Effect of MEHP on testosterone synthesis via Sirt1/Foxo1/Rab7 signaling pathway inhibition of lipophagy in TM3 cells.

Mono-2-ethylhexyl phthalic acid (MEHP) is the most toxic metabolite of the plasticizer di-2-ethylhexyl phthalic acid (DEHP), and studies have shown that MEHP causes serious reproductive effects. However, its exact mechanisms of action remain elusive. In this study, we aimed to investigate the reproductive effects of MEHP and preliminarily explore its underlying molecular mechanisms. We found that TM3 cells gradually secreted less testosterone and intracellular free cholesterol with increasing MEHP exposure. MEHP exposure inhibited lipophagy and the Sirt1/Foxo1/Rab7 signaling pathway in TM3 cells, causing aberrant accumulation of intracellular lipid droplets. Addition of the Sirt1 agonist SRT1720 and Rab7 agonist ML-098 alleviated the inhibition of lipophagy and increased free cholesterol and testosterone contents in TM3 cells. SRT1720 alleviated the inhibitory effect of MEHP on the Sirt1/Foxo1/Rab7 signaling pathway, whereas ML-098 only alleviated the inhibition of Rab7 protein expression by MEHP and had no effect on Sirt1 and Foxo1 protein expression. This suggests that MEHP inhibits lipophagy in TM3 cells by suppressing the Sirt1/Foxo1/Rab7 signaling pathway, ultimately leading to a further decrease in cellular testosterone secretion. This study improves our current understanding of the toxicity and molecular mechanisms of action of MEHP and provides new insights into the reproductive effects of phthalic acid esters.

Overexpression of PIK3CG in Cancer Cells Promotes Lung Cancer Cell Migration and Metastasis Through Enhanced MMPs Expression and Neutrophil Recruitment and Activation.

Metastasis is a major cause of death in lung cancer. The aim of this study is to analyze the role and mechanism of PI3K catalytic subunit gamma (PIK3CG, also known as p110γ) in lung cancer cell migration and metastasis. Knockdown (KD) and overexpression (OE) of PIK3CG expression in lung cancer cell lines A549 and H1299 in vitro cultured was achieved. Two PIK3CG-specific inhibitors, Eganelisib and CAY10505, were used to treat A549 and H1299 cells. An experimental lung metastasis mouse model was constructed using tail vein injection of LLC cells. Finally, a co-culture system was established using Transwell chambers. Compared with the NC group, the number of cells that completed migration and the expression levels of matrix metalloproteinases (MMPs) were significantly reduced in the KD group and Eganelisib and CAY10505 treatment groups, while the number of cells that migrated successfully and the expression levels of MMPs were significantly increased in the OE group. Lung tissues of mice injected with PIK3CG-stabilized overexpressed LLC cells showed more pronounced lung cancer growth, lung metastatic nodules, neutrophil infiltration and MMPs expression. Co-culture with neutrophils, soluble extracts of neutrophils and cathepsin G all promoted the migration of lung cancer cells. PIK3CG overexpression in tumor cells significantly promoted the migration and metastasis of lung cancer cell.

The mechanism of monobutyl phthalate -induced ferroptosis via TNF/IL6/STAT3 signal pathway in TM-3 cells.

As a common environmental endocrine disruptor, monobutyl phthalate (MBP) has been connected to reports of ROS accumulation, sperm destruction and reproductive damage. However, the specific mechanism of reproductive injury caused by MBP remains uncertain. Ferroptosis is a non-apoptotic, controlled oxidative damage-related cell death that is usually connected with reactive oxygen species and lipid peroxidation. In this work, to evaluate the mechanism of MBP-induced ferroptosis in reproductive damage, bioinformation analysis and experimental validation were used. Based on bioinformatics analysis, the interleukin-6 (IL-6) and signal transducer and activator of transcription 3 (STAT3) genes may be involved in the tumor necrosis factor (TNF) signaling pathway, which controls inflammation. Experimental study validated the significance of IL6 and STAT3 in MBP-induced ferroptosis. Western blotting and quantitative real-time PCR revealed that Acyl-CoA Synthetase Long Chain Family Member 4 (ACSL4), Tumor necrosis factor-α (TNF-α), IL6, and STAT3 were all elevated with treatment of MBP, but Glutathione peroxidase 4 was significantly decreased. To determine the participation of IL6/STAT3, we added the ferroptosis inhibitor Ferrastain-1 (Fer-1) and the IL6/STAT3 pathway inhibitor Angoline. In conclusion, we found that MBP induced ferroptosis in TM3 cells to damage male reproductive system through the TNF/IL6/STAT signal pathway, resulting in lipid peroxidation and iron metabolite degradation.

