential drug against COVID-19 and other viral infections. Generally, this article provides a theoretical basis for the clinical application of MYR and a reference for its further use.

Norcantharidin: research advances in pharmaceutical activities and derivatives in recent years.

Cantharidin (CTD) is the main bioactive component of Cantharides, which is called Banmao in Traditional Chinese Medicine (TCM). Norcantharidin (NCTD) is a structural modifier of CTD. To compare with CTD, NCTD has lighter side effects and stronger bioactivity in anti-cancer through inhibiting cell proliferation, causing apoptosis and autophagy, overwhelming migration and metastasis, affecting immunity as well as lymphangiogenesis. Examples of these effects include suppressing Protein Phosphatase 2A and modulating Wnt/beta catenin signal, with Caspase family proteins, AMPK pathway and c-Met/EGFR pathway involving respectively. Moreover, NCTD has the effects of immune enhancement, anti-platelet aggregation and inhibition of renal interstitial fibrosis with distinct signaling pathways. The immunological effects induced by NCTD are related to the regulation of macrophage polarization and LPS-mediated immune response. The antiplatelet activity that NCTD induced is relevant to the inhibition of platelet signaling and the downregulation of α2 integrin. Furthermore, some of novel derivatives designed and synthesized artificially show stronger biological activities (e.g., anticancer effect, enzyme inhibition effect, antioxidant effect) and lower toxicity than NCTD itself. Plenty of literatures have reported various pharmacological effects of NCTD, particularly the anticancer effect, which has been widely concerned in clinical application and laboratory research. In this review, the pharmaceutical activities and derivatives of NCTD are discussed, which can be reference for further study.

A Review of the Pharmacological Properties of Psoralen.

Psoralen is the principal bioactive component in the dried fruits of Cullen corylifolium (L.) Medik (syn. Psoralea corylifolia L), termed "Buguzhi" in traditional Chinese medicine (TCM). Recent studies have demonstrated that psoralen displays multiple bioactive properties, beneficial for the treatment of osteoporosis, tumors, viruses, bacteria, and inflammation. The present review focuses on the research evidence relating to the properties of psoralen gathered over recent years. Firstly, multiple studies have demonstrated that psoralen exerts strong anti-osteoporotic effects via regulation of osteoblast/osteoclast/chondrocyte differentiation or activation due to the participation in multiple molecular mechanisms of the wnt/ß-catenin, bone morphogenetic protein (BMP), inositol-requiring enzyme 1 (IRE1)/apoptosis signaling kinase 1 (ASK1)/c-jun N-terminal kinase (JNK) and the Protein Kinase B(AKT)/activator protein-1 (AP-1) axis, and the expression of miR-488, peroxisome proliferators-activated receptor-gamma (PPARγ), and matrix metalloproteinases (MMPs). In addition, the antitumor properties of psoralen are associated with the induction of ER stress-related cell death via enhancement of PERK: Pancreatic Endoplasmic Reticulum Kinase (PERK)/activating transcription factor (ATF), 78kD glucose-regulated protein (GRP78)/C/EBP homologous protein (CHOP), and 94kD glucose-regulated protein (GRP94)/CHOP signaling, and inhibition of P-glycoprotein (P-gp) or ATPase that overcomes multidrug resistance. Furthermore, multiple articles have shown that the antibacterial, anti-inflammatory and neuroprotective effects of psoralen are a result of its interaction with viral polymerase (Pol), destroying the formation of biofilm, and regulating the activation of tumor necrosis factor alpha (TNF-α), transforming growth factor beta (TGF-ß), interleukin 4/5/6/8/12/13 (IL-4/5/6/8/12/13), GATA-3, acetylcholinesterase (AChE), and the hypothalamic-pituitary-adrenal (HPA) axis. Finally, the toxic effects and mechanisms of action of psoralen have also been reviewed.

Anti-inflammatory effects of cordycepin: A review.

