Search

• The excessive pyroptosis obstructs the endotoxin tolerance in Kupffer cells. • STAT5a alleviates pyroptosis and contribute to endotoxin tolerance. • STAT5a inhibits NF-κb/Nlrp3 signal pathway to impede caspase1 activation. Pyroptosis, a newly discovered type of programmed cell death, affects endotoxin tolerance in macrophages. However, the factors acting on the nod-like receptor 3 (Nlrp3) inflammasome and caspase1 activation to impede pyroptosis and resulting in tolerance and survival in sepsis were needed to discovered. Here, we found that signal transducer and activator of transcription 5A (STAT5a) restrains pyroptosis in Kupffer cells (KCs) and induces endotoxin tolerance (ET) in a sepsis model. The lentiviral knockdown of STAT5a led to enhanced pyroptosis in KCs, increased IL-1β production and decreased IL-10 production via intricate NF-κb signaling regulation. Thus, our findings reveal a novel mechanism of STAT5a-midiated endotoxin tolerance in KCs. [ABSTRACT FROM AUTHOR]

Pteridines are an important class of heterocyclic compounds with diverse biological activities. Here, we report a series of pteridin-7(8 H )-one derivatives and their antiproliferative activities toward MKN-45, MGC-803, EC-109, and H1650. Structure-activity relationship studies showed that compound 12 exerted the most potent antiproliferative activity against MKN-45 and MGC-803 with the IC 50 values of 4.32 and 7.01 μM, respectively. Besides, compound 12 induced morphological changes and apoptosis of MKN-45 cells, increased expression of Bax, down-regulated expression of Bcl-2 and caused cleavage of caspase-3/9. Additionally, we first reported the construction of the novel bicyclic 8,9-dihydro-7 H -purine-8-carboxylate scaffold through the competitive 5-endo cyclization reaction with two C-N bonds and a chiral carbon center established. [ABSTRACT FROM AUTHOR]

A series of new [1,2,3]triazolo[4,5- d ]pyrimidine/thiourea hybrids were designed and synthesized through the scaffold replacement/ring cleavage strategy. SARs studies revealed that the N -heteroarene moiety attached to the thiourea is preferred over the phenyl ring for the R 2 substituents, while the hydrophobic aromatic group is beneficial for improving the activity. Among these compounds, compound 5r significantly inhibited cell growth of lung cancer cell lines H1650 and A549 (IC 50 = 1.91, 3.28 μM, respectively), but was less toxic against the normal cell line GES-1 (IC 50 = 27.43 μM). Mechanistic studies showed that compound 5r could remarkably inhibit the colony formation of H1650 cells, induced apoptosis possibly through the intrinsic apoptotic pathways, and arrested the cell cycle at G2/M phase. Our studies suggest that the [1,2,3]triazolo[4,5- d ]pyrimidine/thiourea hybrids are a new class of chemotypes possessing interesting antiproliferative activity against lung cancer cells and could be potentially utilized for designing new antitumor agents. [ABSTRACT FROM AUTHOR]

A series of thiazolo[5,4- d ]pyrimidine derivatives were designed through the atom replacement strategy based on biologically validated scaffolds and then evaluated for their antiproliferative activities on cancer cell lines. The structure-activity relationship studies were conducted, leading to the identification of compound 22 , which exhibited good antiproliferative activity against HGC-27 with an IC 50 value of 1.22 μM and low toxicity against GES-1 cells. Mechanistic studies showed that compound 22 inhibited the colony formation and migration of HGC-27 as well as induced apoptosis. The western blot experiments proved that compound 22 up-regulated expression of Bax, down-regulated expression levels of Bcl-2 and cleaved caspased-3/9. These findings indicate that compound 22 may serve as a template for designing new agents for the treatment of human gastric cancers. The atom replacement strategy could be viable strategy for designing new anticancer drugs and may find its applications in drug design. [ABSTRACT FROM AUTHOR]

A series of structurally new diheteroaryl thioether analogs was designed, prepared and screened toward MGC-803, MKN-45, EC-109 and H1650. Most of the target compounds displayed moderate to potent antiproliferative activities. Among them, compound 5 showed the best antiproliferative activity against the tested cell lines with the half maximal inhibitory concentration (IC 50 ) values below 10 μM. In addition, flow cytometry analysis showed that compound 5 increased Bax expression, down-regulated expression of Bcl-2, cleaved caspases-3/9, finally inducing apoptosis of MKN-45 cells as well as arrested the cell cycle at G2/M phase. This study suggests that the diheteroaryl thioethers are a class of emerging chemotypes for developing antitumor agents or biological probes, and compound 5 could serve as a good starting point to design new apoptosis inducers. [ABSTRACT FROM AUTHOR]

