Month: October 2022

Mudaliar, Prashant; Pradeep, Parvanendhu; Abraham, Rachy; Sreekumar, Easwaran published the artcile< Targeting cap-dependent translation to inhibit Chikungunya virus replication: selectivity of p38 MAPK inhibitors to virus-infected cells due to autophagy-mediated down regulation of phospho-ERK>, Related Products of 1223001-51-1, the main research area is translational suppression p38 MAPK inhibitor autophagy Chikungunya virus infection; Chikungunya; LC3; Wortmannin; autophagy; cap-dependent translation; phospho-ERK; torin.

The 5 capped, message-sense RNA genome of Chikungunya virus (CHIKV) utilizes the host cell machinery for translation. Translation is regulated by eIF2 alpha at the initiation phase and by eIF4F at cap recognition. Translational suppression by eIF2 alpha phosphorylation occurs as an early event in many alphavirus infections. We observe that in CHIKV-infected HEK293 cells, this occurs as a late event, by which time the viral replication has reached an exponential phase, implying its minimal role in virus restriction. The regulation by eIF4F is mediated through the PI3K-Akt-mTOR, p38 MAPK and RAS-RAF-MEK-ERK pathways. A kinetic anal. revealed that CHIKV infection did not modulate AKT phosphorylation, but caused a significant reduction in p38 MAPK phosphorylation. It caused degradation of phospho-ERK 1/2 by increased autophagy, leaving the PI3K-Akt-mTOR and p38 MAPK pathways for pharmacol. targeting. mTOR inhibition resulted in moderate reduction in viral titer, but had no effect on CHIKV E2 protein expression, indicating a minimal role of the mTOR complex in virus replication. Inhibition of p38 MAPK using SB202190 caused a significant reduction in viral titer and CHIKV E2 and nsP3 protein expression. Furthermore, inhibiting the two pathways together did not offer any synergism, indicating that inhibiting the p38 MAPK pathway alone is sufficient to cause restriction of CHIKV replication. Meanwhile, in uninfected cells the fully functional RAS-RAF-MEK-ERK pathway can circumvent the effect of p38 MAPK inhibition on cap-dependent translation. Thus, our results show that host-directed antiviral strategies targeting cellular p38 MAPK are worth exploring against Chikungunya as they could be selective against CHIKV-infected cells with minimal effects on uninfected host cells.

Journal of General Virology published new progress about Apoptosis. 1223001-51-1 belongs to class naphthyridine, and the molecular formula is C24H15F3N4O, Related Products of 1223001-51-1.

Referemce:
1,8-Naphthyridine – Wikipedia,
1,8-Naphthyridine | C8H6N2 – PubChem

Zhu, Lingling; Huang, Shanshan; Li, Junhe; Chen, Jun; Yao, Yangyang; Li, Li; Guo, Hui; Xiang, Xiaojun; Deng, Jun; Xiong, Jianping published the artcile< Sophoridine inhibits lung cancer cell growth and enhances cisplatin sensitivity through activation of the p53 and Hippo signaling pathways>, Safety of (41S,7aR,13aR,13bR)-Dodecahydro-1H-dipyrido[2,1-f:3′,2′,1′-ij][1,6]naphthyridin-10(41H)-one, the main research area is lung cancer sophoridine cisplatin sensitizer p53 Hippo signaling pathways; Cisplatin sensitivity; Hippo; Lung cancer; Sophoridine; p53.

Sophoridine, a quinolizidine alkaloid extracted from the Chinese herb Sophora alopecuroides L., has been reported to exert antitumor effects against multiple human cancers. However, few studies have evaluated its tumor-suppressing effects and associated mechanism with respect to lung cancer, in addition to its potential to be used for clin. lung cancer treatment. Different types of lung cancer cells were used to investigate the antitumor effects of sophoridine using cell viability, colony formation, and cell invasion, and migration assays. To determine the signaling pathways involved, western blot anal., quant. real-time polymerase chain reaction, an in vivo ubiquitination assay, and immunohistochem. were used in cellular assays and with a s.c. xenograft model in BALB/c mice. Sophoridine significantly suppressed the proliferation of and colony formation by lung cancer cells in vitro. Transwell assays demonstrated that sophoridine also inhibited invasion and migration in lung cancer cells. In addition, sophoridine enhanced the effects of cisplatin on lung cancer cells. A mechanistic study revealed that sophoridine significantly activated the Hippo and p53 signaling pathways, and mouse xenograft experiments further confirmed in vitro findings in lung cancer cells. Taken together, these results suggest that sophoridine can inhibit lung cancer progression and enhance the effects of the anticancer drug cisplatin against lung cancer cells. The mechanism of action of sophoridine might involve the Hippo and p53 signaling pathways.

