7-O-(2- (Propylamino)-2-oxoethyl) hesperetin attenuates inflammation and protects against alcoholic liver injury by NLRP12.

Alcoholic liver disease (ALD) is a liver disease caused by long-term heavy drinking. Alcoholic liver injury is a part of alcoholic liver disease. A large number of studies have shown that alcohol metabolism and endotoxin / lipopolysaccharide (LPS) and cycles can cause massive activation of macrophages, leading alcoholic liver injury. Hesperetin is a dihydro-flavonoid extracted from the fruits of Citrus in Rutaceae. It has a variety of pharmacological activities, including antibacterial, anti-inflammatory, antioxidant and so on, but recent studies have shown that hesperetin derivatives have stronger anti-inflammatory effects than hesperetin. In order to improve the anti-inflammatory activity of hesperetin, our group used ethyl-bromoacetate to replace the hydroxyl group at the 7 position of hesperetin to obtain the hesperetin derivative 7-O-(2-(Propylamino)-2-oxoethyl) hesperetin (HD-4d). In this study, we found that HD-4d had hepatoprotective and anti-inflammatory effects on alcoholic liver injury in C57BL/6J mice, and it also had noticeable anti-inflammatory effects in EtOH and LPS-induced RAW264.7 cells. Besides, we found that HD-4d can reduce the expression of inflammatory factors by up-regulating NLRP12 in vivo and in vitro. We found that the expression of NLRP12 was significantly increased in EtOH and LPS-induced RAW264.7 cells compared with the control group. Moreover, the inhibitory effect of HD-4d on inflammation weakened considerably after silencing NLRP12 in RAW264.7 cells. However, when NLRP12 was overexpressed with plasmid pEX-3-NLRP12, the effect of HD-4d on alcohol and LPS induced inflammation was remarkably increased. In addition, further studies indicated that HD-4d inhibited the activation and phosphorylation of the p65 protein by up-regulating NLRP12. In conclusion, HD-4d activated NLRP12 to reduce liver injury and inflammatory response through the NF-кB pathway.

O-alkyl and o-benzyl hesperetin derivative-1L attenuates inflammation and protects against alcoholic liver injury via inhibition of BRD2-NF-κB signaling pathway.

Alcoholic liver injury (ALI) is a major risk factor for alcoholic liver disease, characterized by excessive inflammatory response and abnormal liver dysfunction. Previous studies have indicated that O-alkyl and o-benzyl hesperetin derivative-1 L (HD-1 L) has anti-inflammatory and hepato-protective effects in CCl4-induced liver injury. However, its effect on ALI and underlying mechanism has not been elucidated. This study was designed to evaluate the protective effects of HD-1 L on alcoholic liver injury and reveal the underlying mechanisms. ALI model was established in male C57BL/6 J mice (aged 6-8 weeks) by Gao-Binge protocol. The mice were received different doses of HD-1 L (25 mg/kg, 50 mg/kg, 100 mg/kg) by daily intragastric administration, respectively. Liver function and inflammation were measured. Mechanism underlying the anti-inflammatory and hepato-protective effect of HD-1 L were studied in RAW264.7 cells. In alcoholic liver injury mice, HD-1 L effectively improved the liver pathology, and remarkably reduced the levels of alanine transaminase (ALT), aspartate transaminase (AST), triglyceride (TG) and total cholesterol (T-CHO) in serum. Moreover, HD-1 L markedly suppressed inflammation in vivo and inhibited the secretion of inflammatory factors in vitro. Our results showed that HD-1 L decreased the activity of Bromodomain-containing Protein 2 (BRD2) and inhibited expression of BRD2 in vivo and in vitro. Furthermore, HD-1 L further alleviated alcohol-induced inflammation after blocking BRD2 with inhibitor (JQ1) or BRD2 small interfering (si)-RNA in RAW264.7 cells. Besides, HD-1 L failed to effectively exert its anti-inflammatory effects after over expression of BRD2. In addition, HD-1 L significantly inhibited the phosphorylation and activation of NF-κB-P65 mediated by BRD2. In conclusion, HD-1 L alleviated liver injury and inflammation mainly by inhibiting BRD2-NF-κB signaling pathway, and HD-1 L may be a potential anti-inflammatory compound in treatment of alcoholic liver disease.

