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Chunmei Geng,1 Yujin Guo,1 Changshui Wang,2 Changmeng Cui,3 Wenxiu Han,1 Dehua Liao,4 Pei Jiang1 1Department of Pharmacy, Jining First People’s Hospital, Jining Medical University, Jining 272000, People’s Republic of China; 2Department of Clinical Translational Medicine, Jining Life Science Center, Jining 272000, People’s Republic of China; 3Department of Neurosurgery, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining 272000, People’s Republic of China; 4Department of Pharmacy, Hunan Cancer Hospital, Central South University, Changsha 410011, People’s Republic of ChinaCorrespondence: Pei JiangDepartment of Pharmacy, Jining First People’s Hospital, Jining Medical University, Jining 272000, People’s Republic of ChinaTel/Fax +86 537 2106208Email jiangpeicsu@sina.comPurpose: Substantial evidence indicates that lipopolysaccharide (LPS) exposure can lead to systemic inflammatory response syndrome (SIRS) and multiple organ failure. Previous metabolomic studies have mainly focused on LPS-induced depression or hepatic and renal effects. However, no comprehensive metabolomics-based analysis of the serum, liver, kidney, hippocampus, and heart following exposure to LPS has been undertaken to date.Material and Methods: Male Sprague–Dawley rats were randomly allocated to a control and a LPS-treated group (n=8). LPS for 2 weeks (0.5 mg/kg every other day) was given via intraperitoneal injection. Gas chromatography–mass spectrometry (GC–MS) was used for metabolite determination, while multivariate statistical analysis was performed to identify differentially expressed metabolites between the two groups.Results: Our study revealed that 24, 13, 12, 7, and 12 metabolites were differentially expressed between the LPS treatment group and the control group in the serum, liver, kidney, hippocampus, and heart, respectively. We further identified that these metabolic changes were mainly involved with aminoacyl-tRNA biosynthesis; glutathione metabolism; glyoxylate and dicarboxylate metabolism; glycine, serine, and threonine metabolism; arginine biosynthesis; bile acid biosynthesis; and glycerolipid metabolism.Conclusion: We have systematically elucidated the metabolic changes underlying LPS-induced SIRS, thereby providing insight into the mechanisms associated with these alterations.Keywords: systemic inflammatory response syndrome, metabolites, gas chromatography–mass spectrometry, multivariate statistical analysis

Dehua Liao,1,2,* Yun Chen,1,* Yujin Guo,3 Changshui Wang,4 Ni Liu,1 Qian Gong,1 Yingzhou Fu,1 Yilan Fu,1 Lizhi Cao,1 Dunwu Yao,1 Pei Jiang3 1Department of Pharmacy, Hunan Cancer Hospital, Changsha, Hunan 410013, People’s Republic of China; 2Department of Pharmacy, Second Xiangya Hospital, Central South University, Changsha, Hunan 410013, People’s Republic of China; 3Institute of Clinical Pharmacy & Pharmacology, Jining First People’s Hospital, Jining, Shandong 272000, People’s Republic of China; 4Department of Clinical Translational Medicine, Jining Life Science Center, Jining, Shandong 272000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Pei Jiang Tel/ Fax + 86 537 2106208Email jiangpeicsu@sina.comIntroduction: Depression is one of the most common neuropsychiatric illnesses which leads to a huge social and economic burden on modern society. So, it is necessary to develop an effective and safe pharmacological intervention for depression. Accumulating evidence has shown that adenosine monophosphate-activated protein kinase/sirtuin 1 (AMPK/SIRT1) signaling pathway plays a pivotal role in the development of depression. Our present study aimed to investigate the antidepressant effect and possible mechanisms of salvianolic acid B (SalB) in a chronic mild stress (CMS)-induced depression model in rats.Materials and Methods: The rats were randomly divided into three groups: control group with no stressor, CMS group and CMS+SalB (30 mg/kg/d) group. After administration for 28 consecutive days, the behavior tests were performed. The rats were sacrificed after behavior tests, and the brain tissues were collected for biochemical analysis.Results: It was observed that the administration of SalB for 28 consecutive days successfully corrected the depressive-like behaviors in CMS-treated rats. SalB could effectively reduce the gene expression of pro-inflammatory cytokines such as interleukin-6 (IL-6), interleukin-1β (IL-1β) and tumor necrosis factor α (TNF-α), as well as nuclear factor-kappa B (NF-κB) p65 protein. In addition, inhibitor of NF-κB (IκB) protein expression was significantly increased after the administration of SalB. Moreover, SalB could effectively decrease protein expression of oxidative stress