Metabotropic glutamate receptor subtype 7 controls maternal care,maternal motivation and maternal aggression in mice

The group III metabotropic glutamate receptor subtype 7 (mGlu7) is an important regulator of glutamatergic and GABAergic neurotransmission and known to mediate emotionality and male social behavior. However, a possible regulatory role in maternal behavior remains unknown to date. Adequate expression of maternal behavior is essential for successful rearing and healthy development of the young. By understanding genetic and neural mechanisms underlying this important prosocial behavior, we gain valuable insights into possible dysregulations. Using genetic ablation as well as pharmacological modulation, we studied various parameters of maternal behavior in two different mouse strains under the influence of mGlu7. We can clearly show a regulatory role of mGlu7 in maternal behavior. Naïve virgin female C57BL/6 mGlu7 knockout mice showed more often nursing postures and less spontaneous maternal aggression compared to their heterozygous and wildtype littermates. In lactating C57BL/6 wildtype mice, acute central activation of mGlu7 by the selective agonist AMN082 reduced arched back nursing and accelerated pup retrieval without affecting maternal aggression. In addition, in lactating CD1 wildtype mice the selective mGlu7 antagonist XAP044 increased both pup retrieval and maternal aggression. With respect to receptor expression levels, mGlu7 mRNA expression was higher in lactating vs virgin C57BL/6 mice in the prefrontal cortex, but not hypothalamus or hippocampus. In conclusion, these findings highlight a significant role of the mGlu7 receptor subtype in mediating maternal behavior in mice. Region‐dependent studies are warranted to further extend our knowledge on the specific function of the brain glutamate system in maternal behavior.     

Glutamate dehydrogenase deficiency disrupts glutamate homeostasis in hippocampus and prefrontal cortex and impairs recognition memory

Glutamate Dehydrogenase 1 (GDH), encoded by the Glud1 gene in rodents, is a mitochondrial enzyme critical for maintaining glutamate homeostasis at the tripartite synapse. Our previous studies indicate that the hippocampus may be particularly vulnerable to GDH deficiency in central nervous system (CNS). Here, we first asked whether mice with a homozygous deletion of Glud1 in CNS (CNS‐Glud1 ?/? mice) express different levels of glutamate in hippocampus, and found elevated glutamate as well as glutamine in dorsal and ventral hippocampus, and increased glutamine in medial prefrontal cortex (mPFC). l ‐serine and d ‐serine, which contribute to glutamate homeostasis and NMDA receptor function, are increased in ventral but not dorsal hippocampus, and in mPFC. Protein expression levels of the GABA synthesis enzyme glutamate decarboxylase (GAD) GAD67 were decreased in the ventral hippocampus as well. Behavioral analysis revealed deficits in visual, spatial and social novelty recognition abilities, which require intact hippocampal‐prefrontal cortex circuitry. Finally, hippocampus‐dependent contextual fear retrieval was deficient in CNS‐Glud1 ?/? mice, and c‐Fos expression (indicative of neuronal activation) in the CA1 pyramidal layer was reduced immediately following this task. These data point to hippocampal subregion‐dependent disruption in glutamate homeostasis and excitatory/inhibitory balance, and to behavioral deficits that support a decline in hippocampal‐prefrontal cortex connectivity. Together with our previous data, these findings also point to different patterns of basal and activity‐induced hippocampal abnormalities in these mice. In sum, GDH contributes to healthy hippocampal and PFC function; disturbed GDH function is relevant to several psychiatric and neurological disorders.     

miR‐126 reduces trastuzumab resistance by targeting PIK3R2 and regulating AKT/mTOR pathway in breast cancer cells

MicroRNAs (miRNAs) have been found to play a key role in drug resistance. In the current study, we aimed to explore the potential role of miR‐126 in trastuzumab resistance in breast cancer cells. We found that the trastuzumab‐resistant cell lines SKBR3/TR and BT474/TR had low expression of miR‐126 and increased ability to migrate and invade. The resistance, invasion and mobilization abilities of the cells resistant to trastuzumab were reduced by ectopic expression of miR‐126 mimics. In comparison, inhibition of miR‐126 in SKBR3 parental cells had the opposite effect of an increased resistance to trastuzumab as well as invasion and migration. It was also found that miR‐126 directly targets PIK3R2 in breast cancer cells. PIK3R2‐knockdown cells showed decreased resistance to trastuzumab, while overexpression of PIK3R2 increased trastuzumab resistance. In addition, our finding showed that overexpression of miR‐126 reduced resistance to trastuzumab in the trastuzumab‐resistant cells and that inhibition of the PIK3R2/PI3K/AKT/mTOR signalling pathway was involved in this effect. SKBR3/TR cells also showed increased sensitivity to trastuzumab mediated by miR‐126 in vivo. In conclusion, the above findings demonstrated that overexpression of miR‐126 or down‐regulation of its target gene may be a potential approach to overcome trastuzumab resistance in breast cancer cells.     

