Hepatic NCoR1 deletion exacerbates alcohol-induced liver injury in mice by promoting CCL2-mediated monocyte-derived macrophage infiltration.

Nuclear receptor corepressor 1 (NCoR1) is a corepressor of the epigenetic regulation of gene transcription that has important functions in metabolism and inflammation, but little is known about its role in alcohol-associated liver disease (ALD). In this study, we developed mice with hepatocyte-specific NCoR1 knockout (NCoR1Hep-/-) using the albumin-Cre/LoxP system and investigated the role of NCoR1 in the pathogenesis of ALD and the underlying mechanisms. The traditional alcohol feeding model and NIAAA model of ALD were both established in wild-type and NCoR1Hep-/- mice. We showed that after ALD was established, NCoR1Hep-/- mice had worse liver injury but less steatosis than wild-type mice. We demonstrated that hepatocyte-specific loss of NCoR1 attenuated liver steatosis by promoting fatty acid oxidation by upregulating BMAL1 (a circadian clock component that has been reported to promote peroxisome proliferator activated receptor alpha (PPARα)-mediated fatty ß-oxidation by upregulating de novo lipid synthesis). On the other hand, hepatocyte-specific loss of NCoR1 exacerbated alcohol-induced liver inflammation and oxidative stress by recruiting monocyte-derived macrophages via C-C motif chemokine ligand 2 (CCL2). In the mouse hepatocyte line AML12, NCoR1 knockdown significantly increased ethanol-induced CCL2 release. These results suggest that hepatocyte NCoR1 plays distinct roles in controlling liver inflammation and steatosis, which provides new insights into the development of treatments for steatohepatitis induced by chronic alcohol consumption.

Cathepsin L-like Cysteine Proteinase Genes Are Associated with the Development and Pathogenicity of Pine Wood Nematode, Bursaphelenchus xylophilus.

The pine wood nematode (PWN), Bursaphelenchus xylophilus, is the pathogen of pine wilt disease (PWD), resulting in huge losses in pine forests. However, its pathogenic mechanism remains unclear. The cathepsin L-like cysteine proteinase (CPL) genes are multifunctional genes related to the parasitic abilities of plant-parasitic nematodes, but their functions in PWN remain unclear. We cloned three cpl genes of PWN (Bx-cpls) by rapid amplification of cDNA ends (RACE) and analyzed their characteristics using bioinformatic methods. The tissue specificity of cpl gene of PWN (Bx-cpl) was studied using in situ mRNA hybridization (ISH). The functions of Bx-cpls in development and pathogenicity were investigated using real-time quantitative PCR (qPCR) and RNA interference (RNAi). The results showed that the full-length cDNAs of Bx-cpl-1, Bx-cpl-2, and Bx-cpl-3 were 1163 bp, 1305 bp, and 1302 bp, respectively. Bx-cpls could accumulate specifically in the egg, intestine, and genital system of PWN. During different developmental stages of PWN, the expression of Bx-cpls in the egg stage was highest. After infection, the expression levels of Bx-cpls increased and reached their highest at the initial stage of PWD, then declined gradually. The silencing of Bx-cpl could reduce the feeding, reproduction, and pathogenicity of PWN. These results revealed that Bx-cpls play multiple roles in the development and pathogenic processes of PWN.

Polygalasaponin F against rotenone-induced apoptosis in PC12 cells via mitochondria protection pathway.

To investigate the protective effect and the underlying mechanism of polygalasaponin F (PS-F) against rotenone-induced PC12 cells, the cell viability was evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide assay. The cell apoptosis rate was analyzed using flow cytometry. The reactive oxygen species was examined using 2',7'-dichlorofluorescin diacetate, and the adenosine triphosphate depletion was examined using a luciferase-coupled quantification assay. JC-1 staining was used to detect the mitochondrial membrane potential. Western blotting analysis was used to determine cytochrome c, p53, Bax, Bcl-2, and caspase-3. Treatment of PC12 cells with rotenone (1-10 µmol/l) significantly reduced the cell viability in a concentration-dependent manner. Treatment with PS-F (0.1, 1, and 10 µmol/l) increased the viability of rotenone-induced PC12 cells, decreased rotenone-induced apoptosis, restored rotenone-induced mitochondrial dysfunction, and suppressed rotenone-induced protein expression. PS-F showed a dose-dependent manner in all the treatments. PS-F protects PC12 cells against rotenone-induced apoptosis via ameliorating the mitochondrial dysfunction. Thus, PS-F may be a potential bioactive compound for the treatment of Parkinson's disease.