Design and synthesis of 7-O-1,2,3-triazole hesperetin derivatives to relieve inflammation of acute liver injury in mice.

Based on the previous research results of our research group, to further improve the anti-inflammatory activity of hesperetin, we substituted triazole at the 7-OH branch of hesperetin. We also evaluated the anti-inflammatory activity of 39 new hesperetin derivatives. All compounds showed inhibitory effects on nitric oxide (NO) and inflammatory factors in lipopolysaccharide-induced RAW264.7 cells. Compound d5 showed a strong inhibitory effect on NO (half maximal inhibitory concentration = 2.34 ± 0.7 µM) and tumor necrosis factor-α, interleukin (IL)-1ß, and (IL-6). Structure-activity relationships indicate that 7-O-triazole is buried in a medium-sized hydrophobic cavity that binds to the receptor. Compound d5 can also reduce the reactive oxygen species production and significantly inhibit the expression of inducible NO synthase and cyclooxygenase-2 through the nuclear factor-κB signaling pathway. In vivo results indicate that d5 can reduce liver inflammation in mice with acute liver injury (ALI) induced by CCI4. In conclusion, d5 may be a candidate drug for treating inflammation associated with ALI.

PfSWIB, a potential chromatin regulator for var gene regulation and parasite development in Plasmodium falciparum.

BACKGROUND: Various transcription factors are involved in the process of mutually exclusive expression and clonal variation of the Plasmodium multigene (var) family. Recent studies revealed that a P. falciparum SWI/SNF-related matrix-associated actin-dependent regulator of chromatin (PfSWIB) might trigger stage-specific programmed cell death (PCD), and was not only crucial for the survival and development of parasite, but also had profound effects on the parasite by interacting with other unknown proteins. However, it remains unclear whether PfSIWB is involved in transcriptional regulation of this virulence gene and its functional properties. METHODS: A conditional knockdown system "PfSWIB-FKBP-LID" was introduced to the parasite clone 3D7, and an integrated parasite line "PfSWIB-HA-FKBP-LID" was obtained by drug cycling and clone screening. Growth curve analysis (GCA) was performed to investigate the growth and development of different parasite lines during 96 h in vitro culturing, by assessing parasitemia. Finally, we performed qPCR assays to detect var gene expression profiling in various comparison groups, as well as the mutually exclusive expression pattern of the var genes within a single 48 h life-cycle of P. falciparum in different parasite lines. In addition, RNA-seq was applied to analyze the var gene expression in different lines. RESULTS: GCA revealed that conditional knockdown of PfSWIB could interfere with the growth and development of P. falciparum. The parasitemia of PfSWIB∆ showed a significant decline at 96 h during in vitro culture compared with the PfSWIB and 3D7 lines (P < 0.0001). qPCR and RNA-seq analysis confirmed that depletion of PfSWIB not only silences upsA, upsC and partial upsB var genes, as well as removes the silencing of partial upsB var genes at the ring stage in PfSWIB∆ line, but also leads to aberrant expression of upsA and partial upsB/upsC var genes at the mature stage of P. falciparum, during a single 48-h life-cycle. CONCLUSIONS: We demonstrated that PfSWIB was involved in the process of clonal variation in var gene expression, and crucial for the survival and development of Plasmodium parasite. These findings could provide better understanding of the mechanism and function of PfSWIB contributing to the pathogenesis in malaria parasites.

4-Methylcoumarin-[5,6-g]-hesperetin attenuates inflammatory responses in alcoholic hepatitis through PPAR-γ activation.