Gene published new progress about Antitumor agents. 6882-68-4 belongs to class naphthyridine, and the molecular formula is C15H24N2O, Safety of (41S,7aR,13aR,13bR)-Dodecahydro-1H-dipyrido[2,1-f:3′,2′,1′-ij][1,6]naphthyridin-10(41H)-one.

Referemce:
1,8-Naphthyridine – Wikipedia,
1,8-Naphthyridine | C8H6N2 – PubChem

Yang, Haijuan; Rudge, Derek G.; Koos, Joseph D.; Vaidialingam, Bhamini; Yang, Hyo J.; Pavletich, Nikola P. published the artcile< mTOR kinase structure, mechanism and regulation>, Safety of 9-(6-Aminopyridin-3-yl)-1-(3-(trifluoromethyl)phenyl)benzo[h][1,6]naphthyridin-2(1H)-one, the main research area is mTOR active site gating bipartite substrate binding crystal structure.

The mammalian target of rapamycin (mTOR), a phosphoinositide 3-kinase-related protein kinase, controls cell growth in response to nutrients and growth factors and is frequently deregulated in cancer. Here we report co-crystal structures of a complex of truncated mTOR and mammalian lethal with SEC13 protein 8 (mLST8) with an ATP transition state mimic (MgF3-) and with ATP-site inhibitors (Torin2, PP242, and PI-103). The structures reveal an intrinsically active kinase conformation, with catalytic residues and a catalytic mechanism remarkably similar to canonical protein kinases. The active site is highly recessed owing to the FKBP12-rapamycin-binding (FRB) domain and an inhibitory helix protruding from the catalytic cleft. MTOR-activating mutations map to the structural framework that holds these elements in place, indicating that the kinase is controlled by restricted access. In vitro biochem. shows that the FRB domain acts as a gatekeeper, with its rapamycin-binding site interacting with substrates to grant them access to the restricted active site. Rapamycin-FKBP12 inhibits the kinase by directly blocking substrate recruitment and by further restricting active-site access. The structures also reveal active-site residues and conformational changes that underlie inhibitor potency and specificity.

Nature (London, United Kingdom) published new progress about Conformational transition. 1223001-51-1 belongs to class naphthyridine, and the molecular formula is C24H15F3N4O, Safety of 9-(6-Aminopyridin-3-yl)-1-(3-(trifluoromethyl)phenyl)benzo[h][1,6]naphthyridin-2(1H)-one.

Referemce:
1,8-Naphthyridine – Wikipedia,
1,8-Naphthyridine | C8H6N2 – PubChem

Lopatynska-Mazurek, Malgorzata; Komsta, Lukasz; Gibula-Tarlowska, Ewa; Kotlinska, Jolanta H. published the artcile< Aversive Learning Deficits and Depressive-Like Behaviors Are Accompanied by an Increase in Oxidative Stress in a Rat Model of Fetal Alcohol Spectrum Disorders: The Protective Effect of Rapamycin>, Recommanded Product: 9-(6-Aminopyridin-3-yl)-1-(3-(trifluoromethyl)phenyl)benzo[h][1,6]naphthyridin-2(1H)-one, the main research area is rapamycin fetal alc spectrum disorder oxidative stress depression learning; Rapamycin; adult rats; depressive-like behavior; learning; neonatal ethanol exposure; oxidative stress.

