Protective effects of tannic acid on acute doxorubicin-induced cardiotoxicity: Involvement of suppression in oxidative stress, inflammation, and apoptosis.

Doxorubicin (DOX) is a highly effective drug, but its cardiotoxicity restricts its therapeutic index. Oxidative stress is the major etiopathological factor in DOX-induced cardiotoxicity. Tannic acid (TA) has various anti-cancer, antioxidant, and anti-inflammatory activities. The purpose of the study was to survey the possible effects of TA against acute DOX-induced cardiotoxicity. Male Sprague-Dawleyrats were randomly divided into five groups: control, DOX (10mg/kg) alone, DOX with TA (20 and 40mg/kg), or DOX withcaptopril (30mg/kg) treatments. TA or captopril was administered once daily for six days, and DOX was injected intraperitoneally on the fourth day. TA significantlyattenuated DOX myocardial effects. Pretreatment with TA caused a decrease in levels of the serum enzymes lactate dehydrogenase, creatine kinase, and creatine kinase isoenzyme-MB to normal values. As indicators of oxidative stress, the levels of glutathione peroxidasesuperoxide dismutase and catalasesignificantly increased while the levels of malondialdehyde decreased after TA treatment. Additionally, DOX provoked inflammatory responses by causing anincrease in levels of pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß), endothelin (ET)-1 levels, and nuclear factor kappa-B (NF-κB) expression while TA pretreatment significantly inhibited TNF-α, IL-1ß, ET-1, and NF-κB. Furthermore, DOX induced apoptosis by increasing bcl-2like protein and caspase-3 activities and c-fos and c-jun levels while causing a decrease in B-cell lymphoma-2 levels. Overall, there was evidence that TA could inhibit DOX-induced cardiotoxicity by inhibiting oxidative stress, inflammation and apoptotic damage.

Targeting methyltransferase PRMT5 eliminates leukemia stem cells in chronic myelogenous leukemia.

Imatinib-insensitive leukemia stem cells (LSCs) are believed to be responsible for resistance to BCR-ABL tyrosine kinase inhibitors and relapse of chronic myelogenous leukemia (CML). Identifying therapeutic targets to eradicate CML LSCs may be a strategy to cure CML. In the present study, we discovered a positive feedback loop between BCR-ABL and protein arginine methyltransferase 5 (PRMT5) in CML cells. Overexpression of PRMT5 was observed in human CML LSCs. Silencing PRMT5 with shRNA or blocking PRMT5 methyltransferase activity with the small-molecule inhibitor PJ-68 reduced survival, serial replating capacity, and long-term culture-initiating cells (LTC-ICs) in LSCs from CML patients. Further, PRMT5 knockdown or PJ-68 treatment dramatically prolonged survival in a murine model of retroviral BCR-ABL-driven CML and impaired the in vivo self-renewal capacity of transplanted CML LSCs. PJ-68 also inhibited long-term engraftment of human CML CD34+ cells in immunodeficient mice. Moreover, inhibition of PRMT5 abrogated the Wnt/ß-catenin pathway in CML CD34+ cells by depleting dishevelled homolog 3 (DVL3). This study suggests that epigenetic methylation modification on histone protein arginine residues is a regulatory mechanism to control self-renewal of LSCs and indicates that PRMT5 may represent a potential therapeutic target against LSCs.

Endometrial breakdown with sustained progesterone release involves NF-κB-mediated functional progesterone withdrawal in a mouse implant model.