A multiple-step screening protocol to identify norepinephrine and dopamine reuptake inhibitors for depression.

Depression severely impairs the health of people all over the world. Cognitive dysfunction due to depression has resulted in a severe economic burden to family and society induced by the reduction of social functioning of patients. Norepinephrine-dopamine reuptake inhibitors (NDRIs) targeted with the human norepinephrine transporter (hNET) and distributed with the human dopamine transporter (hDAT) simultaneously treat depression and improve cognitive function, and they effectively prevent sexual dysfunction and other side effects. Because many patients continue to poorly respond to NDRIs, it is urgent to discover novel NDRI antidepressants that do not interfere with cognitive function. The aim of this work was to selectively identify novel NDRI candidates acting against hNET and hDAT from large compound libraries by a comprehensive strategy integrating support vector machine (SVM) models, ADMET, molecular docking, in vitro binding assays, molecular dynamics simulation, and binding energy calculation. First, 6522 compounds that do not inhibit the human serotonin transporter (hSERT) were obtained by SVM models of hNET, hDAT, and non-target hSERT with similarity analyses from compound libraries. ADMET and molecular docking were then used to identify compounds that could potently bind to the hNET and hDAT with satisfactory ADMET, and 4 compounds were successfully identified. According to their docking scores and ADMET information, 3719810 was advanced for profiling by in vitro assays as a novel NDRI lead compound due to its strongest druggability and balancing activities. Encouragingly, 3719810 performed comparative activities on two targets, with Ki values of 7.32 µM for hNET and 5.23 µM for hDAT. To obtain candidates with additional activities and balance the activities of 2 targets, 5 analogs were optimized, and 2 novel scaffold compounds were successively designed. By assessment of molecular docking, molecular dynamics simulations, and binding energy calculations, 5 compounds were validated as NDRI candidates with high activities, and 4 of them performed acceptable balancing activities acting on hNET and hDAT. This work supplied promising novel NDRIs for treatment of depression with cognitive dysfunction or other related neurodegenerative disorders, and also provided a strategy for highly efficient and cost-effective identification of inhibitors for dual targets with homologous non-targets.

Exploring the binding mechanism of positive allosteric modulators in human metabotropic glutamate receptor 2 using molecular dynamics simulations.

Positive allosteric modulators (PAMs) of human metabotropic glutamate receptor 2 (hmGlu2) are well-known in the treatment of psychiatric disorders for their higher selectivity and lower tolerance risk. A variety of PAMs have been reported over the last decade and two compounds were in Phase II clinical trials for schizophrenia and anxiety. These trials were discontinued on account of the unsatisfactory therapeutic efficacy, but PAMs were explored as novel treatments for addiction and epilepsy. Thus, it is still important to explore novel hmGlu2 PAMs in the near future. Nowadays, the challenges in optimizing drug potency and improving scaffold diversity for PAMs are the noncomprehensive character analyses of multiple scaffolds; the exploration of the binding modes of PAMs in the allosteric binding site have been proposed to reduce this difficulty. However, there has been no comprehensive research about the binding profiles of PAMs in the hmGlu2 receptor. To address this issue, this work explores the binding characters of eight PAMs representing five chemical series by multiple computational methods. As a result, the shared binding modes of the eight studied PAMs interacting with 15 residues in the allosteric binding site were defined. In addition, the reduced hydrophobicity with low electronegativity of R1, increased hydrophobicity with low negative electron density of R2 and the electronegativity of the linker were identified as indicators that regulate the affinity of PAMs. This finding agrees well with the physicochemical properties of reported multiple series PAMs. This comprehensive work sheds additional light on the binding mechanism and physicochemical regularity underlining PAMs affinity and could be further utilized as a structural and energetic blueprint for discovering and assessing novel PAMs for hmGlu2.