A series of thiazolo[5,4-d]pyrimidine derivatives were synthesized and evaluated for their antiproliferative activities on three cancer cell lines. The structure-activity relationship studies were conducted through the variation in the three regions of the thiazolo-pyrimidine core. Substitution with morpholine led to compound 24 , which exerted the most potent antiproliferative activity as well as good selectivity between cancer and normal cells (IC 50 values of 1.03 μM against MGC803 and 38.95 μM against GES-1). In addition, compound 24 inhibited the colony formation and migration of MGC803 as well as induced apoptosis. Western blot experiments indicated the expression changes of apoptosis-related proteins, including up-regulation of Bax and caspase-3/9, as well as down-regulation of Bcl-2. [ABSTRACT FROM AUTHOR]

A series of [1,2,3]triazolo[4,5- d ]pyrimidine derivatives bearing a hydrazone moiety were designed, synthesized and evaluated for their antiproliferative activity against several cancer cell lines of different origins by MTT assay. Most of the synthesized compounds demonstrated moderate to good activity against the cancer cell lines selected. Especially, compound 43 showed the most potent antiproliferative activity as well as good selectivity between cancer and normal cells (IC 50 values of 0.85 μM against MGC-803 and 56.17 μM against GES-1). In addition, compound 43 evidently inhibited the colony formation of MGC-803 cells at 0.8 μM. Further mechanism studies revealed that compound 43 could induce apoptosis of MGC-803 cells probably through the mitochondrial pathway accompanied with decrease of the mitochondrial membrane potential (MMP), activations of caspase-9/3, up-regulation of the expression of Bax, Bak and PUMA, as well as down-regulation of that of Bcl-2 and Mcl-1. [ABSTRACT FROM AUTHOR]

Conventional chemotherapy for leukemia inevitably causes systemic toxicity. Acanthopanax senticosus , a naturally occurring herb used in traditional Chinese medicine, has been found to be a multipotent bioflavonoid with great potential in the prevention and treatment of malignant diseases. However, the mechanism underlying the action of A. senticosus in epigenetic regulation is poorly understood. In the study described here, we focused on the efficacy of A. senticosus in inducing apoptosis of leukemia cells and a possible mechanism. By evaluating the inhibition ratio and morphologic changes, we found that A. senticosus can inhibit growth and induce apoptosis of human leukemia HL-60 and HL60/ADM cells in a dose- and time-dependent manner. Furthermore, A. senticosus induced Fas ligand (FasL) expression and blocked the cell cycle in S phase. In addition, A. senticosus exhibited a potential for inhibition of histone deacetylase (HADC), which contributes to histone acetylation. It possibly resulted in the promotion of the expression of FasL. It is suggested that A . senticosus could be recognized as a new HDAC inhibitor which was able to reactivate aberrantly silenced genes. We discuss the clinical aspects of using A. senticosus for treatment of leukemia. [ABSTRACT FROM AUTHOR]

Abstract: Zearalenone (ZEN) is commonly found in many food commodities and is known to cause reproductive disorders and genotoxic effects. However, the mode of ZEN-induced cell death of macrophages and the mechanisms by which ZEN causes cytotoxicity remain unclear. The present study shows that ZEN treatment reduces viability of RAW264.7 cells in a dose-dependent manner. ZEN causes predominantly necrotic and late apoptotic cell death. ZEN treatment also results in the loss of mitochondrial membrane potential (MMP), mitochondrial changes in Bcl-2 and Bax proteins, and cytoplasmic release of cytochrome c and apoptosis-inducing factor (AIF). Pre-treatment of the cells with either z-VAD-fmk or z-IETD-fmk does not attenuate ZEN-mediated cell death, whereas catalase suppresses the ZEN-induced decrease in viability in RAW264.7 cells. Treating the cells with c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinase (MAPK), or p53 inhibitor prevented ZEN-mediated changes, such as MMP loss, cellular reactive oxygen species (ROS) increase, and cell death. JNK or p38 MAPK inhibitor inhibited mitochondrial alterations of Bcl-2 and Bax proteins with attendant decreases in cellular ROS levels. Knockdown of AIF via siRNA transfection also diminished ZEN-induced cell death. Further, adenosine triphosphate was markedly depleted in the ZEN-exposed cells. Collectively, these results suggest that ZEN induces cytotoxicity in RAW264.7 cells via AIF- and ROS-mediated signaling, in which the activations of p53 and JNK/p38 play a key role. [Copyright &y& Elsevier]