Irregular uterine bleeding is a major side effect of long-acting progestogen-only contraceptives in women, and is the primary reason women discontinue their use. In this study, a mouse model of endometrial breakdown was established using a subcutaneous progesterone implant to understand how irregular bleeding begins. Although progestogens sustained decidualization, endometrial breakdown was still observed in this model. We, therefore, hypothesized that endometrial breakdown might involve functional progesterone withdrawal. Using co-immunoprecipitation assays, we observed the constitutive activation of nuclear factor kappa-b (NF-κB) p65 and its interaction with the progesterone receptor (PGR); moreover, transcriptional activity of the PGR was also repressed by NF-κB activity in primary mouse and human decidual stromal cells that mimic progesterone maintenance. Yet the ratio of PGR-B to PGR-A was not increased in the mouse model. In vivo comparison of endometrial breakdown induced by progesterone withdrawal to that seen during sustained progesterone exposure, in the presence of NF-κB inhibitors, revealed that NF-κB-mediated functional progesterone withdrawal is involved in endometrial breakdown in this implant model. These data prompt further studies to determine the homology of this functional progesterone withdrawal mechanism in human endometrium. Mol. Reprod. Dev. 83: 780-791, 2016 © 2016 Wiley Periodicals, Inc.

Continuing treatment with Salvia miltiorrhiza injection attenuates myocardial fibrosis in chronic iron-overloaded mice.

Iron overload cardiomyopathy results from iron accumulation in the myocardium that is closely linked to iron-mediated myocardial fibrosis. Salvia miltiorrhiza (SM, also known as Danshen), a traditional Chinese medicinal herb, has been widely used for hundreds of years to treat cardiovascular diseases. Here, we investigated the effect and potential mechanism of SM on myocardial fibrosis induced by chronic iron overload (CIO) in mice. Kunming male mice (8 weeks old) were randomized to six groups of 10 animals each: control (CONT), CIO, low-dose SM (L-SM), high-dose SM (H-SM), verapamil (VRP) and deferoxamine (DFO) groups. Normal saline was injected in the CONT group. Mice in the other five groups were treated with iron dextran at 50 mg/kg per day intraperitoneally for 7 weeks, and those in the latter four groups also received corresponding daily treatments, including 3 g/kg or 6 g/kg of SM, 100 mg/kg of VRP, or 100 mg/kg of DFO. The iron deposition was estimated histologically using Prussian blue staining. Myocardial fibrosis was determined by Masson's trichrome staining and hydroxyproline (Hyp) quantitative assay. Superoxide dismutase (SOD) activity, malondialdehyde (MDA) content and protein expression levels of type I collagen (COL I), type I collagen (COL III), transforming growth factor-ß1 (TGF-ß1) and matrix metalloproteinase-9 (MMP-9) were analyzed to investigate the mechanisms underlying the effects of SM against iron-overloaded fibrosis. Treatment of chronic iron-overloaded mice with SM dose-dependently reduced iron deposition levels, fibrotic area percentage, Hyp content, expression levels of COL I and COL III, as well as upregulated the expression of TGF- ß1 and MMP-9 proteins in the heart. Moreover, SM treatment decreased MDA content and increased SOD activity. In conclusion, SM exerted activities against cardiac fibrosis induced by CIO, which may be attributed to its inhibition of iron deposition, as well as collagen metabolism and oxidative stress.

SAHA and S116836, a novel tyrosine kinase inhibitor, synergistically induce apoptosis in imatinib-resistant chronic myelogenous leukemia cells.

Limited treatment options are available for chronic myelogenous leukemia (CML) patients who develop imatinib mesylate (IM) resistance. Here we proposed a novel combination regimen, a co-administration of S116836, a novel small molecule multi-targeted tyrosine kinase inhibitor that was synthesized by rational design, and histone deacetylases inhibitor (HDACi) suberoylanilide hydroxamic acid (SAHA), to overcome IM resistance in CML. S116836 at low concentrations used in the present study mildly downregulates auto-tyrosine phosphorylation of Bcr-Abl. SAHA, an FDA-approved HDACi drug, at 1 µM has modest anti-tumor activity in treating CML. However, we found a synergistic interaction between SAHA and S116836 in Bcr-Abl-positive CML cells that were sensitive or resistant to IM. Exposure of KBM5 and KBM5-T315I cells to minimal or non-toxic concentrations of SAHA and S116836 synergistically reduced cell viability and induced cell death. Co-treatment with SAHA and S116838 repressed the expressions of anti-apoptosis proteins, such as Mcl-1 and XIAP, but promoted Bim expression and mitochondrial damage. Of importance, treatment with both drugs significantly reduced cell viability of primary human CML cells, as compared with either agent alone. Taken together, our findings suggest that SAHA exerts synergistically with S116836 at a non-toxic concentration to promote apoptosis in the CML, including those resistant to imatinib or dasatinib.

