C8-ceramide modulates microglia BDNF expression to alleviate postoperative cognition dysfunction via PKCδ/NF-κB signaling pathway.

Postoperative cognitive dysfunction (POCD) is a kind of serious postoperative complication in surgery with general anesthesia and it may affect patients' normal lives. Activated microglia are thought to be one of the key factors in the regulation of POCD process. Once activated, resident microglia change their phenotype and secrete kinds of cytokines to regulate inflammatory response in tissues. Among these secretory factors, brain-derived neurotrophic factor (BDNF) is considered to be able to inhibit inflammation response and protect nervous system. Therefore, the enhancement of BDNF expression derived from resident microglia is suggested to be potential treatment for POCD. In our study, we focused on the role of C8-ceramide (a kind of interventional drug) and assessed its regulatory effect on improving the expression of BDNF secreted from microglia to treat POCD. According to the results of our study, we observed that C8-ceramide stimulated primary microglia to up-regulate the expression of BDNF mRNA after being treated with lipopolysaccharide (LPS) in vitro. We proved that C8-ceramide had ability to effectively improve POCD of mice after being accepted carotid artery exposure and their abnormal behavior recovered better than that of mice from the surgery group. Furthermore, we also demonstrated that C8-ceramide enhanced the cognitive function of mice via the PKCδ/NF-κB signaling pathway. In general, our study has confirmed a potential molecular mechanism that led to the occurrence of POCD caused by surgery and provided a new clinical strategy to treat POCD.

Development and validation of a nomogram for predicting the overall survival in non-small cell lung cancer patients with liver metastasis.

Background: Among all metastatic lesions in non-small cell lung cancer (NSCLC), liver metastasis (LM) is the most lethal site with a median survival of less than 5 months. Few studies exclusively report on prognostic factors for these unique patients. We aimed to construct and validate a practical model to predict the prognosis of NSCLC patients with LM. Methods: Cases of NSCLC with LM diagnosed between 2010 and 2015 were collected from the Surveillance, Epidemiology, and End Results (SEER) database, and were randomly split into training and validation cohort (7:3). The overall survival (OS) was measured from diagnosis until date of death or last follow-up. Cox regression analyses were performed to identify potential predictors of the model. A nomogram incorporating those independent factors was constructed and validated by the concordance index (C-index) and calibration plots. The decision curve analysis (DCA) and a risk stratification system were used to evaluate its clinical value. Results: A total of 2,367 cases were selected for analysis and randomized to the training cohort (n=1,677) and the validation cohort (n=690). The patients were mainly male (59.3%), married (83.1%) and White (77.3%). Apart from LM, 54.2%, 26.7%, and 36.7% of patients also present with bone, brain, and lung metastases, respectively. The median follow-up was 4.0 months for all patients and 23 months for alive cases. The median OS was 5 months [interquartile range (IQR), 2-11 months]. Sex, age, race, grade, T stage, bone metastasis, brain metastasis, surgery, and chemotherapy were identified as the independent risk factors of the OS and used to develop the nomogram. The calibration curves exhibited excellent agreement between the predicted and actual survival in both the training and validation set, with a C-index of 0.700 [95% confidence interval (CI): 0.684-0.716] and 0.677 (95% CI: 0.653-0.701), respectively. The DCA and the risk classification system further supported that the prediction model was clinically effective. Conclusions: This is the first study to build a prediction model for NSCLC patients with LM. It aids in treatment decisions, focused care, and physician-patient communication. The global prospective data is needed to further improve this model.

The role of PERK-eIF2α-ATF4-CHOP pathway in sevoflurane induced neuroapoptosis and cognitive dysfunction in aged mice.