Therapeutic effect of nicotinamide mononucleotide on Alzheimer's disease through activating autophagy and anti-oxidative stress.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the deposition of ß-amyloid (Aß) plaques and neurofibrillary tangles composed of tau protein in the brain. These neuropathological hallmarks contribute to cognitive impairment by inducing neuronal loss in the cerebral cortex and hippocampus. Unfortunately, current therapeutic approaches only target symptomatic relief and do not impede disease progression. Nicotinamide mononucleotide (NMN), a precursor of nicotinamide adenine dinucleotide (NAD+), has emerged as a promising candidate for the treatment of age-related neurodegenerative disorders. NMN supplementation could restore NAD+ levels, thereby alleviating neuronal damage and slowing the progression of AD and other aging-associated diseases. AD is closely associated with autophagic impairment and oxidative stress. Our in vivo experiments demonstrated that NMN could ameliorate pathological and behavioral impairments in AD mice. Specifically, NMN enhanced autophagy and promoted p-tau clearance. Meanwhile, NMN could activate the Nrf2/Keap1/NQO1 pathway, thereby reducing the oxidative stress. Immunofluorescence results demonstrated that NMN could alleviate neuronal damage in AD mice. Furthermore, in vitro results showed that the p-tau clearance and antioxidant stress effects of NMN were suppressed by autophagy inhibitor, chloroquine (CQ) or bafilomycin A1 (BafA1), in Aß-induced PC12 cells. Lastly, when Nrf2 was knocked down, the antioxidant stress, autophagy enhancement, and p-tau clearance effects of NMN were all inhibited. In conclusion, our research indicates that NMN exerts therapeutic effect against AD by activating autophagy and the Nrf2/Keap1/NQO1 pathway through a mutual regulating mechanism of autophagy and antioxidative stress. These findings highlight the promising potential of NMN for the treatment of AD.

Rotenone could activate microglia through NFκB associated pathway.

Parkinson's disease (PD) is a common neurodegenerative disease, and its etiology remains obscure. Increasing evidence has suggested an important role for environmental factors such as exposure to pesticides in increasing the risk of developing PD and inflammation is the early incident during the process of PD. In this study, we measure the pro-inflammatory cytokines by enzyme-linked immunosorbnent assay and RT-PCR methods; analyze the reactive oxygen species by DCFH-DA; detected nuclear factor κB (NFκB) translocation by western blot and immunofluorescence methods; and analyze the phosphorylation of mitogen-activated protein (MAP) kinase and protein level of Nurr1 by western blot. Results showed that rotenone could induce tumor neurosis factor α (TNFα) and interleukin 1ß (IL-1ß) release from BV-2 cells, enhance TNFα and IL-1ß mRNA levels in substantia nigra lesioned by rotenone; also, rotenone could increase the phosphorylation of inhibitor of κB (IκB), extracellular regulated protein kinase , c-Jun N-terminal kinase, p38 MAP kinases and promote p65 subunit of NFκB translocation to nuclear; at the same time, rotenone could decrease the protein level of Nurr1 in nuclear. So, rotenone exerted toxicity through activating microglia, and its mechanism might be associated with NFκB signal pathway.

Photoelectron spectroscopy and theoretical study of M(IO3)2(-) (M = H, Li, Na, K): structural evolution, optical isomers, and hyperhalogen behavior.

H(IO3)2(-) and M(IO3)2(-) (M = Li, Na, K) anions were successfully produced via electrospray ionization of their corresponding bulk salt solutions, and were characterized by combining negative ion photoelectron spectroscopy and quantum chemical calculations. The experimental vertical detachment energies (VDEs) of M(IO3)2(-) (M = H, Li, Na, K) are 6.25, 6.57, 6.60, and 6.51 eV, respectively, and they are much higher than that of IO3(-) (4.77 eV). The theoretical calculations show that each of these anions has two energetically degenerate optical isomers. It is found that the structure of H(IO3)2(-) can be written as IO3(-)(HIO3), in which the H atom is tightly bound to one of the IO3(-) groups and forms an iodic acid (HIO3) molecule; while the structures of M(IO3)2(-) can be written as (IO3(-))M(+)(IO3(-)), in which the alkali metal atoms interact with the two IO3(-) groups almost equally and bridge the two IO3(-) groups via two O atoms of each IO3(-) with the two MOOI planes nearly perpendicular to each other. In addition, the high VDEs of M(IO3)2(-) (M = Li, Na, K) can be explained by the hyperhalogen behavior of their neutral counterparts.

Photoelectron spectroscopy and density functional calculations of CuSi(n)- (n = 4-18) clusters.

