Tumor Metabolism: A New Field for the Treatment of Glioma.

The clinical treatment of glioma remains relatively immature. Commonly used clinical treatments for gliomas are surgery combined with chemotherapy and radiotherapy, but there is a problem of drug resistance. In addition, immunotherapy and targeted therapies also suffer from the problem of immune evasion. The advent of metabolic therapy holds immense potential for advancing more efficacious and tolerable therapies against this aggressive disease. Metabolic therapy alters the metabolic processes of tumor cells at the molecular level to inhibit tumor growth and spread, and lead to better outcomes for patients with glioma that are insensitive to conventional treatments. Moreover, compared with conventional therapy, it has less impact on normal cells, less toxicity and side effects, and higher safety. The objective of this review is to examine the changes in metabolic characteristics throughout the development of glioma, enumerate the current methodologies employed for studying tumor metabolism, and highlight the metabolic reprogramming pathways of glioma along with their potential molecular mechanisms. Importantly, it seeks to elucidate potential metabolic targets for glioblastoma (GBM) therapy and summarize effective combination treatment strategies based on various studies.

Development and Evaluation of a Novel Hyaluronic Acid and Chitosan-modified Phytosome for Co-delivery of Oxymatrine and Glycyrrhizin for Combination Therapy.

BACKGROUND: Multidrug resistance (MDR) of cancer cells is a major obstacle to efficient cancer chemotherapy. Combination therapy is expected to enhance the anticancer effect and reverse MDR. Numerous patents involve different kinds of nanoparticles for the co-delivery of multiple chemotherapeutics, but the FDA has approved none. OBJECTIVE: In this study, oxymatrine (OMT) and glycyrrhizin (GL) were co-loaded into phytosomes as the core of nanocarriers, and the shell was cross-linked with chitosan (CS) and hyaluronic acid (HA) with the capability for the controlled, sequential release and the targeted drug uptake. METHODS: Phospholipid complexes of OMT and GL (OGPs) were prepared by a solvent evaporation technique and could self-assemble in an aqueous solution to form phytosomes. CS and HA were sequentially coated on the surface of OGPs via electrostatic interactions to obtain CS coated OGPs (CS-OGPs) and HA modified CS-OGPs (HA-CS-OGPs), respectively. The particle size and zeta potential were measured to optimize the formulations. In vitro cytotoxicity and cellular uptake experiments on HepG2 cells were performed to evaluate the anticancer activity. RESULTS: OGPs were obtained with nano-size around 100 nm, and CS and HA coating on phytosomes could change the particle size and surface potential. The drug loading of OMT and GL showed that the nanocarriers could maintain a fixed ratio of 1:1. The in vitro release experiments indicated the release of OMT and GL was pH-dependent and sequential: the release of OMT from CS-OGPs and HA-CS-OGPs was significantly increased at pH 5.0 compared to the release at pH 7.4, while GL exhibited sustained released from CS-OGPs and HA-CS-OGPs at pH 5.0. Furthermore, in vitro cytotoxicity and cellular uptake experiments on HepG2 cells demonstrated that the co-delivery system based on phytosomes had significant synergistic anti-tumor activities, and the effects were enhanced by CS and HA modification. CONCLUSION: The delivery of OMT and GL via HA-CS-OGPs might be a promising treatment to reverse MDR in cancer therapy.

The basic leucine zipper transcription factor MeaB is critical for biofilm formation, cell wall integrity, and virulence in Aspergillus fumigatus.

