Exploring chromone-2-carboxamide derivatives for triple-negative breast cancer targeting EGFR, FGFR3, and VEGF pathways: Design, synthesis, and preclinical insights.

Chromone-based compounds have established cytotoxic, antiproliferative, antimetastatic, and antiangiogenic effects on various cancer cell types via modulating different molecular targets. Herein, 17 novel chromone-2-carboxamide derivatives were synthesized and evaluated for their in vitro anticancer activity against 15 human cancer cell lines. Among the tested cell lines, MDA-MB-231, the triple-negative breast cancer cell line, was found to be the most sensitive, where the N-(2-furylmethylene) (15) and the α-methylated N-benzyl (17) derivatives demonstrated the highest growth inhibition with GI50 values of 14.8 and 17.1 µM, respectively. In vitro mechanistic studies confirmed the significant roles of compounds 15 and 17 in the induction of apoptosis and suppression of EGFR, FGFR3, and VEGF protein levels in MDA-MB-231 cancer cells. Moreover, compound 15 exerted cell cycle arrest at both the G0-G1 and G2-M phases. The in vivo efficacy of compound 15 as an antitumor agent was further investigated in female mice bearing Solid Ehrlich Carcinoma. Notably, administration of compound 15 resulted in a marked decrease in both tumor weight and volume, accompanied by improvements in biochemical, hematological, histological, and immunohistochemical parameters that verified the repression of both angiogenesis and inflammation as additional Anticancer mechanisms. Moreover, the binding interactions of compounds 15 and 17 within the binding sites of all three target receptors (EGFR, FGFR3, and VEGF) were clearly illustrated using molecular docking.

Antimycobacterial and healing effects of Pranlukast against MTB infection and pathogenesis in a preclinical mouse model of tuberculosis.

It is essential to understand the interactions and relationships between Mycobacterium tuberculosis (Mtb) and macrophages during the infection in order to design host-directed, immunomodulation-dependent therapeutics to control Mtb. We had reported previously that ornithine acetyltransferase (MtArgJ), a crucial enzyme of the arginine biosynthesis pathway of Mtb, is allosterically inhibited by pranlukast (PRK), which significantly reduces bacterial growth. The present investigation is centered on the immunomodulation in the host by PRK particularly the activation of the host's immune response to counteract bacterial survival and pathogenicity. Here, we show that PRK decreased the bacterial burden in the lungs by upregulating the population of pro-inflammatory interstitial macrophages (IMs) and reducing the population of Mtb susceptible alveolar macrophages (AMs), dendritic cells (DCs), and monocytes (MO). Additionally, we deduce that PRK causes the host macrophages to change their metabolic pathway from fatty acid metabolism to glycolytic metabolism around the log phage of bacterial multiplication. Further, we report that PRK reduced tissue injury by downregulating the Ly6C-positive population of monocytes. Interestingly, PRK treatment improved tissue repair and inflammation resolution by increasing the populations of arginase 1 (Arg-1) and Ym1+Ym2 (chitinase 3-like 3) positive macrophages. In summary, our study found that PRK is useful not only for reducing the tubercular burden but also for promoting the healing of the diseased tissue.

Iguratimod prevents renal fibrosis in unilateral ureteral obstruction model mice by suppressing M2 macrophage infiltration and macrophage-myofibroblast transition.

Iguratimod is a novel synthetic, small-molecule immunosuppressive agent used to treat rheumatoid arthritis. Through ongoing exploration of its role and mechanisms of action, iguratimod has been observed to have antifibrotic effects in the lung and skin; however, its effect on renal fibrosis remains unknown. This study aimed to investigate whether iguratimod could affect renal fibrosis progression. Three different concentrations of iguratimod (30 mg/kg/day, 10 mg/kg/day, and 3 mg/kg/day) were used to intervene in unilateral ureteral obstruction (UUO) model mice. Iguratimod at 10 mg/kg/day was observed to be effective in slowing UUO-mediated renal fibrosis. In addition, stimulating bone marrow-derived macrophages with IL-4 and/or iguratimod, or with TGF-ß and iguratimod or SRC inhibitors in vitro, suggested that iguratimod mitigates the progression of renal fibrosis in UUO mice, at least in part, by inhibiting the IL-4/STAT6 signaling pathway to attenuate renal M2 macrophage infiltration, as well as by impeding SRC activation to reduce macrophage-myofibroblast transition. These findings reveal the potential of iguratimod as a treatment for renal disease.