Postoperative cognitive dysfunction (POCD) is a common surgical complication that causes additional pain in patients and affects their quality of life. To address this problem, emerging studies have focused on the POCD. Recent studies have shown that aging and anesthetic exposure are the two major risk factors for developing POCD. However, few reports described the exact molecular mechanisms underlying POCD in elderly patients. In the previous studies, the endoplasmic reticulum (ER) stress and neuroapoptosis in the hippocampus were associated with inducing POCD; however, no further information on the related signaling pathways could be disclosed. The PERK-eIF2α-ATF4-CHOP pathway is identified as the main regulatory pathway involved in ER stress and cell apoptosis. Therefore, we assume that the occurrence of POCD induced by sevoflurane inhalation may potentially result from ER stress and neuroapoptosis in the hippocampus of aged mice mediated by the PERK-eIF2α-ATF4-CHOP pathway. In our study, we found a relationship between sevoflurane inhalation concentration and memory decline in aged mice, with a 'ceiling effect'. We have confirmed that POCD induced by sevoflurane results from ER stress and neuroapoptosis in the hippocampus of aged mice, which is regulated by the over-expression of PERK-eIF2α-ATF4-CHOP pathway. Furthermore, we also showed that the dephosphorylation inhibitor of eIF2α (salubrinal) could down-regulate PERK-eIF2α-ATF4-CHOP pathway expression to inhibit ER stress and enhance the cognitive function of aged mice. In general, our study has elucidated one of the molecular mechanisms of sevoflurane-related cognitive dysfunction in aged groups and provided new strategies for treating sevoflurane-induced POCD.

Case Report: ICIs-induced Guillain-Barré syndrome recovered from mycophenolate mofetil.

The emergence of immune checkpoint inhibitors (ICIs) has significantly prolonged the survival time of cancer patients. However, it may also lead to various immune-related adverse events (irAEs), including Guillain-Barré syndrome (GBS), a rare type of irAE. Most GBS patients can recover spontaneously due to the self-limited nature of the disease, but severe cases can result in respiratory failure or even death. Here we report a rare case of GBS occurring in a 58-year-old male patient with non-small cell lung cancer (NSCLC) who developed muscle weakness and numbness of the extremities during chemotherapy combined with KN046, a PD-L1/CTLA-4 bispecific antibody. Despite receiving methylprednisolone and γ-globulin, the patient's symptoms did not improve. However, there was significant improvement after treatment with mycophenolate mofetil (MM) capsules, which is not a routine regimen for GBS. To the best of our knowledge, this is the first reported case of ICIs-induced GBS that responded well to mycophenolate mofetil instead of methylprednisolone or γ-globulin. Thus, it provides a new treatment option for patients with ICIs-induced GBS.

A narrative review of methane in treating neurological diseases.

Methane has shown protective effects on a variety of diseases. Among these, neurological diseases have attracted much attention. However, there are many different indicators and application methods of methane in the treatment of neurological diseases. In this review, we summarize the indicators related to the protective effects of methane and evaluate the preparation and administration of methane. Thus, we hope to offer available indicators and effective ways to produce and administer methane in future research.

Combination of Cefotaxime and Cisplatin Specifically and Selectively Enhances Anticancer Efficacy in Nasopharyngeal Carcinoma.

