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An infrared laser (808 nm) has been coupled with dielectric barrier discharge (DBD) for optical emission spectrometric determination of S and Cl in organic compounds. The use of a continuous wave IR laser with an output power of 1-2 W allows volatilization of analytes from condensed surfaces. Analytes thermally delivered to the gas phase are excited and atomized by the DBD plasma triggered by an alternative voltage of 10 kV at 25 kHz at atmospheric pressure. Direct analysis of S- and Cl-containing organics in manufactured tablets by measuring the S and Cl emissions resulted in a dynamic range of 0.5%-20% with linearities (R2) above 0.93 and limits of detection (LODs) in the μg/g level. Detection precision was examined by measuring inter-day and intra-day reproducibilities, leading to relative standard deviations (RSDs) ranging from 4.6% to 15.0%. The feasibility of LA-DBD-OES was further demonstrated with commercial pharmaceutical tablets of sulfadiazine (SDZ) and chloramphenicol (CAP). There is the potential for probing the tablet uniformity by monitoring elemental emissions of S and Cl. Quantitative results of the commercial tablets were consistent with the indication amounts and were verified by HPLC measurements. All these results suggest the proposed methodology as a promising tool for on-line analysis of solids and pharmaceutical tablets with minimal sample treatments and rapid detection respond.

Lasers have long been used in the field of mass spectrometric analysis for characterization of condensed matter. However, emission of neutrals upon laser irradiation surpasses the number of ions. Typically, only one in about one million analytes ejected by laser desorption/ablation is ionized, which has fueled the quest for postionization methods enabling ionization of desorbed neutrals to enhance mass spectrometric detection schemes. The development of postionization techniques can be an endeavor that integrates multiple disciplines involving photon energy transfer, electrochemistry, gas discharge, etc. The combination of lasers of different parameters and diverse ion sources has made laser desorption/ablation postionization (LD/API) a growing and lively research community, including two-step laser mass spectrometry, laser ablation atmospheric pressure photoionization mass spectrometry, and those coupled to ambient mass spectrometry. These hyphenated techniques have shown potentials in bioanalytical applications, with major inroads to be made in simultaneous location and quantification of pharmaceuticals, toxins, and metabolites in complex biomatrixes. This review is intended to provide a timely comprehensive view of the broadening bioanalytical applications of disparate LD/API techniques. We also have attempted to discuss these applications according to the classifications based on the postionization methods and to encapsulate the latest achievements in the field of LD/API by highlighting some of the very best reports in the 21st century. © 2020 John Wiley & Sons Ltd.

An enamine-mediated [3+2] organocatalytic 1,3-dipolar cy­cloaddition reaction of curcumin derivatives with azides has been developed. This strategy could generate 1,4,5-trisubstituted 1,2,3-triazoles in high yields and regioselectivities under mild conditions.

Accumulation of α‑synuclein (α‑SYN) is a common pathology for Parkinson's disease (PD). There is abundant evidence that the toxic‑gain‑of‑function of α‑SYN's is associated with aggregation and consequent effects. To assess the potential of chondroitin sulfate (CS) in this regard, the present study investigated its neuroprotective on SH‑SY5Y cells overexpressing wild‑type (WT) or A53T mutant α‑SYN. Cell viability was measured by MTT assay. Apoptosis, reactive oxygen species (ROS) and mitochondrial membrane potential were detected by flow cytometry. The protein expression levels of total α‑SYN, phosphorylated Ser129 α‑SYN, B‑cell lymphoma 2 (Bcl‑2), Bcl‑2‑associated X protein (Bax) and cytochrome‑c (Cyt‑c ) were analyzed by western blotting. It was observed that CS reduced the expression levels of total α‑SYN and phosphorylated Ser129 α‑SYN, prevented cell loss and inhibited apoptosis. The subsequent mechanism study indicated that CS inhibited ROS overproduction. CS also significantly attenuated WT and A53T mutant α‑SYN‑induced dysfunction, including decrease of mitochondrial membrane potential, decrease of Bcl‑2 expression, and increase of Bax expression, release of Cyt‑c from the mitochondria and activation of caspase‑3 and caspase‑9, which demonstrated that CS suppressed α‑SYN‑induced apoptosis possibly through mitochondria protection. These results suggested that CS protects SH‑SY5Y cells overexpressing WT or A53T mutant α‑SYN by inhibiting the expression and phosphorylation of α‑SYN, and ROS overproduction and mitochondrial apoptosis. These results implicate CS as a potential therapeutic agent for the treatment of PD.