4-Methylcoumarin-[5,6-g]-hesperetin (4-MCH) is a hesperidin derivative produced by the structural modification of hesperetin. Alcoholic hepatitis (AH) is the origin of many serious liver diseases that are accompanied by hepatic inflammation. In this study, we detected the anti-inflammatory activity of 4-MCH in EtOH fed mice and examined the potential molecular mechanism of this activity. We found that 4-MCH suppressed the release of inflammatory cytokines such as interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) in primary liver macrophages isolated from mice and in EtOH-treated RAW264.7 cells. In addition, we showed that the expression of peroxisome proliferator-activated receptor-γ (PPAR-γ) was down-regulated in vivo and in vitro in AH. Furthermore, 4-MCH acted as an activator of PPAR-γ, which could therefore ameliorate the inhibitory effects of EtOH on the expression of PPAR-γ. The impairment of PPAR-γ function (T0070907 or PPAR-γ siRNA treatment) resulted in greater inflammation than that in the control group. Conversely, over-expression of PPAR-γ further reduced the release of inflammatory cytokines from EtOH-stimulated RAW264.7 cells. Additional investigations showed that 4-MCH significantly inhibited the phosphorylation of p65. Collectively, these results indicate that 4-MCH alleviated the inflammatory reaction through PPAR-γ activation via the NF-κB-p65 signaling pathway, which regulates the expression of IL-6 and TNF-α in AH.

Association between symptom control and functional improvement in patients with acute schizophrenia: A post hoc analysis of an open-label, single-arm, multi-center study of paliperidone-extended release formulation.

Both symptom control and functional improvement are important goals in schizophrenia treatment. A post hoc analysis of an 8-week, open-label, single-arm, multi-center study of paliperidone-extended release formulation was conducted to evaluate the correlation between personal/social functioning and symptom control in the acute phase, and to identify factors associated with psychosocial functioning, in patients with acute schizophrenia. Of 608 enrolled patients, 602 (99%) were included in the full analysis set. Correlation and regression analyses were applied to identify the association of Personal and Social Performance (PSP) total scores with Positive and Negative Syndrome Scale (PANSS) total scores and other factors. A significant negative correlation was observed between PSP and PANSS at all visits (week 1: r = -0.55; week 2: r = -0.79, p < 0.0001). Patients with PSP score improvement (≥10 point) showed a higher possibility of symptom improvement (PANSS reduction ≥30%). Duration of illness, PANSS Marder factors, and satisfaction with prior treatment, sleep quality, and daytime drowsiness influenced change in PSP total score at endpoint. These results suggest symptom outcome as an important factor to predict functional improvement in acute schizophrenia.

Design, synthesis and investigation of potential anti-inflammatory activity of O-alkyl and O-benzyl hesperetin derivatives.

Hesperetin has been known to exert several activities such as anti-oxidant, antitumor and anti-inflammatory. To find hesperetin derivatives showing better activity, sixteen novel hesperetin derivatives were designed and synthesized. The new obtained compounds were investigated for their anti-inflammatory activity by inhibiting interleukin-1ß (IL-1ß), interleukin-6 (IL-6) and production of nitric oxide (NO) in mouse RAW264.7 macrophages, and the structure-activity relationship of them was discussed. Among them, the compound 1l, 2c demonstrated more effective inhibitory activity of IL-1ß and IL-6, meanwhile, the compound 1l showed the best inhibition of NO production. The results of NO inhibition study were basically accord with the molecular docking results of inducible nitric oxide synthase (iNOS). Furthermore, the expression of LPS-induced iNOS and components of NF-κB signaling pathway were reduced by compound 1l. Our results suggest that the inhibitory effect of compound 1l on LPS-stimulated inflammatory mediator production in RAW 264.7 cells is associated with the suppression of NF-κB signaling pathway and inhibition of iNOS protein and iNOS activity. From in vivo study, it was also observed that compound 1l had hepato-protective and anti-inflammatory effects in CCl4-induced acute liver injury mouse models.