Transcriptome analysis and differential expression in Arabidopsis thaliana in response to rohitukine (a chromone alkaloid) treatment.

Rohitukine is a chromone alkaloid and precursor of potent anticancer drugs flavopiridol, P-276-00, and 2,6-dichloro-styryl derivative (11d) (IIIM-290). The metabolite is reported to possess anticancer, anti-inflammatory, antiadipogenic, immunomodulatory, gastroprotective, anti-implantation, antidyslipidemic, anti-arthritic, and anti-fertility properties. However, the physiological role of rohitukine in plant system is yet to be explored. Here, we studied the effect of rohitukine isolated from Dysoxylum gotadhora on Arabidopsis thaliana. The A. thaliana plants grown on a medium fortified with different rohitukine concentrations showed a significant effect on the growth and development. The root growth of A. thaliana seedlings showed considerable inhibition when grown on medium containing 1.0 mM of rohitukine. Transcriptomic analysis indicated the expression of 895 and 932 genes in control and treated samples respectively at a cut-off of FPKM ≥ 1 and P-value < 0.05. Gene ontology (GO) analysis revealed the upregulation of genes related to photosynthesis, membrane transport, antioxidation, xenobiotic degradation, and some transcription factors (TFs) in response to rohitukine. Conversely, rohitukine downregulated several genes including RNA helicases and those involved in nitrogen compound metabolism. The RNA-seq result was also validated by real-time qRT-PCR analysis. In light of these results, we discuss (i) likely ecological importance of rohitukine in parent plant as well as (ii) comparison between responses to rohitukine treatment in plants and mammals.

Design, Synthesis, and Biological Evaluation of Novel Chromanone Derivatives as Multifunctional Agents for the Treatment of Alzheimer's Disease.

Based on a multitarget strategy, a series of novel chromanone-1-benzyl-1,2,3,6-tetrahydropyridin hybrids were identified for the potential treatment of Alzheimer's disease (AD). Biological evaluation demonstrated that these hybrids exhibited significant inhibitory activities toward acetylcholinesterase (AChE) and monoamine oxidase B (MAO-B). The optimal compound C10 possessed excellent dual AChE/MAO-B inhibition both in terms of potency and equilibrium (AChE: IC50 = 0.58 ± 0.05 µM; MAO-B: IC50 = 0.41 ± 0.04 µM). Further molecular modeling and kinetic investigations revealed that compound C10 was a dual-binding inhibitor bound to both the catalytic anionic site and peripheral anionic site of AChE. In addition, compound C10 exhibited low neurotoxicity and potently inhibited AChE enzymatic activity. Furthermore, compound C10 more effectively protected against mitochondrial dysfunction and oxidation than donepezil, strongly inhibited AChE-induced amyloid aggregation, and moderately reduced glutaraldehyde-induced phosphorylation of tau protein in SH-SY5Y cells. Moreover, compound C10 displayed largely enhanced improvements in cognitive behaviors and spatial memory in a scopolamine-induced AD mice model with better efficacy than donepezil. Overall, the multifunctional profiles of compound C10 suggest that it deserves further investigation as a promising lead for the prospective treatment of AD.

Naturally Occurring Chromone Glycosides: Sources, Bioactivities, and Spectroscopic Features.

Chromone glycosides comprise an important group of secondary metabolites. They are widely distributed in plants and, to a lesser extent, in fungi and bacteria. Significant biological activities, including antiviral, anti-inflammatory, antitumor, antimicrobial, etc., have been discovered for chromone glycosides, suggesting their potential as drug leads. This review compiles 192 naturally occurring chromone glycosides along with their sources, classification, biological activities, and spectroscopic features. Detailed biosynthetic pathways and chemotaxonomic studies are also described. Extensive spectroscopic features for this class of compounds have been thoroughly discussed, and detailed 13C-NMR data of compounds 1-192, have been added, except for those that have no reported 13C-NMR data.

Farrerol suppresses the progression of laryngeal squamous cell carcinoma via the mitochondria-mediated pathway.