Ghrelin is an endogenous ligand for the growth hormone secretagogue receptor (GHS-R) and a peptide hormone that promotes food intake and gastric motility. Our aims are to explore the effects of ghrelin on gastric distension (GD) sensitive neurons in the lateral septum, and the possible regulation of gastric motility by ghrelin through the hypothalamic arcuate nucleus (ARC).Single-unit discharges were recorded, extracellularly, and the gastric motility was monitored by the administration of ghrelin in the lateral septum. The projection of nerve fiber and expression of ghrelin were observed by retrograde tracer and fluo-immunohistochemistry staining. The expression of GHS-R and ghrelin was determined by real-time polymerase chain reaction and western blotting analysis.There were GD neurons in the lateral septum. The administration of ghrelin could excite both GD-excitatory (GD-E) and GD-inhibitory (GD-I) neurons in the lateral septum. Gastric motility was significantly enhanced by the administration of ghrelin in the lateral septum in a dose-dependent manner. Pretreatment with [D-Lys-3]-GHRP-6, however, could completely abolish the ghrelin-induced effects. Electrical stimulation of the ARC could significantly excite the response of GD neurons to ghrelin, increase ghrelin protein expression in the lateral septum and promote gastric motility. Nevertheless, these effects could be mitigated by pretreatment of [D-Lys-3]-GHRP-6. Electrical lesion of the lateral septum resulted in decreased gastric motility. The GHS-R and Ghrelin/FG-double labeled neurons were observed in the lateral septum and ARC, respectively.It is suggested that the lateral septum may receive afferent information from the gastrointestinal tract and promote gastric motility. Ghrelin plays an important role in promoting gastric motility in the lateral septum. The ARC may be involved in the regulation of the lateral septum's influence on gastric motility.

Small cell lung cancer (SCLC) is one of the most aggressive forms of lung cancer with a 5-year survival rate of less than 10%. Despite the initial high response rate to the frontline platinum based chemotherapy, relapse is common and rapid. The clinical activity of PARP inhibitors has shown good correlation with platinum sensitivity in breast and ovarian cancers. Thus, there is good rationale to test PARP inhibitors in SCLC. BGB-290 is a novel PARP-1/2 inhibitor, which is currently under clinical investigation in solid tumors. In this study, we evaluated the in vitro and in vivo activities of BGB-290, and its combination activity with chemotherapies in patient biopsy derived SCLC xenograft models. In the biochemical assays, BGB-290 demonstrated great potency for PARP1/2 (IC50 = 0.83 and 0.11 nM, respectively) and high selectivity over other PARP enzymes. The DNA-trapping activity of BGB-290 was measured in a fluorescence polarization (FP) binding assay. BGB-290 showed potent DNA-trapping activity with IC50 of 13 nM. In the cellular assays, BGB-290 inhibited intracellular PAR formation with an IC50 of 0.24 nM. Tumor cell lines with homologous recombination defects were profoundly sensitive to BGB-290. Oral administration of BGB-290 resulted in time-dependent and dose-dependent inhibition of PARylation in MDA-MB-436 (BRCA1 mutant) breast cancer xenograft, correlating well with the tumor drug concentrations. Compared to olaparib, BGB-290 induced PAR inhibition was more sustained. Consistent with this finding, BGB-290 demonstrated excellent anti-tumor activity in this model, over 10-fold more potent than olaparib. In a panel of 7 SCLC cell lines tested, 3 of them were sensitive to BGB-290. SCLC primary tumor models were established in house using patient biopsy samples obtained from Beijing Cancer Hospital. The anti-tumor activities of BGB-290 as single agent or in combination with etoposide/carboplatin (E/C) were evaluated in 8 SCLC primary tumor models. BGB-290 showed weak single agent activity in these models. Six of the 8 models (75%) were sensitive to E/C treatment, consistent with the clinical response observed in these patients. Addition of BGB-290 as concomitant treatment or maintenance therapy significantly prolonged the response duration in these chemo-sensitive models. In the two chemo-insensitive models, BGB-290 and E/C combo was less effective. Addition of BGB-290 to the chemo regiment was well-tolerated throughout the study. In conclusion, BGB-290 is a potent and selective inhibitor of PARP1/2. It is highly active both in vitro and in vivo in BRCA mutant tumors. BGB-290 has also demonstrated good combination activity with chemotherapeutics in patient biopsy derived SCLC models, supporting further investigation in the clinic. Citation Format: Zhiyu Tang, Ye Liu, Qin Zhen, Bo Ren, Hexiang Wang, Zhenyan Shi, Wenfeng Gong, Yong Liu, Xing Wang, Yajuan Gao, Fenglong Yu, Yiyuan Wu, Bing Jiang, Xuebing Sun, Min Wei, Changyou Zhou, Lusong Luo, Zhengxiang Li, Jiangyong Yu, Jun Zhao, Jie Wang, Lai Wang. BGB-290: A highly potent and specific PARP1/2 inhibitor potentiates anti-tumor activity of chemotherapeutics in patient biopsy derived SCLC models. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1653. doi:10.1158/1538-7445.AM2015-1653