New Constituents from the Low Polar Fraction of the Fruits of Crataegus dahurica and Their Anti‐Inflammatory Activity in RAW264.7 Cells

The fruit of Crataegus dahurica Koehne was used to treat the disease of infantile indigestion and dyspepsia as an ethnic medicine and food. As a continuous work on finding the active constituents from the edible herbs, four new biphenyl derivatives ( 1 – 4 ), together with two known compounds ( 5 and 6 ), were obtained from the petroleum ether fraction of the fruits of C. dahurica. Their structures were determined by the extensive 1D and 2D NMR spectra and HR‐MS spectrometry. Furthermore, the anti‐inflammatory activities of all the isolated compounds were investigated, in which compound 4 showed moderately inhibitory effects on NO production in RAW264.7 cells without inducing cytotoxicity.     

Profiling the Lipophilic Fractions of Pithecellobium dulce Bark and Leaves Using GC/MS and Evaluation of Their Antioxidant,Antimicrobial and Cytotoxic Activities

Pithecellobium dulce has been used in traditional medicine to treat various ailments owing to its restorative properties. The biological activities and chemical profiles of the lipophilic fraction of P. dulce bark and leaves were assessed herein. Fatty acid methyl esters (FAME) and unsaponifiable matter (USM) were prepared and analyzed by GC/MS. A total of 40 compounds were identified in the bark saponifiable fraction, whereas 9 compounds were annotated in the leaves. Palmitic acid methyl ester was the major compound identified accounting for 41.48 % of the bark and 19.03 % of the leaves composition. Besides, linolenic acid methyl ester (22.40 %) and linoleic acid (12.69 %) were annotated in the leaves saponifiable fraction. A total of 63 compounds were detected in the bark USM and 4 compounds were identified in the leaves. Phytol represented the major component in the leaves (52.57 %) followed by lupeol (20.68 %) and lupenone (8.60 %). Meanwhile, n‐dodecane dominated in the bark USM accounting for 24.69 % of the total composition. The leaves and bark lipophilic fractions revealed moderate antioxidant and antibacterial activities. Both extracts showed no antifungal activity. No cytotoxicity was observed for both lipophilic fractions. P. dulce offers a good source of antioxidant compounds that can be introduced to food and pharmaceutical industry.     

Caffeoylquinic Acids,Cytotoxic, Antioxidant,Acetylcholinesterase and Tyrosinase Enzyme Inhibitory Activities of Six Inula Species from Bulgaria

Chlorogenic (5‐CQA), 1,5‐, 3,5‐, 4,5‐ and 3,4‐dicaffeoylquinic (DCQA) acids were identified and quantified in the methanol extracts of Inula oculus‐christi L., I. bifrons L., I. aschersoniana Janka var. aschersoniana, I. ensifolia L., I. conyza (Griess .) DC. and I. germanica L. by HPLC analysis. The amount of 5‐CQA varied from 5.48 to 28.44 mg/g DE and the highest content was detected in I. ensifolia. 1,5‐DCQA (4.05–55.25 mg/g DE) was the most abundant dicaffeoyl ester of quinic acid followed by 3,5‐DCQA, 4,5‐DCQA and 3,4‐DCQA. The extract of I. ensifolia showed the highest total phenolic content (119.92±0.95 mg GAE/g DE) and exhibited the strongest DPPH radical scavenging activity (69.41±0.55 %). I. bifrons extract was found to be the most active sample against ABTS^.+ (TEAC 0.257±0.012 mg/mL) and the best tyrosinase inhibitor. The studied extracts demonstrated a low inhibitory effect towards acetylcholinesterase and possessed low cytotoxicity in concentration range from 10 to 300 μg/mL toward non‐cancer (MDCK II) and cancer (A 549) cells.     