markers such as 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA) and increase the activity of catalase (CAT). SalB treatment also reversed CMS-induced inhibition of Nrf2 signaling pathway, along with increasing the mRNA expression of NAD(P)H:quinone oxidoreductase (NQO-1) and heme oxygenase 1 (HO-1). Regarding the endoplasmic reticulum (ER) stress markers, the protein expressions of C/EBP-homologous protein (CHOP) and glucose-regulated protein 78 kD (GRP78) were also significantly reduced after SalB administration. Furthermore, the supplementation of SalB could effectively activate the AMPK/SIRT1 signaling pathway, which indicated significant increase in pAMPK/AMPK ratio and SIRT1 protein expression.Conclusion: Our study demonstrated that SalB relieved CMS-induced depressive-like state through the mitigation of inflammatory status, oxidative stress, and the activation of AMPK/SIRT1 signaling pathway.Keywords: SalB, depression, CMS, AMPK/SIRT1

This nonrandomized clinical trial examines the efficacy and safety of apatinib plus vinorelbine in patients in China with wild-type advanced non–small cell lung cancer (NCSLC) that was resistant to 2 or more lines of chemotherapy., Key Points Question What are the safety and efficacy of apatinib plus vinorelbine for patients with wild-type advanced non–small cell lung cancer who are experiencing progression after 2 or more lines of chemotherapy? Findings In this phase 2 nonrandomized controlled trial of 30 patients with wild-type advanced non–small cell lung cancer, apatinib plus vinorelbine administered after failure of at least 2 lines of previous chemotherapy regimen was associated with significantly increased overall response rate and prolonged median progression-free survival and overall survival, and they were associated with manageable toxic effects. The potential efficacy of apatinib plus vinorelbine combination was identified using a 3-dimensional coculture platform. Meaning These findings suggest that apatinib plus vinorelbine may be an effective and safe regimen as subsequent-line therapy in patients with wild-type advanced non–small cell lung cancer., Importance There is currently no standard treatment strategy for patients with advanced non–small cell lung cancer (NSCLC) without driver gene variation after failure of 2 or more lines of chemotherapy. Objective To assess the efficacy and safety of apatinib combined with oral vinorelbine. Design, Setting, and Participants This phase 2 prospective nonrandomized clinical trial evaluating the efficacy and safety of apatinib plus vinorelbine recruited patients from Hunan Cancer Center, Hunan, China, from January 1, 2017, to November 30, 2018. Eligible patients were those with wild-type advanced NSCLC whose disease did not respond to at least 2 lines of chemotherapy. Patients were evaluated until December 31, 2019. Data were analyzed from July 2019 to December 2019. Intervention Apatinib at an initial dose of 500 mg once daily and oral vinorelbine 60 mg/m2 once weekly were administered until disease progression, patient withdrawal, or occurrence of unacceptable toxic effects. Main Outcomes and Measures The primary end point was overall response rate. Secondary end points were overall survival, progression-free survival, and safety. Results The potential efficacy of apatinib plus vinorelbine was identified using drug susceptibility assay based on 3-dimensional coculture of tumor cells derived from 3 patients with lung adenocarcinoma. Among 30 patients enrolled, the median (range) age was 63 (34-78) years and 18 (60%) were men. Most patients (27 patients [90%]) had stage IV disease, and the median (range) number of prior unsuccessful treatments was 2 (2-5) lines of chemotherapy. Twenty-five patients (83%) completed the treatment, while 5 patients (17%) discontinued treatment owing to intolerable adverse events. The overall response rate was 36.7% (11 patients) and the disease control rate was 76.7% (23 patients). The median progression-free survival was 4.5 (95% CI, 2.4-6.6) months, and the median overall survival was 10.0 (95% CI, 4.8-17.1) months. Hand-foot syndrome was the most common adverse event observed, including grade 3 hand-foot syndrome observed in 5 patients (17%) and grade 4 hand-foot observed in 1 patient (3%). Grade 3 weakness was observed in 1 patient (3%). Conclusions and Relevance These findings suggest that apatinib combined with oral vinorelbine is a potentially effective regimen with an acceptable safety profile. This regimen may have potential as a treatment option for patients with wild-type advanced NSCLC whose disease failed at least 2 prior lines of chemotherapy. Trial Registration ClinicalTrials.gov Identifier: NCT03652857