Temozolomide (TMZ) is a DNA alkylating agent, used for treating several malignancies, including glioblastoma multiforme (GBM) and small cell lung cancer (SCLC) with brain metastasis. PARP inhibition could potentially enhance the cytotoxicity of TMZ by hindering the base excision repair (BER) pathway. BGB-290 is a potent and selective inhibitor of PARP1 and PARP2, which is currently under clinical investigation in solid tumors. BGB-290 has significant brain penetration, making it attractive for combining with TMZ in treating brain tumors or tumors with brain metastasis. In this study, we evaluated the combination effect of BGB-290 and TMZ in cellular assays and in animal models. The in vitro combination effect of BGB-290 and TMZ was evaluated in 7 SCLC and 8 GBM cell lines. BGB-290 demonstrated strong synergism with TMZ in most of those cells lines, lowering EC50 of TMZ by at least 5-fold in 4 out of 7 SCLC cell lines, and 7 out of 8 GBM cell lines. The in vivo combination activity was explored in H209 SCLC xenograft model. TMZ single agent was quite effective in this model. One cycle of treatment resulted in all animals tumor-free. However, resistance occurred quickly during the second cycle. Combination of BGB-290 and TMZ significantly delayed resistance without additional toxicity. Tumors remained sensitive to the combination treatment after multiple cycles. In order to investigate whether BGB-290 could overcome the TMZ resistance, TMZ-resistant (TR) H209 tumors were generated by treating the H209 tumors with multiple cycles of TMZ in vivo. The derived H209-TR lines remained sensitive to the combination of BGB-290 and TMZ both in vitro and in vivo, suggesting BGB-290/TMZ combo might work in the TMZ-resistant settings. Approximately 50% of SCLC patients have brain metastases at the time of postmortem examination. BGB-290 showed significant brain penetration in C57 mice. The drug exposure in brain vs. that in plasma was close to 20% after oral administration of BGB-290. Mice with established intracranial H209 xenografts were used to further investigate the combination activity of BGB-290 and TMZ on SCLC in brain. PARylation in brain/tumor tissues was well inhibited at 4 hours after single oral administration of 3 mg/kg of BGB-290. Addition of BGB-290 significantly prolonged animal survival compared to TMZ single agent in this intracranial model. In conclusion, BGB-290 demonstrated strong synergism with TMZ in cellular assays and in SCLC subcutaneous and intracranial xenograft models. When combined with TMZ, BGB-290 can overcome the induced TMZ resistance. Its favorable brain penetration ability warrants further evaluation of BGB-290 in combination with TMZ in GBMs as well as in SCLCs with brain metastasis. Citation Format: Zhiyu Tang, Bin Jiang, Zhenyan Shi, Wenfeng Gong, Yong Liu, Xing Wang, Yajuan Gao, Fenglong Yu, Changyou Zhou, Lusong Luo, Min Wei, Lai Wang. BGB-290, a novel PARP inhibitor with unique brain penetration ability, demonstrated strong synergism with temozolomide in subcutaneous and intracranial xenograft models. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1651. doi:10.1158/1538-7445.AM2015-1651