PURPOSE: In the context of well-known inhibitory effects of Farrerol on the invasion of lung squamous cell carcinoma cells, the unexplored effect and regulatory mechanism of Farrerol on laryngeal squamous cell carcinoma (LSCC) emerged as the target in this study. METHODS: After treatment with Farrerol alone, or together with MitoTempo, the viability, apoptosis, cell cycle distribution, migration, and invasion of LSCC cells were measured using MTT, flow cytometry, wound-healing, and transwell assays, respectively. Meanwhile, the levels of cytochrome C (Cyt C), Cleaved caspase-3/9, Cyclin D1, E-cadherin, N-cadherin, and Vimentin in LSCC cells were evaluated by Western blot; the reactive oxygen species (ROS) formation intensity and the disruption of mitochondrial membrane potential (MMP) of LSCC cells were assessed using flow cytometry; and the effect of Farrerol on xenograft tumor formation was evaluated in animal experiment. RESULTS: Farrerol (10, 20, 50 µM) inhibited the viability, proliferation, cell cycle progression, migration and invasion, but promoted apoptosis, ROS formation intensity and disruption of MMP of LSCC cells. Moreover, Farrerol up-regulated Cyt C (in the cytoplasm), Cleaved caspase-3/9 and E-cadherin levels, but down-regulated Cyclin D1, N-cadherin and Vimentin levels in LSCC cells. Additionally, we uncovered that MitoTempo reversed the promoting effects of Farrerol on ROS formation intensity, apoptosis, and Cyt C and Cleaved caspase-3/9 levels in LSCC cells, while improving the disruption of MMP in Farrerol-treated LSCC cells. Also, Farrerol lessened the volume and weight of mice tumors. CONCLUSIONS: Farrerol suppressed the migration, invasion, and induced the apoptosis of LSCC cells via the mitochondria-mediated pathway.

PIM1 Inhibition Affects Glioblastoma Stem Cell Behavior and Kills Glioblastoma Stem-like Cells.

Despite comprehensive therapy and extensive research, glioblastoma (GBM) still represents the most aggressive brain tumor in adults. Glioma stem cells (GSCs) are thought to play a major role in tumor progression and resistance of GBM cells to radiochemotherapy. The PIM1 kinase has become a focus in cancer research. We have previously demonstrated that PIM1 is involved in survival of GBM cells and in GBM growth in a mouse model. However, little is known about the importance of PIM1 in cancer stem cells. Here, we report on the role of PIM1 in GBM stem cell behavior and killing. PIM1 inhibition negatively regulates the protein expression of the stem cell markers CD133 and Nestin in GBM cells (LN-18, U-87 MG). In contrast, CD44 and the astrocytic differentiation marker GFAP were up-regulated. Furthermore, PIM1 expression was increased in neurospheres as a model of GBM stem-like cells. Treatment of neurospheres with PIM1 inhibitors (TCS PIM1-1, Quercetagetin, and LY294002) diminished the cell viability associated with reduced DNA synthesis rate, increased caspase 3 activity, decreased PCNA protein expression, and reduced neurosphere formation. Our results indicate that PIM1 affects the glioblastoma stem cell behavior, and its inhibition kills glioblastoma stem-like cells, pointing to PIM1 targeting as a potential anti-glioblastoma therapy.

Integrated pan-cancer of AURKA expression and drug sensitivity analysis reveals increased expression of AURKA is responsible for drug resistance.

INTRODUCTION: The AURKA gene encodes a protein kinase involved in cell cycle regulation and plays an oncogenic role in many cancers. The main objective of this study is to analyze AURKA expression in 13 common cancers and its role in prognostic and drug resistance. METHOD: Using the cancer genome atlas (TCGA) as well as CCLE and GDSC data, the level of AURKA gene expression and its role in prognosis and its association with drug resistance were evaluated, respectively. In addition, the expression level of AURKA was assessed in colorectal cancer (CRC) and gastric cancer (GC) samples. Besides, using Gene Expression Omnibus (GEO) data, drugs that could affect the expression level of this gene were also identified. RESULTS: The results indicated that the expression level of AURKA gene in 13 common cancers increased significantly compared to normal samples or it survived poorly (HR >1, p < 0.01) in lung, prostate, kidney, bladder, and uterine cancers. Also, the gene expression data showed increased expression in CRC and GC samples compared to normal ones. The level of AURKA was significantly associated with the resistance to SB 505124, NU-7441, and irinotecan drugs (p < 0.01). Eventually, GEO data showed that JQ1, actinomycin D1, and camptothecin could reduce the expression of AURKA gene in different cancer cell lines (logFC < 1, p < 0.01). CONCLUSION: Increased expression of AURKA is observed in prevalent cancers and associated with poor prognostic and the development of drug resistance. In addition, some chemotherapy drugs can reduce the expression of this gene.