BACKGROUND: HMOX1 has a dual role in cancers, especially involving chemoresistance. We demonstrate that cephalosporin antibiotics exert strong anticancer activity in nasopharyngeal carcinoma mainly via drastic upregulation of HMOX1. OBJECTIVES: Cephalosporin antibiotics are commonly used for the treatment or prophylaxis of bacterial infectious diseases in cancer patients. It is unknown whether they lead to chemoresistance in cancer patients, especially in nasopharyngeal carcinoma patients, who are being treated or required prophylaxis for an infectious syndrome with cephalosporin antibiotics. METHODS: MTT and clonogenic colony formation assays assessed the viability and proliferation of cultured cancer cells. Flow cytometry was used to detect apoptosis. Tumor growth was assessed using a xenograft model. Microarray and RT-qPCR expression analyses investigated differential gene expression. RESULTS: Cefotaxime enhanced anticancer efficacy of cisplatin in nasopharyngeal carcinoma without enhancing the toxic side effects both in vitro and in vivo. However, cefotaxime significantly reduced the cytotoxicity of cisplatin in other cancer cell lines. Cefotaxime and cisplatin co-regulated 5 differential genes in CNE2 cells in a direction supporting the enhancement of anticancer efficacy, of which, THBS1 and LAPTM5 were further upregulated, STAG1, NCOA5, and PPP3CB were further downregulated. Out of the 18 apoptotic pathways significantly enriched in the combination group, THBS1 and HMOX1 overlapped in 14 and 12 pathways, respectively. Extrinsic apoptotic signaling pathway (GO: 2001236) was the only apoptotic pathway commonly enriched in cefotaxime group, cisplatin group and combination group, and THBS1 and HMOX1 were the overlapped genes of this pathway. THBS1 also overlapped in P53 signaling pathway and ECM-receptor interaction signaling pathway enriched by KEGG. CONCLUSION: Cephalosporin antibiotics are chemosensitizers of conventional chemotherapeutic drugs in the chemotherapy of nasopharyngeal carcinoma, but they may lead to chemoresistance by cytoprotection in other cancers. Cefotaxime and cisplatin co-regulate THBS1, LAPTM5, STAG1, NCOA5 and PPP3CB suggesting their involvement in the enhancement of anticancer efficacy in nasopharyngeal carcinoma. Targeting of P53 signaling pathway and ECM-receptor interaction signaling pathway was correlated to the enhancement. With additional benefit for treatment or prophylaxis of an infectious syndrome, cephalosporin antibiotics can benefit the therapy of nasopharyngeal carcinoma either as anticancer agents or as chemosensitizers of chemotherapeutic drugs in combination chemotherapy.

A novel viral vaccine platform based on engineered transfer RNA.

In recent years, an increasing number of emerging and remerging virus outbreaks have occurred and the rapid development of vaccines against these viruses has been crucial. Controlling the replication of premature termination codon (PTC)-containing viruses is a promising approach to generate live but replication-defective viruses that can be used for potent vaccines. Here, we used anticodon-engineered transfer RNAs (ACE-tRNAs) as powerful precision switches to control the replication of PTC-containing viruses. We showed that ACE-tRNAs display higher potency of reading through PTCs than genetic code expansion (GCE) technology. Interestingly, ACE-tRNA has a site preference that may influence its read-through efficacy. We further attempted to use ACE-tRNAs as a novel viral vaccine platform. Using a human immunodeficiency virus type 1 (HIV-1) pseudotyped virus as an RNA virus model, we found that ACE-tRNAs display high potency for read-through viral PTCs and precisely control their production. Pseudorabies virus (PRV), a herpesvirus, was used as a DNA virus model. We found that ACE-tRNAs display high potency for reading through viral PTCs and precisely controlling PTC-containing virus replication. In addition, PTC-engineered PRV completely attenuated and lost virulence in mice in vivo, and immunization with PRV containing a PTC elicited a robust immune response and provided complete protection against wild-type PRV challenge. Overall, replication-controllable PTC-containing viruses based on ACE-tRNAs provide a new strategy to rapidly attenuate virus infection and prime robust immune responses. This technology can be used as a platform for rapidly developing viral vaccines in the future.

Effects of hyperbaric oxygen on Notch signaling pathway after severe carbon monoxide poisoning in mice.

Demyelination of the cerebral white matter is the most common pathological change after carbon monoxide (CO) poisoning. Notch signaling, the mechanism underlying the differentiation of astrocytes and oligodendrocytes, is critical to remyelination of the white matter after brain lesion. The purpose of this work was to determine the effects of hyperbaric oxygen (HBO) on Notch signaling pathway after CO poisoning for the explanation of the protective effects of HBO on CO-poisoning-related cerebral white matter demyelination. The male C57 BL/6 mice with severe CO poisoning were treated by HBO. And HBO therapy shortened the escape latency and improved the body mass after CO poisoning. HBO therapy also significantly suppressed protein and mRNA levels of Notch1 and Hes5 after CO poisoning. Our findings suggested that HBO could suppress the activation of Notch signaling pathway after CO poisoning, which is the mechanism underlying the neuroprotection of HBO on demyelination after severe CO poisoning.

