Dihydroartemisinin suppresses glioma growth by repressing ERRα-mediated mitochondrial biogenesis.

Malignant gliomas are an exceptionally lethal form of cancer with limited treatment options. Dihydroartemisinin (DHA), a sesquiterpene lactone antimalarial compound, has demonstrated therapeutic effects in various solid tumors. In our study, we aimed to investigate the mechanisms underlying the anticancer effects of DHA in gliomas. To explore the therapeutic and molecular mechanisms of DHA, we employed various assays, including cell viability, flow cytometry, mitochondrial membrane potential, glucose uptake and glioma xenograft models. Our data demonstrated that DHA significantly inhibited glioma cell proliferation in both temozolomide-resistant cells and glioma stem-like cells. We found that DHA-induced apoptosis occurred via the mitochondria-mediated pathway by initiating mitochondrial dysfunction before promoting apoptosis. Moreover, we discovered that DHA treatment substantially reduced the expression of the mitochondrial biogenesis-related gene, ERRα, in glioma cells. And the ERRα pathway is a critical target in treating glioma with DHA. Our results also demonstrated that the combination of DHA and temozolomide synergistically inhibited the proliferation of glioma cells. In vivo, DHA treatment remarkably extended survival time in mice bearing orthotopic glioblastoma xenografts. Thus, our findings suggest that DHA has a novel role in modulating cancer cell metabolism and suppressing glioma progression by activating the ERRα-regulated mitochondrial apoptosis pathway.

Research progress on tamoxifen and its analogs associated with nuclear receptors.

Tamoxifen, a triphenylethylene-based selective estrogen-receptor modulator, is a landmark drug for the treatment of breast cancer and is also used for treating liver cancer and osteoporosis. Structural studies of tamoxifen have led to the synthesis of more than 20 novel tamoxifen analogs as receptor modulators, including 16 ERα modulators 2-17, an ERRß inverse agonist 19 and six ERRγ inverse agonists 20-25. This paper summarizes the research progress and structure-activity relationships of tamoxifen analogs modulating these three nuclear receptors reported in the literature, and introduces the relationship between these three nuclear receptor-mediated diseases and tamoxifen analogs to guide the research of novel tamoxifen analogs.

Research progress of anticancer drugs targeting CDK12.

Cyclin-dependent kinase 12 (CDK12) is a transcription-associated CDK that plays key roles in transcription, translation, mRNA splicing, the cell cycle, and DNA damage repair. Research has identified that high expression of CDK12 in organs such as the breast, stomach, and uterus can lead to HER2-positive breast cancer, gastric cancer and cervical cancer. Inhibiting high expression of CDK12 suppresses tumor growth and proliferation, suggesting that it is both a biomarker for cancer and a potential target for cancer therapy. CDK12 inhibitors can competitively bind the CDK12 hydrophobic pocket with ATP to avoid CDK12 phosphorylation, blocking subsequent signaling pathways. The development of CDK12 inhibitors is challenging due to the high homology of CDK12 with other CDKs. This review summarizes the research progress of CDK12 inhibitors, their mechanism of action and the structure-activity relationship, providing new insights into the design of CDK12 selective inhibitors.

Advances in Medicinal Chemistry of Estrogen-related Receptor Alpha (ERRα) Inverse Agonists.

Estrogen-related receptor alpha (ERRα), a member of the nuclear receptor superfamily, is strongly expressed in breast cancer cells. Its overexpression is associated with poor prognosis in triple- negative Breast Cancer (TNBC). ERRα expression could be inhibited by the downregulation of upstream oncogenic growth factors mTOR, HER2, and PI3K. Low expression of ERRα could suppress the migration and angiogenesis of tumor cells by inhibiting the activity of its downstream signals VEGF and WNT11. Studies have confirmed that ERRα inverse agonists can inhibit ERRα expression to treat breast cancer. Inverse agonists of ERRα could disrupt the interactions of ERRα with its coactivators and inhibit tumor development. Existing ERRα inverse agonists have shown moderate efficacy in inhibiting the growth of breast cancer cells. Clinical inverse agonists of ERRα have not been found in the literature. This review focuses on the research progress and the structureactivity relationship of ERRα inverse agonists, providing guidance for the research and discovery of new anti-tumor compounds for TNBC.