LY294002 and sorafenib as inhibitors of intracellular survival pathways in the elimination of human glioma cells by programmed cell death.

Gliomas are aggressive brain tumors with very high resistance to chemotherapy throughout the overexpression of multiple intracellular survival pathways. Therefore, the aim of the present study was to investigate for the first time the anticancer activity of LY294002, phosphatidylinositol 3-kinase (PI3K) inhibitor and sorafenib, and rapidly accelerated fibrosarcoma kinase (Raf) inhibitor in the elimination of human glioma cells by programmed cell death. MOGGCCM (anaplastic astrocytoma, III) and T98G (glioblastoma multiforme, IV) cell lines incubated with LY294002 and/or sorafenib were used in the experiments. Simultaneous treatment with both drugs was more effective in the elimination of cancer cells on the way of apoptosis with no significant necrotic effect than single application. It was correlated with decreasing the mitochondrial membrane potential and activation of caspase 3 and 9. The expression of Raf and PI3K was also inhibited. Blocking of those kinases expression by specific siRNA revealed significant apoptosis induction, exceeding the level observed after LY294002 and sorafenib treatment in non-transfected lines but only in MOGGCCM cells. Our results indicated that combination of LY294002 and sorafenib was very efficient in apoptosis induction in glioma cells. Anaplastic astrocytoma cells turned out to be more sensitive for apoptosis induction than glioblastoma multiforme after blocking PI3K and Raf expression with siRNA.

Effectiveness of iguratimod as monotherapy or combined therapy in patients with rheumatoid arthritis: a systematic review and meta-analysis of RCTs.

BACKGROUND: This study aims to evaluate the efficacy and safety of the iguratimod (IGU) as monotherapy or combined therapy in patients with rheumatoid arthritis (RA) by using meta-analysis. METHODS: We searched Medline, EMBASE, Cochrane library, CNKI, Wanfang medical network from initial to 30 June, 2020, for randomized clinical trials (RCTs). Two authors independently screened the studies via reading the title, abstract, and full text. The risk of bias in individual studies was assessed using the Cochrane Risk of Bias tool. STATA 12.0 was used for pooled analysis of all included studies. RESULTS: A total of 23 RCTs were included in this analysis. Meta-analysis showed that patients in the IGU monotherapy or combined therapy group had significantly higher ACR20 (OR = 1.97, 95% CI 1.29 to 3.00, P = 0.002), lower DAS28-CRP (SMD = -3.49, 95% CI -5.40 to -1.58, P < 0.001) and DAS28-ESR (SMD = -2.61, 95% CI -3.64 to -1.57, P < 0.001), as well as shorter duration of morning stiffness (SMD = -2.06, 95% CI -2.86 to -1.25, P < 0.001) and lower HAQ score (SMD = -0.91, 95% CI -1.61 to -0.21, P = 0.011), than those received other disease-modifying antirheumatic drugs (DMARDs) monotherapy (primarily comprising methotrexate). For the safety profile, IGU monotherapy had similar risks for gastrointestinal reactions (P = 0.070), leucopenia (P = 0.309), increment in transaminase (P = 0.321), increase of ALT (P = 0.051), and liver damage (P = 0.182) to methotrexate monotherapy, and IGU combined with other DMARDs therapy did not increase the risks of these AEs (P > 0.05). CONCLUSIONS: Our evidence suggests that IGU is effective and tolerant as monotherapy or combined therapy especially with methotrexate in patients with active RA. IGU may be regarded as a potential alternative to methotrexate, and a preferable choice when combined with other DMARDs for the treatment of RA.