Abstract: Albumin, which is the most abundant component of urine proteins, exerts injurious effects on renal cells in chronic kidney diseases. However, the toxicity of albumin to podocytes is not well elucidated. Here, we show that a high concentration of albumin triggers intracellular calcium ([Ca2+]i) increase through mechanisms involving the intracellular calcium store release and extracellular calcium influx in conditionally immortalized podocytes. The canonical transient receptor potential-6 (TRPC6) channel, which is associated with a subset of familial forms of focal segmental glomerulosclerosis (FSGS) and several acquired proteinuric kidney diseases, was shown to be one of the important Ca2+ permeable ion channels in podocytes. Therefore we explored the role of TRPC6 on albumin-induced functional and structural changes in podocytes. It was found that albumin-induced increase in [Ca2+]i was blocked by TRPC6 siRNA or SKF-96365, a blocker of TRP cation channels. Long-term albumin exposure caused an up-regulation of TRPC6 expression in podocytes, which was inhibited by TRPC6 siRNA. Additionally, the inhibition of TRPC6 prevented the F-actin cytoskeleton disruption that is induced by albumin overload. Moreover, albumin overload induced expression of the endoplasmic reticulum (ER) stress protein GRP78, led to caspase-12 activation and ultimately podocyte apoptosis, all of which were abolished by the knockdown of TRPC6 using TRPC6 siRNA. These results support the view that albumin overload may induce ER stress and the subsequent apoptosis in podocytes via TRPC6-mediated Ca2+ entry. [Copyright &y& Elsevier]

Pteridines are an important class of fused heterocycles found in natural products and drug molecules, and have shown diverse biological activities. A focused library of 5,8-dihydropteridine-6,7-dione derivatives were designed and evaluated for their antiproliferative activity against MGC-803, SGC-7901, A549 and PC-3 cancer cell lines. The SARs studies highlighted the importance of the piperazine substituted 5,8-dihydropteridine-6,7-dione frameworks for the activity and revealed essential structural elements. Among these compounds, compound 5n displayed the most potent and broad-spectrum antiproliferative inhibition against the tested cell lines and was sensitive to MGC-803 cell line, slightly more potent than 5-FU. Preliminary mechanistic studies showed that compound 5n could inhibit the colony formation and migration of MGC-803 cells. Besides, flow cytometry analysis showed that compound 5n concentration-dependently induced apoptosis of MGC-803 cells. Our studies suggest that the piperazine substituted 5,8-dihydropteridine-6,7-dione frameworks may be regarded as new chemotypes for designing effective antitumor agents targeting gastric cancer cells. [ABSTRACT FROM AUTHOR]

Abstract To explore anti-gastric cancer agents with high efficacy and selectivity, we report the design, synthesis and optimization of a novel series of 3-(2,6,9-trisubstituted-9H-purine)-8-chalcone derivatives starting from the compound PCA-15 reported by us previously. Most of the target compounds demonstrated significant antiproliferative effects on MGC803 cancer cell line, and more potent than the positive control (PCA-15 and 5-Fu). Among them, compound 6o was identified to be the most active compound against MGC803 cell line with an IC 50 value of 0.84 μM. Additionally, high selectivity was also observed between cancer and normal cells (23.35 μM against GES-1). Further mechanism studies confirmed that compound 6o could inhibit colony formation and migration, induce the apoptosis of MGC803 cells through both the mitochondrial-mediated intrinsic pathway and death receptor-mediated extrinsic pathway, which were evidenced by the up-regulation of Bax, cleaved-caspase 9/3/8, cleaved PARP and down-regulation of Bcl-2. Our systematic studies implied a new scaffold targeting gastric cancer cells for further development of small-molecule compounds with improved potency and selectivity. Graphical abstract Image 1 Highlights • A novel purine-chalcone scaffold was established by structural optimization, which led to a gradually improved activity. • Compound 6o exerted the potent anti-gastric cancer activity and good selectivity between cancer and normal cells. • Compound 6o could inhibit migration and induce the apoptosis of MGC803 cells. [ABSTRACT FROM AUTHOR]

