Neutrophil extracellular traps as a unique target in the treatment of chemotherapy-induced peripheral neuropathy.

BACKGROUND: Chemotherapy-induced peripheral neuropathy (CIPN) is a severe dose-limiting side effect of chemotherapy and remains a huge clinical challenge. Here, we explore the role of microcirculation hypoxia induced by neutrophil extracellular traps (NETs) in the development of CIPN and look for potential treatment. METHODS: The expression of NETs in plasma and dorsal root ganglion (DRG) are examined by ELISA, IHC, IF and Western blotting. IVIS Spectrum imaging and Laser Doppler Flow Metry are applied to explore the microcirculation hypoxia induced by NETs in the development of CIPN. Stroke Homing peptide (SHp)-guided deoxyribonuclease 1 (DNase1) is used to degrade NETs. FINDINGS: The level of NETs in patients received chemotherapy increases significantly. And NETs accumulate in the DRG and limbs in CIPN mice. It leads to disturbed microcirculation and ischemic status in limbs and sciatic nerves treated with oxaliplatin (L-OHP). Furthermore, targeting NETs with DNase1 significantly reduces the chemotherapy-induced mechanical hyperalgesia. The pharmacological or genetic inhibition on myeloperoxidase (MPO) or peptidyl arginine deiminase-4 (PAD4) dramatically improves microcirculation disturbance caused by L-OHP and prevents the development of CIPN in mice. INTERPRETATION: In addition to uncovering the role of NETs as a key element in the development of CIPN, our finding provides a potential therapeutic strategy that targeted degradation of NETs by SHp-guided DNase1 could be an effective treatment for CIPN. FUNDING: This study was funded by the National Natural Science Foundation of China81870870, 81971047, 81773798, 82271252; Natural Science Foundation of Jiangsu ProvinceBK20191253; Major Project of "Science and Technology Innovation Fund" of Nanjing Medical University2017NJMUCX004; Key R&D Program (Social Development) Project of Jiangsu ProvinceBE2019732; Nanjing Special Fund for Health Science and Technology DevelopmentYKK19170.

Hippocampal nuclear factor kappa B accounts for stress-induced anxiety behaviors via enhancing neuronal nitric oxide synthase (nNOS)-carboxy-terminal PDZ ligand of nNOS-Dexras1 coupling.

Anxiety disorders are associated with a high social burden worldwide. Recently, increasing evidence suggests that nuclear factor kappa B (NF-κB) has significant implications for psychiatric diseases, including anxiety and depressive disorders. However, the molecular mechanisms underlying the role of NF-κB in stress-induced anxiety behaviors are poorly understood. In this study, we show that chronic mild stress (CMS) and glucocorticoids dramatically increased the expression of NF-κB subunits p50 and p65, phosphorylation and acetylation of p65, and the level of nuclear p65 in vivo and in vitro, implicating activation of NF-κB signaling in chronic stress-induced pathological processes. Using the novelty-suppressed feeding (NSF) and elevated-plus maze (EPM) tests, we found that treatment with pyrrolidine dithiocarbamate (PDTC; intra-hippocampal infusion), an inhibitor of NF-κB, rescued the CMS- or glucocorticoid-induced anxiogenic behaviors in mice. Microinjection of PDTC into the hippocampus reversed CMS-induced up-regulation of neuronal nitric oxide synthase (nNOS), carboxy-terminal PDZ ligand of nNOS (CAPON), and dexamethasone-induced ras protein 1 (Dexras1) and dendritic spine loss of dentate gyrus (DG) granule cells. Moreover, over-expression of CAPON by infusing LV-CAPON-L-GFP into the hippocampus induced nNOS-Dexras1 interaction and anxiety-like behaviors, and inhibition of NF-κB by PDTC reduced the LV-CAPON-L-GFP-induced increases in nNOS-Dexras1 complex and anxiogenic-like effects in mice. These findings indicate that hippocampal NF-κB mediates anxiogenic behaviors, probably via regulating the association of nNOS-CAPON-Dexras1, and uncover a novel approach to the treatment of anxiety disorders.