PI3K/AKT/mTOR and TLR4/MyD88/NF-κB Signaling Inhibitors Attenuate Pathological Mechanisms of Allergic Asthma.

Asthma is an inflammatory airway disease wherein bronchoconstriction, airway inflammation, and airway obstruction during asthma attacks are the main problems. It is recognized that imbalance of Th1/Th2 and Th17/Treg is a critical factor in asthma pathogenesis. Manipulation of these with signaling molecules such as mTOR, PI3K, Akt, and MyD88 can control asthma. Mouse model of allergic asthma was produced and treated with ketamine, metformin, metformin and ketamine, triciribine, LY294002, and torin2. MCh challenge test, BALf's Eos Count, the IL-4, 5, INF-γ, eicosanoid, total IgE levels were determined. The MUC5a, Foxp3, RORγt, PI3K, mTOR, Akt, PU.1, and MyD88 gene expressions and histopathology study were done. Asthma groups that were treated with all six components had reduced Penh value, total IgE, IL-4 and IL-5 levels, MUC5a, RORγt, MyD88 and mTOR expression, goblet cell hyperplasia, and mucus hyper-secretion. The eosinophil percentage and Cys-LT level were decreased by metformin and ketamine, triciribine, LY294002, and torin2. The level of IFN-γ was increased in triciribine, LY294002, and torin2. Metformin, metformin and ketamine, triciribine, LY294002, and torin2 reduced Akt and PI3K expression, peribronchial and perivascular inflammation, and increased expression of Foxp3. Torin2 had an effect on PU.1 expression. Inhibition of PI3K/AKT/mTOR and TLR4/MyD88/NF-κB signaling with targeted molecules can attenuate asthma pathology and play an important role in airways protection.

Synergistic effects of LY294002 and ABT199 on the cell cycle in K562, HL60 and KG1a cells.

The aim of the present study was to investigate the synergistic effect of LY294002 (a PI3K inhibitor) and ABT199 (a BCL2 inhibitor) on the cell cycle in acute myeloid leukemia (AML). The optimal concentration and duration of combined LY294002 and ABT199 were determined in human erythroleukemia (K562), promyelocytic leukemia (HL60) and myeloid leukemia (KG1a) cell lines. The mRNA and protein expression levels of cell cycle­related molecules, including S­phase kinase­associated protein 2 (Skp2), p27, BCL2, Bax, cleaved caspase 3 (caspase­3) and caspase 9 (caspase­9) were detected via reverse transcription­quantitative PCR and western blot analysis, respectively. At the molecular level, LY294002 and ABT199 combination treatment significantly downregulated Skp2, Bcl2, procaspase­3 and procaspase­9 expression levels, but markedly upregulated p27, Bax, cleaved caspase­3 and caspase­9 expression levels in K562, HL­60 and KG1a cells. The results of the present study demonstrated that LY294002 and ABT199 combination treatment may serve as a novel therapeutic strategy for AML.

Effect of Oxaliplatin, Olaparib and LY294002 in Combination on Triple-Negative Breast Cancer Cells.

Triple-negative breast cancer (TNBC) has a poor prognosis as the therapy has several limitations, most importantly, treatment resistance. In this study we examined the different responses of triple-negative breast cancer line MDA-MB-231 and hormone receptor-positive breast cancer line MCF7 to a combined treatment including olaparib, a poly-(ADP ribose) polymerase (PARP) inhibitor, oxaliplatin, a third-generation platinum compound and LY294002, an Akt pathway inhibitor. We applied the drugs in a single, therapeutically relevant concentration individually and in all possible combinations, and we assessed the viability, type of cell death, reactive oxygen species production, cell-cycle phases, colony formation and invasive growth. In agreement with the literature, the MDA-MB-231 cells were more treatment resistant than the MCF7 cells. However, and in contrast with the findings of others, we detected no synergistic effect between olaparib and oxaliplatin, and we found that the Akt pathway inhibitor augmented the cytostatic properties of the platinum compound and/or prevented the cytoprotective effects of PARP inhibition. Our results suggest that, at therapeutically relevant concentrations, the cytotoxicity of the platinum compound dominated over that of the PARP inhibitor and the PI3K inhibitor, even though a regression-based model could have indicated an overall synergy at lower and/or higher concentrations.