We conducted a combined anion photoelectron spectroscopy and density functional theory study on the structural evolution of copper-doped silicon clusters, CuSi(n)(-) (n = 4-18). Based on the comparison between the experiments and theoretical calculations, CuSi(12)(-) is suggested to be the smallest fully endohedral cluster. The low-lying isomers of CuSi(n)(-) with n ≥ 12 are dominated by endohedral structures, those of CuSi(n)(-) with n < 12 are dominated by exohedral structures. The most stable structure of CuSi(12)(-) is a double-chair endohedral structure with the copper atom sandwiched between two chair-style Si(6) rings or, in another word, encapsulated in a distorted Si(12) hexagonal prism cage. CuSi(14)(-) has an interesting C(3h) symmetry structure, in which the Si(14) cage is composed by three four-membered rings and six five-membered rings.

Noncirrhotic portal hypertension due to peripheral T-cell lymphoma, not otherwise specified: A case report.

BACKGROUND: Peripheral T-cell lymphoma (PTCL), an aggressive and rare disease that belongs to a heterogeneous group of mature T-cell lymphomas, develops rapidly and has a poor prognosis. Early detection and treatment are essential to improve patient cure and survival rates. Here, we report a rare case of PTCL with clinical presentation of noncirrhotic portal hypertension, which provides a basis for early vigilance of lymphomas in the future. CASE SUMMARY: A 65-year-old Chinese woman was admitted to our hospital because of abdominal distension for 3 months and pitting oedema of both lower limbs for 2 months. Physical examinations and associated auxiliary examinations showed the presence of hepatosplenomegaly, and her hepatic venous pressure gradient was 10 mmHg. Immunohistochemical analysis of the liver biopsy confirmed the diagnosis of PTCL. The patient underwent combination therapy with dexamethasone, VP-16, and chidamide. Unfortunately, after 41 days of chemotherapy, the patient died of multiple organ failure. CONCLUSION: PCTL accompanied by noncirrhotic portal hypertension is rarely reported. This case report discusses the diagnosis of a patient according to the literature.

Au(CN)n complexes: superhalogens with pseudohalogen as building blocks.

Electron affinity (EA) is one of the most important factors that govern reactivity of atoms and molecules. Chlorine, with the highest electron affinity (3.6 eV) of all elements in the periodic table, is a classic example of reactive elements. Over past thirty years, much research has been done to expand the scope of molecules with electron affinities even larger than that of Cl. These molecules, called superhalogens, have the general formula MX(n+1) where M is a metal atom, X is a halogen atom, and n is the valency of the metal. In this paper we explore the potential of pseudohalogens such as CN, which mimic the chemistry of halogens, to serve as building blocks of new superhalogens. Using calculations based on density functional theory, we show that when a central Au atom is surrounded by CN moieties, superhalogens can be created with electron detachment energies as high as 8.4 eV. However, there is a stark contrast between the stability of these superhalogens and that of conventional AuF(n) superhalogens. Whereas AuF(n) complexes are stable up to n = 5 for neutrals and n = 6 for anions, Au(CN)(n) complexes (with CN moieties attached individually) are metastable beyond n = 1 for neutrals and n = 3 for anions. We investigate the nature and origin of these differences. In addition, we elucidate important distinctions between electron affinity (EA) and adiabatic detachment energy (ADE), two terms that are often used synonymously in literature.

Reaction-induced magnetic transition in Mn2 dimers.

The magnetic coupling between Mn atoms in Mn(2) dimers embedded in a rare gas matrix is antiferromagnetic but undergoes ferromagnetic transition at a higher temperature or when ionized to the Mn(2)(+) state. By use of density functional theory and hybrid functional for exchange-correlation potentials, we show that ferromagnetic transition can also be induced when Mn(2) reacts with Cl and/or BO(2). Because of their highly electronegative character, both Cl and BO(2) draw electrons from the Mn(2) dimer leaving it in a positively charged state. The resulting shrinkage in the Mn-Mn bond brought about by the removal of an antibonding electron causes the magnetic transition. We further show that the coupling between Mn atoms remains ferromagnetic when two Mn(2)Cl units are allowed to interact with each other. The ability to induce a magnetic transition through a chemical reaction provides a way to synthesize new magnetic materials.

Identification of Potential Inhibitors Against the TGF-ß/BMPs-Activin Receptor- like Kinase 1 Signal Pathway.