Bioinformatic identification and validation of autophagy-related genes in rheumatoid arthritis.

OBJECTIVES: Rheumatoid arthritis (RA) is a chronic systemic autoimmune disorder characterized by progressive synovial inflammation and joint destruction, with a largely unknown etiology. Studies have suggested that autophagy and its expression may be involved in the pathogenesis of RA; however, autophagy-related genes in RA are still largely unidentified. Therefore, in this study, we aimed to identify and validate autophagy-related genes in RA. METHODS: We identified differentially expressed autophagy-related genes between patients with RA and healthy individuals using gene expression profiles in the GSE55235 dataset and R software. Subsequently, correlation analysis, protein-protein interaction, gene ontology enrichment, and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were carried out using these differentially expressed autophagy-related genes. Finally, our results were validated by examining the expression of differentially expressed autophagy-related hub genes in clinical samples using qRT-PCR. RESULTS: We identified 52 potential autophagy-related genes in RA based on bioinformatic analyses. Ten hub genes, CASP8, CTSB, TNFSF10, FADD, BAX, MYC, FOS, CDKN1A, GABARAPL1, and BNIP3, were validated to be differentially expressed and may serve as valuable prognostic markers and new potential therapeutic targets for RA via the regulation of autophagy. CONCLUSIONS: Our results may help improve the understanding of RA pathogenesis. Autophagy-related genes in RA could be valuable biomarkers for diagnosis and prognosis and they might be exploited clinically as therapeutic targets in the future.

The strength and selectivity of perfluorinated nano-hoops and buckybowls for anion binding and the nature of anion-π interactions.

Perfluorinated cycloparaphenylenes (F-[n]CPP, n = 5-8), boron nitride nanohoop (F-[5]BNNH), and buckybowls (F-BBs) were proposed as anion receptors via anion-π interactions with halide anions (Cl- , Br- and I- ), and remarkable binding strengths up to -294.8 kJ/mol were computationally verified. The energy decomposition approach based on the block-localized wavefunction method, which combines the computational efficiency of molecular orbital theory and the chemical intuition of ab initio valence bond theory, was applied to the above anion-π complexes, in order to elucidate the nature and selectivity of these interactions. The overall attraction is mainly governed by the frozen energy component, in which the electrostatic interaction is included. Remarkable binding strengths with F-[n]CPPs can be attributed to the accumulated anion-π interactions between the anion and each conjugated ring on the hoop, while for F-BBs, additional stability results from the curved frameworks, which distribute electron densities unequally on π-faces. Interestingly, the strongest host was proved to be the F-[5]BNNH, which exhibits the most significant anisotropy of the electrostatic potential surface due to the difference in the electronegativities of nitrogen and boron. The selectivity of each host for anions was explored and the importance of the often-overlooked Pauli exchange repulsion was illustrated. Chloride anion turns out to be the most favorable anion for all receptors, due to the smallest ionic radius and the weakest destabilizing Pauli exchange repulsion.

High aquaporin expression correlates with increased translocation of quinclorac from shoots to roots in resistant Echinochloa crus-galli var. zelayensis.

BACKGROUND: Echinochloa crus-galli var. zelayensis is a troublesome weed in rice fields and can be controlled by using quinclorac. However, over-reliance on quinclorac has resulted in resistant (R) barnyardgrass, which differs significantly in its ability to transport quinclorac compared to susceptible (S) barnyardgrass. This study aimed to investigate the underlying mechanisms for this different translocation between R and S barnyardgrass. RESULTS: Larger amount of quinclorac was transferred from shoots to roots in R compared to S barnyardgrass. After 1 day of quinclorac [300 g active ingredient (a.i.) ha-1 ] foliar treatment, its content in shoots of R was 81.92% of that in S barnyardgrass; correspondingly, in roots of R was 1.17 fold of that in S barnyardgrass. RNA-sequencing and quantitative real-time polymerase chain reaction (qRT-PCR) confirmed the expression levels of PIPs belonging to aquaporins (AQPs) in R were higher than in S barnyardgrass, with or without quinclorac treatment. With co-application of quinclorac and AQPs inhibitors [mercury(II) chloride (HgCl2 )] treatment, even though the expression levels of PIPs and the transport rates of quinclorac were both suppressed in R and S barnyardgrass, this process was less pronounced in R than in S barnyardgrass. CONCLUSION: This report provides clear evidence that higher PIPs expression results in rapid quinclorac translocation from shoots to roots and reduces the quinclorac accumulation in the shoot meristems in R barnyardgrass, thus reducing the control efficacy of quinclorac. © 2022 Society of Chemical Industry.