Chemical Characterization and Phytotoxic Effects of the Aerial Parts of Ruzigrass (Urochloa ruziziensis)

Studies of the phytotoxic effects between plants can be a crucial tool in the discovery of innovative compounds with herbicide potential. In this sense, we can highlight ruzigrass (Urochloa ruziziensis), which is traditionally used in the crop rotation system in order to reduce weed emergence. The aim of this work was to characterize the secondary metabolites of ruzigrass and to evaluate its phytotoxic effects. In total, eight compounds were isolated: friedelin, oleanolic acid, α‐amyrin, 1‐dehydrodiosgenone, sitosterol and stigmasterol glycosides, tricin and p‐coumaric acid. Phytotoxic effects of the crude methanolic extract and fractions of ruzigrass were assessed using germination rate, initial seedling growth, and biomass of Bidens pilosa, Euphorbia heterophylla and Ipomoea grandifolia. Chemometric analysis discriminated the weed species into three groups, and B. pilosa was the most affected by fractions of ruzigrass. The phytotoxic activities of 1‐dehydrodiosgenone, tricin, and p‐coumaric acid are also reported, and p‐coumaric acid and 1‐dehydrodiosgenone were active against B. pilosa.     

Odoriferous Therapy: A Review Identifying Essential Oils against Pathogens of the Respiratory Tract

This review explores the body of scientific information available on the antimicrobial properties of essential oils against pathogens responsible for respiratory infections and critically compares this to what is recommended in the Layman's aroma‐therapeutic literature. Essential oils are predominantly indicated for the treatment of respiratory infections caused by bacteria or viruses (total 79.0 %), the efficacy of which has not been confirmed through clinical trials. When used in combination, they are often blended for presumed holistic synergistic effects. Of the essential oils recommended, all show some degree of antioxidant activity, 50.0 % demonstrate anti‐inflammatory effects and 83.3 % of the essential oils showed antihistaminic activity. Of the essential oils reviewed, 43.8 % are considered non‐toxic while the remaining essential oils are considered slightly to moderately toxic (43.7 %) or the toxicity is unknown (12.5 %). Recommendations are made for further research into essential oil combinations.     

Synthesis,Antimicrobial Activity and Molecular Docking Study of Novel α‐(Diphenylphosphoryl)‐ and α‐(Diphenylphosphorothioyl)cycloalkanone Oximes

A series of novel α‐(diphenylphosphoryl)‐ and α‐(diphenylphosphorothioyl)cycloalkanone oximes have been synthesized in search for novel bioactive molecules. Their structures were characterized by various spectroscopic methods including IR, NMR (¹H, ³¹P, ¹³C), mass spectrometry and single crystal X‐ray diffraction. The newly synthesized phosphorus‐containing oximes were screened for their in vitro antimicrobial activity against Gram‐positive bacteria (Staphylococcus aureus and Bacillus subtilis), Gram‐negative bacteria (Escherichia coli and Salmonella typhimurium) and fungal strains (Candida albicans and Candida glabrata). The biological assays showed that all the studied compounds exhibited high antibacterial and antifungal activities at only 0.1–2.1 μg/mL. In silico molecular docking studies in FabH enzyme active site were performed in order to predict the possible interaction modes and binding energies of the drug candidates at the molecular level.     

In Vitro Effects of Ginseng and the Seed of Zizyphus jujuba var. spinosa on Gut Microbiota of Rats with Spleen Deficiency

Ginseng and the seed of Zizyphus jujuba var. spinosa, which are traditional Chinese medicinal materials, were often used in ancient Chinese recipes as a pair of medicines. They can replenish the primordial qi and tonify the spleen. This study investigated the effects of ginseng and the seed of Zizyphus jujuba var. spinosa (GS) extract on gut microbiota diversity in rats with spleen deficiency syndrome (SDS). A total of 52 compounds (including 16 flavonoids, 35 saponins, and 1 alkaloid) were identified and analyzed from the GS extract by UPLC‐Q‐Orbitrap‐MS/MS. The GS extract significantly increased the relative abundance of Firmicutes and Bacteroidetes in rats with SDS but decreased that of Proteobacteria and Actinobacteria. At the genus level, the GS extract significantly increased the relative abundance of Lactobacillus and Bifidobacterium in rats with SDS but decreased that of Streptococcus, Escherichia‐Shigella, Veillonella, and Enterococcus. In addition, the GS extract influenced glucose and amino acid metabolism. In summary, the results showed that the GS extract changed the structure and diversity of gut microbiota in rats with SDS and balanced the metabolic process.