The regulation of fungal cell wall biosynthesis is crucial for cell wall integrity maintenance and directly impacts fungal pathogen virulence. Although numerous genes are involved in fungal cell wall polysaccharide biosynthesis through multiple pathways, the underlying regulatory mechanism is still not fully understood. In this study, we identified and functionally characterized a direct downstream target of SomA, the basic-region leucine zipper transcription factor MeaB, playing a certain role in Aspergillus fumigatus cell wall integrity. Loss of meaB reduces hyphal growth, causes severe defects in galactosaminogalactan-mediated biofilm formation, and attenuates virulence in a Galleria mellonella infection model. Furthermore, the meaB null mutant strain exhibited hypersensitivity to cell wall-perturbing agents and significantly alters the cell wall structure. Transcriptional profile analysis revealed that MeaB positively regulates the expression of the galactosaminogalactan biosynthesis and ß-1,3-glucanosyltransferase genes uge3, agd3, and sph3 and gel1, gel5, and gel7, respectively, as well as genes involved in amino sugar and nucleotide sugar metabolism. Further study demonstrated that MeaB could respond to cell wall stress and contribute to the proper expression of mitogen-activated protein kinase genes mpkA and mpkC in the presence of different concentrations of congo red. In conclusion, A. fumigatus MeaB plays a critical role in cell wall integrity by governing the expression of genes encoding cell wall-related proteins, thus impacting the virulence of this fungus.IMPORTANCEAspergillus fumigatus is a common opportunistic mold that causes life-threatening infections in immunosuppressed patients. The fungal cell wall is a complex and dynamic organelle essential for the development of pathogenic fungi. Genes involved in cell wall polysaccharide biosynthesis and remodeling are crucial for fungal pathogen virulence. However, the potential regulatory mechanism for cell wall integrity remains to be fully defined in A. fumigatus. In the present study, we identify basic-region leucine zipper transcription factor MeaB as an important regulator of cell wall galactosaminogalactan biosynthesis and ß-1,3-glucan remodeling that consequently impacts stress response and virulence of fungal pathogens. Thus, we illuminate a mechanism of transcriptional control fungal cell wall polysaccharide biosynthesis and stress response. As these cell wall components are promising therapeutic targets for fungal infections, understanding the regulatory mechanism of such polysaccharides will provide new therapeutic opportunities.

A Qualitative Assessment of Social Norms Related to Seeking Help for Intimate Partner Violence in Honduras.

Intimate partner violence (IPV) is a major public health issue in Honduras and other low- and middle-income countries, with few victims seeking help. While structural factors, such as lack of services and economic barriers, are often cited as reasons for not seeking help, social and cultural factors may also play a role. This study aims to describe the normative social environment that may hinder women's help-seeking behaviors for IPV. Thematic analysis was conducted on data from four focus group discussions with 30 women at a busy health center in urban Tegucigalpa, Honduras. Data were coded inductively and themes were identified deductively using the theory of normative social behavior and its components (descriptive and injunctive social norms, expected outcomes, and groups of reference). Four themes emerged: social norms and expected outcomes that discourage IPV help-seeking; factors that determine the direction of a social norm, either discouraging or encouraging help-seeking; groups of reference for IPV victims; and society sets women up for failure. Social norms, expected outcomes, and groups of reference hinder women's help-seeking behavior after IPV. These findings have significant implications for designing effective interventions and policies to support women and their families affected by IPV.

Network Pharmacology Analysis and Experimental Validation to Explore the Anti-inflammatory Mechanism of Asiatic Acid on Alcoholic Steatohepatitis.

Objective: The mechanism of action of asiatic acid (AA) on alcoholic steatohepatitis (ASH) was investigated using network pharmacology and experiments. Methods: Through data retrieval, network construction, and enrichment analysis, the potential mechanism of AA in the treatment of alcoholic steatohepatitis was explored. Animal and cell models were established in this study. Animal Model. The mouse model was divided into six groups: normal group; model group; low, medium, and high AA group; and silibinin-positive group. Cell Model. An in vitro inflammatory model of RAW264.7 cells was established by alcohol stimulation. Results: Compared with the model group, the low, medium, and high AA group showed decreased serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), triglyceride (TG), and total cholesterol (T-CHO). The inflammatory factor tumor necrosis factor alpha (TNF-α), interleukin 1 beta (IL-1ß), and interleukin 6 (IL-6) in a dose-dependent manner were decreased. In addition, hematoxylin-eosin staining showed that liver tissue damage and inflammatory cell infiltration in mice were significantly reduced with increasing doses. Further, oil red staining showed that lipid accumulation in hepatocytes in the low, medium, and high AA group was significantly reduced, with increasing dose. In addition, in the cellular model, real-time reverse transcriptase-polymerase chain reaction (Real-Time RT-PCR) and enzyme-linked immunosorbent assay (ELISA) results showed that AA could alleviate alcohol-induced cellular inflammation, while western blot and immunofluorescence results showed that AA might alleviate alcohol-induced cellular inflammation by inhibiting the nuclear factor-κB (NF-κB) pathway. Conclusion: This study provides multiple lines of evidence that asiatic acid may alleviate alcoholic hepatitis in mice by modulating the NF-κB pathway.