Hydrogen exerts neuroprotective effects by inhibiting oxidative stress in experimental diabetic peripheral neuropathy rats.

Diabetic peripheral neuropathy (DPN) is a complex disorder caused by long-standing diabetes. Oxidative stress was considered the critical creed in this DPN pathophysiology. Hydrogen has antioxidative effects on diabetes mellitus and related complications. However, there is still no concern on the beneficial effects of hydrogen in DPN. This paper aimed to evaluate the effects of exogenous hydrogen to reduce the severity of DPN in streptozotocin-induced diabetic rats. Compared with hydrogen-rich saline treatment, hydrogen inhalation significantly reduced blood glucose levels in diabetic rats in the 4th and 8th weeks. With regard to nerve function, hydrogen administration significantly attenuated the decrease in the velocity of motor nerve conduction in diabetic animals. In addition, hydrogen significantly attenuated oxidative stress by reducing the level of malondialdehyde, reactive oxygen species, and 8-hydroxy-2-deoxyguanosine and meaningfully enhanced the antioxidant capability by partially restoring the activities of superoxide dismutase. Further studies showed that hydrogen significantly upregulated the expression of nuclear factor erythroid-2-related factor 2 and downstream proteins such as catalase and hemeoxygenase-1 in the nerves of diabetic animals. Our paper showed that hydrogen exerts significant protective effects in DPN by downregulating oxidative stress via the pathway of nuclear factor erythroid-2-related factor 2, which suggests its potential value in clinical applications.

Preparation, characterization, and property evaluation of Hericium erinaceus peptide-calcium chelate.

Recently, owing to the good calcium bioavailability, peptide-calcium chelates made of various foods have been emerging. Hericium erinaceus, an edible fungus, is rich in proteins with a high proportion of calcium-binding amino acids. Thus, mushrooms serve as a good source to prepare peptide-calcium chelates. Herein, the conditions for hydrolyzing Hericium erinaceus peptides (HP) with a good calcium-binding rate (CBR) were investigated, followed by the optimization of HP-calcium chelate (HP-Ca) preparation. Furthermore, the structure of the new chelates was characterized along with the evaluation of gastrointestinal stability and calcium absorption. Papain and a hydrolysis time of 2 h were selected for preparing Hericium erinaceus peptides, and the conditions (pH 8.5, temperature 55°C, time 40 min, and mass ratio of peptide/CaCl2 4:1) were optimal to prepare HP-Ca. Under this condition, the chelates contained 6.79 ± 0.13% of calcium. The morphology and energy disperse spectroscopy (EDS) analysis showed that HP-Ca was loose and porous, with an obvious calcium element signal. The ultraviolet-visible (UV) absorption and Fourier transform infrared spectroscopy (FT-IR) analysis indicated that calcium possibly chelates to HP via interaction with free -COO- from acidic amino acids and C = O from amide. HP-Ca displayed good stability against stimulated gastrointestinal digestion. Moreover, HP-Ca significantly improved the calcium absorption by Caco-2 epithelial cells. Thus, HP-Ca is a promising Ca supplement with high calcium bioavailability.

Diversity-Oriented Synthesis of a Molecular Library of Immunomodulatory α-Galactosylceramides with Fluorous-Tag-Assisted Purification and Evaluation of Their Bioactivities in Regard to IL-2 Secretion.

