MiR-135b Alleviates Airway Inflammation in Asthmatic Children and Experimental Mice with Asthma via Regulating CXCL12.

OBJECTIVE: To clarify the possible influence of miR-135b on CXCL12 and airway inflammation in children and experimental mice with asthma. METHODS: The expressions of miR-135b and CXCL12 were detected using quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) in the serum of asthmatic children. Besides, the experimental asthmatic mice were established by aerosol inhalation of ovalbumin (OVA) followed by the treatment with agomiR-135b and antagomir-135b. Pathological changes of lung tissues were observed via HE staining and PAS staining. Besides, the airway hyperresponsiveness of mice was elevated and bronchoalveolar lavage fluid (BALF) was isolated for cell categorization and counting. The inflammatory cytokines in BALF were determined by enzyme-linked immunosorbent assay (ELISA), and the infiltration of Th17 cells in lung tissues was measured using flow cytometry. RESULTS: MiR-135b was downregulated and CXCL12 was upregulated in asthmatic children and mice. Overexpression of miR-135b may down-regulate CXCL12 expression in the lung of OVA mice, resulting in significant decreases in inflammatory infiltration, hyperplasia of goblet cell, airway hyperresponsiveness, cell quantity, as well as the quantity of eosinophilic granulocytes, neutrophils and lymphocytes in BALF. Also, the levels of inflammatory cytokines (IL-4, IL-5, IL-13 and IL-17) and the ratio of Th17 cells and IL-17 levels in lung tissues were decreased. However, miR-135b downregulation reversed these changes in OVA mice. CONCLUSION: MiR-135b may inhibit immune responses of Th17 cells to alleviate airway inflammation and hyperresponsiveness in asthma possibly by targeting CXCL12, showing the potential value in asthma treatment.

IP3R-mediated activation of BK channels contributes to mGluR5-induced protection against spinal cord ischemia-reperfusion injury.

Spinal cord ischemia-reperfusion injury (SCIRI) can cause dramatic neuron loss and lead to paraplegia in patients. In this research, the role of mGluR5, a member of the metabotropic glutamate receptors (mGluRs) family, was investigated both in vitro and in vivo to explore a possible method to treat this complication. In vitro experiment, after activating mGluR5 via pretreating cells with (RS)-2-Chloro-5-hydroxyphenylglycine (CHPG) and 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl) benzamide (CDPPB), excitotoxicity induced by glutamate (Glu) was attenuated in primary spinal cord neurons, evidenced by higher neuron viability, decreased lactate dehydrogenase (LDH) release and less detected TUNEL-positive cells. According to Western Blot (WB) results, Glu treatment resulted in a high level of large-conductance Ca2+- and voltage-activated K+ (BK) channels, with activation relying on the mGluR5-IP3R (inositol triphosphate) pathway. In vivo part, a rat model of SCIRI was built to further investigate the role of mGluR5. After pretreating them with CHPG and CDPPB, the rats showed markedly lower spinal water content, attenuated motor neuron injury in the spinal cord of L4 segments, and better neurological function. This effect could be partially reversed by paxilline, a blocker of BK channels. In addition, activating BK channels alone using specific openers: NS1619 or NS11021 can protect spinal cord neurons from injury induced by either SCIRI or Glu. In conclusion, in this research, we proved that mGluR5 exerts a protective role in SCIRI, and this effect partially works via IP3R-mediated activation of BK channels.

Palladium-Catalyzed Electrophilic Functionalization of Pyridine Derivatives through Phosphonium Salts.

Herein, we report a highly efficient and practical method for pyridine-derived heterobiaryl synthesis through palladium-catalyzed electrophilic functionalization of easily available pyridine-derived quaternary phosphonium salts. The nice generality of this reaction was goes beyond arylation, enabling facile incorporation of diverse carbon-based fragments, including alkenyl, alkynyl, and also allyl fragments, onto the pyridine core. Notably, the silver salt additive is revealed to be of vital importance for the success of this transformation and its pivotal role as transmetallation mediator, which guarantees a smooth transfer of pyridyl group to palladium intermediate, is also described.

Improved drug delivery and anti-tumor efficacy of combinatorial liposomal formulation of genistein and plumbagin by targeting Glut1 and Akt3 proteins in mice bearing prostate tumor.

Despite the plethora of significant research progress made to develop novel strategies for the treatment of prostate cancer, this disease remains one of the major global health challenges among men. However, using a co-treatment approach utilizing two or more anticancer drugs has shown tremendous success in the treatment of many cancer types. Nanoliposomes are well known to encapsulate multiple drugs and deliver them at the desired site. In this work, we report the synthesis of nanoliposomes (∼100 nm) encapsulating two drugs, plumbagin, and genistein, to synergistically inhibit the growth of prostate cancer cells. The combination of plumbagin and genistein drugs was found inhibiting xenograft prostate tumor growth by ∼80 % without any appreciable toxicity. Mechanistically, the combination of plumbagin and genistein containing nanoliposomes leads to the inhibition of PI3K/AKT3 signaling pathway as well as the decreased population of Glut-1 transporters to impart the retardation in tumor growth. Decrease in proliferative cells and blood vessels are early biological processes that laid the foundation of the observed anti-tumor effect. Thus, a novel, and non-toxic liposomal formulation, containing plumbagin and genistein drugs, is reported, which can deliver anticancer agents to prostate tumors and inhibit the growth.

Synthesis and Kinetics of the N-(2-Methyl-6-ethyl phenyl)-1-methoxypropyl-2-imine Schiff Base Catalyzed by NKC-9 Cation Exchange Resin.

The kinetics of condensation reaction of methoxyacetone with 2-methyl-6-ethyl aniline catalyzed by NKC-9 cation exchange resin was studied for the first time. The reaction temperature of Schiff base synthesis was determined in the range of 367.15 to 401.15 K by the batch experiments, and influences of reactant molar ratio, temperature, catalyst dosage, and particle size on the ultimate conversion were also studied. The dynamic data were used to be relevant with PH, ER(1), ER(2), and Langmuir Hinshelwood Hougen Watson homogeneity models. Model parameters, including reaction equilibrium constants, activation energy, enthalpy change, entropy change, and rate constants, were solved. The accuracy of the model was validated by means of both experimental proofs and standard deviation between the predicted and experimental data. Finally, a series of characterization tests such as Fourier transform infrared spectroscopy, X-ray diffraction, and polarizing microscopy were performed to investigate the structure and properties of NKC-9.

Sulfinate-Engaged Nucleophilic Addition Induced Allylic Alkylation of Allenoates.

A strategically novel Pd-catalyzed nucleophilic addition induced allylic alkylation reaction (NAAA) of allenoates has been successfully accomplished. By judiciously integrating ZnCl2-promoted Michael addition with Pd-catalyzed allylic alkylation, allenoates readily undergo allyl-sunfonylation at the internal double bond, thus providing a straightforward avenue for the rapid assembly of a host of structurally diversified α-allyl-ß-sufonylbut-3-enoate derivatives. The success of this transformation profits from a delicate control of the reaction kinetic of each elementary step, thanks to the synergistic interaction of Pd/Zn bimetallic system, thus suppressing either direct allylic sulfonylation or premature quenching of therein in situ generated ester enolate intermediate. Furthermore, by expanding the scope of workable Michael acceptor beyond those previously required doubly activated ones, such as methylenemalononitrile, the present work substantially enriches the repertoire of NAAA reactions.