Development and Evaluation of a Novel Diammonium Glycyrrhizinate Phytosome for Nasal Vaccination.

The objective of the present research was to formulate diammonium glycyrrhizinate (DG) into phytosomes (DG-P) to induce nasal immune responses and enhance absorption. Plackett- Burman design was used for process optimization, incorporating specific formulation and process variables to obtain the optimal parameters. Fourier transform infrared spectroscopy (FTIR), X-ray power diffraction (P-XRD), and transmission electron microscopy (TEM) were used for characterization. The adjuvant activity of the DG-P was evaluated by using bone marrow dendritic cells. In vitro nasal mucosal permeation and in situ nasal perfusion were also investigated to evaluate nasal absorption. The DG phytosomes were in the size range of 20~30 nm and zeta-potential range of -30~-40 mV. DG-P demonstrated 4.2-fold increased solubility in n-octanol. Coculturing bone marrow dendritic cells with DG-P led to enhanced dendritic cell maturation. Apparent permeability coefficient of the phytosomal formulation was almost four times higher than that of free DG determined by ex vivo permeation studies on excised porcine mucosa. In situ nasal perfusion studies in rats demonstrated that the nasal absorption of DG-P was significantly higher than that of free DG. Conclusively, the results confirmed that DG-P have potential for use as an adjuvant for nasal vaccine.

Particle Design and Inhalation Delivery of Iodine for Upper Respiratory Tract Infection Therapy.

Diseases caused by upper respiratory tract (URT) and pulmonary infections have been a serious threat to human health for millennia and lack of targeted effective therapeutic techniques. In this study, two kinds of cyclodextrin particles with typical particle shapes of nanocubes and microbars were synthesized through a facile process. Subsequently, the particles were used as carriers for loading and stabilizing iodine and characterizations were performed to demonstrate the loading mechanism. Next-generation impactor (NGI) experiments showed that iodine-loaded microbars (I2@microbars) had a deposition rate of 79.75% in URT, while iodine-loaded nanocubes (I2@nanocubes) were delivered to the deep lungs with a fine particle fraction (FPF) of 46.30%. Minimal inhibitory concentration (MIC) and minimal bactericidal concentration (MBC) indicated that the iodine-loaded nanocubes and microbars had similar bactericidal effect to povidone iodine solution. Cell viability studies and extracellular pro-inflammatory factor (TNF-α, IL-1ß, IL-6) evaluations demonstrate noncytotoxic effects of the blank carriers and anti-inflammatory effects of iodine-loaded samples. The irritation of the rat pharynx by I2@microbars was evaluated for the behavioral observations, body weight changes, histopathological studies, and TNF-α, IL-1ß, and IL-6 levels in pharyngeal tissues. The results showed that I2@microbars had no irritation to rat pharyngeal tissues at therapeutic doses. In conclusion, the present study provides novel treatment of URT infections via supramolecular cyclodextrin carriers for URT local therapy with iodine loading by a solvent-free method, which enhances the stability and reduces the inherent irritation without inhibiting their antimicrobial effects. Two kinds of cyclodextrin particles with typical shapes of microbars and nanocubes were synthesized by a facile process. Subsequently, iodine was successfully loaded into the particles by gas-solid interaction. The iodine-loaded microbars showed air dynamics characteristics for inhalation delivery to the upper respiratory tract with little alveolar deposition in the lungs.

Neuroprotective effects of CysLTR antagonist on Streptococcus pneumoniae-induced meningitis in rats.

Cysteinyl leukotrienes (CysLTs) modulate central nervous system inflammatory responses via their receptors, CysLT1R and CysLT2R. It has been demonstrated that CysLTR participates in the infection process of Streptococcus pneumoniae (SP)-induced meningitis. In the present study, the effects and possible underlying mechanisms of CysLTR antagonists (pranlukast and HAMI 3379) on SP meningitis were further determined. SP meningitis was induced by intracerebroventricular injection of serotype III SP in Sprague-Dawley rats which were administrated intraperitoneally with 0.1 mg/kg antagonists. The clinical disease status of rats was evaluated by body weight and behavioral changes with neurological scoring. Survival neuron density, activated microglial and astrocytes were assessed by Nissl staining and immunohistochemical staining. The expression levels of inflammatory cytokines and NLRP3 inflammasome were detected by reverse transcription-quantitative PCR and western blotting, respectively. Pranlukast and HAMI 3379 treatment markedly alleviated the clinical disease status, which was manifested by improving body weight loss and neurological deficit. Furthermore, pranlukast and HAMI 3379 treatment ameliorated neuronal injury and inhibited microgliosis and astrogliosis. In addition, significant downregulation of inflammatory cytokines and NLRP3 expression was observed in pranlukast and HAMI 3379-treated rats. These in vivo findings indicated the neuroprotective effects of CysLTR antagonists against experimental SP-induced meningitis, and the mechanism of anti-inflammatory effects may partly be by inhibiting NLRP3 inflammasome overactivation.