Fetal alc. spectrum disorders (FASDs) are one of the most common consequences of ethanol exposure during pregnancy. In adulthood, these disorders can be manifested by learning and memory deficits and depressive-like behavior. Ethanol-induced oxidative stress may be one of the factors that induces FASD development. The mammalian target of the Rapamycin (mTOR) signaling pathway that acts via two distinct multiprotein complexes, mTORC1 and mTORC2, can affect oxidative stress. We investigated whether mTOR-dependent or mTOR-independent mechanisms are engaged in this phenomenon. Thus, Rapamycin-a selective inhibitor of mTORC1, Torin-2-a non-selective mTORC1/mTORC2 inhibitor, and FK-506-a drug that impacts oxidative stress in an mTOR-independent manner were used. Behavioral tests were performed in adult (PND60-65) rats using a passive avoidance (PA) task (aversive learning and memory) and forced swimming test (FST) (depressive-like behaviors). In addition, the biochem. parameters of oxidative stress, such as lipid peroxidation (LPO), as well as apurinic/apyrimidinic (AP)-sites were determined in the hippocampus and prefrontal cortex in adult (PND65) rats. The rat FASD model was induced by intragastric ethanol (5 g/kg/day) administration at postnatal day (PND)4-9 (an equivalent to the third trimester of human pregnancy). All substances (3 mg/kg) were given 30 min before ethanol. Our results show that neonatal ethanol exposure leads to deficits in context-dependent fear learning and depressive-like behavior in adult rats that were associated with increased oxidative stress parameters in the hippocampus and prefrontal cortex. Because these effects were completely reversed by Rapamycin, an mTORC1 inhibitor, this outcome suggests its usefulness as a preventive therapy in disorders connected with prenatal ethanol exposure.

International Journal of Molecular Sciences published new progress about Adult, mammalian. 1223001-51-1 belongs to class naphthyridine, and the molecular formula is C24H15F3N4O, Recommanded Product: 9-(6-Aminopyridin-3-yl)-1-(3-(trifluoromethyl)phenyl)benzo[h][1,6]naphthyridin-2(1H)-one.

Referemce:
1,8-Naphthyridine – Wikipedia,
1,8-Naphthyridine | C8H6N2 – PubChem

Vogel, Kara R.; Ainslie, Garrett R.; Walters, Dana C.; McConnell, Alice; Dhamne, Sameer C.; Rotenberg, Alexander; Roullet, Jean-Baptiste; Gibson, K. Michael published the artcile< Succinic semialdehyde dehydrogenase deficiency, a disorder of GABA metabolism: an update on pharmacological and enzyme-replacement therapeutic strategies>, Reference of 1223001-51-1, the main research area is NCS 382 enzyme replacement therapy succinic semialdehyde dehydrogenase deficiency; Enzyme replacement therapy; GABA; Gamma-hydroxybutyric aciduria; Succinic semialdehyde dehydrogenase deficiency; Torin 2; mTOR.

We present an update to the status of research on succinic semialdehyde dehydrogenase (SSADH) deficiency (SSADHD), a rare disorder of GABA metabolism This is an unusual disorder featuring the accumulation of both GABA and its neuromodulatory analog, gamma-hydroxybutyric acid (GHB), and recent studies have advanced the potential clin. application of NCS-382, a putative GHB receptor antagonist. Animal studies have provided proof-of-concept that enzyme replacement therapy could represent a long-term therapeutic option. The characterization of neuronal stem cells (NSCs) derived from aldehyde dehydrogenase 5a1-/- (aldh5a1-/-) mice, the murine model of SSADHD, has highlighted NSC utility as an in vitro system in which to study therapeutics and associated toxicol. properties. Gene expression analyses have revealed that transcripts encoding GABAA receptors are down-regulated and may remain largely immature in aldh5a1-/- brain, characterized by excitatory as opposed to inhibitory outputs, the latter being the expected action in the mature central nervous system. This indicates that agents altering chloride channel activity may be therapeutically relevant in SSADHD. The most recent therapeutic prospects include mTOR (mechanistic target of rapamycin) inhibitors, drugs that have received attention with the elucidation of the effects of elevated GABA on autophagy. The outlook for novel therapeutic trials in SSADHD continues to improve.

Journal of Inherited Metabolic Disease published new progress about Autophagy. 1223001-51-1 belongs to class naphthyridine, and the molecular formula is C24H15F3N4O, Reference of 1223001-51-1.