[Roller compaction research of Banlangen effervsce tablets].

OBJECTIVE: To study the conditions and parameters of roller compaction of Banlangen effervsce tablet. METHOD: The experimentation adopts L9 (3(4)) orthogonal experiment to study the conditions and parameters of roller compaction of Banlangen effervsce tablet; studied factors that included roller pressure, roller speed and moisture content of power, which influence the result of granule yield and granule friability. RESULT: The optimal technique is: roller pressure at 1.5 MPa; roller speed at 15 Hz; moisture content of power at 1.5%. CONCLUSION: The study of roller compaction technique of Banlangen effervsce tablets provides some technicial consults of its research and production.

[Review of effervescent technique in pharmaceutics research].

Effervescent technique, which can accelerate drug disintegration and dissolution, is usually applied in quick release preparations. Along with the development of pharmaceutical technique and theory, effervescent technique is used more and more extensively to adjust the behavior of drug release, such as in sustained and controlled release preparations, pulsatile drug delivery systems, and so on. This review demonstrated the new applying of effervescent technique in effervescent tablets, stomach floating forms, osmotic pump tablets and pulsatile drug delivery systems, adding to the critical common technique of effervescent forms in drug research. This will be benefit for the further research and development of effervescent technique.

[Studies on IR spectroscopy and quantum chemical calculation of chloroaluminate ionic liquids acidity].

The acidity of chloroaluminate ionic liquids and the interaction mechanism of Lewis acid site Al2Cl7(-) of chloroaluminate ionic liquid and pyridine were experimentally investigated by IR characterization by using pyridine as molecular probe and increasing pyridine adsorption, and theoretically confirmed by quantum chemical calculations at density functional theory (DFT) and ab initio levels. It was found that the anions, Al2Cl7(-) and AlCl4(-), which could withdraw lone pair electrons of pyridine, were characteristic of Lewis acid. Therefore, they displayed pyridine coordinated to Lewis acidic site using pyridine as probe. The acidity of Al2Cl7(-) was found stronger than that of AlCl4(-) by analyzing IR absorption frequency, bond length and charge distribution. The mechanism of forming and evolvement of the Lewis acid site Al2Cl7(-) of chloroaluminate ionic liquid was proposed. When the amount of pyridine is small, only the adsorption state of Py-Al2Cl7(-) exists. The highly Lewis acidic adsorption state of Py-Al2Cl7(-) complex was converted into Py-AlCl4(-) complex and Py-AlCl3 complex with increasing pyridine contents, leading to the changes in IR absorption spectra.

[Studies on acidity of chloroaluminate ionic liquids and its catalytic performance for alkylation of benzene with long-chain alkenes].

The acidity of chloroaluminate ionic liquids (ILs) was determined by using pyridine and acetonitrile as IR spectroscopic probes. Based on the characterization method of acidity of solid acid, IR vCCN absorption frequencies of pyridine in ionic liquids were assigned. By using the pyridine probe, it was found that when the anion molar composition x of ionic liquid varies within 0.4-0.5, ionic liquids exhibit weak Lewis acidity. Strongly basic molecular pyridine can be used as a probe to measure the acidity of ionic liquids whether their acidity is strong or weak, while weakly basic molecular acetonitrile is only fit for strong acid. In addition, the Lewis acidity-activity correlation for the chloroaluminate ionic liquids catalyst in the alkylation reaction was studied. The weakly acidic ILs with x < or = 0.5 does not exhibit any catalytic activity in the alkylation reaction. When the anion molar composition x is more than 0.55, the activity of ionic liquids is greatly enhanced due to the increase in the strength of the strong Lewis acidic species Al2Cl7-. But with the increase in alkenes conversion, the selectivity of 2-alkylbenzene is slightly reduced.