Efficient capture and stabilization of iodine via gas-solid reaction using cyclodextrin metal-organic frameworks.

For treatment of wound infection with stabilized iodine, potassium iodide cyclodextrin metal-organic frameworks (KI-CD-MOF) was prepared to carry iodine via gas-solid reaction. Apart from highly ordered porous frameworks, KI-CD-MOF contains uniformly distributed iodide ions which stabilize iodine (I2). X-ray photoelectron spectroscopy and potentiometric titration were utilized to confirm the formation of I3- in the highly porous KI-CD-MOF as I2@KI-CD-MOF. Molecular simulation and characterizations of the synchrotron radiation Fourier transform infrared spectroscopy, differential scanning calorimeter, powder X-ray diffraction and N2 adsorption were conducted to illustrate the inclusion mechanism of iodine in I2@KI-CD-MOF. The apparent solubility of iodine in water was 3.86 times enhanced. The stability and antibacterial activity tests demonstrated that the highly-dispersed iodide ions in KI-CD-MOF are crucial in improvement to the solubility, stability, and bacteriostatic effects of active iodide. Therefore, KI-CD-MOF has broad application prospects and advantages in efficiently capturing and stabilizing iodine.

Compulsive immobility: Understanding the role of health on collective efficacy.

Most health care approaches to understanding social ills are rooted in strain or ecological models. Strain models assume that the impact of poor physical health operates through the individual, that it is the individual suffering from poor health who engages in social ills as a means of adapting, and that the impact of poor health is rather direct and immediate. Meanwhile, ecological approaches of health acknowledge how poor health may impact others and the collective, but poorly account for the case in which this is not so, leaving unexplained the many instances of people who are in poor health but remain actively engaged with their communities and preserve relationships that nurture trust, shared norms, and cooperation. To rectify this problem, we introduce the concept of "compulsive immobility": the situation in which those in poor health are compelled to stay indoors and refrain from community socialization. We argue that compulsive immobility mediates the relationship between poor physical health and collective efficacy, suggesting that illness, specifically to a point of physical immobility (e.g., bedridden), enables poor health to detract from collective efficacy. This allows scholars to both acknowledge how poor health may impact the individual and community, while specifying the mechanism through which it operates. To support our claim, we draw on GSS data to examine the relationship among poor health, health-related immobility, and collective efficacy. Our results provide empirical support for our argument, revealing that general health conditions influenced the level of generalized trust directly and indirectly through compulsive immobility. We conclude with suggestions on how compulsive immobility might impact neighborhood crime and propose ways through which subsequent research may refine and further test compulsive immobility as a mediator between poor health and collective efficacy.

Physical disorder and crime revisited: New evidence from intensive longitudinal data.

OBJECTIVES: The purpose of this study is to investigate whether the often-debated association between physical disorder and crime exists longitudinally and operates through a specific spatial process. METHODS: We combine four administrative and official databases to analyze patterns of crime occurring each month in New Orleans, LA, between 2012 and 2018 at the block group level. We adopt a generalized additive model (GAM) framework to efficiently account for potential spatial, temporal, and spatiotemporal autocorrelation to investigate this association. RESULTS: The resident-driven self-report measure of physical disorder (i.e., 311 calls) consistently predicts neighborhood criminal activities in New Orleans. The spatial effects of 311 calls in adjacent areas on drug violations, property crime, and violence in a focal neighborhood are also observed. In contrast, official reports of physical disorder, captured with code violation, is either weakly related to crime or lacking an empirical relationship. CONCLUSION: Overall, our findings suggest that the association between physical disorder and neighborhood crimes is robust over time. In addition, this association is conditioned by how physical disorder is operationalized, with dimensions such as residential report and official report of physical disorder playing a unique, and occasionally important role in understanding overall patterns of neighborhood criminal activity.