Referemce:
1,8-Naphthyridine – Wikipedia,
1,8-Naphthyridine | C8H6N2 – PubChem

Vogel, K. R.; Ainslie, G. R.; McConnell, A.; Roullet, J.-B.; Gibson, K. M. published the artcile< Toxicologic/transport properties of NCS-382, a γ-hydroxybutyrate (GHB) receptor ligand, in neuronal and epithelial cells: Therapeutic implications for SSADH deficiency, a GABA metabolic disorder>, Quality Control of 1223001-51-1, the main research area is NCS382 hydroxybutyrate receptor ligand toxicol transport neuron epithelium; GABA metabolism; NCS-382; Neuronal stem cells; SSADH deficiency (SSADHD); Succinic semialdehyde dehydrogenase (SSADH); γ-Hydroxybutyric acid (GHB).

We report the in vitro assessment of pharmacotoxicity for the high-affinity GHB receptor ligand, NCS-382, using neuronal stem cells derived from mice with a targeted deletion of the aldehyde dehydrogenase 5a1 gene (succinic semialdehyde dehydrogenase (SSADH)-deficient mice). These animals represent a phenocopy of the human disorder of GABA metabolism, SSADH deficiency, that metabolically features accumulation of both GABA and the GABA-analog γ-hydroxybutyric acid in conjunction with a nonspecific neurol. phenotype. We demonstrate for the first time using MDCK cells that NCS-382 is actively transported and capable of inhibiting GHB transport. Following these in vitro assays with in vivo studies in aldh5a1-/- mice, we found the ratio of brain/liver GHB to be unaffected by chronic NCS-382 administration (300 mg/kg; 7 consecutive days). Employing a variety of cellular parameters (reactive oxygen and superoxide species, ATP production and decay, mitochondrial and lysosomal number, cellular viability and necrosis), we demonstrate that up to 1 mM NCS-382 shows minimal evidence of pharmacotoxicity. As well, studies at the mol. level indicate that the effects of NCS-382 at 0.5 mM are minimally toxic as evaluated using gene expression assay. The cumulative data provides increasing confidence that NCS-382 could eventually be considered in the therapeutic armament for heritable SSADH deficiency.

Toxicology In Vitro published new progress about Animal gene Role: BSU (Biological Study, Unclassified), BIOL (Biological Study) (aldh5a1). 1223001-51-1 belongs to class naphthyridine, and the molecular formula is C24H15F3N4O, Quality Control of 1223001-51-1.

Referemce:
1,8-Naphthyridine – Wikipedia,
1,8-Naphthyridine | C8H6N2 – PubChem

Kumar, Pavan; Awasthi, Ankita; Nain, Vikrant; Issac, Biju; Puria, Rekha published the artcile< Novel insights into TOR signaling in Saccharomyces cerevisiae through Torin2>, Quality Control of 1223001-51-1, the main research area is gene transcription repression mTOR signaling Saccharomyces Torin2 inhibition; Asymmetric cell division; Budding pattern; Iron toxicity; Saccharomyces; Torin2.

Target of rapamycin (TOR) regulates cellular homeostasis by coordinating cellular growth pathways in response to different environmental signals. Rapamycin, an allosteric TOR complex 1 (TORC1) inhibitor, has proven to be invaluable for elucidating various aspects of the TOR signaling pathway; however, its applications are limited due to its inability to completely suppress TORC2. In the present study, we examined the effects of a newly discovered potent TOR inhibitor, Torin2, which inhibits both TORC1 and TORC2, on Saccharomyces cerevisiae growth. Genome-scale expression profiling of Torin2 treated yeast cells showed an expression profile similar to that of other TOR inhibitors such as rapamycin and caffeine. Distinct inhibition of cell growth by Torin2 treatment is indicated by the fact that a smaller number of transcripts are altered, compared to the changes after rapamycin and caffeine treatments. Our results revealed that Torin2 leads to increased expression of the calcineurin pathway genes favoring a synergistic therapeutic response of Torin2 in combination with calcineurin inhibitors. Further, Torin2 causes defective bud site selection during asym. cell division, indicating a role of TOR signaling in regulation of the budding pattern. Torin2 treated yeast cells exhibit increased expression of metalloreductases which affects iron homeostasis leading to iron toxicity. Notably, the enhanced expression of TOR1 and TOR2 rescue the Torin2 augmented iron toxicity of yeast cell. This study has revealed novel conduits and our results suggest that using Torin2 will enable the dissection of TORC2 mediated functions of the TOR signaling pathway.