Structural variants of α-galactosylceramide (α-GalCer) that stimulate invariant natural killer T (iNKT) cells constitute an emerging class of immunomodulatory agents in development for numerous biological applications. Variations in lipid chain length and/or fatty acids in these glycoceramides selectively trigger specific pro-inflammatory responses. Studies that would link a specific function to a structurally distinct α-GalCer rely heavily on the availability of homogeneous and pure materials. To address this need, we report herein a general route to the diversification of the ceramide portion of α-GalCer glycolipids. Our convergent synthesis commences from common building blocks and relies on the Julia-Kocienski olefination as a key step. A cleavable fluorous tag is introduced at the non-reducing end of the sugar that facilitates quick purification of products by standard fluorous solid-phase extraction. The strategy enabled the rapid generation of a focused library of 61 α-GalCer analogs by efficiently assembling various lipids and fatty acids. Furthermore, when compared against parent α-GalCer in murine cells, many of these glycolipid variants were found to have iNKT cell stimulating activity similar to or greater than KRN7000. ELISA assaying indicated that glycolipids carrying short fatty N-acyl chains (1fc and 1ga), an unsubstituted (1fh and 1fi) or CF3-substituted phenyl ring at the lipid tail, and a flexible, shorter fatty acyl chain with an aromatic ring (1ge, 1gf, and 1gg) strongly affected the activation of iNKT cells by the glycolipid-loaded antigen-presenting molecule, CD1d. This indicates that the method may benefit the design of structural modifications to potent iNKT cell-binding glycolipids.

Study on the role of immune­related genes after intracranial subarachnoid hemorrhage.

We aimed to screen the feature genes related to subarachnoid hemorrhage (SAH). The datasets (GSE73378 and GSE36791) were downloaded from National Center for Biotechnology Information database. Limma package in R was used to screen the differentially expressed genes (DEGs). Single sample gene set enrichment analysis algorithm was used to evaluate the type of immune infiltration. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were used to analyze function of DEGs. The support vector machine (SVM) was used to constructed classifier, which was evaluated using receiver operating characteristic curves. The E­TABM­421 was used to verify the DEGs related to immunity and the classifier. Seven types of immune cells with significant differences were screened, such as activated CD8 T cell and center memory CD4 T cell. We then obtained 408 DEGs related to immune cell. Subsequently, 10 overlapped KEGG pathways related to the DEGs were obtained, such as hematopoietic cell lineage, NOD­like receptor signaling pathway and T cell receptor signaling pathway. Finally, 9 DEGs related to immune cells (CCL5, CD27, CD3D, CREB5, FYN, ITPR3, TAB1, NCR3 and S1PR5) were screened to constructed SVM classifier. The area under the curve was 0.865 in training dataset and the AUC was 0.75 in the validation set. A SVM classifier based on the 9 DEGs (CCL5, CD27, CD3D, CREB5, FYN, ITPR3, TAB1, NCR3 and S1PR5) related to immune cells might effectively identify SAH patients or healthy people.

Time-course transcriptome analyses of spleen in rainbow trout (Oncorhynchus mykiss) post-Flavobacterium psychrophilum infection.

Flavobacterium psychrophilum, the etiological agent of bacterial coldwater disease and rainbow trout fry syndrome, causes considerable losses in salmonid aquaculture globally. Systemic F. psychrophilum infections in rainbow trout (Oncorhynchus mykiss) lead to a range of clinical signs, including ulcerative lesions in the skin and muscle and splenitis. Previous studies offered an integrative analysis of the skeletal muscle response to F. psychrophilum infection in rainbow trout. However, little is known about the molecular mechanism of immune response in the spleen, which is an important immune organ of rainbow trout. Here, we investigated the time-course splenic transcriptome profiles in uninfected rainbow trout (CK) and F. psychrophilum-infected rainbow trout at day 3 and day 7 (D3, D7) by RNA-seq analyses. Among the 7,170 differentially expressed genes (DEGs) in the three comparisons (D3 vs. CK, D7 vs. CK, D3 vs. D7), 1,286 DEGs showed consistent upregulation or downregulation at D3 and D7 and were associated with pattern recognition, acute-phase response, complement cascade, chemokine and cytokine signaling, and apoptosis. The Real time quantitative PCR (RT-qPCR) analysis of eight DEGs confirmed the accuracy of the RNA-Sequencing (RNA-seq) data. Our results reflected a general process from pathogen recognition to inflammatory cytokine generation and delineated a putative Toll-like receptor signaling pathway in rainbow trout spleen, following F. psychrophilum infection. Taken together, these results provide new insights into the molecular mechanism of the immune response to F. psychrophilum infection and are a valuable resource for future research on the prevention and control of bacterial coldwater disease during salmon culture.