INTRODUCTION: In many diseased states, especially fibrosis and cancer, TGF-ß family members are overexpressed and the outcome of signaling is diverted toward disease progression. As the result of activin receptor-like kinase 1 (ALK1) plays a key role in TGF-ß signaling, discovering inhibitors of ALK1 to block TGF-ß signaling for a therapeutic benefit has become an effective strategy. METHODS: In this work, ZINC15894217 and ZINC12404282 were identified as potential ALK1 inhibitors using molecular docking, molecular dynamics simulation and MM/PBSA calculations studies. The analysis of energy decomposition found that Val208, Val216, Lys229, Gly283, Arg334 and Leu337 acted as crucial residues for ligand binding and system stabilizing. RESULTS: In addition, these compounds displayed excellent pharmacological and structural properties, which can be further evaluated through in vitro and in vivo experiments for the inhibition of ALK1 to be developed as drugs against fibrosis and tumor. CONCLUSION: Overall, our study illustrated a time- and cost-effective computer aided drug design procedure to identify potential ALK1 inhibitors. It would provide useful information for further development of ALK1 inhibitors to improve disease related to TGF-ß signal pathway.

First-principles study of hydrogen adsorption in metal-doped COF-10.

Covalent organic frameworks (COFs), due to their low-density, high-porosity, and high-stability, have promising applications in gas storage. In this study we have explored the potential of COFs doped with Li and Ca metal atoms for storing hydrogen under ambient thermodynamic conditions. Using density functional theory we have performed detailed calculations of the sites Li and Ca atoms occupy in COF-10 and their interaction with hydrogen molecules. The binding energy of Li atom on COF-10 substrate is found to be about 1.0 eV and each Li atom can adsorb up to three H(2) molecules. However, at high concentration, Li atoms cluster and, consequently, their hydrogen storage capacity is reduced due to steric hindrance between H(2) molecules. On the other hand, due to charge transfer from Li to the substrate, O sites provide additional enhancement for hydrogen adsorption. With increasing concentration of doped metal atoms, the COF-10 substrate provides an additional platform for storing hydrogen. Similar conclusions are reached for Ca doped COF-10.

Doping induced anisotropic growth in C60.

Using density functional theory with generalized gradient approximation for exchange and correlation energy, we show that substitution of a Si atom at one of the C sites in C(60) not only allows C(59)Si to have a hydrophobic head with a hydrophilic tail but also the Si atom acts as a seed for anisotropic growth of the heterofullerene. This is demonstrated by interacting C(59)Si with N(7)Sc and B(8)Si. The resulting complex structures exhibit enhanced electric dipole moments and anisotropy. Thus, doping induced anisotropic growth of nanostructures provides a novel route for the synthesis of bifunctional particles with atomic-level control on selectivity and diversity. These particles may have important applications in biomedical, solar, and display industry.

Metabolic gene NR4A1 as a potential therapeutic target for non-smoking female non-small cell lung cancer patients.

BACKGROUND: Although cigarette smoking is considered one of the key risk factors for lung cancer, 15% of male patients and 53% of female patients with lung cancer are non-smokers. Metabolic changes are critical features of cancer. Therapeutic target identification from a metabolic perspective in non-small cell lung cancer (NSCLC) tissue of female non-smokers has long been ignored. RESULTS: Based on microarray data retrieved from Affymetrix expression arrays E-GEOD-19804, we found that the downregulated genes in non-smoking female NSCLC patients tended to participate in protein/amino acid and lipid metabolism, while upregulated genes were more involved in protein/amino acid and carbohydrate metabolism. Combining nutrient metabolic co-expression, protein-protein interaction network construction and overall survival assessment, we identified NR4A1 and TIE1 as potential therapeutic targets for NSCLC in female non-smokers. To accelerate the drug development for non-smoking female NSCLC patients, we identified nilotinib as a potential agonist targeting NR4A1 encoded protein by molecular docking and molecular dynamic stimulation. We also show that nilotinib inhibited proliferation and induced senescence of cells in non-smoking female NSCLC patients in vitro. CONCLUSIONS: These results not only uncover nutrient metabolic characteristics in non-smoking female NSCLC patients, but also provide a new paradigm for identifying new targets and drugs for novel therapy for such patients.

Interaction of C(59)Si with Si based clusters: a study of Janus nanostructures.

Using density functional theory with the generalized gradient approximation (GGA), we show that carbon-silicon Janus anisotropic nanostructures can be synthesized by using C(59)Si heterofullerene as a seed where the doped Si atom preferentially attaches to some well-known silicon and silicon based clusters such as Si(10), WSi(12), TiSi(16), and BaSi(20). The interaction energy of these clusters with C(59)Si varies from 0.9 to 1.9 eV. The anisotropy of the resulting carbon-silicon Janus structures produces large dipole moments (4-9 D), anisotropic distributions of electronic orbitals, and the anisotropic reactivity.