Gene published new progress about Asymmetric cell division. 1223001-51-1 belongs to class naphthyridine, and the molecular formula is C24H15F3N4O, Quality Control of 1223001-51-1.

Referemce:
1,8-Naphthyridine – Wikipedia,
1,8-Naphthyridine | C8H6N2 – PubChem

Bruning, Ulrike; Morales-Rodriguez, Francisco; Kalucka, Joanna; Goveia, Jermaine; Taverna, Federico; Queiroz, Karla C. S.; Dubois, Charlotte; Cantelmo, Anna Rita; Chen, Rongyuan; Loroch, Stefan; Timmerman, Evy; Caixeta, Vanessa; Bloch, Katarzyna; Conradi, Lena-Christin; Treps, Lucas; Staes, An; Gevaert, Kris; Tee, Andrew; Dewerchin, Mieke; Semenkovich, Clay F.; Impens, Francis; Schilling, Birgit; Verdin, Eric; Swinnen, Johannes V.; Meier, Jordan L.; Kulkarni, Rhushikesh A.; Sickmann, Albert; Ghesquiere, Bart; Schoonjans, Luc; Li, Xuri; Mazzone, Massimiliano; Carmeliet, Peter published the artcile< Impairment of Angiogenesis by Fatty Acid Synthase Inhibition Involves mTOR Malonylation>, Quality Control of 1223001-51-1, the main research area is fatty acid synthase mTOR acetyl CoA malonylation angiogenesis; angiogenesis; endothelial cell; fatty acid synthase; lipids; mTOR; mTORC1; malonyl-CoA; metabolism; post-translational modifications; protein malonylation.

The role of fatty acid synthesis in endothelial cells (ECs) remains incompletely characterized. We report that fatty acid synthase knockdown (FASNKD) in ECs impedes vessel sprouting by reducing proliferation. Endothelial loss of FASN impaired angiogenesis in vivo, while FASN blockade reduced pathol. ocular neovascularization, at >10-fold lower doses than used for anti-cancer treatment. Impaired angiogenesis was not due to energy stress, redox imbalance, or palmitate depletion. Rather, FASNKDelevated malonyl-CoA levels, causing malonylation(a post-translational modification) of mTOR at lysine 1218 (K1218). MTOR K-1218 malonylation impaired mTOR complex 1 (mTORC1) kinase activity, thereby reducing phosphorylation of downstream targets(p70S6K/4EBP1). Silencing acetyl-CoA carboxylase 1 (an enzyme producing malonyl-CoA) normalized malonyl-CoA levels and reactivated mTOR in FASNKD ECs. Mutagenesis unveiled the importance of mTOR K1218 malonylation for angiogenesis. This study unveils a novel role of FASN in metabolite signaling that contributes to explaining the anti-angiogenic effect of FASN blockade.

Cell Metabolism published new progress about Angiogenesis. 1223001-51-1 belongs to class naphthyridine, and the molecular formula is C24H15F3N4O, Quality Control of 1223001-51-1.

Referemce:
1,8-Naphthyridine – Wikipedia,
1,8-Naphthyridine | C8H6N2 – PubChem

Tang, Qing; Luo, Ding; Lin, Ding-Chai; Wang, Wen-Zhi; Li, Can-Jie; Zhuo, Xue-Fang; Wu, Zhong-Nan; Zhang, Yu-Bo; Wang, Guo-Cai; Li, Yao-Lan published the artcile< Five matrine-type alkaloids from Sophora tonkinensis>, Safety of (41S,7aR,13aR,13bR)-Dodecahydro-1H-dipyrido[2,1-f:3′,2′,1′-ij][1,6]naphthyridin-10(41H)-one, the main research area is Sophora root 1213 dehydrosophoridine isosophocarpine sophoridine; 12,13-dehydrosophoridine; 13β-hydroxymatrine; Anti-inflammatory activity; Matrine-type alkaloid; Sophora tonkinensis.