Design, synthesis and biological evaluation of hesperetin derivatives as potent anti-inflammatory agent.

A flavonoid hesperetin is reported to have a variety of biological activities, including anticancer, antiviral, antioxidant, neuroprotective and anti-inflammatory properties. Thirty-one novel hesperetin derivatives were designed, synthesized and evaluated for anti-inflammatory activity using RAW264.7 cells and CCl4-induced acute liver injury model. Among these compounds, 5b displayed the excellent anti-inflammatory activity on decreasing NO, IL-6 and TNF-α both in vitro and vivo. In addition, 5b could also reduce the release of NO, IL-6 and TNF-α production by LPS stimulated RAW 264.7 cell through MAPK and NF-κB signaling pathway in a concentration dependent manner. From in vivo study, it was also observed that 5b attenuated liver histopathologic changes in mouse models.

Design, Synthesis and Evaluation of Hesperetin Derivatives as Potential Multifunctional Anti-Alzheimer Agents.

In this study we designed and synthesized a series of new hesperetin derivatives on the basis of the structural characteristics of acetylcholinesterase (AChE) dual-site inhibitors. The activity of the novel derivatives was also evaluated. Results showed that the synthesized hesperetin derivatives displayed stronger inhibitory activity against AChE and higher selectivity than butyrylcholine esterase (BuChE) (selectivity index values from 68 to 305). The Lineweaver-Burk plot and molecular docking study showed that these compounds targeted both the peripheral anionic site (PAS) and catalytic active site (CAS) of AChE. The derivatives also showed a potent self-induced ß-amyloid (Aß) aggregation inhibition and a peroxyl radical absorbance activity. Moreover, compound 4f significantly protected PC12 neurons against H2O2-induced cell death at low concentrations. Cytotoxicity assay showed that the low concentration of the derivatives does not affect the viability of the SH-SY5Y neurons. Thus, these hesperetin derivatives are potential multifunctional agents for further development for the treatment of Alzheimer's disease.

Hesperetin derivative-14 alleviates inflammation by activating PPAR-γ in mice with CCl4-induced acute liver injury and LPS-treated RAW264.7 cells.

Hesperetin is a flavanone glycoside compound naturally occurring in the fruit peel of Citrusaurantium L. (Rutaceae). Previous studies revealed that hesperetin possesses various pharmacological effects, including anti-inflammation, anti-tumor, anti-oxidant and neuroprotective properties. Hesperetin derivative-14 (HD-14) is a derivative of hesperetin improved in water solubility and bioavailability. In this study, we indicated that HD-14 (2µM) significantly attenuated inflammation in LPS-treated RAW264.7 cells, besides, HD-14 (100mg/kg) exhibited hepato-protective effects and anti-inflammatory effects on C57BL/6J mice with CCl4-induced acute liver injury. In addition, it was demonstrated that HD-14 dramatically up-regulated the expression of PPAR-γ in vivo and in vitro. Interestingly, over-expression of PPAR-γ had anti-inflammatory effects on the expressions of TNF-α, IL-6, and IL-1ß, whereas, knockdown of PPAR-γ with small interfering RNA had pro-inflammatory effects in LPS-treated RAW264.7 cells. Thus, our findings demonstrated that HD-14 alleviated inflammation by activating PPAR-γ expression at least in part. Further studies founded that HD-14 remarkably inhibited the expression of p-JAK1 and p-STAT1 through up-regulating PPAR-γ. Together, these results suggested that HD-14 served as an activator of PPAR-γ and the JAK1/STAT1 signaling pathway may be involved in the progress of inflammation. Collectively, HD-14 may be utilized as a potential anti-inflammation monomeric compound in the treatment of acute liver injury.

Correlation analysis of osteoporotic vertebral compression fractures and spinal sagittal imbalance.