2-Cyano-anilinium perchlorate.

In the title compound, C(7)H(7)N(2) (+)·ClO(4) (-), the cation is almost planar (r.m.s. deviation = 0.042 Å). In the crystal structure, the cations and anions are linked into a two-dimensional network parallel to (100) by N-H⋯O hydrogen bonds.

Isonicotinonitrile-benzoic acid (1/1).

In the title 1:1 adduct, C(6)H(4)N(2)·C(7)H(6)O(2), the carboxyl group and its attached phenyl ring are essentially coplanar, being twisted from each other by a dihedral angle of only 2.05 (3)°. In the crystal, the mol-ecules are connected via O-H⋯N and C-H⋯O hydrogen bonds, building an R(2) (2)(7) ring. Mol-ecules are further linked through π-π inter-actions [centroid-centroid distance of 3.8431 (8) and 3.9094 (8) Å], leading to a one-dimensional chain parallel to the b axis.

2-(3-Pyridinio)benzimidazolium penta-chloridobismuthate(III) monohydrate.

In the title compound, (C(12)H(11)N(3))[BiCl(5)]·H(2)O, the Bi(III) atom is coordinated by five chloride anions in a distorted square-pyramidal geometry. The planar imidazole ring system [maximum deviation = 0.012 (3) Å] is oriented at a dihedral angle of 6.08 (5)° with respect to the protonated pyridine ring. An O-H⋯Cl inter-action links the water mol-ecule to the dianion. In the crystal structure, inter-molecular O-H⋯Cl, N-H⋯O and N-H⋯Cl inter-actions link the mol-ecules into a three-dimensional network.

3-[4-(Dimethyl-amino)benzyl-ideneamino]benzonitrile.

The mol-ecule of the title Schiff base, C(16)H(15)N(3), is non-planar and displays a trans configuration with respect to the C=N double bond. The two benzene rings make a dihedral angle of 49.24 (3)°.

2,4,6-Trimethyl-anilinium bromide.

In the title compound, C(9)H(14)N(+)·Br(-), an intra-molecular N-H⋯Br inter-action links the anion to the cation. In the crystal structure, inter-molecular N-H⋯Br inter-actions link the mol-ecules into a three-dimensional network.

3-(1H-Tetra-zol-5-yl)pyridinium 3-(2H-tetra-zol-5-yl)pyridinium dinitrate.

In the title compound, C(6)H(6)N(5) (+)·NO(3) (-), there are two different isomers of the cation within the asymmetric unit. The dihedral angles between the the pyridinium and tetra-zole rings are 2.54 (15) and 13.36 (18)° in the two cations. In the crystal, the packing of ions is stabilized by N-H⋯O and N-H⋯(O,O) hydrogen bonds, forming clusters composed of four ion pairs.

catena-Poly[potassium-di-µ-aqua-µ-4-(5-tetra-zolio)pyridine].

The title compound, [K(C(6)H(4)N(5))(H(2)O)(2)](n), was synthesized by hydro-thermal reaction of KOH with 4-(5-tetra-zolio)pyridine. The K atom has a distorted octa-hedral coordination environment and is coordinated by two axial N atoms from the organic ligand and by four water mol-ecules in the equatorial plane. The mol-ecules as a whole are located on crystallographic mirror planes; the K atom is also located on an inversion center. Both the water mol-ecules and the organic ligands act as bridges to link symmetrically the adjacent K atoms into polymeric chains parallel to the c axis. O-H⋯N hydrogen bonds involving the water O atoms and aromatic π-π inter-actions [centroid-centroid distance 3.80 (2) Å] between the pyridine and tetra-zole rings build up an infinite three-dimensional network.