Profiling the structural determinants of aminoketone derivatives as hNET and hDAT reuptake inhibitors by field-based QSAR based on molecular docking.

BACKGROUND: Bupropion, one of the dual norepinephrine and dopamine reuptake inhibitors (NDRIs), is an aminoketone derivative performed effect in improving cognitive function for depression. However, its therapeutic effect is unsatisfactory due to poor clinical response, and there are only few derivatives in pre-clinical settings. OBJECTIVE: This work attempted to elucidate the essential structural features for the activity and designed a series of novel derivatives with good inhibitive ability, pharmacokinetic and medicinal chemistry properties. METHODS: The field-based QSAR of aminoketone derivatives of two targets were established based on docking poses, and the essential structural properties for designing novel compounds were supplied by comparing contour maps. RESULTS: The selected two models performed good predictability and reliability with R2 of 0.8479 and 0.8040 for training set, Q2 of 0.7352 and 0.6266 for test set respectively, and the designed 29 novel derivatives performed no less than the highest active compound with good ADME/T pharmacokinetic properties and medicinal chemistry friendliness. CONCLUSIONS: Bulky groups in R1, bulky groups with weak hydrophobicity in R3, and potent hydrophobic substituted group with electronegative in R2 from contour maps provided important insights for assessing and designing 29 novel NDRIs, which were considered as candidates for cognitive dysfunction with depression or other related neurodegenerative disorders.

Synthesis and luminescence characterization of a new yellowish-orange phosphor: Ba2 B10 O17 :Sm3.

A new yellowish-orange emitting phosphor, Ba2 B10 O17 :Sm3+ for use as a white light-emitting diode (W-LED) was synthesized by a solid-state reaction method. The X-ray diffraction results indicated that a pure Ba2 B10 O17 material was obtained. As a potential yellowish-orange luminescent material for W-LEDs, the Ba2 B10 O17 :Sm3+ phosphor could be excited effectively by near-ultraviolet (n-UV) light and exhibited yellowish-orange emission centered at 560 nm corresponding to the 4 G5/2  â†’ 6 H5/2 transition of Sm3+ ions. The optimum concentration of Sm3+ ions in Ba2 B10 O17 , critical transfer distance (Ra) and concentration quenching mechanism of the presented phosphor were investigated. Moreover, CIE chromaticity coordinates and color purity performance of the Ba2 B10 O17 :Sm3+ phosphor were also discussed. The present work suggests that the Ba2 B10 O17 :Sm3+ phosphor has potential as a type of yellowish-orange emitting phosphor. Copyright © 2016 John Wiley & Sons, Ltd.

Aqua-(2,9-dimethyl-1,10-phenanthroline-κN,N')bis-(2-hydroxy-benzoato-κO)manganese(II) 2,9-dimethyl-1,10-phenanthroline hemisolvate.

In the asymmetric unit of the title complex, [Mn(C(7)H(5)O(3))(2)(C(14)H(12)N(2))(H(2)O)]·0.5C(14)H(12)N(2), the Mn(II) ion is coordinated by a bidentate 2,9-dimethyl-1,10-phenanthroline (dmphen) mol-ecule, one water mol-ecule and two monodentate 2-hydroxy-benzoate anions in a distorted trigonal-bipyramidal geometry. The OH group of the 2-hydroxy-benzoate anion is disordered over two positions with site-occupancy factors of 0.5. The asymmetric unit is completed with by an uncoordinated half-mol-ecule of dmphen, disordered about a crystallographic twofold axis. In the crystal structure, mol-ecules are linked into a two-dimensional framework by O-H⋯N, O-H⋯O and C-H⋯O hydrogen bonds. The packing of the structure is further stabilized by π-π stacking inter-actions involving dmphen mol-ecules, with centroid-centroid separations of 3.8027 (3) and 3.6319 (3) Å.