PURPOSE: To evaluate the correlation between osteoporotic vertebral compression fractures and spinal sagittal imbalance, in order to provide a reference for clinical treatment. METHODS: From September 2013 to March 2015, 60 elderly patients with old osteoporotic vertebral compression factures (observation group) and 60 healthy elderly people (control group) were studied. Whole-spine anteroposterior and lateral view X­ray photographs were taken from all participants, the number and location of fractured vertebrae were recorded, and sagittal parameters in both groups were compared. The observation group was divided into three subgroups according to the number of fractured vertebrae. The C7/sacrofemoral distance (SFD) ratio in the three subgroups was compared, and the correlation between the number of fractured vertebrae and the C7/SFD ratio was analyzed. RESULTS: The thoracic kyphotic angle in patients in the observation group was higher than in the control group (P < 0.05), the lumbar lordotic angle in patients in the observation group was lower than in the control group (P < 0.05), the absolute value of the T1 spinopelvic inclination angle in patients in the observation group was lower than in the control group (P < 0.05), and the C7/SFD ratio of patients in the observation group was higher than in the control group (P < 0.05). C7/SFD ratios of the subgroups differed from each other, and the number of fractured vertebrae and C7/SFD ratio were positively correlated. CONCLUSION: Osteoporotic vertebral compression fractures can change local spinal sagittal alignment, multiple vertebral compression fractures can cause spinal sagittal imbalance, and the number of fractured vertebrae and the degree of forward movement of the spine were positively correlated.

[Research on symmetrical optical waveguide based surface plasmon resonance sensing with spectral interrogation].

Surface plasmon resonance (SPR) sensors with spectral interrogation can adopt fiber to transmit light signals, thus leaving the sensing part separated, which is very convenient for miniaturization, remote-sensing and on-site analysis. Symmetrical optical waveguide (SOW) SPR has the same refractive index of the-two buffer media layers adjacent to the metal film, resulting in longer propagation distance, deeper penetration depth and better performance compared to conventional SPR In the present paper, we developed a symmetrical optical, waveguide (SOW) SPR sensor with wavelength interrogation. In the system, MgF2-Au-MgF2 film was used as SOW module for glucose sensing, and a fiber based light source and detection was used in the spectral interrogation. In the experiment, a refractive index resolution of 2.8 x 10(-7) RIU in fluid protocol was acquired. This technique provides advantages of high resolution and could have potential use in compact design, on-site analysis and remote sensing.

[Research Progress on Artemisinin Resistance in Plasmodium falciparum].

Artemisinin (ART) is a novel and effective antimalarial drug discovered in China. As recommended by the World Health Organization, the ART-based combination therapies (ACTs) have become the first-line drugs for the treatment of falciparum malaria. ART and its derivatives have contributed greatly to the effective control of malaria globally, leading to yearly decrease of malaria morbidity and mortality. However, there have recently been several reports on the resistance of Plasmodium falciparum to ART in Southeast Asia. This is deemed a serious threat to the global malaria control programs. In this paper, we reviewed recent research progress on ART resistance to P. falciparum, including new tools for resistance measurement, resistance-associated molecular markers, and the origin and spread of the ART-resistant parasite strains.

[Spectra modulated surface plasmon resonance sensor based on side polished multi-mode optical fiber].

Surface plasmon resonance, which utilizes the resonance of optical evanescent wave with the metal surface plasmon wave, has been developed into a high sensitivity, rapid, label-less measurement method for chemical and biological analysis. In order to improve the spectral sensitivity in refractive index for a side polished fiber surface plasmon resonance sensor, the whole cladding layer and part of core of a multimode fiber was polished off. Additionally, an extra chrome layer with relatively high refractive index was coated on the polished zone before a gold film. The results showed that the sensor can measure the refractive index range from 1.333 to 1. 431 RIU, with the average spectral sensitivity of 4.11 x 10(3) nm RIU(-1), which is better than the reported results. Especially, in the refractive index range of 1. 417 1. 431 RIU, the sensitivity reaches to 1.09 x 10(4) nm RIU(-1). The minimum resolution of approximately 3.6 x 10(-5) RIU was estimated by a combination analysis with the sensor sensitivity and stability. The superiorities possessed by the proposed sensor in high sensitivity, wide detection range, small size and good stability and reproducibility, etc., make it a good candidate for food testing, environmental monitoring, biomedical testing and other related fields.