A new series of 6-chloro-2-(propylthio)-8,9-dihydro-7H-purine-8-caboxamide derivatives were designed, synthesized, and further evaluated for their antiproliferative activities on four human cancer cell lines (A549, MGC803, PC-3 and TE-1). The structure-activity relationships (SARs) studies were conducted through the variation in the two regions, which including position 8 and 9, of purine core. One of the compounds, 8 , containing a terminal piperazine appendage with a carboxamide moiety at position 8 and phenyl group at position 9 of 6-chloro-8,9-dihydro-7H-purine core, showed the most potent antiproliferative activity and good selectivity between cancer and normal cells (IC 50 values of 2.80 μM against A549 and 303.03 μM against GES-1, respectively). In addition, compound 8 could inhibit the colony formation and migration of A549 cells in a concentration-dependent manner, as well as induce the apoptosis possibly through the intrinsic pathway. [ABSTRACT FROM AUTHOR]

A series of hybrid molecules containing [1,2,3]triazolo[4,5-d]pyrimidine and thiosemicarbazide moieties were designed, synthesized and evaluated for their antiproliferative activities against MGC-803, NCI-H1650 and PC-3 human cancer cells. Some of the synthesized compounds showed moderate to good activity against three selected cancer cell lines. Among these compounds, compound 29 displayed the most potent antiproliferative activity as well as good selectivity between cancer cells and normal cells. Further mechanism studies revealed that compound 29 could obviously inhibit the colony formation and migration of MGC-803 as well as induced apoptosis. [ABSTRACT FROM AUTHOR]

A series of 5,6-diaryl-1,2,4-triazines hybrids bearing a 1,2,3-triazole linker were synthesized by molecular hybridization strategy and evaluated for antiproliferative activity against three selected cancer cell lines (MGC-803, EC-109 and PC-3). The first structure-activity relationship (SAR) for these 5,6-diaryl-1,2,4-triazines is explored in this report with evaluation of 15 variants of the structural class. Among these chemical derivatives, 3-(((1-(4-fluorobenzyl)-1H-1,2,3-triazol-4-yl)methyl)thio)-5,6-diphenyl-1,2,4-triazine ( 11E ) showed the more potent inhibitory effect against three cell lines than 5-Fu. Cellular mechanism studies in MGC-803 cells elucidated 11E inhibited colony formation and arrested cell cycle at G2/M phase. Furthermore, compound 11E caused morphological changes, decreased mitochondrial membrane potential, and induced apoptosis through the apoptosis-related proteins in MGC-803 cells. It was the first time, to our knowledge, that 5,6-diaryl-1,2,4-triazines bearing a 1,2,3-triazole linker were used as potential apoptosis inducers. [ABSTRACT FROM AUTHOR]

Ferroptosis is a novel type of programmed cell death, characterized by a dysregulated iron metabolism and accumulation of lipid peroxides. It features the alteration of mitochondria and aberrant accumulation of excessive iron as well as loss of the cysteine-glutathione-GPX4 axis. Eventually, the accumulated lipid peroxides result in lethal damage to the cells. Ferroptosis is induced by the overloading of iron and the accumulation of ROS and can be inhibited by the activation of the GPX4 pathway, FS1-CoQ10 pathway, GCH1-BH4 pathway, and the DHODH pathway, it is also regulated by the oncogenes and tumor suppressors. Ferroptosis involves various physiological and pathological processes, and increasing evidence indicates that ferroptosis play a critical role in cancers and other diseases. It inhibits the proliferation of malignant cells in various types of cancers and inducing ferroptosis may become a new method of cancer treatment. Many inhibitors targeting the key factors of ferroptosis such as SLC7A11, GPX4, and iron overload have been developed. The application of ferroptosis is mainly divided into two directions, i.e. to avoid ferroptosis in healthy cells and selectively induce ferroptosis in cancers. In this review, we provide a critical analysis of the concept, and regulation pathways of ferroptosis and explored its roles in various diseases, we also summarized the compounds targeting ferroptosis, aiming to promote the speed of clinical use of ferroptosis induction in cancer treatment. [Display omitted] • Ferroptosis is a novel type of programmed cell death characterized by iron overload and phospholipid peroxidation. • The involvement of ferroptosis pathways provide profound insights into cancer therapy. • Targeting ferroptosis provides potent strategies for clinical cancer therapy. • Developing novel compounds targeting ferroptosis will be new hope for as-yet-incurable diseases. [ABSTRACT FROM AUTHOR]