Combination of levofloxacin and cisplatin enhances anticancer efficacy via co-regulation of eight cancer-associated genes.

Chemosensitizer or combined chemotherapy can sensitize cancer cells to therapy and minimize drug resistance. We reveal that levofloxacin has broad-spectrum anticancer activity. Here we report that combination of levofloxacin and cisplatin further enhanced cytotoxicity in cancer cells by further promotion of apoptosis. Levofloxacin concentration-dependently promoted the inhibition of clone formation in cancer cells treated by cisplatin, and their combination further suppressed the tumor growth in mice. Levofloxacin and cisplatin co-regulated genes in directions supporting the enhancement of anticancer efficacy, of which, THBS1, TNFAIP3, LAPTM5, PI3 and IL24 were further upregulated, NCOA5, SRSF6 and SFPQ were further downregulated. Out of the 24 apoptotic pathways significantly enriched in the combination group, TNFAIP3, THBS1, SRSF6 and SFPQ overlapped in 14, 13, 3 and 1 pathway respectively. Jak-STAT/Cytokine-cytokine receptor interaction pathway network and extrinsic apoptotic signaling pathway were significantly enriched in levofloxacin group, cisplatin group and combination group. Jak-STAT/Cytokine-cytokine receptor interaction/Focal adhesion/EMC-receptor interaction pathway network was significantly enriched in the combination group, and IL24 and THBS1 were the overlapped genes. In conclusion, enhancement of anticancer efficacy in combination group was associated with the further regulation of THBS1, TNFAIP3, LAPTM5, PI3, IL24 and NCOA5, SFPQ, SRSF6. Targeting of Jak-STAT/Cytokine-cytokine receptor interaction/Focal adhesion/EMC-receptor interaction pathway network was correlated to the enhancement. With additional benefit to cancer patients for treatment or prophylaxis of an infectious syndrome, levofloxacin can benefit cancer chemotherapy no matter it is used independently or used with other chemotherapeutic drugs.

[Neonicotinoid Insecticides Threaten Surface Waters at the National Scale in China].

This study was conducted in response to the current situation in our country in which neonicotinoid pesticides (NNIs) are used in large quantities and their concentration in surface water is gradually increasing. Based on the species sensitivity distribution (SSD), the hazard quotient (HQ) and probabilistic risk assessment (PRA) were used to compare single and mixture risks of NNIs in the surface water in China. The target and recommended values of NNIs in China's surface water quality supervision were also presented. The results showed that:① in the single acute hazard assessment, imidacloprid (IMI) was the most harmful insecticide, and in the single chronic hazard assessment, imidacloprid (IMI) and acetamiprid (ACE) were more harmful. Furthermore, insects were the most sensitive creatures. ② Hainan province was the region with the highest single acute and chronic hazard in the study area. ③ Based on the joint probability curves of five neonicotinoids, the probability in which 5% of species would be affected by long-term exposure was approximately 91.12%. Thus, the combined ecological risk of these five neonicotinoids cannot be ignored. ④ Based on the toxicity reference value from SSD and the combined results of HQ and PRA, the regulatory values of surface water quality in China were as follows:acetamiprid (ACE) 0.04 µg·L-1, clothianidin (CLO) 0.22 µg·L-1, imidacloprid (IMI) 0.01 µg·L-1, thiacloprid (THI) 0.03 µg·L-1, and thiamethoxam (THIA) 0.24 µg·L-1. In short, the concentration of NNIs in the surface water in China has threatened the safety of aquatic organisms, and its supervision must be improved.