Self-Control, Risky Lifestyles, and Victimization among Chinese Adolescents.

Violent and property victimization among Chinese adolescents remains a social problem, yet studies that incorporate individual characteristics and situational/contextual factors to explain such victimization remain scarce. Drawing upon survey data collected from a large, representative sample of middle school students from two areas in Guizhou Province, China, we test Schreck's integrated model of victimization, finding that self-control has both direct and indirect influences on violent and property victimization among Chinese adolescents. Delinquent peers play the most significant intermediate role in connecting self-control and adolescent victimization. Results reconfirm the importance of both self-control and risky lifestyles/situations in shaping victimization, and identify a victimization pathway that accentuates the key linking mechanism of delinquent peers in the self-control-victimization nexus.

Parental Migration and Children's Exposure to Polyvictimization in Rural China.

The present study aims to investigate (1) the difference in polyvictimization rate between children left behind and those living with non-migrant parents in rural China, and (2) the social processes through which the effects of parental migration are conveyed through children's behaviors and interaction with the immediate external environment (e.g., family, school, and peers). The research hypotheses were tested by using a probability sample consisting of 1,681 middle school students in rural areas in Guizhou province (Mean age = 13.55, SD = 1.01; 50% of the participants were boys). Findings from multivariate logistic regression models and indirect effect analyses suggest that (1) overall, left-behind children are exposed to a higher level of polyvictimization than children living with both non-migrant parents in rural China and (2) whereas all left-behind children face similar challenges in school and family settings, each type of parental migration and caretaking arrangement entails unique protective or risk factors of polyvictimization. As one of the first studies to systematically investigate the rate and etiology of polyvictimization among children left behind in rural China, this study highlights the prominent role of parental migration in reproducing and reinforcing children's differential exposure to polyvictimization among China's rural families.

Honokiol combined with curcumin sensitizes multidrug-resistant human lung adenocarcinoma A549/DDP cells to cisplatin.

The aim of the present study was to discuss the effects and underlying mechanisms of honokiol (HNK) and/or curcumin (CUR) in sensitization of multidrug-resistant human lung adenocarcinoma A549/DDP cells to cisplatin (DDP). An MTS assay was performed to detect the cytotoxicity of HNK, CUR and DDP in A549 and A549/DDP cells and compare their sensitivity. The A549/DDP cells were then divided into 8 groups: Control, HNK, CUR, DDP, HNK + CUR, HNK + DDP, CUR + DDP and HNK + CUR + DDP. Cell proliferation was measured by MTS assay and colony formation assay, cell apoptosis was detected by flow cytometry, cell invasion was evaluated by Transwell assay and cell migration was determined by a wound healing assay. In order to investigate the possible mechanisms, P-glycoprotein (P-gp) protein expression was measured by western blotting and immunofluorescence assays. The mRNA expression levels of AKT, Erk1/2, cyclin-dependent kinase inhibitor 1 (P21), caspase 3, cleaved caspase 3, caspase 9, cleaved caspase 9, poly (ADP-ribose) polymerase (PARP), cleaved PARP, matrix metalloproteinase (MMP)-2 and MMP-9 were examined by reverse transcription-quantitative (RT-q) PCR assay, and the protein expression levels of phosphorylated (p)-AKT, p-Erk1/2, P21, caspase 3, cleaved caspase 3, caspase 9, cleaved caspase 9, PARP, cleaved PARP, MMP-2 and MMP-9 proteins expression by western blot assay. The MTS assay demonstrated that HNK (5 µg/ml), CUR (10 µg/ml) and DDP (5 µg/ml) had no obvious toxicity to A549/DDP cells, and HNK, CUR and DDP were more sensitive in A549 cells compared with A549/DDP cells. The optimal concentrations of HNK (5 µg/ml), CUR (10 µg/ml) and DDP (5 µg/ml) were chosen to carry out the further experiments. Compared with the control group, no significant change was observed in cell proliferation, apoptosis, migration, invasion and related mRNA and protein expression in HNK, CUR, DDP and HNK + CUR groups. The cell proliferation rate in the HNK + DDP and CUR + DDP groups was significantly suppressed with cell apoptosis significantly increased, respectively. The invasion cell number and wound healing rate of HNK + DDP and CUR + DDP groups were significantly depressed compared with the control group, respectively. Immunofluorescence demonstrated that the nuclear volume of P-gp in HNK + DDP and CUR + DDP groups were significantly downregulated compared with the control group, respectively. The RT-qPCR assay demonstrated that the AKT, Erk1/2 and P21 mRNA expression levels were significantly decreased and cleaved caspase 3, cleaved caspase 9 and cleaved PARP were increased in HNK + DDP and CUR + DDP groups compared with the control group. The western blotting results were consistent with the RT-qPCR results. NK + CUR + DDP had improved effects on A549/DDP compared with HNK + DDP or CUR + DDP group, respectively. HNK and/or CUR could improve the sensitivity of DDP to A549/DDP cell by the regulation of P-gp, inducing apoptosis, and inhibiting migration and invasion via AKT/ERK signal pathway in an in vitro study.