Research progress in Estrogen-related receptor gamma (ERRγ) agonists and inverse agonists.

Estrogen-related receptor gamma (ERRγ), one of three members of the ERR family, is an inducible transcription factor. ERRγ has dual functions in different tissues. The decreased expression of ERRγ in the brain, stomach, prostate, and fat cells can cause neuropsychological dysfunction, gastric cancer, prostate cancer, and obesity. However, when ERRγ is present in the liver, pancreas, and thyroid follicular cells, ERRγ overexpression is related to liver cancer, type II diabetes, oxidative liver injury, and anaplastic thyroid carcinoma. Signaling pathway studies have confirmed that ERRγ agonists or inverse agonists can regulate ERRγ expression to treat related diseases. The collision between residue Phe435 and the modulator is a key factor determining the activation or inhibition of ERRγ. Although more than 20 agonists and inverse agonists of ERRγ have been reported, no clinical studies have been found in the literature. This review summarizes the important relationship between ERRγ-related signaling pathways and diseases, research progress, and the structure-activity relationship of modulators. These findings provide guidance for further study on new ERRγ modulators.

The discovery of a novel series of potential ERRα inverse agonists based on p-nitrobenzenesulfonamide template for triple-negative breast cancer in vivo.

Oestrogen related receptor α participated in the regulation of oxidative metabolism and mitochondrial biogenesis, and was overexpressed in many cancers including triple-negative breast cancer. A set of new ERRα inverse agonists based on p-nitrobenzenesulfonamide template were discovered and compound 11 with high potent activity (IC50 = 0.80 µM) could significantly inhibit the transcription of ERRα-regulated target genes. By regulating the downstream signalling pathway, compound 11 could suppress the migration and invasion of the ER-negative MDA-MB-231 cell line. Furthermore, compound 11 demonstrated a significant growth suppression of breast cancer xenograft tumours in vivo (inhibition rate 23.58%). The docking results showed that compound 11 could form hydrogen bonds with Glu331 and Arg372 in addition to its hydrophobic interaction with ligand-binding domain. Our data implied that compound 11 represented a novel and effective ERRα inverse agonist, which had broad application prospects in the treatment of triple-negative breast cancer.

Molecular modeling studies of [4-(3H-benzoimidazol-5-yl)-pyrimidin-2-yl]-amine-based CDK4 inhibitors.

Aim: CDK4 is a promising target for breast cancer therapy. This study aimed to explore the structure-activity relationship of CDK4 inhibitor abemaciclib analogs and design potent CDK4 inhibitors for breast cancer treatment. Methods & results: A faithful 3D quantitative structure-activity relationship model was established by molecular docking, comparative molecular field analysis and comparative molecular similarity index analysis based on 56 abemaciclib analogs. Molecular dynamics simulation studies revealed the key residues of the interaction between CDK4 and inhibitors. Four novel inhibitors with satisfactory predicted binding affinity to CDK4 were designed. Conclusion: The 3D quantitative structure-activity relationship and molecular dynamics simulation studies provide valuable insight into the development of novel CDK4 inhibitors.

Molecular Dynamics Simulations Based on 1-Phenyl-4-Benzoyl-1-Hydro-Triazole ERRα Inverse Agonists.

Estrogen-related receptor α (ERRα), which is overexpressed in a variety of cancers has been considered as an effective target for anticancer therapy. ERRα inverse agonists have been proven to effectively inhibit the migration and invasion of cancer cells. As few crystalline complexes have been reported, molecular dynamics (MD) simulations were carried out in this study to deepen the understanding of the interaction mechanism between inverse agonists and ERRα. The binding free energy was analyzed by the MM-GBSA method. The results show that the total binding free energy was positively correlated with the biological activity of an inverse agonist. The interaction of the inverse agonist with the hydrophobic interlayer composed of Phe328 and Phe495 had an important impact on the biological activity of inverse agonists, which was confirmed by the decomposition of energy on residues. As Glu331 flipped and formed a hydrogen bond with Arg372 in the MD simulation process, the formation of hydrogen bond interaction with Glu331 was not a necessary condition for the compound to act as an inverse agonist. These rules provide guidance for the design of new inverse agonists.