Introduction Pre-eclampsia (PE) can endanger the survival of the mother and fetus. Currently, the pathogenesis of PE is not completely understood and no fundamental therapeutics are available. The present study was performed to determine the function of miR-128a in HTR-8/SVneo trophoblast cells and to ascertain its underlying role in the pathogenesis of PE. Methods We investigated the function of miR-128a in HTR-8/SVneo cells by overexpressing. We analyzed the apoptosis of HTR-8/SVneo cells by performing apoptosis assays and measured the loss of mitochondrial membrane potential (Δym), the generation of reactive oxygen species (ROS) and caspase activity. In addition, miR-128a target genes were predicted. Results Using computer-based programs, we identified Bax as a direct target of miR-128a. In the apoptosis assays of HTR-8/SVneo cells, miR-128a decreased the Δψm, depleted ATP levels and increased ROS generation, cytochrome c release as well as caspase activation. Further studies showed that miR-128a induced the apoptosis of HTR-8/SVneo cells by down-regulating Bax through the mitochondrial apoptosis pathway. Conclusions miR-128a is an up-regulated miRNA in patient with PE. Our study demonstrated that the miR-128a-induced apoptosis of HTR-8/SVneo cells may contribute to PE and miR-128a may be a novel potential therapeutic target for PE. [ABSTRACT FROM AUTHOR]

Abstract: Ceramide, as a second messenger, initiates one of the major signal transduction pathways in tumor apoptosis. Glucosylceramide synthase (GCS) catalyzes glycosylation of ceramide and produces glucosylceramide. Through GCS, ceramide glycosylation allows cellular escape from ceramide-induced programmed cell death. Here we investigated the expression of GCS in human leukemia cells and an association between GCS and multidrug resistance of leukemia cells. Using RT-PCR technique the level of GCS gene was detected in 65 clinical multidrug resistance/non-resistance cases with leukemia, and in K562 and K562/A02 cell lines. AlamarBlue Assay was applied to confirm the multidrug resistant of K562/A02 cells. PPMP, which is a chemical inhibitor for GCS, was used to determine the relationship between GCS and drug-resistance in K562/A02 cells. In addition, multidrug resistance gene (mdr1), Bcl-2 and Bax mRNA was also analyzed by RT-PCR. The expression of GCS and mdr1 mRNA in clinic multidrug resistance samples exhibited significantly increased compared with clinic drug sensitive group (P <0.05). There was the positive correlation both the expression of GCS and mdr1 genes in leukemia samples (P <0.01, γ =0.7). AlamarBlue Assay showed that the K562/A02 cell line was 115-fold more resistant to adriamycin and 36-fold more resistant to vincristine compared with drug-sensitive K562 cell line. There also was significant expression difference of GCS and mdr1 genes between K562 and K562/A02 cells. Bcl-2 gene exhibited higher expressions whatever in clinic drug-resistance samples or K562/A02 cells, whereas the expressions of Bax gene were higher in drug-sensitive samples and K562 cells. PPMP increased sensitivity to adriamycin toxicity by inhibiting GCS in K562/A02 cells. Therefore, it is suggested that a high level of GCS in leukemia is possible contributed to multidrug resistance of leukemia cells. Abnormally expressions of the genes in associated with cell apoptosis might be one of the main molecular pathology mechanisms of multidrug resistance caused by GCS gene. [Copyright &y& Elsevier]

A couple of molecular-targeting medications, such as Lenvatinib, are available for the treatment of hepatocellular carcinoma (HCC) in addition to Sorafenib in an advanced stage. Approval for the use of immune check-point inhibitors, such as Nivolumab and Pembrolizumab has shifted the paradigm of current HCC treatment, and the monotherapy or in combination with Lenvatinib or Sorafenib has significantly extended overall survival or progression-free survival in a large portion of patients. A combination of programmed cell death ligand-1 (PD-L1) inhibitor Atezolizumab with a vascular endothelial growth factor (VEGF) inhibitor, Bevacizumab, has recently achieved promising outcome in unresectable HCC patients. Other immunotherapy, such as chimeric antigen receptor T (CAR-T) cell therapy has achieved an evolutional success in hematologic malignancies, and has extended its use in deadly solid tumors, such as HCC. Although there exist various barriers, novel approaches are developed to move potential adoptive T cell therapy strategies, including cytokine-induced killer (CIK) cells, tumor-infiltrating lymphocytes (TIL), T cell receptor (TCR) T cells, CAR-T cells, to clinical application. Unlabelled Image [ABSTRACT FROM AUTHOR]