Effects of iguratimod on glucocorticoid-induced disorder of bone metabolism in vitro.

INTRODUCTION: Glucocorticoids are widely used to treat various diseases including rheumatoid arthritis (RA); however, one of the most frequent and severe adverse effects is glucocorticoid-induced osteoporosis (GIOP). Iguratimod (IGU) is a novel conventional synthetic disease-modifying anti-rheumatic drug developed in Japan. The aim of this study is to investigate the effects of IGU on glucocorticoid-induced disorder of bone metabolism in vitro. MATERIALS AND METHODS: In osteoclastogenesis of mouse bone marrow-derived cells, tartrate-resistant acid phosphatase staining, resorption pit assay, western blotting, real-time polymerase chain reaction (PCR), and mRNA sequencing were performed. In osteoblastogenesis of MC3T3-E1 cells, alkaline phosphatase (ALP) staining and activity, alizarin red staining, and mRNA sequencing were performed, and real-time PCR and western blotting were conducted in MC3T3-E1 cells and murine osteocyte-like cell line MLO-Y4 cells. RESULTS: IGU significantly suppressed a dexamethasone-induced increase in osteoclasts, differentiation, and bone resorption activity by inhibition of the receptor activator of the nuclear factor kappa-B (RANK)/tumor necrosis factor receptor (TNFR)-associated factor 6 (TRAF6)/nuclear factor kappa-B (NFκB)-p52 pathway. In MC3T3-E1 cells, IGU significantly upregulated dexamethasone-induced downregulation of ALP activity, bone mineralization, and osteoblast-related gene and protein expression. In MLO-Y4 cells, IGU significantly upregulated dexamethasone-induced downregulation of the gene expression of ALP and osteocalcin, and also downregulated receptor activator of NFκB ligand (RANKL)/osteoprotegerin gene expression ratio without dexamethasone. CONCLUSION: These results suggest that IGU may improve glucocorticoid-induced disorder of bone metabolism and may exhibit positive effects against GIOP associated with RA.

Augmented Antitumor Activity for Novel Dual PI3K/BDR4 Inhibitors, SF2523 and SF1126 in Ewing Sarcoma.

Ewing sarcoma (ES) is the second most common pediatric bone cancer. Despite recent advances in the treatment, patients with metastatic tumors have dismal prognosis and hence novel therapies are urgently needed to combat this cancer. A recent study has shown that phosphoinositide-3 kinase (PI3K) inhibitors can synergistically increase sensitivity to bromodomain and extraterminal domain inhibitors in ES cells and therefore combined inhibition of PI3K and bromodomain and extraterminal domain bromodomain proteins might provide benefit in this cancer. Herein, we have investigated the efficacy of dual PI3K/BRD4 inhibitors, SF2523 and SF1126, for their antitumor activity in ES cell lines. The effect of SF1126 and SF2523 on cell viability and PI3K signaling was assessed on a panel of human ES cell lines. To evaluate the antitumor activity of SF1126, A673 cells were injected intrafemorally into RAG-2-/- mice and treated with 50 mg/kg SF1126 6 days per week, for 30 days. Both SF1126 and SF2523 decreased cell survival and inhibited phosphorylation of AKT in human ES cell lines. In vivo, SF1126 showed a significant reduction in tumor volume. These results suggest that dual PI3K/BRD4 inhibitor, SF1126, has antitumor activity in ES models.

Efficacy of add-on iguratimod in patients with rheumatoid arthritis who inadequately respond to either tocilizumab or tumor necrosis factor alpha inhibitors.