Biotransformation of alkylamides and alkaloids by lactic acid bacteria strains isolated from Zanthoxylum bungeanum meal.

Zanthoxylum bungeanum meal (ZBM) is the by-product of Z. bungeanum seeds after pressing. It is restricted as a feed additive because it contains stimulating and potentially harmful substances, which are alkylamides and alkaloids. This study described the use of Lactobacillus paracasei and L. acidipiscis isolated from ZBM in solid-state fermentation of ZBM to reduce the concentration of undesirable alkylamides and alkaloids. By optimizing the substrate and fermentation conditions, the minimum contents of alkylamide and alkaloid were 2.96 and 3.20 mg/g, and the degradation rates reached 51.86% and 39.59%, respectively. Moreover, the biotransformation pathways of hydroxyl-α-sanshool and chelerythrine were established by identifying the metabolites. Bacterial diversity was shift significantly, and the relative abundance of Lactobacillus increased from 0.10% to 99.0% after fermentation. In conclusion, this study introduced a reliable strategy for processing ZBM as a feed additive.

Variable Light Condition Improves Root Distribution Shallowness and P Uptake of Soybean in Maize/Soybean Relay Strip Intercropping System.

In this study, soybean root distribution in an inter-cropping system was influenced by various environmental and biotic cues. However, it is still unknown how root development and distribution in inter-cropping responds to aboveground light conditions. Herein, soybeans were inter- and monocropped with P (phosphorus) treatments of 0 and 20 kg P ha yr-1 (P0 and P20, respectively) in field experiment over 4 years. In 2019, a pot experiment was conducted as the supplement to the field experiment. Shade from sowing to V5 (Five trifoliolates unroll) and light (SL) was used to imitate the light condition of soybeans in a relay trip inter-cropping system, while light then shade from V5 to maturity (LS) was used to imitate the light condition of soybeans when monocropped. Compared to monocropping, P uptake and root distribution in the upper 0-15 cm soil layer increased when inter-cropped. Inter-cropped soybeans suffered serious shade by maize during a common-growth period, which resulted in the inhibition of primary root growth and a modified auxin synthesis center and response. During the solo-existing period, plant photosynthetic capacity and sucrose accumulation increased under ameliorated light in SL (shade-light). Increased light during the reproductive stage significantly decreased leaf P concentration in SL under both P-sufficient and P-deficient conditions. Transcripts of a P starvation response gene (GmPHR25) in leaves and genes (GmEXPB2) involved in root growth were upregulated by ameliorated light during the reproductive stage. Furthermore, during the reproductive stage, more light interception increased the auxin concentration and expression of GmYUCCA14 (encoding the auxin synthesis) and GmTIR1C (auxin receptor) in roots. Across the field and pot experiments, increased lateral root growth and shallower root distribution were associated with inhibited primary root growth during the seedling stage and ameliorated light conditions in the reproductive stage. Consequently, this improved topsoil foraging and P uptake of inter-cropped soybeans. It is suggested that the various light conditions (shade-light) mediating leaf P status and sucrose transport can regulate auxin synthesis and respond to root formation and distribution.

Ligliptin for treatment of type 2 diabetes mellitus with early renal injury: Efficacy and impact on endogenous hydrogen sulfide and endothelial function.

BACKGROUND: Diabetes is a clinically common chronic disease, and its incidence has been increasing in recent years. Diabetes is believed to accelerate the process of atherosclerosis in patients, and abnormal endothelial function is an important factor leading to diabetic kidney damage. AIM: To investigate the efficacy of ligliptin in the treatment of type 2 diabetes mellitus (T2DM) with early renal injury and its effect on serum endogenous hydrogen sulfide (H2S), endothelial cell particles, and endothelial function. METHODS: From January 2018 to April 2019, 110 patients with T2DM and early kidney injury treated at our hospital were divided into an observation group (receiving ligliptin treatment, n = 54) and a control group (receiving gliquidone therapy, n = 56). Blood glucose and renal function before and after treatment were compared between the two groups. RESULTS: The differences in fasting blood glucose, 2 h blood glucose, and glycated hemoglobin were not statistically significant between the two groups after treatment. The urinary albumin excretion rate after treatment in the ligliptin group was 70.32 ± 11.21 µg/min, which was significantly lower than that of the gliquidone group (P = 0.000). Serum endogenous H2S and endothelial cell microparticles of the ligliptin treatment group were 40.04 ± 8.82 mol/L and 133.40 ± 34.39, respectively, which were significantly lower than those of the gliquidone treatment group (P = 0.000 for both); endothelin-dependent diastolic function and nitric oxide after treatment in the ligliptin group were 7.98% ± 1.22% and 190.78 ± 30.32 mol/L, significantly higher than those of the gliquidone treatment group (P = 0.000 for both). CONCLUSION: Ligliptin treatment of T2DM with early renal injury has the same glucose-lowering effect as gliquidone treatment. Ligliptin treatment has a better effect and it can significantly improve the renal function and vascular endothelial function of patients, and reduce serum endogenous H2S and endothelial cell particle levels.