2-(3-Pyridinio)benzimidazolium penta-chloridoanti-monate(III) monohydrate.

In the title compound, (C(12)H(11)N(3))[SbCl(5)]·H(2)O, the Sb(III) centre is surrounded by five Cl atoms and displays a distorted square-pyramidal coordination geometry. The dihedral angle formed by the plane of the imidazole ring system with the pyridine ring is 4.380 (15)°. The crystal structure is stabilized by N-H⋯Cl, O-H⋯Cl and N-H⋯O hydrogen bonds, forming a three-dimensional network.

2-(2H-Tetra-zol-5-yl)pyridinium nitrate.

In the cation of the title compound, C(6)H(6)N(5) (+)·NO(3) (-), the dihedral angle between the pyridinium and tetra-zole rings is 8.2 (2)°. The constituent ions of the compound are linked via N-H⋯O hydrogen bonds, forming helical chains running along the b axis. C-H⋯N and C-H⋯O hydrogen bonds are also observed.

1,2-Bis(1H-tetra-zol-5-yl)benzene dihydrate.

The asymmetric unit of the title compound, C(8)H(6)N(8)·2H(2)O, contains one half-mol-ecule, with the benzene ring on a centre of symmetry, and two uncoordinated water mol-ecules. The benzene ring is oriented at a dihedral angle of 34.43 (12)° with respect to the tetra-zole ring. Strong O-H⋯N hydrogen bonds link the water mol-ecules to the N atoms of the tetra-zole ring. In the crystal structure, strong inter-molecular O-H⋯O and O-H⋯N hydrogen bonds link the mol-ecules into a network. One of the water H atoms is disordered over two positions and was refined with occupancies of 0.50.

4,5-Diphenyl-2-p-tolyl-1H-imidazol-3-ium nitrate.

In the cation of the title compound, C(22)H(19)N(2) (+)·NO(3) (-), the N atom in the 3-position of the imidazole is protonated. The three pendant aromatic rings are twisted from the plane of the imadazolium ring by dihedral angles of 38.1 (1), 43.74 (9) and 20.4 (1)°. In the crystal structure, N-H⋯O and N-H⋯(O,O) hydrogen bonds link the mol-ecules to form an infinite one-dimensional chain parallel to the c axis.

4-Methyl-3-nitro-benzonitrile.

In the title compound, C(8)H(6)N(2)O(2), the nitro group is rotated by 23.2 (3)° out of the plane of the benzene ring. The crystal structure is stabilized by van der Waals inter-actions.

2-(3-Nitro-phen-yl)-4,5-diphenyl-1H-imidazol-3-ium chloride.

The title compound, C(21)H(16)N(3)O(2) (+)·Cl(-), contains two organic cations with similar conformation and two chloride ions in the asymmetric unit. The imidazole and benzene rings are twisted with respect to each other [dihedral angles of 24.05 (16), 24.31 (16) and 50.38 (13) in one cation and 27.70 (15), 25.07 (16) and 45.86 (14)° in the other]. The crystal packing is stabilized by N-H⋯Cl hydrogen bonds, forming an infinite one-dimensional chain parallel to the c axis.

2-Cyano-anilinium nitrate.

In the title compound, C(7)H(7)N(2) (+)·NO(3) (-), all atoms of the cation, with the exception of two H atoms of the NH(3) group, lie on a mirror plane, while the anion lies across this plane with the N and one O atom on the mirror plane. In the crystal structure, the organic cations and NO(3) (-) anions are linked by N-H⋯N and N-H⋯O hydrogen bonds, forming a two-dimensional network parallel to (100).