OBJECTIVES: This study aimed to evaluate the efficacy of add-on iguratimod (IGU) in patients with rheumatoid arthritis (RA patients) who inadequately respond to either tocilizumab (TCZ) or tumor necrosis factor alpha inhibitors (TNFi). METHODS: Twenty-three RA patients treated with TCZ (the TCZ group) and 23 RA patients treated with TNFi (the TNFi group) were enrolled in this 24-week retrospective study from our multicenter registry. All inadequate responders to either TCZ or TNFi received add-on IGU. Baseline demographics and disease activity at 24 weeks after initiating add-on IGU were compared between the two groups. RESULTS: Baseline clinical disease activity index (CDAI) values in the TCZ group and TNFi group were 14.1 and 11.8 (p = .24 between the two groups). At 24 weeks, CDAI values in the TCZ group and TNFi group were 5.1 and 7.5 (p = .002 and .002 compared to baseline, respectively) and ΔCDAI values were -9.0 and -4.3 (p = .007 between the two groups). Multiple linear regression analysis revealed that add-on IGU in the TCZ group was associated with greater improvement in CDAI relative to the TNFi group. CONCLUSION: Add-on IGU was more effective in inadequate responders to TCZ than in inadequate responders to TNFi.

1-Chromonyl-5-Imidazolylpentadienone Demonstrates Anti-Cancer Action against TNBC and Exhibits Synergism with Paclitaxel.

Curcumin has been well studied for its anti-oxidant, anti-inflammatory, and anti-cancer action. Its potential as a therapy is limited due to its low bioavailability and rapid metabolism. To overcome these challenges, investigators are developing curcumin analogs, nanoparticle formulations, and combining curcumin with other compounds or dietary components. In the present study, we used a 1-chromonyl-5-imidazolylpentadienone named KY-20-22 that contains both the pharmacophore of curcumin and 1,4 benzopyrone (chromone) moiety typical for flavonoids, and also included specific moieties to enhance the bioavailability. When we tested the in vitro effect of KY-20-22 in triple-negative breast cancer (TNBC) cell lines, we found that it decreased the cell survival and colony formation of MDA-MB-231 and MDA-MB-468 cells. An increase in mitochondrial reactive oxygen species was also observed in TNBC cells exposed to KY-20-22. Furthermore, KY-20-22 decreased epithelial-mesenchymal formation (EMT) as evidenced by the modulation of the EMT markers E-cadherin and N-cadherin. Based on the fact that KY-20-22 regulates interleukin-6, a cytokine involved in chemotherapy resistance, we combined it with paclitaxel and found that it synergistically induced anti-proliferative action in TNBC cells. The results from this study suggested that 1-chromonyl-5-imidazolylpentadienone KY-20-22 exhibited anti-cancer action in MDA-MB-231 and MDA-MB-468 cells. Future studies are required to evaluate the anti-cancer ability and bioavailability of KY-20-22 in the TNBC animal model.

Syringic acid mitigates myocardial ischemia reperfusion injury by activating the PI3K/Akt/GSK-3ß signaling pathway.

Syringic acid is an abundant phenolic acid compound that possesses anti-oxidant, anti-microbial, anti-inflammatory, and anti-endotoxic properties. However, the research of pretreatment with syringic acid against myocardial ischemia reperfusion is still limited. Thus, our research revealed the protective effect of syringic acid in the rat model with myocardial ischemia reperfusion injury. Histological analysis was performed by hematoxylin and eosin (H&E). The myocardial systolic function was detected by echocardiographic. Myocardial infarct size was measured by Evans blue and 2,3,5-triphenyltetrazolium chloride (TTC) double staining. The apoptosis index was recorded by Terminal deoxynucleotidyl transferase dUTP nick end labeling staining (TUNEL). The contents of creatine kinase MB (CK-MB) and lactate dehydrogenase (LDH) in the serum were determined by a commercial kit. The expression of the PI3K/Akt/GSK-3ß signaling pathway-related molecules and apoptosis-associated indicators was detected by western blotting or real-time PCR. We found that pretreatment with syringic acid obviously increased the myocardial systolic function (LVEF and LVFS) and decreased the infarct size, the apoptosis index as well as the serum level of CK-MB and LDH. Meanwhile, syringic acid also remarkably augmented the contents of p-PI3K, p-Akt, p-GSK-3ß, Bcl-2 and mitochondria cytochrome c. However, the expression of caspase-3, -9 and Bax significantly reduced. Interestingly, co-treatment with PI3K inhibitor of LY294002 counteracted those effects induced by syringic acid. In conclusion, pretreatment with syringic acid can mitigate myocardial ischemia reperfusion injury by inhibiting mitochondria-induced apoptosis which is regulated by the PI3K/Akt/GSK-3ß signaling pathway.