Exploring the binding mode and thermodynamics of inverse agonists against estrogen-related receptor alpha.

Since estrogen-related receptor alpha (ERRα), one of three estrogen-related receptors, displays constitutively active transcriptional activities and important implications in both physiological and pathological processes of breast cancers, ERRα was recently recognized as a new target to fight breast cancers, and regulating the activity of ERRα with inverse agonists has thus become a promising new therapeutic strategy. A few inverse agonists cyclohexylmethyl-(1-p-tolyl-1H-indol-3-ylmethyl)-amine (compound 1), thiadiazoacrylamide (XCT790), and 1-(2,5-diethoxy-benzyl)-3-phenyl-area analogues (compounds 2 and 3) were reported to be capable of targeting ERRα. However, the detailed mechanism by which the inverse agonists deactivate ERRα remains unclear, especially in the aspects of quantitative binding and hot spot residues. Therefore, to gain insights into the interaction modes between inverse agonists and ERRα ligand binding domain, all-atom molecular dynamics (MD) simulations were firstly carried out for the complexes of inverse agonists and ERRα. The binding free energies were then calculated with MM-PBSA method to quantitatively discuss the binding of the inverse agonists with ERRα. The binding affinities were finally decomposed to per-residue contributions to identify the hot spot residues as well as assess their role in the binding mechanism. MD simulations show that the inverse agonists stretch downwards into the ERRα ligand binding pocket (LBP) formed by H3 and H11 helices, and upon the binding H12 adopts a well-defined position in the coactivator groove, where PGC-1α binds to ERRα. Binding energy analysis indicates that compound 3 and XCT790 bind more tightly to ERRα than compounds 1 and 2, and the energy difference mainly results from the contribution of van der Waals interaction. Both binding mode analysis and affinity decomposition per-residue indicate that compound 1, XCT790, and compound 3 have similar binding spectra to ERRα, primarily interacting with the residues of H3, H5, H6/H7 loop, and H11 helix, while compound 2 lacks a significant interaction with the H5 region. The hot spot residues significantly binding to the three inverse agonists in common include Leu324, Phe328, Phe382, Leu398, Phe495, and Leu500. It is essential for an effective inverse agonist to strongly bind with the aromatic ring cluster consisting of Phe328(H3), Phe495(H11), and Phe382(H5/H6 loop) as well as Leu500.

Pre-treatment of salicylic acid enhances resistance of soybean seedlings to Fusarium solani.

KEY MESSAGE: Pre-treatment of soybean seedlings with 200 µM salicylic acid before fungal inoculation significantly alleviated disease resistance in soybean seedlings against Fusarium solani infection. Sudden death syndrome of soybean is largely caused by Fusarium solani (F. solani). Salicylic acid (SA) has been reported to induce resistance in plants against many pathogens. However, the effect of exogenous SA application on F. solani infection of soybean is less reported. This study investigated the effect of foliar application of SA on soybean seedlings before F. solani infection. Seedlings were sprayed with 200 µM SA and inoculated with F. solani after 24 h of last SA application. After 3 days post-inoculation, seedlings treated with 200 µM SA showed significantly fewer disease symptoms with increased endogenous SA level, SA marker genes expression and antioxidant activities in the SA-treated seedlings more than the untreated control seedlings. Furthermore, the decrease in hydrogen peroxide (H2O2) and malondialdehyde (MDA) levels was observed in the SA-treated plants as compared to the untreated plants. Analysis of the effect of SA application on F. solani showed that the mycelia growth of F. solani was not affected by SA treatment. Further investigation in this study revealed a decreased in F. solani biomass content in the SA treated seedlings. Results from the present study show that pre-treatment of 200 µM SA can induce resistance of soybean seedlings against F. solani infection.