Simultaneous improvement to solubility and bioavailability of active natural compound isosteviol using cyclodextrin metal-organic frameworks.

Cyclodextrin metal-organic framework (CD-MOF) as a highly porous supramolecular carrier could be one of the solutions to the insolubility of isosteviol (STV). The solubility of STV was lower than 20.00 ng/mL at pH 1.0 and pH 4.5, whilst its solubility increased to 20,074.30 ng/mL at pH 6.8 and 129.58 ng/mL in water with a significant pH-dependence. The in vitro release profiles of STV from STV@CD-MOF (0.5:1) were pH-independent in distinct pH media and closed to be thoroughly released but no such release profiles were observed for STV@CD-MOF (1:1) owing to nanoclusters formation. The bioavailability of STV@CD-MOF (1:1) in rats was 8.67-fold higher than that of STV, and was 1.32- and 1.27-fold higher than that of STV@CD and STV@CD-MOF (0.5:1). Our results indicated that the inclusion mechanism played a primary role when STV in CD-MOF was at a low loading ratio, while the increasement in bioavailability at a high loading ratio, which was attributed to the nanocluster mechanism. This was confirmed by molecular simulation. In conclusion, CD-MOF is a promising system for STV loading, overcoming the insolubility and to improve the bioavailability of this natural compound.

Children's immigrant generational status and delinquency: The mediating effects of friendship networks.

A mounting body of empirical studies demonstrates that first-generation immigrant children have a lower level of delinquency and crime but second and third-plus generations report a precipitous increase in these behaviors. Adopting a social network approach, we analyzed the behavioral and structural characteristics of children's friendship networks across the first, second, and third-plus immigrant generations, and investigated the mediating role of these friendship traits in explaining generational disparity. Our results reveal that children's friendship networks differ in structural (e.g., popularity) and behavioral features (e.g., network deviance) across immigrant generations. These friendship features, particularly network peer deviance, the percentage of second-generation friends, and children's popularity mediate the association between immigrant generational status and children's delinquency. Extending previous research, our study highlights the importance of applying the social network approach to understand delinquency disparity across immigrant generations and suggests that the composition of friendship networks play an important role in immigrant children's delinquency involvement.

Self-Control, External Environment, and Delinquency: A Test of Self-Control Theory in Rural China.

Although self-control consistently emerges as one of the most robust correlates of delinquent behavior, limited empirical attempts have been made to explore the contextual variability of the relationship between self-control and delinquency outside of Western societies. Using data collected from 587 seventh- to ninth-grade students across 10 middle schools in a rural county of Southeast China, we examine self-control's efficacy in explaining juvenile delinquency in the presence of external environmental factors, and investigate relative strength of self-control and contextual factors in predicting delinquent behaviors. Our results confirm that self-control is an important predictor of delinquent behavior in a non-Western cultural context. However, certain environmental factors rooted in family, school, and peer groups are also shown to be the predictors of delinquent behavior where strength seems to exceed that of self-control. These findings shed more nuanced insights on the nexus between self-control, external situations, and delinquency, and in a broader sense, contribute to the elaboration of a more comprehensive understanding of self-control theory.

NLG919/cyclodextrin complexation and anti-cancer therapeutic benefit as a potential immunotherapy in combination with paclitaxel.