[Performance of wavelength modulation surface plasmon resonance biosensor].

Surface plasmon resonance (SPR) is a rapid, label-free, high-precision technique of biological sensing and analysis. The investigation on the characteristics of provides theoretical basis and instructions for the applications of SPR A Kretschmann-structure surface plasmon resonance (SPR) biosensor based on wavelength modulation was developed, and also its sensing performances in the bulk solution was investigated. Measurements with different concentrations of bulk ethanol and ethylene glycol solutions show that the resonant wavelength shows a low sensitivity, but a higher linear response to the change in refractive index (RI), when RI is relatively smaller. With increasing refractive index , the sensitivity of resonance wavelength to changes in the refractive index increases. In the refractive index range of 1. 407 0-1. 430 RIU, sensitivity reaches to 11 487 nm RIU-1. The sensor resonance wavelength stability is 0. 213 8 nm, and the minimum resolution of refractive index approaches to 10-6 RIU. The advantages of the surface plasmon resonance sensor developed here results in simple operation, high sensitivity, wide detection range, low resolution, makes it an important candidate in chemical and biological sensing.

Four flavanocoumarins from the leaves of Litsea coreana LEVL.

Two new flavanocoumarins, 1 and 2, together with phyllocoumarin (3) and epiphyllocoumarin (4), were isolated from the leaves of Litsea coreana LEVL. in Anhui Province, China. The structures of 1-4 were elucidated by spectroscopic methods. Biological tests revealed that 1-4 exhibited moderate anti-inflammatory activities through inhibition of TNF-α and IL-1 production in primary mouse peritoneal macrophages activated with lipopolysaccharides (LPS).

[Application of ultrasonic surface location for internal jugular vein catheterization via central approach].

OBJECTIVE: To explore the clinical value of ultrasonic surface localization in internal jugular vein catheterization. METHODS: Totally 150 patients with American Society of Anesthesiologists physical status I -III who were planning to receive elective surgeries were randomized into anatomical landmark group, ultrasonic surface positioning group, and ultrasound-guided group using computed random table, with 50 cases in each group. The right internal jugular vein catheterization was performed after tracheal intubation. In the anatomic landmark group, patients were punctured using surface marks through central approach. In ultrasonic surface positioning group and ultrasound-guided group, patients were punctured with ultrasonic localization and guidance through central approach. The relationship between internal jugular vein and carotid artery, the position of the needle into the vein, the success rate of puncture, the change times of puncture point, and the complications were recorded. RESULTS: Ultrasound scan revealed that the relationship between the right internal jugular vein and the right common carotid artery could be divided into three types: parallel (12.7%), partial overlapping (69.3%), and complete overlapping (18.0%). The average "safety distance" of jugular vein puncture was (1.15 +/- 0.47) cm. The success rate of the first puncture attempt in ultrasonic surface positioning group and ultrasound-guided group were 78.0% and 82.0%, respectively, which was significantly higher than that in anatomic landmark group (22.0%) (P < 0.05), whereas the complication incidence in anatomic landmark group (12.0%) were significantly higher than those in ultrasonic surface positioning group (0) and ultrasound-guided group (0) (P < 0.05). CONCLUSIONS: Ultrasonic surface positioning applied during internal jugular vein catheterization is helpful to reveal the inner diameters as well as the origin and course of arteries and veins in the puncture and identify the abnormalities as early as possible. As a simple support technique for internal jugular vein puncture, it is suitable for clinical application.