Interactions Between Light Intensity and Phosphorus Nutrition Affect the P Uptake Capacity of Maize and Soybean Seedling in a Low Light Intensity Area.

To capture more nutrients, root systems of maize (Zea mays L.) and soybean (Glycine max L.) exhibit morphological and physiological plasticity to a localized supply of phosphorus (P). However, the mechanisms of the interaction between light intensity and P affecting root morphological and physiological alterations remain unclear. In the present study, the regulation of P uptake capacity of maize and soybean by light intensity and localized P supply was investigated in a low solar radiation area. The plants were grown under continual and disrupted light conditions with homogeneous and heterogeneous P supply. Light capture of maize and soybean increased under the disrupted light condition. Plant dry weight and P uptake were increased by more light capture, particularly when plants were grown in soil with heterogeneous P supply. Similarly, both localized P supply and disrupted light treatment increased the production of fine roots and specific root length in maize. Both homogeneous P supply and disrupted light treatment increased the malate and citrate exudation in the root of soybean. Across all of the experimental treatments, high root morphological plasticity of maize and root physiological plasticity of soybean were associated with lower P concentrations in leaves and greater sucrose concentrations in roots. It is suggested that the carbon (C), exceeded shoot growth capabilities and was transferred to roots as sucrose, which may serve as both a nutritional signal and a C-substrate for root morphological and physiological changes.

The development of protein tyrosine phosphatase1B inhibitors defined by binding sites in crystalline complexes.

Protein tyrosine phosphatase1B (PTP1B), a significant negative regulator in insulin and leptin signaling pathways, has emerged as a promising drug target for Type II diabetes mellitus and obesity. Numerous potent PTP1B inhibitors have been discovered within both academia and pharmaceutical industry. However, nearly all medicinal chemistry efforts have been severely hindered because a vast majority of them demonstrate poor membrane permeability and low-selectivity, especially over T-cell protein tyrosine phosphatase (TCPTP). To search the rules about the selectivity over TCPTP and membrane permeability of PTP1B inhibitors, based on the PTP1B/inhibitor crystal complexes, the development PTP1B inhibitors defined as AB, AC, ABC and ADC types have been concluded in the review.

Molecular Modeling Studies on Carbazole Carboxamide Based BTK Inhibitors Using Docking and Structure-Based 3D-QSAR.

Rheumatoid arthritis (RA) is the second common rheumatic immune disease with chronic, invasive inflammatory characteristics. Non-steroidal anti-inflammatory drugs (NSAIDs), slow-acting anti-rheumatic drugs (SAARDs), or glucocorticoid drugs can improve RA patients’ symptoms, but fail to cure. Broton’s tyrosine kinase (BTK) inhibitors have been proven to be an efficacious target against autoimmune indications and B-cell malignancies. Among the current 11 clinical drugs, only BMS-986142, classified as a carbazole derivative, is used for treating RA. To design novel and highly potent carbazole inhibitors, molecular docking and three dimensional quantitative structure⁻activity relationship (3D-QSAR) were applied to explore a dataset of 132 new carbazole carboxamide derivatives. The established comparative molecular field analysis (CoMFA) (q² = 0.761, r² = 0.933) and comparative molecular similarity indices analysis (CoMSIA) (q² = 0.891, r² = 0.988) models obtained high predictive and satisfactory values. CoMFA/CoMSIA contour maps demonstrated that bulky substitutions and hydrogen-bond donors were preferred at R1 and 1-position, respectively, and introducing hydrophilic substitutions at R1 and R4 was important for improving BTK inhibitory activities. These results will contribute to the design of novel and highly potent BTK inhibitors.

Inhibition of PDGF-BB-induced proliferation and migration in VSMCs by proanthocyanidin A2: Involvement of KDR and Jak-2/STAT-3/cPLA2 signaling pathways.