Cordycepin is the major bioactive component extracted from Cordyceps militaris. In recent years, cordycepin has received increasing attention owing to its multiple pharmacological activities. This study reviews recent researches on the anti-inflammatory effects and the related activities of cordycepin. The results from our review indicate that cordycepin exerts protective effects against inflammatory injury for many diseases including acute lung injury (ALI), asthma, rheumatoid arthritis, Parkinson's disease (PD), hepatitis, atherosclerosis, and atopic dermatitis. Cordycepin regulates the NF-κB, RIP2/Caspase-1, Akt/GSK-3ß/p70S6K, TGF-ß/Smads, and Nrf2/HO-1 signaling pathways among others. Several studies focusing on cordycepin derivatives were reviewed and found to down metabolic velocity of cordycepin and increase its bioavailability. Moreover, cordycepin enhanced immunity, inhibited the proliferation of viral RNA, and suppressed cytokine storms, thereby suggesting its potential to treat COVID-19 and other viral infections. From the collected and reviewed information, this article provides the theoretical basis for the clinical applications of cordycepin and discusses the path for future studies focusing on expanding the medicinal use of cordycepin. Taken together, cordycepin and its analogs show great potential as the next new class of anti-inflammatory agents.

Erlotinib is effective against FLT3-ITD mutant AML and helps to overcome intratumoral heterogeneity via targeting FLT3 and Lyn.

Erlotinib has potential therapeutic effect on acute myeloid leukemia (AML) in patients, but the mechanism is not clear. Effective tumor biomarkers for erlotinib in the treatment of AML remain poorly defined. Here, we demonstrate that erlotinib in vitro significantly inhibits the growth of the FLT3-ITD mutant AML cell MV4-11 and Ba/F3-FLT3-ITD cell via targeting FLT3, a certified valid target for the effective treatment of AML. In vivo, oral administration of erlotinib at 100 mg/kg/day induced rapid MV4-11 tumor regression and significantly prolonged the survival time of bone marrow engraftment AML mice via inhibiting the FLT3 signal. Thus, the therapeutic benefits of erlotinib on AML are due to its ability to target FLT3. FLT3-ITD mutation is an effective biomarker for erlotinib during AML treatment. In addition, we also demonstrate that erlotinib inhibits the activity of AML cell KG-1 (no FLT3 expression) by targeting Lyn. Recently, single cell analysis demonstrated that intratumoral heterogeneity are one of the contributors in the relapse and FLT3 inhibitor resistance. Erlotinib could effectively inhibit the MV4-11 cells via targeting FLT3, and inhibit KG-1 cells via targeting Lyn. Therefore, Erlotinib also has the potential to overcome intratumoral heterogeneity via targeting FLT3 and Lyn.

A review of pharmacological and pharmacokinetic properties of stachydrine.

Stachydrine is extracted from the leaves of Leonurus japonicus Houtt (or Motherwort, "Yi Mu Cao" in Traditional Chinese Medicine) and is the major bioactive ingredient. So far, stachydrine has demonstrated various bioactivities for the treatment of fibrosis, cardiovascular diseases, cancers, uterine diseases, brain injuries, and inflammation. The pharmacological and pharmacokinetic properties of stachydrine up to 2019 have been comprehensively searched and summarized. This review provides an updated summary of recent studies on the pharmacological activities of stachydrine. Many studies have demonstrated that stachydrine has strong anti-fibrotic properties (on various types of fibrosis) by inhibiting ECM deposition and decreasing inflammatory and oxidative stress through multiple molecular mechanisms (including TGF-ß, ERS-mediated apoptosis, MMPs/TIMPs, NF-κB, and JAK/STAT). The cardioprotective and vasoprotective activities of stachydrine are related to its inhibition of ß-MHC, excessive autophagy, SIRT1, eNOS uncoupling and TF, promotion of SERCA, and angiogenesis. In addition to its anticancer action, regulation of the uterus, neuroprotective effects, etc. the pharmacokinetic properties of stachydrine are also discussed.

Pharmacological properties and derivatives of shikonin-A review in recent years.