NLG919 is an effective small molecule inhibitor of indoleamine 2, 3-dioxygenase-1 (IDO-1) in anti-tumour immunotherapy, but the poor aqueous solubility limits its application for effective intravenous dosing. In this study a cyclodextrin (CD) complexation strategy has been systematically evaluated to achieve a simple and feasible method to prepare an NLG919 injectable formulation. From a series of CDs, HP-ß-CD proved to be the most conducive for NLG919 solubilization (approx 800-fold increase). Characterization studies using DSC, 1H NMR, XRPD and molecular simulation demonstrated that the NLG919/HP-ß-CD loading mechanism involved an increasing pH-dependent binding affinity. Importantly cell-based studies in vitro and anti-tumour activity in vivo demonstrated that the pharmacological activity of NLG919 as an IDO-1 inhibitor was not influenced by HP-ß-CD complexation. Furthermore, the combination of NLG919/HP-ß-CD with paclitaxel (PTX) significantly improved anti-tumour chemotherapy compared to PTX alone. In summary, NLG919/HP-ß-CD is shown to highly enhance the aqueous solubility of NLG919 with activity unaffected, greatly facilitating the intravenous use of this small molecule immunotherapeutic to improve the efficacy of PTX.

Expression of cysteinyl leukotriene receptor in brain tissues of rats with Streptococcus pneumoniae meningitis.

Streptococcus pneumoniae meningitis is an infection of the central nervous system associated with high mortality rates and serious neurologic sequelae in children. The principal reason for the severity of S. pneumoniae meningitis is widespread ignorance of the pathogenesis of the disease. This study aimed at exploring whether cysteinyl leukotriene receptor (CysLTR) participates in the inflammatory response and elucidates the pathologic process of S. pneumoniae meningitis. Bacterial meningitis disease models were constructed by intracisternal inoculation of rats with serotype III Streptococcus pneumoniae while control models were inoculated with the same volume of normal saline. Rats were sacrificed at different time points (1 d, 2 d, and 5 d) following the administration of Streptococcus pneumoniae. Results from the body-weight, Loeffler neurologic deficit score, and cerebrospinal fluid culture confirmed that a successful pneumococcal meningitis rat model was established. Pathologic changes in brain tissues mainly consisted of inflammation in the meninges and subarachnoid space and significant neuronal injury in the cerebral cortex and hippocampus (P < 0.05). Immunohistochemical analysis revealed that microglial activation and astrocyte proliferation were associated with the development of bacterial meningitis. The expression levels of CysLTR and inflammatory factor tumor necrosis factor-α (TNF-α) were examined by quantitative real-time polymerase chain reaction (qRT-PCR) and western blot analysis. The results of this study indicate that CysLTR expression was markedly elevated in the 5 d infection group (P < 0.05), which was consistent with time-dependent release of TNF-α. The findings of this study indicate that CysLTR participates in the pneumococcal meningitis infection process by mediating neuronal injury and glial cell proliferation. Cysteinyl leukotriene receptors could, therefore, be novel targets to mitigate the progression of pneumococcal meningitis.

Physiological and TMT-based proteomic analysis of oat early seedlings in response to alkali stress.

Oats are an important cereal crop worldwide, and they also serve as a phytoremediation crop to ameliorate salinized and alkalized soils. However, the mechanism of the oat response to alkali remains unclear. Physiological and tandem mass tag (TMT)-based proteomic analyses were employed to elucidate the mechanism of the oat response to alkali stress. Physiological and phenotypic data showed that oat root growth was inhibited more severely than shoot growth after alkali stress. In total, 164 proteins were up-regulated and 241 proteins were down-regulated in roots, and 93 proteins were up-regulated and 139 proteins were down-regulated in shoots. Under high pH stress, transmembrane proton transporters were down-regulated; conversely, organic acid synthesis related enzymes were increased. Transporters of N, P, Fe, Cu and Ca in addition to N assimilation enzymes in the root were highly increased. This result revealed that higher efficiency of P, Fe, Cu and Ca transport, especially higher efficiency of N intake and assimilation, greatly promoted oat root resistance to alkali stress. Furthermore, many resistance proteins, such as late embryogenesis abundant (LEA) mainly in shoots, GDSL esterase lipase mainly in roots, and WD40-like beta propeller repeat families, greatly accumulated to contribute to oat resistance to alkali stress. SIGNIFICANCE: In this study, physiological and tandem mass tag (TMT)-based proteomic analyses were employed to elucidate oats early seedlings in response to alkali stress. Many difference expression proteins were found involving in oats response to alkali stress. Also, higher efficiency transport of P, Fe, Cu, Ca and N greatly promoted oat resistance to alkali stress.