Proanthocyanidin A2 (PA2), one of A-type proanthocyanidins, has been shown to harbor a broad spectrum of pharmacological activities, including anti-inflammatory, antioxidant, anti-HIV, anti-CDV and anti-?-glucosidase activities. However, little is known about the role for PA2 in regulating PDGF-induced VSMC proliferation and migration. In the present study, we investigated the possible effects of PA2 on PDGF-BB-induced proliferation, migration and inflammation in VSMCs in vitro to mimic a postangioplasty PDGF shedding condition. Herein, the data clearly show that PA2 markedly inhibited proliferation, migration and inflammatory responses at 0-30??g/ml concentration in VSMCs in vitro. 10-30??g/ml PA2 inhibited PDGF-mediated NAD(P)H oxidase activation and intracellular ROS formation in VSMCs. Furthermore, the effects exerted by PA2 involve the participation of KDR and Jak-2/STAT-3/cPLA2 signaling pathways. These data also highlight the possible therapeutic use of PA2 in vascular proliferative diseases, where abnormal proliferation and migration play important pathological roles.

Discovery of novel high potent and cellular active ADC type PTP1B inhibitors with selectivity over TC-PTP via modification interacting with C site.

PTP1B serving as a key negative regulator of insulin signaling is a novel target for type 2 diabetes and obesity. Modification at ring B of N-{4-[(3-Phenyl-ureido)-methyl]-phenyl}-methane-sulfonamide template to interact with residues Arg47 and Lys41 in the C site of PTP1B by molecular docking aided design resulted in the discovery of a series of novel high potent and selective inhibitors of PTP1B. The structure activity relationship interacting with the C site of PTP1B was well illustrated. Compounds 8 and 18 were shown to be the high potent and most promising PTP1B inhibitors with cellular activity and great selectivity over the highly homologous TCPTP and other PTPs.

A novel compound LingH2-10 inhibits the growth of triple negative breast cancer cells in vitro and in vivo as a selective inverse agonist of estrogen-related receptor α.

Unlike other breast cancer subtypes, targeted therapies for triple negative breast cancer (TNBC) have yet to progress past clinical trial stage to approval. Accumulating evidences demonstrated that expression of estrogen-related receptor alpha (ERRα) indicated worse prognosis and correlated with poor outcome in breast cancers including TNBC. Therefore, ERRα modulators/regulators may be potential in the therapeutic treatment of breast cancers. In the current study, we presented a novel compound LingH2-10 that bound to ERRα, as identified using a time-resolved fluorescence resonance energy transfer assay (TR-FRET) with the IC50 value of 0.64±0.12µM. Further, functional activity was determined by transient transfection luciferase reporter assay in order to validate the utility of the binding affinity in a cellular context. LingH2-10 showed selective inhibition on ERRα transcriptional activity with the IC50 value of 0.58±0.09µM in cell-based luciferase reporter assay. Moreover, representative in vitro results showed that LingH2-10 suppressed the proliferation of various human cancer cells, and inhibited the migration of triple negative breast cancer cell MDA-MB-231. In addition, our results demonstrated that well known ERRα target genes such as PDK4, Osteopontin and pS2, were all significantly down modulated by LingH2-10. In vivo experiments showed that LingH2-10 (30mg/kg, every other day) observably suppressed the growth of MDA-MB-231 xenograft tumors by 42.02% compared to untreated xenograft tumors. Taken together, all these data suggested that LingH2-10, as a selective inverse agonist of ERRα, was a lead compound of anti-cancer agents for treating TNBC patients.

A brief perspective of drug resistance toward EGFR inhibitors: the crystal structures of EGFRs and their variants.

The EGFR is one of the most popular targets for anticancer therapies and many drugs, such as erlotinib and gefitinib, have got enormous success in clinical treatments of cancer in past decade. However, the efficacy of these agents is often limited because of the quick emergence of drug resistance. Fundamental structure researches of EGFR in recent years have generally elucidated the mechanism of drug resistance. In this review, based on systematic resolution of full structures of EGFR and their variants via single crystal x-ray crystallography, the working and drug resistance mechanism of EGFR-targeted drugs are fully illustrated. Moreover, new strategies for avoiding EGFR drug resistance in cancer treatments are also discussed.