[Relation between complexes iotramolecular transfer and structure of [M(SS) (NN)](M = Zn2+, Cd2+)].

The title complexes of [M(SS)(NN)](M = Zn2+, Cd+; SS = 1,2-dicyano 1,2-ethylene -dithiolate or maleonitriledithiolate; NN = 5-nitro-1,10 phenanthroline) were synthesized. The electronic absorption spectra of complexes [M(SS)(NN)] in DMSO, DMF, acetone and Py were reported. The spectra absorption bands 270-280 nm, 320-350 nm and 350-390 nm are the intraligand pi(b) --> pi* transfer of ligand mnt(2-) and 5-NOz-phen. The spectra absorption band 400-500 nm is intramolecular charge transfer (LL'CT) from a ligand (mnt(2-)) to another ligand (5-NO2- phen) The relation between electronic spectra absorption band and correlative transition in the molecular orbital energy level diagram of the complexes was investigated. The LL'CT band of the title complexes is weaker by comparison with M(SS) (NN) (M = Co2+, Fe2+, Ni2+ and Cu2+). The LL'CT band of [M(SS) (NN)](M = Zn2+, Cd2+) (7b2 to 7b1) is symmetry forbidden.

(2,9-Dimethyl-1,10-phenanthroline-κN,N')(4-hydroxy-benzoato-κO,O')(nitrato-κO)copper(II).

In the title compound, [Cu(C(7)H(5)O(3))(NO(3))(C(14)H(12)N(2))], the Cu(II) ion is five-coordinated in a slightly distorted square-pyramidal geometry by one O atom of a nitrate anion, two O atoms of a 4-hydroxy-benzoate anion, and two N atoms from a bidentate 2,9-dimethyl-1,10-phenanthroline (dmphen) ligand. In the crystal structure, inversion-related mol-ecules are linked into dimers by O-H⋯O hydrogen bonds. The packing is further stabilized by π-π inter-actions involving the benzene rings of the dmphen and hydroxy-benzoate units, with centroid-centroid distances of 3.4930 (14) or 3.5727 (14) Å.

(2,9-Dimethyl-1,10-phenanthroline-κN,N')bis-(2-hydroxy-benzoato-κO)copper(II).

The Cu(II) atoms in the two independent mol-ecules of the title compound, [Cu(C(7)H(5)O(3))(2)(C(14)H(12)N(2))], are each coordinated by a bidentate 2,9-dimethyl-1,10-phenanthroline (dmphen) mol-ecule and two monodentate 2-hydroxy-benzoate anions in a distorted tetra-hedral geometry. The crystal packing is stabilized by intra-molecular hydrogen bonding and π-π inter-actions between the dmphen rings of neighboring mol-ecules, with distances between their ring planes of 3.5670 (4) and 3.5181 (9) Å.

Diaqua-(2,9-dimethyl-1,10-phenanthroline-κN,N')(4-hydroxy-benzoato-κO,O')cobalt(II) nitrate dihydrate.

In the title compound, [Co(C(7)H(5)O(3))(C(14)H(12)N(2))(H(2)O)(2)]NO(3)·2H(2)O, the Co(II) ion is six-coordinated by two N atoms of a 2,9-dimethyl-1,10-phenanthroline (dmphen) ligand, two carboxyl-ate O atoms of one 4-hydroxy-benzoate anion and two O atoms of two water mol-ecules, in a distorted octa-hedral environment; the two water mol-ecules occupy the apical positions. In the crystal structure, the ionic units and water mol-ecules are linked through O-H⋯O hydrogen bonds, leading to the formation of a three-dimensional network. In addition, π-π inter-actions between a pyridine ring of the dmphen ligand and the benzene ring of the hydroxy-benzoate anion [centroid-centroid separation = 3.6861 (3) Å] are observed.