Five matrine-type alkaloids (1-5) including two new compounds (1 and 3) and a new natural product (2) were isolated from the roots of Sophora tonkinesis. Their structures were identified by extensive spectroscopic anal. (UV, IR, HRESIMS and NMR). The absolute configurations of 2 and 3 were determined by X-ray diffraction. Compounds 1-5 were evaluated their activity against inflammatory cytokines TNF-α and IL-6 levels on LPS-induced RAW 264.7 macrophages, and compound 1 showed the most significant activity, potent than that of matrine, the representative ingredient from Sophora plants. Graphic abstract: [graphic not available: see fulltext]

Journal of Natural Medicines published new progress about Alkaloids Role: BSU (Biological Study, Unclassified), BIOL (Biological Study). 6882-68-4 belongs to class naphthyridine, and the molecular formula is C15H24N2O, Safety of (41S,7aR,13aR,13bR)-Dodecahydro-1H-dipyrido[2,1-f:3′,2′,1′-ij][1,6]naphthyridin-10(41H)-one.

Referemce:
1,8-Naphthyridine – Wikipedia,
1,8-Naphthyridine | C8H6N2 – PubChem

Wang, Congcong; Zhang, Ruiguo; Tan, Jian; Meng, Zhaowei; Zhang, Yueqian; Li, Ning; Wang, Hanjie; Chang, Jin; Wang, Renfei published the artcile< Effect of mesoporous silica nanoparticles co-loading with 17-AAG and Torin2 on anaplastic thyroid carcinoma by targeting VEGFR2>, Product Details of C24H15F3N4O, the main research area is anaplastic thyroid carcinoma mesoporous silica nanoparticle; anaplastic thyroid carcinoma; vascular endothelial growth factor receptor 2; molecular targeted drugs; drug combination therapy; resistance; nanoparticles.

Anaplastic thyroid carcinoma (ATC) is a highly aggressive tumor with a poor prognosis and a low median survival rate because of insufficient effective therapeutic modalities. Recently, mesoporous silica nanoparticles (MSNs) as a green non-toxic and safe nanomaterial have shown advantages to be a drug carrier and to modify the targeting group to the targeted therapy. To aim of the study was to explore the effects of MSNs co-loading with 17-allylamino-17-demethoxy-geldanamycin (17-AAG; HSP90 inhibitor) and 9-(6-aminopyridin-3-yl)-1-(3-(trifluoromethyl)phenyl)benzo[h][1,6]naphthyridin-2(1H)-one (Torin2; mTOR inhibitor) by targeting vascular endothelial growth factor receptor 2 (VEGFR2) on the viability of human anaplastic thyroid carcinoma FRO cells. The cytotoxicity of 17-AAG and Torin2 were analyzed by MTT assay. The possible synergistic antitumor effects between 17-AAG and Torin2 were evaluated by CompuSyn software. Flow cytometry was performed to assess the VEGFR2 targeting of (17-AAG + Torin2)@MSNs-anti-VEGFR2 ab and uptake by FRO cells. An ATC xenograft mouse model was established to assess the antitumor effect of (17-AAG + Torin2)@MSNs-anti-VEGFR2 ab in vivo. The results revealed that the combination of 17-AAG and Torin2 inhibited the growth of FRO cells more effectively compared with single use of these agents. Addnl., the synergistic antitumor effect appeared when concentration ratio of the two drugs was 1:1 along with total drug concentration greater than 0.52μM. Furthermore, in an ATC animal model, it was revealed that the (17-AAG + Torin2)@MSNs-anti-VEGFR2 ab therapy modality could most effectively prolong the median survival time [39.5 days vs. 33.0 days (non-targeted) or 27.5 days (control)]. Compared to (17-AAG + Torin2)@MSNs, the (17-AAG + Torin2)@MSNs-anti-VEGFR2 ab could not only inhibit ATC cell growth but also prolong the median survival time of tumor-bearing mice in vivo and vitro more effectively, which may provide a new promising therapy for ATC.

Oncology Reports published new progress about Anaplastic thyroid gland carcinoma. 1223001-51-1 belongs to class naphthyridine, and the molecular formula is C24H15F3N4O, Product Details of C24H15F3N4O.

Referemce:
1,8-Naphthyridine – Wikipedia,
1,8-Naphthyridine | C8H6N2 – PubChem