Shikonin is the major bioactive component extracted from the roots of Lithospermum erythrorhizon which is also known as "Zicao" in Traditional Chinese Medicine (TCM). Recent studies have shown that shikonin demonstrates various bioactivities related to the treatment of cancer, inflammation, and wound healing. This review aimed to provide an updated summary of recent studies on shikonin. Firstly, many studies have demonstrated that shikonin exerts strong anticancer effects on various types of cancer by inhibiting cell proliferation and migration, inducing apoptosis, autophagy, and necroptosis. Shikonin also triggers Reactive Oxygen Species (ROS) generation, suppressing exosome release, and activate anti-tumor immunity in multiple molecular mechanisms. Examples of these effects include modulating the PI3K/AKT/mTOR and MAPKs signaling; inhibiting the activation of TrxR1, PKM2, RIP1/3, Src, and FAK; and regulating the expression of ERP57, MMPs, ATF2, C-MYC, miR-128, and GRP78 (Bip). Next, the anti-inflammatory and wound-healing properties of shikonin were also reviewed. Furthermore, several studies focusing on shikonin derivatives were reviewed, and these showed that, with modification to the naphthazarin ring or side chain, some shikonin derivatives display stronger anticancer activity and lower toxicity than shikonin itself. Our findings suggest that shikonin and its derivatives could serve as potential novel drug for the treatment of cancer and inflammation.

Isoliquiritigenin, an Orally Available Natural FLT3 Inhibitor from Licorice, Exhibits Selective Anti-Acute Myeloid Leukemia Efficacy In Vitro and In Vivo.

Licorice is a medicinal herb widely used to treat inflammation-related diseases in China. Isoliquiritigenin (ISL) is an important constituent of licorice and possesses multiple bioactivities. In this study, we examined the selective anti-AML (acute myeloid leukemia) property of ISL via targeting FMS-like tyrosine kinase-3 (FLT3), a certified valid target for treating AML. In vitro, ISL potently inhibited FLT3 kinase, with an IC50 value of 115.1 ± 4.2 nM, and selectively inhibited the proliferation of FLT3-internal tandem duplication (FLT3-ITD) or FLT3-ITD/F691L mutant AML cells. Moreover, it showed very weak activity toward other tested cell lines or kinases. Western blot immunoassay revealed that ISL significantly inhibited the activation of FLT3/Erk1/2/signal transducer and activator of transcription 5 (STAT5) signal in AML cells. Meanwhile, a molecular docking study indicated that ISL could stably form aromatic interactions and hydrogen bonds within the kinase domain of FLT3. In vivo, oral administration of ISL significantly inhibited the MV4-11 flank tumor growth and prolonged survival in the bone marrow transplant model via decreasing the expression of Ki67 and inducing apoptosis. Taken together, the present study identified a novel function of ISL as a selective FLT3 inhibitor. ISL could also be a potential natural bioactive compound for treating AML with FLT3-ITD or FLT3-ITD/F691L mutations. Thus, ISL and licorice might possess potential therapeutic effects for treating AML, providing a new strategy for anti-AML.

Polyphyllin I induces autophagy and cell cycle arrest via inhibiting PDK1/Akt/mTOR signal and downregulating cyclin B1 in human gastric carcinoma HGC-27 cells.

Paris polyphylla. is a traditional medicinal herb that has long been used to prevent cancer in many Asian countries. Polyphyllin I (PPI), an important bioactive constituent of Paris polyphylla, has been found to exhibit a wide variety of anticancer activities in many types of cancer cells. However, the effects of PPI on human gastric carcinoma cells and its mechanism of action remain unclear. In this study, we examined the effective anti-gastric carcinoma activity of PPI and its underlying mechanism of action in HGC-27 cells. In vitro, sub-micromolar concentrations of PPI inhibited HGC-27 cell proliferation with an IC50 of 0.34 ± 0.06 µM after a 72-h treatment. In vivo, 3 mg/kg PPI significantly inhibited proliferation of HGC-27 tumor cells, with a 78.8% inhibition rate compared to paclitaxel, and demonstrated higher safety. Analysis of MDC and mGFP-LC3 fluorescence, Western blotting and flow cytometry indicated that PPI induced cell cycle arrest in HGC-27 cells by promoting the conversion of LC3-I to LC3-II and by downregulating cyclin B1. Furthermore, Western blotting showed that PPI inhibited the autophagy-regulating PDK1/Akt/mTOR signaling pathway in vitro and in vivo. In addition, immunohistochemistry and TUNEL staining revealed that PPI decreased Ki67 expression and increased the percentage of apoptotic cells in HGC-27 xenograft tumors. These data indicate that PPI is an PDK1/Akt/mTOR signaling inhibitor and of therapeutic relevance for gastric cancer treatment and that the rhizome of Paris polyphylla deserves further clinical investigation as an alternative therapy for gastric cancer.